alpha-synuclein and Lewy-Body-Disease

The accumulation of misfolded proteins as amyloid fibrils in the brain is characteristic of most neurodegenerative disorders. These misfolded proteins are capable of self-amplifying through protein seeding mechanisms, leading to accumulation in the host. First shown for PrP prions and prion diseases, it is now recognized that self-propagating misfolded proteins occur broadly in neurodegenerative diseases and include amyloid-β (Aβ) and tau in Alzheimer's disease (AD), tau in chronic traumatic encephalopathy (CTE), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), and α-synuclein (α-syn) in Parkinson's disease (PD) and Lewy body dementias (LBD). Techniques able to directly measure these bioactive protein seeds include the real-time quaking-induced conversion (RT-QuIC) assays. Initially developed for the detection of PrP prions and subsequently for the detection of other misfolded protein seeds, these assays take advantage of the mechanism of protein-based self-propagation to result in exponential amplification of the initial protein seeds from biospecimens. Disease-specific "protein seeds" recruit and template the misfolding of native recombinant protein substrates to elongate amyloid fibrils. The amplification power of these assays allows for detection of minute amounts of disease-specific protein seeds to better support early and accurate diagnosis. In addition to the diagnostic capabilities, assay readouts have been shown to reveal biochemical, structural, and kinetic information of protein seed self-propagation. This review examines the various protein seed amplification assays currently available for distinct neurodegenerative diseases, with a focus on RT-QuIC assays, along with the insights their readouts provide into protein seed structures and strain differences.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Brain; Humans; Lewy Body Disease; Prions

Lewy body diseases, such as Parkinson's disease and dementia with Lewy bodies, vary in their clinical phenotype but exhibit the same defining pathological feature, α-synuclein aggregation. Microbiome-gut-brain dysfunction may play a role in the initiation or progression of disease processes, though there are multiple potential mechanisms. We discuss the need to evaluate gastrointestinal mechanisms of pathogenesis across Lewy body diseases, as disease mechanisms likely span across diagnostic categories and a 'body first' clinical syndrome may better account for the heterogeneity of clinical presentations across the disorders. We discuss two primary hypotheses that suggest that either α-synuclein aggregation occurs in the gut and spreads in a prion-like fashion to the brain or systemic inflammatory processes driven by gastrointestinal dysfunction contribute to the pathophysiology of Lewy body diseases. Both of these hypotheses posit that dysbiosis and intestinal permeability are key mechanisms and potential treatment targets. Ultimately, this work can identify early interventions targeting initial disease pathogenic processes before the development of overt motor and cognitive symptoms.

Topics: alpha-Synuclein; Brain; Gastrointestinal Microbiome; Humans; Lewy Bodies; Lewy Body Disease; Neuromuscular Diseases

Alzheimer's disease (AD) is the most common disorder associated with cognitive impairment. Recent observations emphasize the pathogenic role of multiple factors inside and outside the central nervous system, supporting the notion that AD is a syndrome of many etiologies rather than a "heterogeneous" but ultimately unifying disease entity. Moreover, the defining pathology of amyloid and tau coexists with many others, such as α-synuclein, TDP-43, and others, as a rule, not an exception. Thus, an effort to shift our AD paradigm as an amyloidopathy must be reconsidered. Along with amyloid accumulation in its insoluble state, β-amyloid is becoming depleted in its soluble, normal states, as a result of biological, toxic, and infectious triggers, requiring a shift from convergence to divergence in our approach to neurodegeneration. These aspects are reflected-in vivo-by biomarkers, which have become increasingly strategic in dementia. Similarly, synucleinopathies are primarily characterized by abnormal deposition of misfolded α-synuclein in neurons and glial cells and, in the process, depleting the levels of the normal, soluble α-synuclein that the brain needs for many physiological functions. The soluble to insoluble conversion also affects other normal brain proteins, such as TDP-43 and tau, accumulating in their insoluble states in both AD and dementia with Lewy bodies (DLB). The two diseases have been distinguished by the differential burden and distribution of insoluble proteins, with neocortical phosphorylated tau deposition more typical of AD and neocortical α-synuclein deposition peculiar to DLB. We propose a reappraisal of the diagnostic approach to cognitive impairment from convergence (based on clinicopathologic criteria) to divergence (based on what differs across individuals affected) as a necessary step for the launch of precision medicine.

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; DNA-Binding Proteins; Humans; Lewy Body Disease; Prognosis; Synucleinopathies; tau Proteins

Dysfunction of the serotonergic system represents an important feature in synucleinopathies like Parkinson disease (PD), dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA). Serotonergic fibers from the raphe nuclei (RN) extend broadly throughout the central nervous system, innervating several brain areas affected in synucleinopathies. Alterations of the serotonergic system are associated with non-motor symptoms or motor complications in PD as well as with autonomic features of MSA. Postmortem studies, data from transgenic animal models and imaging techniques greatly contributed to the understanding of this serotonergic pathophysiology in the past, even leading to preclinical and clinical candidate drug tests targeting different parts of the serotonergic system. In this article, we review most recent work extending the knowledge of the serotonergic system and highlighting its relevance for the pathophysiology of synucleinopathies.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Serotonin; Synucleinopathies

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Biology; Lewy Body Disease; Receptors, sigma

The ultimate origin of Lewy body disorders, including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), is still incompletely understood. Although a large number of pathogenic mechanisms have been implicated, accumulating evidence support that aggregation and neuron-to-neuron propagation of alpha-synuclein may be the core feature of these disorders. The synuclein, origin, and connectome (SOC) disease model of Lewy body disorders was recently introduced. This model is based on the hypothesis that in the majority of patients, the first alpha-synuclein pathology arises in single location and spreads from there. The most common origin sites are the enteric nervous system and the olfactory system. The SOC model predicts that gut-first pathology leads to a clinical body-first subtype characterized by prodromal autonomic symptoms and REM sleep behavior disorder. In contrast, olfactory-first pathology leads to a brain-first subtype with fewer non-motor symptoms before diagnosis. The SOC model further predicts that body-first patients are older, more commonly develop symmetric dopaminergic degeneration, and are at increased risk of dementia-compared to brain-first patients. In this review, the SOC model is explained and compared to alternative models of the pathogenesis of Lewy body disorders, including the Braak staging system, and the Unified Staging System for Lewy Body Disorders. Postmortem evidence from brain banks and clinical imaging data of dopaminergic and cardiac sympathetic loss is reviewed. It is concluded that these datasets seem to be more compatible with the SOC model than with those alternative disease models of Lewy body disorders.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; REM Sleep Behavior Disorder

The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.

Topics: alpha-Synuclein; Biological Products; Biomarkers; Humans; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Parkinson Disease; Prodromal Symptoms

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing.. Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD.. Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons.. Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Neuropathology; Parkinson Disease

Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Lewy Bodies; Lewy Body Disease; tau Proteins

Currently, no disease modifying therapies (DMTs) have been approved for use in dementia with Lewy bodies (DLB). Clinical trials face difficulties due to the clinical and neuropathological heterogeneity of the condition with a diverse array of neuropathogenic mechanisms contributing to the clinical phenotype. The purpose of this review is to describe how recent advances in the development of biofluid biomarkers may be used in clinical trials to tackle some of these challenges.. Biomarkers are essential both to support the accurate diagnosis of DLB and to delineate the influence of coexisting pathologies. Recent advances in the development of α-synuclein seeding amplification assays (SAA) allow accurate identification of α-synuclein from the prodromal stages in DLB. Additionally, validation of plasma phosphorylated tau assays in DLB is ongoing and offers an accessible biomarker to indicate the existence of AD co-pathology. Use of biomarkers for diagnosis and group stratification in clinical trials of DLB is growing and likely to be of increasing importance in the future.. In vivo biomarkers can enhance patient selection in clinical trials allowing greater diagnostic accuracy, a more homogeneous trial population, and stratification by co-pathology to create subgroups most likely to derive therapeutic benefit from DMTs.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Humans; Lewy Body Disease; Patient Selection; Phenotype; tau Proteins

The accumulation of proteinaceous inclusions in the brain is a common feature among neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and dementia with Lewy bodies (DLB). The main neuropathological hallmark of PD and DLB are inclusions, known as Lewy bodies (LBs), enriched not only in α-synuclein (aSyn), but also in lipid species, organelles, membranes, and even nucleic acids. Furthermore, several genetic risk factors for PD are mutations in genes involved in lipid metabolism, such as GBA1, VSP35, or PINK1. Thus, it is not surprising that mechanisms that have been implicated in PD, such as inflammation, altered intracellular and vesicular trafficking, mitochondrial dysfunction, and alterations in the protein degradation systems, may be also directly or indirectly connected through lipid homeostasis. In this review, we highlight and discuss the recent evidence that suggests lipid biology as important drivers of PD, and which require renovated attention by neuropathologists. Particularly, we address the implication of lipids in aSyn accumulation and in the spreading of aSyn pathology, in mitochondrial dysfunction, and in ER stress. Together, this suggests we should broaden the view of PD not only as a proteinopathy but also as a lipidopathy.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Lipids; Parkinson Disease; Proteostasis Deficiencies; Synucleinopathies

Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson's disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.

Topics: alpha-Synuclein; Cross-Sectional Studies; Dementia; Humans; Inflammation; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

Like many neurodegenerative diseases, Parkinson's disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous aggregates are formed by the α-synuclein (αSyn) and are considered the trademark of this neurodegenerative disease. In addition to PD, αSyn pathological aggregation is also detected in atypical Parkinsonism, including Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), as well as neurodegeneration with brain iron accumulation, some cases of traumatic brain injuries, and variants of Alzheimer's disease. Collectively, these (and other) disorders are referred to as synucleinopathies, highlighting the relation between disease type and protein misfolding/aggregation. Despite these pathological relationships, however, synucleinopathies cover a wide range of pathologies, present with a multiplicity of symptoms, and arise from dysfunctions in different neuroanatomical regions and cell populations. Strikingly, αSyn deposition occurs in different types of cells, with oligodendrocytes being mainly affected in MSA, while aggregates are found in neurons in PD. If multiple factors contribute to the development of a pathology, especially in the cases of slow-developing neurodegenerative disorders, the common presence of αSyn aggregation, as both a marker and potential driver of disease, is puzzling. In this review, we will focus on comparing PD, DLB, and MSA, from symptomatology to molecular description, highlighting the role and contribution of αSyn aggregates in each disorder. We will particularly present recent evidence for the involvement of conformational strains of αSyn aggregates and discuss the reciprocal relationship between αSyn strains and the cellular milieu. Moreover, we will highlight the need for effective methodologies for the strainotyping of aggregates to ameliorate diagnosing capabilities and therapeutic treatments.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Aggregates; Synucleinopathies

The α-synucleinopathies comprise a group of adult-onset neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB,) and - as a restricted non-motor form - pure autonomic failure (PAF). Neuropathologically, the α-synucleinopathies are characterized by aggregates of misfolded α-synuclein in the central and peripheral nervous system. Cardiovascular autonomic failure is a common non-motor symptom in people with PD, a key diagnostic criterion in MSA, a supportive feature for the diagnosis of DLB and disease-defining in PAF. The site of autonomic nervous system lesion differs between the α-synucleinopathies, with a predominantly central lesion pattern in MSA versus a peripheral one in PD, DLB, and PAF. In clinical practice, overlapping autonomic features often challenge the differential diagnosis among the α-synucleinopathies, but also distinguish them from related disorders, such as the tauopathies or other neurodegenerative ataxias. In this review, we discuss the differential diagnostic yield of cardiovascular autonomic failure in individuals presenting with isolated autonomic failure, parkinsonism, cognitive impairment, or cerebellar ataxia.

Topics: alpha-Synuclein; Diagnosis, Differential; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Pure Autonomic Failure; Synucleinopathies

α-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

The abnormal accumulation of α-synuclein in the brain is a common feature of Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and synucleinopathies that present with overlapping but distinct clinical symptoms that include motor and cognitive deficits. Synapse degeneration is the crucial neuropathological event in these synucleinopathies and the neuropathological correlate of connectome dysfunction. The cognitive and motor deficits resulting from the connectome dysfunction are currently measured by scalar systems that are limited in their sensitivity and largely subjective. Ideally, a marker of synapse degeneration would correlate with measures of cognitive or motor impairment, and could therefore be used as a more objective, surrogate biomarker of the core clinical features of these diseases. Furthermore, an objective surrogate biomarker that can detect and monitor the progression of synapse degeneration would improve patient management and clinical trial design, and could provide a measure of therapeutic response. Here, we review the published findings relating to candidate biomarkers of synapse degeneration in PD, PDD, DLB, and MSA patient-derived biofluids and discuss the findings in the context of the mechanisms associated with α-synuclein-mediated synapse degeneration. Understanding these mechanisms is essential not only for discovery of biomarkers, but also to improve our understanding of the earliest changes in disease pathogenesis of synucleinopathies.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy; Synapses; Synucleinopathies

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.

Topics: alpha-Synuclein; Brain; Humans; Leukotrienes; Lewy Body Disease; Parkinson Disease; Signal Transduction; Synucleinopathies

Lewy body dementia encompasses the common neurodegenerative disorders Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Lewy Body disease (LBD) is characterized by abnormal aggregates of α-synuclein (α-syn) in the brain which form Lewy bodies. LBD is commonly misdiagnosed/underdiagnosed, especially in early stages. There remains a great need for reliable biomarkers to assist with LBD diagnosis. Amplification techniques such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) represent an important advance for biomarker detection. Amplification assays detect the ability of pathogenic protein to induce conformational change in normal protein; α-syn has been shown to propagate in a prion-like manner, making it a candidate for such analysis. In this review, we describe the diagnostic potential of amplification techniques for differentiating α-synucleinopathies from other neurodegenerative disorders such as Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism, as well as α-synucleinopathies from each other. Recent studies report accurate detection of α-syn seeding activity in human tissues such as cerebrospinal fluid (CSF), submandibular gland (SMG), and posterior cervical skin. Adaptation to clinical settings may present challenges. However, the high accuracy of recent results, combined with the success of amplification assay diagnostics in clinical practice for Creutzfeldt-Jakob disease, suggest high promise for eventual clinical application.

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Dementia; Humans; Lewy Body Disease; Parkinson Disease; Synucleinopathies

The clinical differentiation between multiple system atrophy (MSA), Parkinson's disease (PD), dementia with Lewy bodies (DLB), as well as the distinction between these synucleinopathies from other neurodegenerative disorders can be challenging, particularly at early disease stages or when the presentation is atypical. That is also true for predicting the fate of patients with limited or prodromal forms of synucleinopathies such as pure autonomic failure (PAF) or idiopathic REM-sleep behavior disorder (iRBD) which are known to be at risk of developing MSA, PD, or DLB. After discussing current classification concepts of the synucleinopathies, this invited mini-review reflects on two recently described and validated spinal fluid biomarkers, namely neurofilament light chain (NfL) and α-synuclein oligomers detected by protein aggregation assays, that have shown great promise not only as markers differentiating MSA from the Lewy-body synucleinopathies but also as markers that predict future phenoconversion to MSA among patients with PAF. Discussed are the strengths and limitations of these markers, and how they appear to complement each other nicely as a biomarker panel, enhancing the specificity of one of these markers, yet adding further robustness and simplicity to a marker that is technically rather challenging. The review concludes with thoughts on potential next steps in the development of fluid biomarkers in this rapidly emerging field.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Pure Autonomic Failure; REM Sleep Behavior Disorder; Synucleinopathies

Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.

Topics: alpha-Synuclein; Humans; Kinetics; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Prions; Synucleinopathies

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

Topics: alpha-Synuclein; Epigenome; Frontal Lobe; Humans; Lewy Bodies; Lewy Body Disease; Methylation; Parkinson Disease

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as

Topics: alpha-Synuclein; Amyotrophic Lateral Sclerosis; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Synucleinopathies

Dementia with Lewy bodies (DLB) is a neurodegenerative disease linked to abnormal accumulation of phosphorylated α-synuclein. GBA1 is the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), whose mutations are a risk factor of DLB.. To report all available data exploring the association between GBA1 mutations and DLB.. All publications focused on GCase and DLB in humans between 2003 and 2022 were identified on PubMed, Cochrane and ClinicalTrials.gov.. 29 studies were included and confirmed the strong association between GBA1 mutations and DLB (Odds Ratio [OR]: 8.28). GBA1 mutation carriers presented a more malignant phenotype, with earlier symptom onset, more severe motor and cognitive dysfunctions, more visual hallucinations and rapid eye movement sleep disorder. GBA1 mutations were associated with "purer" neuropathological DLB. No therapeutic recommendations exist and clinical trials targeting GCase are just starting in DLB patients.. This review reports a link between GBA1 mutations and the DLB phenotype with limited evidence due to the small number of studies.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lewy Body Disease; Mutation; Neurodegenerative Diseases

This article summarizes the underlying biology and current diagnostic and treatment strategies for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with Lewy bodies (DLB).. Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor features and include cognitive impairment, depression, anxiety, psychosis, impulse control disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in patients with PD, in part because of comorbidity and symptom overlap with core PD features. Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions used in the general population and those specific to PD. DLB is a clinical dementia syndrome, often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB has shared underlying pathophysiology with PD, as both are associated with postmortem findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive impairment in DLB, compared with the variable onset of cognitive impairment occurring 1 year or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important implications for maintaining patient independence and providing support for caregivers because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient functional disability.. A careful history and physical examination are often needed to accurately diagnose and treat the heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important, as these are a considerable source of patient disability and caregiver burden.

Topics: alpha-Synuclein; Cognition; Cognitive Dysfunction; Humans; Lewy Body Disease; Parkinson Disease

Alpha-synuclein(αSyn) aggregates are definite pathological hallmarks of α-synucleinopathies. Seeding amplification assays (SAAs) have been developed to detect trace amounts of αSyn oligomers in vivo.. Herein, we assessed the diagnostic accuracy of the αSyn-SAAs across biospecimens, diagnostic references, methods, and subtypes.. A systematic literature search yielded 36 eligible studies for a meta-analysis of the sensitivity and specificity of αSyn-SAAs in patients with α-synucleinopathies(n = 2722) and controls(n = 2278). Pooled sensitivities and specificities with 95% confidence intervals (CIs) were calculated using bivariate random-effects models and a meta-regression analysis was performed.. The summary sensitivity and specificity of αSyn-SAAs positivity for the diagnosis of α-synucleinopathies were 0.88(95% CIs = 0.84-0.91) and 0.95(0.93-0.97), respectively. Two covariates (biospecimen and diagnostic reference) were significant in fitting the meta-regression model (likelihood-ratio test for sensitivity and specificity, p < 0.01, p = 0.01, respectively). Skin αSyn-SAAs exhibited the highest sensitivity 0.92(0.87-0.95), which was not different from that of cerebrospinal fluid (CSF)(0.90(0.86-0.93), p = 0.39). Olfactory mucosa αSyn-SAAs exhibited a lower sensitivity 0.64(0.49-0.76) than those of the other two specimens(p = 0.02, 0.01, compared to CSF and skin, respectively). Application of pathological diagnostic standards were associated with a higher specificity of αSyn-SAAs compared to clinical diagnosis (p < 0.01). The diagnostic sensitivity and specificity of CSF αSyn-SAAs were 0.91(0.87-0.94) and 0.96(0.93-0.98) for Lewy body disease, 0.90(0.79-0.95) and 0.96(0.90-0.98) for prodromal α-synucleinopathies, and 0.63(0.24-0.90) and 0.97(0.93-0.99) for multiple system atrophy.. αSyn-SAAs are promising in vivo detectors of abnormal αSyn aggregates and may aid the early diagnosis of α-synucleinopathies.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Sensitivity and Specificity; Synucleinopathies

Dementia with Lewy bodies is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Dementia with Lewy bodies can provide a diagnostic challenge due to the frequent overlap of clinical signs with other neurodegenerative conditions, namely Parkinson's disease dementia, and Alzheimer's disease. Part of this clinical overlap is due to the neuropathological overlap. Dementia with Lewy bodies is characterized by the accumulation of aggregated α-synuclein protein in Lewy bodies, similar to Parkinson's disease and Parkinson's disease dementia. However, it is also frequently accompanied by aggregation of amyloid-beta and tau, the pathological hallmarks of Alzheimer's disease. Neuroimaging is central to the diagnostic process. This review is an overview of both established and evolving imaging methods that can improve diagnostic accuracy and improve management of this disorder.

Topics: alpha-Synuclein; Alzheimer Disease; Dementia; Diagnosis, Differential; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Aggregation of alpha-synuclein into inclusion bodies, termed Lewy pathology, is a defining feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). In the majority of post mortem cases, the distribution of Lewy pathology seems to follow two overarching patterns: a caudo-rostral pattern with relatively more pathology in the brainstem than in the telencephalon, and an amygdala-centered pattern with the most abundant pathology in the "center of the brain", including the amygdala, entorhinal cortex, and substantia nigra, and relatively less pathology in the lower brainstem and spinal autonomic nuclei. The recent body-first versus brain-first model of Lewy Body Disorders proposes that the initial pathogenic alpha-synuclein in some patients originates in the enteric nervous system with secondary spreading to the brain; and in other patients originates inside the CNS with secondary spreading to the lower brainstem and peripheral autonomic nervous system. Here, we use two existing post mortem datasets to explore the possibility that clinical body-first and brain-first subtypes are equivalent to the caudo-rostral and amygdala-centered patterns of Lewy pathology seen at post mortem.

Topics: alpha-Synuclein; Brain; Brain Stem; Humans; Lewy Body Disease; Parkinson Disease; Substantia Nigra

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Neural plasticity-the ability to alter a neuronal response to environmental stimuli-is an important factor in learning and memory. Short-term synaptic plasticity and long-term synaptic plasticity, including long-term potentiation and long-term depression, are the most-characterized models of learning and memory at the molecular and cellular level. These processes are often disrupted by neurodegeneration-induced dementias. Alzheimer's disease (AD) accounts for 50% of cases of dementia. Vascular dementia (VaD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) constitute much of the remaining cases. While vascular lesions are the principal cause of VaD, neurodegenerative processes have been established as etiological agents of many dementia diseases. Chief among such processes is the deposition of pathological protein aggregates

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain Diseases; Dementia; Humans; Lewy Body Disease; Neuronal Plasticity; Neurons; tau Proteins

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression.

Topics: alpha-Synuclein; Brain; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Neuroglia; Neurons; Parkinson Disease; Phytochemicals; Synucleinopathies

Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; rab GTP-Binding Proteins

Professor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including Alpers-Huttenlocher syndrome, a syndrome of mitochondrial disease caused by POLG mutations, and infantile neuroaxonal dystrophy, a phenotype resulting from PLA2G6 mutations. Despite these rare diseases occurring in early life, they share many important pathological overlaps with age-associated Lewy body disease, particularly dysregulation of α-synuclein. In this review, we describe several neurometabolic diseases linked to Lewy body disease mechanisms, and discuss the wider context to pathological overlaps between neurometabolic and Lewy body diseases. In particular, we will focus on how understanding disease mechanisms in neurometabolic disorders with dysregulated α-synuclein may generate insights into predisposing factors for α-synuclein aggregation in idiopathic Lewy body diseases.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Neurodegenerative Diseases; Phenotype; Rare Diseases

α-Synuclein oligomers and Ca

Topics: alpha-Synuclein; Animals; Calcium; Disease Susceptibility; Homeostasis; Humans; Lewy Body Disease; Neurons; Protein Transport; Risk Factors

Lewy bodies are intraneuronal eosinophilic cytoplasmic inclusions, and their presence in the specific areas of the central nervous system defines the so-called Lewy body disorders such as Parkinson's disease and dementia with Lewy bodies. The protein alpha-synuclein is the major component of Lewy bodies and there is evidence suggesting that it is capable of spreading from cell to cell within the central nervous system thereby propagating the pathological process. The olfactory system, particularly the olfactory bulb, is almost always affected in Parkinson's disease and dementia with Lewy bodies. Moreover, in Parkinson's disease, the olfactory bulb is involved by Lewy pathology at very early stages of the disease. The hypothalamus is also compromised by Lewy pathology in the course of Parkinson's disease; however, unlike the olfactory system in which most regions of the primary olfactory cortex become affected, there is a selective vulnerability of certain hypothalamic regions including the tuberomamillary nucleus, the lateral tuberal nucleus, and orexin/hypocretin neurons, while other nuclear groups remain free of Lewy pathology even in the advanced stages of the disease.

Topics: alpha-Synuclein; Humans; Hypothalamus; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Lewy body disease (LBD) is characterized by the presence of Lewy bodies (LBs) and Lewy neurites and comprises a diagnostic spectrum that includes Parkinson's disease (PD), PD with dementia, and dementia with LBs. LBs and Lewy neurites are insoluble aggregates composed mainly of phosphorylated α-synuclein and can be widely distributed throughout the central and peripheral nervous systems. The distribution of LBs may determine the LBD phenotype. Braak hypothesized that Lewy pathology progresses ascendingly from the peripheral nervous system to the olfactory bulbs and brainstem and then to other brain regions. Braak's PD staging suggests that LBD is a prion-like disease. Most typical PD cases fit with Braak's PD staging, but the scheme fails in some cases. Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, frontotemporal lobar degeneration, Creutzfeldt-Jakob disease, cerebrovascular diseases, and essential tremor are common misdiagnoses for pathologically confirmed LBD. LBD exhibits considerable heterogeneity in both clinical and pathological settings, which makes clinical diagnosis challenging.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Macrophages; Neuropathology

Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.. We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the quality of genetic association studies tool.. Eight thousand five hundred twenty-one articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA, and SNCA variants have been replicated by two or more good quality studies. Our meta-analyses confirmed that APOE-ε4 is significantly associated with dementia with Lewy bodies (pooled odds ratio [POR] = 2.70; 95% CI, 2.37-3.07; P < .001) and Parkinson's disease dementia (POR = 1.60; 95% CI, 1.21-2.11; P = .001). Other reported genetic associations that need further replication include variants in A2M, BCHE-K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mitochondrial DNA (mtDNA) haplogroup H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1.. The reported genetic associations and their potential interactions indicate the importance of α-synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress, and mitochondrial dysfunction in LBD. There is a need for larger genome-wide association study (GWAS) for identifying more LBD-associated genes. Future hypothesis-driven studies should aim to replicate reported genetic associations of LBD and to explore their functional implications.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Female; Genome-Wide Association Study; Humans; Lewy Bodies; Lewy Body Disease; Lysosomal Membrane Proteins; Male; Membrane Glycoproteins; Receptors, Immunologic; Receptors, Scavenger

Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer's disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.. We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.. We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy-lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.. α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Ataxin-2; Autophagy; beta-Synuclein; Biomarkers; Brain; Databases, Factual; Down-Regulation; Gene Expression; Genes, Mitochondrial; Humans; Lewy Body Disease; MicroRNAs; Proteasome Endopeptidase Complex; Proteins; Transcription Factor RelA; Ubiquitin; Ubiquitin-Protein Ligases

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson's disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; Phenols; Protein Aggregation, Pathological; Synucleinopathies

Neuropathological diagnostic criteria of neurodegenerative disorders are based on the presence of specific inclusions in a specific area of brain tissue that correlate with clinical manifestations. Concomitant neurodegenerative disorders correspond to a combination of two (or more) different fully developed diseases in the same patient. Concomitant neurodegenerative pathology represents the presence of definite neurodegeneration and deposits of pathological proteins specific for another disease, which is not, however, fully developed. Very frequent overlaps include Alzheimer's disease and alpha-synuclein inclusions. Nevertheless, careful neuropathological investigations reveal an increasing frequency of different co-pathologies in examined brains. In Alzheimer's disease, protein TDP-43 may co-aggregate, but it is not clear whether this is atypical isolated Alzheimer's disease or overlap of Alzheimer's disease with early frontotemporal lobar degeneration. Comorbidities of Alzheimer's disease and tauopathies are relatively rare. A combination of vascular pathology with primary neurodegeneration (mostly Alzheimer's disease or dementia with Lewy bodies) is historically called mixed dementia. Overlap of different neuropathologically confirmed neurodegenerations could lead to atypical and unusual clinical presentations and may be responsible for faster disease progression. Several CSF biomarkers have been evaluated for their utility in diagnostic processes in different neurodegenerative dementias; however, evidence regarding their role in neurodegenerative overlaps is still limited.

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; DNA-Binding Proteins; Humans; Lewy Body Disease; Protein Aggregation, Pathological; tau Proteins

Lewy body dementia (LBD) is an umbrella term for major neurocognitive disorders caused by Lewy body pathology. Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB) are the two main syndromes in LBD. LBDs typically present with cognitive impairment, cholinergic deficiency, neuropsychiatric symptoms such as visual hallucinations and paranoid delusions, as well as parkinsonian symptoms. Due to the urgency in diagnosing LBD early in the disease course to provide the most optimal management of these syndromes, it is important that clinicians elicit the most clinically significant symptoms during patient encounters. The focus of this chapter is to discuss current LBD classification systems and assessments, neuropathology of LBDs, behavioral symptomatology, contemporary management options, and possible future targets of treatment. PubMed was searched to obtain reviews and studies that pertain to classification, behavioral symptomatology, neurobiology, neuroimaging, and treatment of LBDs. Articles were chosen with a predilection to more recent clinical trials and systematic reviews or meta-analyses. Updates to diagnostic criteria have increased clinical diagnostic sensitivity and specificity. Current therapeutic modalities are limited as there is no current disease-modifying drug available. Cholinesterase inhibitors have been reported to be effective in decreasing neuropsychiatric and cognitive symptoms. Neuroleptics should be avoided unless clinically indicated. There is a paucity of studies investigating treatment options for mood symptoms. Current novel targets of treatment focus on decreasing α-synuclein burden. LBDs are a group of dementia syndromes that affect a significant portion of the elderly population. Early diagnosis and treatment is necessary to improve patient quality of life with current treatment options more focused on alleviating severe symptomatology rather than modifying disease pathology.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Mental Disorders; Neuroimaging; Psychopharmacology

Neurodegenerative diseases are characterized by the aggregation and deposition of misfolded proteins in the brain, most prominently amyloid-β (Aβ), tau and α-synuclein (α-syn), and are thus referred to as proteinopathies. While tau is a hallmark of Alzheimer's disease (AD) and other non-AD tauopathies, and α-synuclein is the pathological feature of the spectrum of synucleinopathies including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), the presence of co-pathologies is very frequent in all these diseases. Positive and synergistic associations between the different types of protein deposits have been reported, leading to worse prognosis and cognitive decline. A large variation in phenotypic clinical presentation of these diseases, largely due to the frequent presence of co-pathologies, makes differential diagnosis challenging. The observed clinico-pathological overlaps suggest common underlying mechanisms, in part due to shared genetic risk factors. The ε4 allele of the apolipoprotein (APOE) gene is one of the major genetic risk factors for the sporadic forms of proteinopathies, but the biological mechanisms linking APOE, tau and α-syn are not fully understood. This chapter describes current experimental evidence on the relationships between APOE variants, tau and α-syn, from clinical studies on fluid biomarkers and positron emission tomography (PET) imaging, and from basic experimental studies in cellular/molecular biology and animal models. The chapter focuses on recent advances and identifies knowledge gaps. In particular, no PET tracer for assessment of brain α-syn deposits is yet available, although it is subject of intense research and development, therefore experimental evidence on in vivo α-syn levels is based on measures in the cerebrospinal fluid (CSF) and plasma. Moreover, tau PET imaging studies comparing the patterns of tracer retention in synucleinopathies versus in other proteinopathies are scarce and much is still unknown regarding the relationships between APOE variants and fluid and/or imaging biomarkers of tau and α-syn. Further research incorporating multimodal imaging, fluid biomarkers and genetic factors will help elucidate the biological mechanisms underlying these proteinopathies, and contribute to differential diagnosis and patient stratification for clinical trials.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Apolipoproteins E; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease; Synucleinopathies; tau Proteins

This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson's disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, "dying back" sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Synuclein; Catecholamines; Dopamine; Heart; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Myocardium; Neuroimaging; Neurons; Parkinson Disease; Sympathetic Nervous System

The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon's horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases.

Topics: alpha-Synuclein; Animals; Encephalitis; Hippocampus; Humans; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

α-Synuclein, the major component of Lewy bodies (LBs) and Lewy neurites (LNs), is expressed in presynapses under physiologically normal conditions and is involved in synaptic function. Abnormal intracellular aggregates of misfolded α-synuclein such as LBs and LNs are pathological hallmarks of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). According to previous studies using pathological models overexpressing α-synuclein, high expression of this protein in neurons is a critical risk factor for neurodegeneration. Therefore, it is important to know the endogenous expression levels of α-synuclein in each neuronal cell type. We previously reported differential expression profiles of α-synuclein in vitro and in vivo. In the wild-type mouse brain, particularly in vulnerable regions affected during the progression of idiopathic PD, α-synuclein is highly expressed in neuronal cell bodies of some early PD-affected regions, such as the olfactory bulb, the dorsal motor nucleus of the vagus, and the substantia nigra pars compacta. Synaptic expression of α-synuclein is mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory synapse marker protein. In contrast, α-synuclein expression in inhibitory synapses differs among brain regions. Recently accumulated evidence indicates the close relationship between differential expression profiles of α-synuclein and selective vulnerability of certain neuronal populations. Further studies on the regulation of α-synuclein expression will help to understand the mechanism of LB pathology and provide an innovative therapeutic strategy to prevent PD and DLB onset.

Topics: alpha-Synuclein; Animals; Brain; Gene Expression Regulation; Humans; Lewy Bodies; Lewy Body Disease; Mice; Neurons; Parkinson Disease; Protein Folding

Dementia with Lewy bodies (DLB) is the underlying aetiology of 10-15% of all cases of dementia and as such is a clinically important diagnosis. In the past few years, substantial advances have been made in understanding the genetics and pathology of this condition. For example, research has expanded our knowledge of the proteinaceous inclusions that characterize the disease, has provided an appreciation of the role of disease-associated processes such as inflammation and has revealed an association between DLB and genes such as GBA. These insights might have broader relevance to other neurodegenerative conditions and are beginning to be translated into clinical trials. In this Review, we provide clinical insights for the basic scientist and a basic science foundation for the clinician. We discuss the history of the condition; the definition of DLB; the relationship between DLB and other neurodegenerative conditions; current understanding of the pathology, genetics, clinical presentation and diagnosis of DLB; options for treatment; and potential future directions for research.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Positron Emission Tomography Computed Tomography

α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why α-synuclein ends up in the astrocytes and the consequences of this dysfunctional proteostasis in immune cells is a major area of research that can have far-reaching implications for future immunobiotherapies in α-synucleinopathies. Accumulation of aggregated α-synuclein can disrupt astrocyte function in general and, more importantly, can contribute to neurodegeneration in α-synucleinopathies through various pathways. Here, we summarize our current knowledge on how astrocytic α-synucleinopathy affects CNS function in health and disease and propose a model of neuroglial connectome altered by α-synuclein proteostasis that might be amenable to immune-based therapies.

Topics: alpha-Synuclein; Animals; Astrocytes; Homeostasis; Humans; Lewy Body Disease; Neurodegenerative Diseases; Neurons

Lewy body diseases share clinical, pathological, genetic and biochemical signatures, and are regarded as a highly heterogeneous group of neurodegenerative disorders. Inclusive of Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), controversy still exists as to whether they should be considered as separate disease entities or as part of the same disease continuum. Here we discuss emerging knowledge relating to both clinical, and neuropathological differences and consider current biomarker strategies as we try to improve our diagnostic capabilities and design of disease modifying therapeutics for this group of debilitating neurodegenerative disorders. This article is part of the Special Issue "Synuclein".

Topics: alpha-Synuclein; Apolipoprotein E4; Biomarkers; Brain; Dementia; Diagnosis, Differential; Disease Progression; Forecasting; Glucosylceramidase; Humans; Lewy Bodies; Lewy Body Disease; Mental Status and Dementia Tests; Neurodegenerative Diseases; Parkinson Disease; Symptom Assessment; Synucleinopathies

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Diagnosis, Differential; Humans; Intermediate Filaments; Lewy Body Disease; Peptide Fragments; Prognosis; tau Proteins

GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB). The pathogenesis of this association is not fully understood, but further elucidation of this link could lead to new therapeutic options.. The characteristic clinical phenotype of GBA1-PD resembles sporadic Parkinson disease, but with an earlier onset and more severe course. Many different GBA1 mutations increase the risk of Parkinson disease, some primarily detected in specific populations. Glucocerebrosidase deficiency appears to be associated with increased α-synuclein aggregation and accumulation, mitochondrial dysfunction because of impaired autophagy, and increased endoplasmic reticulum stress.. As our understanding of GBA1-associated Parkinson disease increases, new treatment opportunities emerge. MicroRNA profiles are providing examples of both up-regulated and down-regulated proteins related to GBA1 and may provide new therapeutic targets. Chaperone therapy, directed at either misfolded glucocerebrosidase or α-synuclein aggregation, is currently under development and there are several early clinical trials ongoing. Substrate reduction therapy, aimed at lowering the accumulation of metabolic by-products, especially glucosylsphingosine, is also being explored. Basic science insights from the rare disorder Gaucher disease are serving to catapult drug discovery for parkinsonism.

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Humans; Lewy Body Disease; Mutation; Parkinsonian Disorders; Protein Aggregates

α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a β-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Callithrix; Humans; Lewy Body Disease; Mice; Neurodegenerative Diseases; Parkinson Disease; Phosphorylation; Prions; Protein Aggregation, Pathological

Topics: alpha-Synuclein; Brain; Humans; In Vitro Techniques; Lewy Body Disease; Prions; Protein Aggregation, Pathological; Protein Folding

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how αS structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the αS protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of αS and PD, and where this information may direct the field.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

In recent years, the diagnostic approach to rapid eye movement (REM) sleep behavior disorder (RBD) has become more objective and accurate. This was achieved mainly by introduction of methods to exactly quantify electromyographic (EMG) activity in various muscles during REM sleep. The most established muscle combination for RBD diagnosis is the mentalis and upper extremity EMG. Computer-assisted systems for this analysis have been described, and an increasing number of studies looked into analysis of video events. Recently, prodromal phases of isolated RBD have been recognized.

Topics: alpha-Synuclein; Disease Progression; Electromyography; Humans; Image Processing, Computer-Assisted; Intestinal Mucosa; Lewy Body Disease; Parkinson Disease; Polysomnography; Precision Medicine; Prodromal Symptoms; REM Sleep Behavior Disorder; Salivary Glands; Skin; Sleep, REM; Synucleinopathies; Video Recording

Olfactory limbic structures, like the amygdala, the entorhinal, and the piriform cortices, are closely involved in cognitive processes. Thus, besides olfactory dysfunctions, it is conceivable that the compromise of these structures can lead to cognitive impairment. The olfactory bulb is affected by alpha-synuclein pathology in almost all cases of both Parkinson's disease and dementia with Lewy bodies. The clinical distinction between these disorders relies on the timing in the appearance of dementia in relationship to motor symptoms. Typically, it occurs late in the course of Parkinson's disease, and within the first year in dementia with Lewy bodies. The close anatomical proximity of the olfactory bulb with limbic regions, together with the early occurrence of cognitive impairment that is observed in dementia with Lewy bodies, raise the question whether the propagation of alpha-synuclein pathology in this condition might originate in the olfactory bulb, spreading from there to other limbic structures, and thereby reaching the associative neocortex. This review will describe the anatomical basis of the olfactory system and discuss the evidence of potential spreading pathways from the olfactory bulb that could support the presence of early dementia in the setting of Lewy body disorders.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Lewy Body Disease; Models, Biological; Olfactory Bulb

α-synuclein (αSyn) still remains a mysterious protein even two decades after SNCA encoding it was identified as the first causative gene of familial Parkinson's disease (PD). Accumulation of αSyn causes α-synucleinopathies including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent advances in therapeutic approaches offer new antibody-, vaccine-, antisense-oligonucleotide- and small molecule-based options to reduce αSyn protein levels and aggregates in patient's brain. Gathering research information of other neurological disease particularly Alzheimer's disease, recent disappointment of an experimental amyloid plaques busting antibody in clinical trials underscores the difficulty of treating people who show even mild dementia as damage in their brain may already be too extensive. Prodromal intervention to inhibit the accumulation of pathogenic protein may advantageously provide a better outcome. However, treatment prior to onset is not ethically justified as standard practice at present. In this review, we initiate a refined concept to define early pathogenic state of αSyn accumulation before occurrence of brain damage as a disease criterion for αSyn dysregulation disease.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Gene Expression; Humans; Lewy Body Disease; Parkinson Disease

Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion-like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, ɑ-synuclein (ɑSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of ɑSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on ɑSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis.

Topics: alpha-Synuclein; Animals; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Prions; Protein Aggregates

Rapid eye movement (REM) sleep behavior disorder (RBD) involves REM sleep without atonia in conjunction with a recurrent nocturnal dream enactment behavior, with vocalizations such as shouting and screaming, and motor behaviors such as punching and kicking. Secondary RBD is well described in association with neurological disorders including Parkinson's disease (PD), multiple system atrophy (MSA), and other conditions involving brainstem structures such as tumors. However, RBD alone is now considered to be a potential harbinger of later development of neurodegenerative disorders, in particular PD, MSA, dementia with Lewy bodies (DLB), and pure autonomic failure. These conditions are linked by their underpinning pathology of alpha-synuclein protein aggregation. In RBD, it is therefore important to recognize the potential risk for later development of an alpha-synucleinopathy, and to investigate for other potential causes such as medications. Other signs and symptoms have been described in RBD, such as orthostatic hypotension, or depression. While it is important to recognize these features to improve patient management, they may ultimately provide clinical clues that will lead to risk stratification for phenoconversion. A critical need is to improve our ability to counsel patients, particularly with regard to prognosis. The ability to identify who, of those with RBD, is at high risk for later neurodegenerative disorders will be paramount, and would in addition advance our understanding of the prodromal stages of the alpha-synucleinopathies. Moreover, recognition of at-risk individuals for neurodegenerative disorders may ultimately provide a platform for the testing of possible neuroprotective agents for these neurodegenerative disorders.

Topics: alpha-Synuclein; Cross-Sectional Studies; Electroencephalography; Humans; Lewy Body Disease; Longitudinal Studies; Multiple System Atrophy; Parkinson Disease; REM Sleep Behavior Disorder

Increasing evidence suggests that amyloid formation, i.e., self-assembly of proteins and the resulting conformational changes, is linked with the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease, prion diseases, and Lewy body diseases. Among the factors that accelerate or inhibit oligomerization, we focus here on two non-genetic and common characteristics of many amyloidogenic proteins: metal binding and asparagine deamidation. Both reflect the aging process and occur in most amyloidogenic proteins. All of the amyloidogenic proteins, such as Alzheimer's β-amyloid protein, prion protein, and α-synuclein, are metal-binding proteins and are involved in the regulation of metal homeostasis. It is widely accepted that these proteins are susceptible to non-enzymatic posttranslational modifications, and many asparagine residues of these proteins are deamidated. Moreover, these two factors can combine because asparagine residues can bind metals. We review the current understanding of these two common properties and their implications in the pathogenesis of these neurodegenerative diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Asparagine; Humans; Iron; Lewy Body Disease; Metals; Prion Diseases; Prion Proteins

Dementia with Lewy body (DLB) is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of neuropathologically defined cases. Two-thirds of the patients affected are not or misdiagnosed. In this review, we evaluate the discriminatory power of cerebrospinal fluid (CSF) alpha-synuclein by focusing more specifically on differential diagnosis between DLB and AD. Alpha-synuclein assay in the CSF has an interest in the discrimination between DLB and AD but not in segregation between DLB and healthy elderly subjects. The development of biomarkers such as phospho-alpha-synuclein and oligomeric alpha-synuclein should help to reinforce this discrimination power.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Diagnosis, Differential; Humans; Lewy Body Disease; Middle Aged

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia following Alzheimer disease. It stems from the formation of Lewy bodies, which contain aggregates of the misfolded protein, α-synuclein. These deposit in areas of the nervous system and brain, leading to neuronal cell death and causing clinically apparent symptoms. Because of its clinical overlap with other forms of dementia, DLB is often underdiagnosed and misdiagnosed. There is currently no cure for DLB and treatments are aimed at ameliorating specific symptoms.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Behavioral Symptoms; Biomarkers; Diagnosis, Differential; Disease Management; Humans; Lewy Body Disease; Parkinson Disease

Topics: alpha-Synuclein; Gene Expression; Genome-Wide Association Study; Humans; Lewy Body Disease; Multiple System Atrophy; Mutation; Parkinson Disease; Phenotype

Dementia syndromes associated with Lewy bodies are subdivided into dementia with Lewy bodies (DLB), an underdiagnosed cause of dementia in the elderly, and Parkinson disease with dementia (PDD), cognitive impairment appearing in people diagnosed with Parkinson disease. Their neuropathologic substrates are the widespread distribution of aggregates of the protein α-synuclein in neurons in cortical brain regions, accompanied by variable Alzheimer pathology. Clinical features of DLB and PDD include distinctive changes in cognition, behavior, movement, sleep, and autonomic function. Diagnostic criteria for DLB and PDD incorporate these features. Current treatment options for DLB and PDD are symptomatic.

Topics: alpha-Synuclein; Brain; Disease Management; Humans; Lewy Body Disease

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.

Topics: alpha-Synuclein; Cholinesterase Inhibitors; Disease Management; Genetic Therapy; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Stem Cell Transplantation; Urea

Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA) are three major synucleinopathies characterized by α-synuclein-containing inclusions in the brains of patients. Because the cell types and brain structures that are affected vary markedly between the disorders, the patients have different clinical manifestations in addition to some overlapping symptoms, which are the basis for differential diagnosis. Cognitive impairment and depression associated with hippocampal dysfunction are frequently observed in these disorders. While various α-synuclein-containing inclusions are found in the hippocampal formation, increasing evidence supports that small α-synuclein aggregates or oligomers may be the real culprit, causing deficits in neurotransmission and neurogenesis in the hippocampus and related brain regions, which constitute the major mechanism for the hippocampal dysfunctions and associated neuropsychiatric manifestations in synucleinopathies.

Topics: alpha-Synuclein; Animals; Hippocampus; Humans; Inclusion Bodies; Lewy Body Disease; Multiple System Atrophy; Neurogenesis; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Synaptic Transmission

Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs). Although dramatic efficacy of levodopa boosted an enthusiasm for this nigra-centralism, extranigral lesions were identified, especially after identification of alpha-synuclein (αS) as a major constituent of LBs. Frequent αS lesions in the lower brainstem with their presumed upward spread were coupled with the self-propagating property of αS molecule, as a molecular template, to constitute the prion-Braak hypothesis. This hybrid concept might expectedly explain clinical, structural and biochemical features of PD/dementia with Lewy bodies (DLB) as if they were stereotypic. In spite of this ordered explanation, recent studies have demonstrated unexpectedly that αS lesions in the human brain, as well as their corresponding clinical manifestations, are much more disordered. Even with such a chaos of LB disorders, affected neuronal groups are uniformly characterized by hyperbranching axons, which may facilitate distal-dominant degeneration and retrograde progression of LB-related degeneration along axons as a fundamental structural order to template LB disorders. This "structural template" hypothesis may explain why: (i) some selective groups are prone to develop Lewy pathology; (ii) their clinical manifestations (especially non-motor components) are vague and generalized without somatotopic accentuation; (iii) distal axons and terminals are preferentially affected early, which is clinically detectable as reduced myocardial uptake of meta-iodobenzylguanidine in PD/DLB. Because each Lewy-prone system develops LBs independently, their isolated presentation as "focal LB disease" or their whatever combinations as "multifocal LB disease" are a more plausible framework to explain clinicopathological diversities of LB disorders. Clinical criteria are now being revised to integrate these clinicopathological disorders of PD/DLB. To gain closer access to the reality of t

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Axons; Brain; Disease Progression; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Retrograde Degeneration; Substantia Nigra

Lewy bodies and Lewy neurites composed primarily of α-synuclein characterize synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Despite decades of research on the impact of α-synuclein, little is known how abnormal inclusion made of this protein compromise neuronal function. Emerging evidence suggests that defects in axonal transport caused by aggregated α-synuclein contribute to neuronal dysfunction. These defects appear to occur well before the onset of neuronal death. Susceptible neurons in PD such as dopamine neurons with long elaborate axons may be particularly sensitive to abnormal axonal transport. Axonal transport is critical for delivery of signaling molecules to the soma responsible for neuronal differentiation and survival. In addition, axonal transport delivers degradative organelles such as endosomes and autophagosomes to lysosomes located in the soma to degrade damaged proteins and organelles. Identifying the molecular mechanisms by which axonal transport is impaired in PD and DLB may help identify novel therapeutic targets to enhance neuron survival and even possibly prevent disease progression. Here, we review the evidence that axonal transport is impaired in synucleinopathies, and describe potential mechanisms by which contribute to these defects.

Topics: alpha-Synuclein; Animals; Axonal Transport; Humans; Lewy Body Disease; Parkinson Disease

Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies. In this Review, we discuss these emerging themes, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation. Finally, we summarize recent efforts toward the development of targeted therapies for PD and related synucleinopathies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autophagy; Axonal Transport; Endoplasmic Reticulum; Golgi Apparatus; Humans; Lewy Body Disease; Lysosomes; Mitochondria; Molecular Targeted Therapy; Multiple System Atrophy; Neurons; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Synapses; tau Proteins

Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.

Topics: alpha-Synuclein; Animals; Astrocytes; Cell Communication; Exosomes; Extracellular Space; Humans; Intracellular Space; Lewy Bodies; Lewy Body Disease; Microglia; Models, Biological; Multiple System Atrophy; Parkinson Disease; Protein Aggregation, Pathological; Protein Binding; Protein Transport

In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

Topics: alpha-Synuclein; History, 20th Century; History, 21st Century; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

α-Synuclein (αSyn) is a highly abundant neuronal protein whose exact structure and function are under debate. Misfolding and aggregation of this normally soluble, 140-residue polypeptide underlies a group of neurodegenerative disorders called synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The αSyn field has focused increasing attention on the hypotheses that certain aggregates of αSyn may be directly toxic to the neurons in which they arise and/or that aggregates can be released from some neurons and diffuse by undefined mechanisms to other neurons to seed αSyn in the recipient cells, thus propagating neuropathology by a non-cell autonomous process ('pathogenic spread'). While intense interest in these hypotheses has led to new approaches and tools to model aspects of the disorders, it is important to analyze which molecular events initiate αSyn aggregation inside neurons in the first place. Here, we review new insights into how neuronal αSyn homeostasis may be maintained under physiological conditions but perturbed by pathological factors.

Topics: alpha-Synuclein; Brain; Cell Membrane; Homeostasis; Humans; Lewy Body Disease; Neurodegenerative Diseases; Neurons; Parkinson Disease; Protein Multimerization

Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), in which the protein alpha-synuclein (α-Syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, using strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared with monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-Syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-Syn accumulation and cell-to-cell transfer, such as immunotherapy against α-Syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies.

Topics: alpha-Synuclein; Animals; Combined Modality Therapy; Humans; Immunotherapy; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Progressive aggregation of alpha-synuclein (αS) through formation of amorphous pale bodies to mature Lewy bodies or in neuronal processes as Lewy neurites may be the consequence of conformational protein changes and accumulations, which structurally represents "molecular template". Focal initiation and subsequent spread along anatomically connected structures embody "structural template". To investigate the hypothesis that both processes might be closely associated and involved in the progression of αS pathology, which can be observed in human brains, αS amyloidogenic precursors termed "seeds" were experimentally injected into the brain or peripheral nervous system of animals. Although these studies showed that αS amyloidogenic seeds can induce αS pathology, which can spread in the nervous system, the findings are still not unequivocal in demonstrating predominant transsynaptic or intraneuronal spreads either in anterograde or retrograde directions. Interpretation of some of these studies is further complicated by other concurrent aberrant processes including neuroimmune activation, injury responses and/or general perturbation of proteostasis. In human brain, αS deposition and neuronal degeneration are accentuated in distal axon/synapse. Hyperbranching of axons is an anatomical commonality of Lewy-prone systems, providing a structural basis for abundance in distal axons and synaptic terminals. This neuroanatomical feature also can contribute to such distal accentuation of vulnerability in neuronal demise and the formation of αS inclusion pathology. Although retrograde progression of αS aggregation in hyperbranching axons may be a consistent feature of Lewy pathology, the regional distribution and gradient of Lewy pathology are not necessarily compatible with a predictable pattern such as upward progression from lower brainstem to cerebral cortex. Furthermore, "focal Lewy body disease" with the specific isolated involvement of autonomic, olfactory or cardiac systems suggests that spread of αS pathology is not always consistent. In many instances, the regional variability of Lewy pathology in human brain cannot be explained by a unified hypothesis such as transsynaptic spread. Thus, the distribution of Lewy pathology in human brain may be better explained by variable combinations of independent focal Lewy pathology to generate "multifocal Lewy body disease" that could be coupled with selective but variable neuroanatomical spread of αS pathology. More flexib

Topics: alpha-Synuclein; Animals; Axons; Brain; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Synucleinopathies are characterized by abnormal proteinaceous aggregates, mainly composed of fibrillar α-synuclein (α-syn). It is now believed that α-syn can form small aggregates in a restricted number of cells, that propagate to neighbouring cells and seed aggregation of endogenous α-syn, in a 'prion-like manner'. This process could underlie the stereotypical progression of Lewy bodies described by Braak and colleagues across different stages of Parkinson's disease (PD). This prion-like behaviour of α-syn has been recently investigated in animal models of PD or multiple system atrophy (MSA). These models investigate the cell-to-cell transfer of α-syn seeds, or the induction and spreading of α-syn pathology in transgenic or wild-type rodent brain. In this review, we first outline the involvement of α-syn in Lewy body diseases and MSA, and discuss how 'prion-like' mechanisms can contribute to disease. Thereon, we debate the relevance of animal models used to study prion-like propagation. Finally, we review current main histological methods used to assess α-syn pathology both in animal models and in human samples and their relevance to the disease. Specifically, we discuss using α-syn phosphorylated at serine 129 as a marker of pathology, and the novel methods available that allow for more sensitive detection of early pathology, which has relevance for modelling synucleinopathies.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Disease Progression; Humans; Lewy Body Disease; Multiple System Atrophy

Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioral deficits induced by excess pathogenic alpha-synuclein in various animal and/or cellular models. However, the process of selecting the anti-alpha-synuclein antibody with the best potential to treat synucleinopathies in humans is not trivial. Critical to this process is a better understanding of the pathological processes involved in the synucleinopathies and how antibodies are able to influence these. We will give an overview of the first proof-of-concept studies in rodent disease models and discuss challenges associated with developing antibodies against alpha-synuclein resulting from the distribution and structural characteristics of the protein. We will also provide a status on the passive immunization approaches targeting alpha-synuclein that have entered, or are expected to enter, clinical evaluation.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Immunization, Passive; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

The lack of effective therapies for neurodegenerative disorders is one of the most relevant challenges of this century, considering that, as the global population ages, the incidence of these type of diseases is quickly on the rise. Among these disorders, synucleinopathies, which are characterized by the abnormal accumulation and spreading of the synaptic protein alpha-synuclein in the brain, already constitute the second leading cause of parkinsonism and dementia in the elderly population. Disorders with alpha-synuclein accumulation include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Numerous therapeutic alternatives for synucleinopathies are being tested in pre-clinical models and in the clinic; however, only palliative treatments addressing the dopaminergic deficits are approved to date, and no disease-modifying options are available yet. In this article, we provide a brief overview of therapeutic approaches currently being explored for synucleinopathies, and suggest possible explanations to the clinical trials outcomes. Finally, we propose that a deeper understanding of the pathophysiology of synucleinopathies, together with a combination of therapies tailored to each disease stage, may lead to better therapeutic outcomes in synucleinopathy patients. Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Clinical Trials as Topic; Dementia; Genetic Therapy; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Stem Cell Transplantation

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology--namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Although the physiological function of α-synuclein is not fully understood, it has been suggested to primarily localize to the presynaptic terminals of mature neurons, where it fulfills roles in synaptic function and plasticity. Based on current knowledge, α-synuclein (αSYN) is thought to be involved in maintaining neurotransmitter homeostasis by regulating synaptic vesicle fusion, clustering, and trafficking between the reserve and ready-releasable pools, as well as interacting with neurotransmitter membrane transporters. In this review, we focus on evidence proposing synapses as the main site of αSYN pathology and its propagation in Parkinson's disease and dementia with Lewy bodies, which belong to a group of neurodegenerative diseases known as α-synucleinopathies. We provide an overview of the evidence supporting presynaptic dysfunction as the primary event in the pathogenesis of these conditions.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Parkinson Disease; Synapses

In this review the structural and functional imaging changes associated with the synucleinopathies PD, MSA, and dementias associated with Lewy bodies are reviewed. The role of imaging for supporting differential diagnosis, detecting subclinical disease, and following disease progression is discussed and its potential use for monitoring disease progression is debated. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Substantia Nigra

Several decades ago, a mysterious transmissible agent was found responsible for a group of progressive and lethal encephalopathies affecting the nervous system of both animals and humans. This infectious agent showed a strain-encoded manner of inheritance even though it lacked nucleic acids. The identification of infectious proteins resolved this apparent conundrum. Misfolded infectious protein particles, or prions, were found to exist as conformational isomers with a unique fingerprint that can be faithfully passaged to next generations. Protein-based strain-encoded inheritance is characterized by strain-specific infectivity and symptomatology. It is found in diverse organisms, such as yeast, fungi, and mammals. Now, this concept is revisited to examine the pathological role of amyloid proteins involved in neurodegenerative diseases where it might underlie certain types of dementia and motor-related neurodegenerative disorders. Given the discovery of the SNCA gene and the identification of its gene product, ɑ-synuclein (ɑ-SYN), as the main histopathological component of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, the scientific community was left puzzled by the fact that a single protein appeared to be involved in different diseases with diverging clinical phenotypes. Recent studies are now indicating that ɑ-SYN may act in a way similar to prions and that ɑ-SYN misfolded structural variants may behave as strains with distinct biochemical and functional properties inducing specific phenotypic traits, which might finally provide an explanation for the clinical heterogeneity observed between Parkinson's disease, MSA, and dementia with Lewy bodies patients. These crucial new findings may pave the way for unexplored therapeutic avenues and identification of new potential biomarkers. Parkinson's disease and other synucleinopathies share ɑ-synuclein deposits as a common histopathological hallmark. New and ongoing developments are now showing that variations in the aggregation process and the formation of ɑ-synuclein strains may be paralleled by the development of distinct synucleinopathies. Here, we review the recent developments and the role of strains in synucleinopathies. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Dementia; Genetic Variation; Humans; Lewy Body Disease; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease

Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in synucleinopathies representing an attractive strategy to elucidate-common and specific-SNCA-genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.

Topics: alpha-Synuclein; Animals; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Aggregation, Pathological; Up-Regulation

Abnormal accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (LBs) is the neurpathological hallmark of Parkinson's disease (PD) and related synucleinopathies. These inclusions are mainly constituted of a presynaptic protein, α-synuclein (α-syn). Over the past decade, growing amounts of studies reported an aberrant accumulation of phosphorylated α-syn at the residue S129 (pS129) in the brain of patients suffering from PD, as well as in transgenic animal models of synucleinopathies. Whereas only a small fraction of α-syn (<4%) is phosphorylated in healthy brains, a dramatic accumulation of pS129 (>90%) has been observed within LBs, suggesting that this post-translational modification may play an important role in the regulation of α-syn aggregation, LBs formation and neuronal degeneration. However, whether phosphorylation at S129 suppresses or enhances α-syn aggregation and toxicity in vivo remains a subject of active debate. The answer to this question has important implications for understanding the role of phosphorylation in the pathogenesis of synucleinopathies and determining if targeting kinases or phosphatases could be a viable therapeutic strategy for the treatment of these devastating neurological disorders. In the present review, we explore recent findings from in vitro, cell-based assays and in vivo studies describing the potential implications of pS129 in the regulation of α-syn physiological functions, as well as its implication in synucleinopathies pathogenesis and diagnosis.

Topics: alpha-Synuclein; Animals; Brain; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phosphorylation

Pure autonomic failure (PAF) is a rare sporadic neurodegenerative autonomic disorder characterized by slowly progressive pan autonomic failure without other features of neurologic dysfunctions. The main clinical symptoms result from neurogenic orthostatic hypotension and urinary and gastrointestinal autonomic dysfunctions. Autonomic failure in PAF is caused by neuronal degeneration of pre- and postganglionic sympathetic and parasympathetic neurons in the thoracic spinal cord and paravertebral autonomic ganglia. The presence of Lewy bodies and α-synuclein deposits in these neural structures suggests that PAF is one of Lewy body synucleinopathies, examples of which include multiple system atrophy, Parkinson disease, and Lewy body disease. There is currently no specific treatment to stop progression in PAF. Management of autonomic symptoms is the mainstay of treatment and includes management of orthostatic hypotension and supine hypertension. The prognosis for survival of PAF is better than for the other synucleinopathies.

Topics: alpha-Synuclein; Disease Progression; Humans; Lewy Body Disease; Prognosis; Pure Autonomic Failure

α-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified α-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic α-synuclein fibrils and pathological α-synuclein from diseased brains can act as triggers to convert normal α-synuclein to an abnormal form via prion-like mechanisms. In this article, we describe the experimental pathologies of α-synuclein both in vitro and in vivo in human and animal models. Prion-like spreading of abnormal α-synuclein from cell to cell can account for the progression of these α-synucleinopathies.

Topics: alpha-Synuclein; Amyloid; Animals; Brain; Disease Models, Animal; Disease Progression; Humans; Lewy Body Disease; Mice; Multiple System Atrophy; Parkinson Disease

Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: 'direct-evidence studies' based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and 'indirect-evidence studies' based on an association being referred to as a secondary outcome. Ten 'direct-evidence papers' were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 'indirect-evidence papers' similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.

Topics: alpha-Synuclein; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Humans; Hypotension, Orthostatic; Hypoxia-Ischemia, Brain; Lewy Body Disease; Longitudinal Studies; Magnetic Resonance Imaging; Mental Status Schedule; Multiple System Atrophy; Neuroglia; Parkinson Disease; Positron Emission Tomography Computed Tomography; Risk Factors; Statistics as Topic

α-Synuclein (α-syn) is the major protein component of Lewy bodies, a key pathological characteristic of the degenerating brain. The misfolding and aggregation of α-syn is associated with both the idiopathic and familial forms of Parkinson's disease (PD) and Lewy body dementia (LBD). However, the function of α-syn is poorly understood, as it shows both neurotoxic and neuroprotective activities. Mutations in phosphatase and tensin homologue-induced putative kinase 1 (PINK1) also cause recessively inherited PD. Studies support the notion of neuroprotective roles for PINK1, as it protects cells from damage-induced mitochondrial dysfunction, oxidative stress and cell apoptosis. PINK1 plays an essential role in mitochondrial quality control and its homeostasis is maintained through mitochondrial stabilization. The α-syn aggregation is linked to various aspects of mitochondrial dysfunction and PINK1-related mitophagy. Determination of the molecular pathways that lead to α-syn oligomerization and further aggregation may be the basis for the successful design and development of treatments for these neurodegenerative diseases. The present review summarizes the function of PINK1 underlying α-syn aggregation and the mechanisms through which mitochondrial dysfunction plays a role in this process.

Topics: alpha-Synuclein; Animals; Diet; Humans; Lewy Body Disease; Mitochondria; Mitophagy; Neurons; Protein Kinases; Signal Transduction

Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.

Topics: Alkyl and Aryl Transferases; alpha-Synuclein; Animals; Disease Models, Animal; Genetic Linkage; Genome-Wide Association Study; Humans; Lewy Body Disease; Multiple System Atrophy; Mutation; Parkinson Disease

The etiology and pathogenesis of neurodegenerative disorders has yet to be elucidated, so their differential diagnosis is a challenge. This is especially true in differentiating Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson disease (PD), and multiple system atrophy (MSA).. A total of 11 eligible articles were identified by search of electronic databases including PubMed, Springer Link, Elsevier, and the Cochrane Library, up to June 2014. In meta-analyses, standardized mean differences (SMD), with 95% confidence intervals (CI), comparing cerebrospinal fluid (CSF) measures of α-synuclein between the above conditions were calculated using random-effects models.. CSF α-synuclein concentrations were significantly higher in AD compared to DLB [SMD: 0.32, 95% CI: (0.02, 0.62), z = 2.07, P = 0.038]; PD [SMD: 0.87, 95% CI: (0.15, 1.58), z = 2.38, P = 0.017]; or MSA [SMD: 1.14, 95% CI: (0.15, 2.14), z = 2.25, P = 0.025]. However, no significant difference was found between patients with AD and neurological cognitively normal controls [SMD: 0.02, 95% CI: (-0.21, 0.24), z = 0.13, P = 0.894].. Results of these meta-analysis suggest that quantification of CSF α-synuclein could help distinguish AD from other neurodegenerative disorders such as DLB, PD, or MSA.

Topics: alpha-Synuclein; Alzheimer Disease; Diagnosis, Differential; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Parkinson's Disease (PD) and alpha synucleinopathies are multifactorial disorders, which manifest through motor symptoms and non-motor symptoms involving the Central Nervous System (CNS), the Peripheral Nervous System (PNS) and, recently, also the Enteric Nervous System (ENS). The typical hallmarks of alpha synucleinopathies are proteinaceous inclusions of alpha synuclein (αS). In PD they are known as Lewy Bodies (LBs) and Lewy Neurites (LNs), discovered in dopaminergic neurons of substantia nigra (pars compacta) as well as in other regions of the central and peripheral nervous systems. Despite the clear causes which lead to LBs/LNs are still unknown, according to Braak's theory, these inclusions appear first in PNS to spread, following neuronal innervation, towards the CNS in a spatio- temporal dissemination described in a staging procedure. In line with these observations, several animal models have been used with the purpose to reproduce PD as well as to propose new therapeutic approaches. Different pathways can cooperate to neurodegeneration in PD such as genetic mutations of αS gene, mitochondrial dysfunctions, neuroinflammation. The present review highlights αS as the key-word for PD pathology and alpha synucleinopathies and a main target in PD research. Several therapeutic approaches can be proposed, however all of them are addressed in advanced stages of the pathology. Our focus will be the alteration of αS physiological pathway, which allows to address therapy in early stages at intracellular or extracellular level, such as the use of anti ER-stress compounds and innovative immunotherapy, which could be promising tools to reduce neuronal degeneration and to halt PD progression.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Biomarkers; Disease Progression; Dopaminergic Neurons; Early Diagnosis; Gastrointestinal Diseases; Humans; Immunotherapy; Lewy Bodies; Lewy Body Disease; Mice; Mice, Transgenic; Mitochondria; Models, Neurological; Molecular Targeted Therapy; Neuroglia; Organ Specificity; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Protein Structure, Tertiary; Rats; Single-Chain Antibodies; Unfolded Protein Response; Vagus Nerve

Neuroinflammation is increasingly recognized as a key factor in the pathogenesis of neurodegenerative conditions. However, it remains unclear whether it has a protective or damaging role. Studies of Alzheimer's disease and Parkinson's disease have provided much of the evidence for inflammatory pathology in neurodegeneration. Here we review the evidence for inflammation in dementia with Lewy bodies and Parkinson's disease dementia. Neuroinflammation has been confirmed in vivo using PET imaging, with microglial activation seen in Parkinson's disease dementia and recently in dementia with Lewy bodies. In Parkinson's disease and Parkinson's disease dementia, microglial activation suggests a chronic inflammatory process, although there is also evidence of its association with cognitive ability and neuronal function. Alpha-synuclein in various conformations has also been linked to activation of microglia, with a broad range of components of the innate and adaptive immune systems associated with this interaction. Evidence of neuroinflammation in Lewy body dementia is further supported by pathological and biomarker studies. Genetic and epidemiological studies support a role for inflammation in Parkinson's disease, but have yet to provide the same for Lewy body dementia. This review highlights the need to identify whether the nature and extent of microglial activation in Lewy body dementia can be linked to structural change, progression of domain specific cognitive symptoms and peripheral inflammation as a marker of central microglial pathology. Answers to these questions will enable the evaluation of immunotherapies as potential therapeutic options for prevention or treatment of dementia with Lewy bodies and Parkinson's disease dementia.

Topics: Adaptive Immunity; alpha-Synuclein; Animals; Biomarkers; Cytokines; Disease Models, Animal; Forecasting; Genetic Predisposition to Disease; Genome-Wide Association Study; HLA-D Antigens; Humans; Inflammation; Lewy Body Disease; Microglia; Positron-Emission Tomography

Topics: alpha-Synuclein; Animals; Female; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

α-Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of α-synuclein aggregates in neurons, nerve fibres or glial cells. While small amounts of these α-synuclein pathologies can occur in some neurologically normal individuals who do not have associated neurodegeneration, the absence of neurodegeneration in such individuals precludes them from having a degenerative α-synucleinopathy, and it has yet to be established whether such individuals have a form of preclinical disease. There are three main types of α-synucleinopathy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), with other rare disorders also having α-synuclein pathologies, such as various neuroaxonal dystrophies. Multiple clinical phenotypes exist for each of the three main α-synucleinopathies, with these phenotypes differing in the dynamic distribution of their underlying neuropathologies. Identifying the factors involved in causing different α-synuclein phenotypes may ultimately lead to more targeted therapeutics as well as more accurate clinical prognosis.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phenotype

Lewy bodies (LBs) and Lewy neurites (LNs), comprised of alpha-synuclein (aSyn), are intraneuronal inclusions that characterize Parkinson's disease. Although the association between the extent of Lewy pathology and clinical symptoms is well established, how these proteinaceous deposits originate and target selectively vulnerable cell populations is unknown. Our knowledge of their role in PD pathogenesis is also limited. Here, we summarize recent findings demonstrating this pathology can be experimentally transmitted between animals by misfolded forms of aSyn that are capable of initiating and inducing LB and LN inclusion formation through a self-propagating mechanism reminiscent of prions. "Seeded" LBs and LNs in animal models also spread to multiple connected nuclei in a predictable pattern, recapitulating a phenomenon observed during human PD progression, leading to the dysfunction and degeneration of afflicted neurons. These models provide new perspectives on how this and other misfolded proteins may contribute to neurodegeneration in human disease.

Topics: alpha-Synuclein; Animals; Disease Progression; Humans; Lewy Bodies; Lewy Body Disease; Models, Biological; Parkinson Disease; Proteostasis Deficiencies

Misfolding and intracellular aggregation of α-synuclein are thought to be crucial factors in the pathogenesis of Lewy body diseases (LBDs), such as Parkinson disease. However, the pathogenic modifications of this protein and the mechanisms underlying its activity have not been fully characterized. Recent studies suggest that small amounts of α-synuclein are released from neuronal cells by unconventional exocytosis, and that this extracellular α-synuclein contributes to the major pathological features of LBD, such as neurodegeneration, progressive spreading of α-synuclein pathology, and neuroinflammation. In this article, we review a rapidly growing body of literature on possible mechanisms by which extracellular α-synuclein contributes to LBD pathology, and discuss therapeutic approaches to target this form of α-synuclein to halt disease progression.

Topics: alpha-Synuclein; Animals; Extracellular Fluid; Humans; Lewy Body Disease; Models, Molecular; Neurons

Immunotherapy targeting α-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. α-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of α-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against α-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting α-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other α-synucleinopathies.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Humans; Immunotherapy; Lewy Bodies; Lewy Body Disease; Mice; Mice, Transgenic; Molecular Targeted Therapy; Parkinson Disease; Unfolded Protein Response

Alpha-Synuclein protein(alphaS) aggregates from a monomer to assemblies such as oligomers, protofibrils, and mature fibrils. The early intermediate aggregate, that is, the oligomer, has been reported to be the most toxic species. We recently reported that melatonin inhibits alphaS aggregation, including protofibril and oligomer formations. While the alphaS concentration in cerebrospinal fluid was reported to significantly decrease in patients with Parkinson's disease (PD) and dementia with Lewy bodies, there have been reports that the alphaS oligomer concentration was elevated in the cerebrospinal fluid of PD patients. Moreover, it was reported that the alphaS oligomer concentration was also elevated in the blood of PD patients. Further studies may establish alphaS in cerebrospinal fluid and blood as a biomarker of alpha-synucleinopathies, including PD.

Topics: alpha-Synuclein; Animals; Endoribonucleases; Humans; Ion Channels; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Mutations in the gene encoding glucocerebrosidase (GBA1) cause Gaucher disease (GD), a lysosomal storage disease with recessive inheritance. Glucocerebrosidase (GCase) is a lysosomal lipid hydrolase that digests glycolipid substrates, such as glucosylceramide and glucosylsphingosine. GBA1 mutations have been implicated in Lewy body diseases (LBDs), such as Parkinson's disease and dementia with Lewy bodies. Parkinsonism occurs more frequently in certain types of GD, and GBA1 mutation carriers are more likely to have LBDs than non-carriers. Furthermore, GCase is often found in Lewy bodies, which are composed of α-synuclein fibrils as well as a variety of proteins and vesicles. In this review, we discuss potential mechanisms of action of GBA1 mutations in LBDs with particular emphasis on α-synuclein aggregation by reviewing the current literature on the role of GCase in lysosomal functions and glycolipid metabolism.

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Glycolipids; Humans; Lewy Body Disease; Lysosomes; Mutation

Dementia with Lewy Bodies (DLB) can be difficult to distinguish clinically from other dementias.. To investigate the diagnostic utility of CSF alpha-synuclein in differentiating between DLB and other dementias.. Electronic databases were systematically searched for studies investigating reproducible alpha synuclein quantification methods. Random effects model was used to calculate weighted mean difference (WMD) and 95% confidence intervals between DLB and other groups.. A total of 13 studies, comprising 2728 patients were included. Mean CSF alpha-synuclein concentration was significantly lower in DLB patients compared to those with Alzheimers disease (AD) [WMD -0.24; 95% CI, -0.45, -0.03; p = 0.02]. No significant difference was found between patients with DLB compared to Parkinsons disease [WMD 0.05; 95% CI, -0.17, 0.28; p = 0.65] or other neurodegenerative conditions.. CSF alpha synuclein may be of diagnostic use in differentiating between DLB and AD. We propose several recommendations to guide better design of future studies.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Data Interpretation, Statistical; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests; Publication Bias; Reproducibility of Results; Research Design; Young Adult

The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies.

Topics: alpha-Synuclein; Animals; beta-Synuclein; Endoplasmic Reticulum; gamma-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phosphorylation; Pure Autonomic Failure; Synaptic Transmission; Ubiquitinated Proteins; Ubiquitination

Although α-synuclein protein (αS) aggregates from a monomer to assemblies such as oligomer, protofibril and mature fibril, the early intermediate aggregate, that is, oligomer has been considered to be most toxic species in recent reports. While it was reported that αS concentration in cerebrospinal fluid was decreased significantly in the patients with Parkinson's disease (PD) and dementia with Lewy bodies, there were reports that αS oligomer concentration was elevated in cerebrospinal fluid of PD patients. Moreover, it was supposed that αS oligomer concentration was also elevated in blood of PD patients. Further studies of αS in cerebrospinal fluid and blood would lead to establishment of the significance of αS as a biomarker for α-synucleinopathies including PD.

Topics: alpha-Synuclein; Biomarkers; Early Diagnosis; Humans; Lewy Body Disease; Parkinsonian Disorders; Protein Aggregates; Protein Aggregation, Pathological

The "proteinopathy" hypothesis, which states that pathological inclusions result in neuronal death, is classically invoked to explain neurodegeneration. In this review on α-synuclein (αS), attention is shifted to the distal axons, where αS deposits earlier than in the cytoplasmic formation of Lewy bodies (LBs). Because LBs are preferentially formed in axons with abundant branching, hyperbranching may accentuate axonal degeneration and αS deposition in their distal ends. This hyperbranching may also explain why motor/non-motor symptoms of Parkinson disease (PD) are so generalized and diffuse with barely any localizing value. Such underlying structure templates both the distal-dominant degeneration with αS deposition, and the non-localizing nature of clinical manifestations of PD, and as such can be considered a "structural template" thereof. The evolution of PD symptoms can be highly variable, ranging from restricted LB lesions and corresponding, long-lived, symptoms (pure autonomic failure, cardiac denervation, essential tremor, and REM-related behavioral disorders, which may be collectively called "focal LB disease") to the more haphazard appearance of dementia or anosmia without developing parkinsonism or brainstem lesions. This variability is better explained by the parallel involvement of multiple systems with hyperbranching axons rather than the stereotyped upward spread of LB in the brainstem. Awareness of presynaptic dysfunctions of these hyperbranching systems may enhance the sensitivity and specificity of clinical diagnoses of PD for earlier therapeutic intervention.

Topics: alpha-Synuclein; Animals; Axons; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Protein Transport

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin-proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD.

Topics: alpha-Synuclein; Animals; Humans; Lewy Bodies; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

Cardiovascular autonomic failure is the second most common dysautonomic feature of α-synucleinopathies and has significant impact on daily activities and quality of life. Here we provide a systematic review of cardiovascular autonomic failure in α-synucleinopathies, emphasizing its impact on cognitive functions and disease outcomes. Articles spanning the period between January 1985 and April 2012 were identified from the PubMed database using a keyword-based search. Epidemiological studies highlight the negative prognostic effect of cardiovascular autonomic failure on cardiovascular and cerebrovascular outcomes and overall mortality in all α-synucleinopathies. Altered cerebral perfusion, vascular pressure stress, and related disruption of the blood-brain barrier may also contribute to the white matter hyperintensities and cognitive dysfunction frequently found in patients affected by neurocardiovascular instability. These findings support the hypothesis that cardiovascular autonomic failure may play a negative prognostic role in α-synucleinopathies and suggest that precocious screening and therapeutic management of cardiovascular autonomic failure may positively impact disease course.

Topics: alpha-Synuclein; Brain; Cardiovascular System; Cognition Disorders; Disease Progression; Fatigue; Humans; Hypotension, Orthostatic; Lewy Body Disease; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; Primary Dysautonomias; Prognosis; Pure Autonomic Failure

Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed.

Topics: alpha-Synuclein; Alternative Splicing; Amino Acid Sequence; Animals; Humans; Lewy Bodies; Lewy Body Disease; Molecular Sequence Data; Neurodegenerative Diseases; Protein Processing, Post-Translational

Although resting tremor, cogwheel rigidity, hypokinesia/bradykinesia and postural instability usually dominate the clinical picture of sporadic Parkinson's disease (PD), both clinical and epidemiological data reveal that a wide variety of additional symptoms impair patients' quality of life considerably, parallel to the chronic progressive neurodegenerative movement disorder. Autopsy based retrospective studies have shown that α-synuclein immunoreactive Lewy pathology (LP) develops in the locus coeruleus (LC) of patients with neuropathologically confirmed sporadic PD, as well as in individuals with incidental (prodromal or premotor) Lewy body disease but not in age and gender matched controls. Using five case studies, this review discusses the possible role of LP (axonopathy, cellular dysfunction and nerve cell loss) in the LC, catecholaminergic tract and related circuitry in the development of PD-related dementia. The contribution of noradrenergic deficit to cognitive dysfunction in PD has been underappreciated. Noradrenergic therapeutic interventions might not only alleviate depressive symptoms and anxiety but also delay the onset of cognitive decline.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Atherosclerosis; Autopsy; Brain; Dementia; Disease Progression; Female; Humans; Lewy Body Disease; Locus Coeruleus; Male; Nerve Net; Norepinephrine; Parkinson Disease; REM Sleep Behavior Disorder; Sleep Initiation and Maintenance Disorders

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is no longer considered a complex motor disorder characterized by extrapyramidal symptoms, but a progressive multisystem or-more correctly-multiorgan disease with variegated neurological and nonmotor deficiencies. It is morphologically featured not only by the degeneration of the dopaminergic nigrostriatal system, responsible for the core motor deficits, but by multifocal involvement of the central, peripheral and autonomic nervous system and other organs associated with widespread occurrence of Lewy bodies and dystrophic Lewy neurites. This results from deposition of abnormal α-synuclein (αSyn), the major protein marker of PD, and other synucleinopathies. Recent research has improved both the clinical and neuropathological diagnostic criteria of PD; it has further provided insights into the development and staging of αSyn and Lewy pathologies and has been useful in understanding the pathogenesis of PD. However, many challenges remain, for example, the role of Lewy bodies and the neurobiology of axons in the course of neurodegeneration, the relation between αSyn, Lewy pathology, and clinical deficits, as well as the interaction between αSyn and other pathologic proteins. Although genetic and experimental models have contributed to exploring the causes, pathomechanisms, and treatment options of PD, there is still a lack of an optimal animal model, and the etiology of this devastating disease is far from being elucidated.

Topics: alpha-Synuclein; Brain; Cognition Disorders; Humans; Lewy Bodies; Lewy Body Disease; Neurons; Parkinson Disease

Accumulation of alpha-synuclein is a pathological feature in several neurological diseases. Its characterization has allowed for a re-grouping of diseases according to the expected pathology. The clinical syndrome of PD can now be classified into forms with and without alpha-synuclein pathology. DLB and PDD are synucleinopathies, and MSA shows alpha-synuclein pathology with glial inclusions. ADHD symptoms commonly occur in persons that will subsequently develop DLB. A similar phenomenon may be the early personality changes and frontotemporal atrophy in patients with SNCA multiplication. RLS is not known to have alpha-synuclein pathology, but as PD and ADHD, involves a hypodopaminergic state. Furthermore, PD and RLS co-occur in families in a way that suggests common inheritance. A proportion of patients with ET have brainstem Lewy body pathology. Gaucher disease and other lysosomal storage disorders also have alpha-synuclein pathology. Alpha-synuclein is a naturally unfolded protein. Non-fibrillar oligomeres may be the toxic species, and Lewy body formation may in fact be protective. Inhibiting alpha-synuclein toxicity seems to be an attractive novel treatment strategy and several approaches are being developed. When such treatments become available, clinicians will need to be familiar with the clinical features that distinguish the synucleinopathies from their look-alikes.

Topics: alpha-Synuclein; Animals; Brain Chemistry; Humans; Lewy Body Disease; Parkinson Disease; Synucleins

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in the elderly. DLB is clinically characterized by fluctuating cognitive dysfunction, visual hallucinations, and parkinsonism. It is sometimes difficult to clinically diagnose patients with DLB because of the overlap of the clinical and pathological findings of this disease with those of Alzheimer's disease. Precise clinical diagnosis is important for determining the drug therapy appropriate for improving DLB symptoms. Biomarkers that enable more accurate diagnosis of DLB and reflect its complex clinical progression are highly desired. Cognitive impairment frequently occurs in patients with Parkinson's disease (PD). The common pathological features of DLB and PD are Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. DLB and PD are now considered to belong to a common spectrum of disorders designated as Lewy body disease (LBD). We have previously reported that the α-synuclein levels in cerebrospinal fluid (CSF) are significantly lower in patients with DLB than in patients with other types of dementia. However, the significance of quantifying the CSF α-synuclein levels as a biomarker for DLB has been a matter of debate because the results for these levels have been inconsistent among different studies. Similar inconsistency has been observed in studies on the plasma α-synuclein levels in patients with LBD. Here, we review the recent progress on biomarkers of LBD, especially in DLB, and discuss their application to clinical diagnosis.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Humans; Lewy Body Disease; Saliva

Dementia with Lewy bodies is a complex brain disorder and a key member of the Lewy body disease spectrum. Its genetic etiology is unclear, and information is scattered. However, the results of molecular genetic studies imply a genetic and mechanistic overlap with Alzheimer disease, Parkinson disease with dementia, and Parkinson disease. In this review, we provide a comprehensive overview of the current studies on dementia with Lewy bodies heritability, genetic etiology, and genetic heterogeneity. We conclude with a critical discussion of the missing heritability in dementia with Lewy bodies and encourage scientists to further explore the underlying mechanisms of this disease.

Topics: alpha-Synuclein; Amyloid beta-Protein Precursor; Brain; Humans; Lewy Bodies; Lewy Body Disease; Presenilins

α-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline of motor and non-motor dysfunctions. α-Synuclein (αS) has been shown to play a causative role in neurodegeneration, but the pathogenic mechanisms are still unclear. Thus, there are no radical therapies that can halt or reverse the disease's progression. β-Synuclein (βS), the non-amyloidogenic homologue of αS, ameliorates the neurodegeneration phenotype of αS in transgenic (tg) mouse models, as well as in cell free and cell culture systems, which suggests that βS might be a negative regulator of neurodegeneration caused by αS, and that "loss of function" of βS might be involved in progression of α-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type βS occurs during the pathogenesis of sporadic α-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H βS develop progressive neurodegeneration phenotypes, such as axonal pathology and dementia. In this short review, we emphasize the aspects of "toxic gain of function" of wild type βS during the pathogenesis of sporadic α-synucleinopathies.

Topics: alpha-Synuclein; Animals; beta-Synuclein; Brain; Disease Progression; Lewy Bodies; Lewy Body Disease; Mice; Mice, Transgenic; Mutation, Missense

The advance in research on the dementia syndrome associated with Parkinson's disease recently gains momentum in part because Parkinson's disease inevitably causes declined cognition and then lead to poor quality of life. More importantly, dementia of Lewy bodies, now known as the second most common neurodegenerative disorder, shares the common neuropathological hallmark with Parkinson's disease and yet exhibits a unique clinical syndrome. Recent genetic, neurochemical and neuropsychological experiments robustly confirm a link between dementia associated with Parkinson's disease and dementia with Lewy bodies. Meanwhile, controversial issues regarding diagnostic criteria and proper treatments remain unresolved. Here I review milestone research conclusions and report a typical case with pathological data in order to clarify different aspects of these two dementia disorders.

Topics: Aged, 80 and over; alpha-Synuclein; Cognition Disorders; Dementia; Female; History, 18th Century; History, 19th Century; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Atypical parkinsonian disorders (APDs) comprise a heterogenous group of disorders including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Based on literature published in 2010, we here review recent advances in the APD field.. Genome-wide association studies have provided robust evidence of increased disease risk conferred by synuclein and tau gene variants in MSA and PSP. Furthermore, advanced imaging tools have been established in the differential diagnosis and as surrogate markers of disease activity in patients with APDs. Finally, although therapeutic options are still disappointing, translational research into disease-modifying strategies has accelerated with the increasing availability of transgenic animal models, particularly for MSA.. Remarkable progress has been achieved in the field of APDs, and advances in the genetics, molecular biology and neuroimaging of these disorders will continue to facilitate intensified clinical trial activity.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Clinical Trials as Topic; Diagnosis, Differential; Genome-Wide Association Study; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinsonian Disorders; Supranuclear Palsy, Progressive; tau Proteins

Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.

Topics: alpha-Synuclein; Alzheimer Disease; Brain; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Substantial genetic, neuropathological, and biochemical evidence implicates the presynaptic neuronal protein α-synuclein in Parkinson's disease and related Lewy body disorders. How dysregulation of α-synuclein leads to neurodegeneration is, however, unclear. Soluble oligomeric, but not fully fibrillar, α-synuclein is thought to be toxic. The major neuronal target of aberrant α-synuclein might be the synapse. The effects of aberrant α-synuclein might include alteration of calcium homoeostasis or mitochondrial fragmentation and, in turn, mitochondrial dysfunction, which could link α-synuclein dysfunction to recessive and toxin-induced parkinsonism. α-Synuclein also seems to be linked to other genetic forms of Parkinson's disease, such as those linked to mutations in GBA or LRRK2, possibly through common effects on autophagy and lysosomal function. Finally, α-synuclein is physiologically secreted, and this extracellular form could lead to the spread of pathological accumulations and disease progression. Consequently, factors that regulate the levels, post-translational modifications, specific aberrant cellular effects, or secretion of α-synuclein might be targets for therapy.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Neurons; Parkinson Disease

The protein family known as synucleins is composed of α-, β- and γ-synuclein. The most widely studied is the α-synuclein protein due to its participation in essential processes of the central nervous system. Neurotoxicity of this protein is related to the presence of multiplications (duplications and triplications) and point mutations in the gene sequence of the α-synuclein gene (SNCA), differential expression of its isoforms and variations in post-transductional modifications. Neurotoxicity is also related to cytoplasmic inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs), which are also present in α-synucleinopathies. In general, the β-synuclein protein, codified by the SNCB gene, acts as a regulator of processes triggered by α-synuclein and its function is altered by variations in the gene sequence, while γ-synuclein, codified by the SNCG gene, seems to play a major role in certain tumoral processes.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; beta-Synuclein; Humans; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

Dementia is a common feature in Parkinson disease (PD), the time of onset determining how patients are classified. Those patients where dementia develops prior to parkinsonism or during the first year of disease are designated as having dementia with Lewy bodies (DLB). In those where dementia develops over a year after the onset of motor signs, the condition is known as Parkinson's disease with dementia (PDD). While this seems at first sight to be a definitive way to distinguish these conditions, reality is rather different. The overlap between them is considerable, and there is much uncertainty associated with patients who have both motor symptoms and early cognitive impairment. The diagnosis is still based on medical history and clinical evaluation. It is not even certain that they can be accurately distinguished at autopsy. For this reason, the data concerning these entities have been reviewed, to examine various markers employed or measured in clinical, neuropathological, neuroimaging, and biochemical investigations. The concept of PDD and DLB being separate conditions is comparatively new, and the most promising tools with which to separate them at present are cerebrospinal fluid (CSF) markers and positron emission tomography (PET) scanning that indicate increased amyloid-beta burden in DLB compared to PDD. However as yet there are no markers that unequivocally distinguish between PDD and DLB.

Topics: Age of Onset; alpha-Synuclein; Amyloid beta-Peptides; Animals; Biomarkers; Dementia; Diagnostic Imaging; Humans; Incidence; Lewy Body Disease; Parkinson Disease; Prevalence; PubMed; tau Proteins

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are usually associated with loss of dopaminergic neurons. Loss of substantia nigra neurons and presence of Lewy body inclusions in some of the remaining neurons are the hallmark pathology seen in the final stages of the disease. Attempts to correlate Lewy body pathology to either cell death or severity of clinical symptoms, however, have not been successful. While the pathophysiology of the neurodegenerative process can hardly be explained by Lewy bodies, the clinical symptoms do indicate a degenerative process located at the presynapse resulting in a neurotransmitter deficiency. Recently it was shown that 90% or even more of alpha-synuclein aggregates in DLB cases were located at the presynapses in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved, suggesting a neurotransmitter deprivation. The same alpha-synuclein pathology can be demonstrated for PD. These findings give rise to the notion that not cell death but rather alpha-synuclein aggregate-related synaptic dysfunction causes the neurodegeneration. This opens new perspectives for understanding PD and DLB. If presynaptic alpha-synuclein aggregation, not neuronal loss, is the key issue of the neurodegenerative process, then PD and DLB may eventually be treatable in the future. The disease may progress via trans-synaptical spread, suggesting that stem cell transplants are of limited use. Future therapies may focus on the regeneration of synapses.

Topics: alpha-Synuclein; Animals; Brain; Lewy Body Disease; Parkinson Disease; Synapses

Alpha-synuclein aggregation is a neuropathological hallmark of many neurodegenerative diseases including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), collectively termed the α-synucleinopathies. Substantial advances in clinical criteria and neuroimaging technology over the last 20 years have allowed great strides in the detection and differential diagnosis of these disorders. Nevertheless, it is clear that whilst the array of different imaging modalities in clinical use allow for a robust diagnosis of α-synucleinopathy in comparison to healthy subjects, there is no clear diagnostic imaging marker that affords a reliable differential diagnosis between the different forms of Lewy body disease (LBD) or that could facilitate tracking of disease progression. This has led to a call for a biomarker based on the pathological hallmarks of these diseases, namely α-synuclein-positive Lewy bodies (LBs). This potentially may be advantageous in terms of early disease detection, but may also be leveraged into a potential marker of disease progression. We here aim to firstly review the current status of neuroimaging biomarkers in PD and related synucleinopathies. Secondly, we outline the rationale behind α-synuclein imaging as a potential novel biomarker as well as the potential benefits and limitations of this approach. Thirdly, we attempt to illustrate the likely technical hurdles to be overcome to permit successful in vivo imaging of α-synuclein pathology in the diseased brain. Our overriding aim is to provide a framework for discussion of how to address this major unmet clinical need.

Topics: alpha-Synuclein; Biomarkers; Disease Progression; Early Diagnosis; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Parkinson Disease; Peripheral Nervous System Diseases; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Ultrasonography

A shared neuropathological feature of idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy is the development of intracellular aggregates of α-synuclein that gradually engage increasing parts of the nervous system. The pathogenetic mechanisms underlying these neurodegenerative disorders, however, are unknown. Several studies have highlighted similarities between classic prion diseases and these neurological proteinopathies. Specifically, identification of Lewy bodies in fetal mesencephalic neurons transplanted in patients with Parkinson's disease raised the hypothesis that α-synuclein, the main component of Lewy bodies, could be transmitted from the host brain to a graft of healthy neurons. These results and others have led to the hypothesis that a prion-like mechanism might underlie progression of synucleinopathy within the nervous system. We review experimental findings showing that misfolded α-synuclein can transfer between cells and, once transferred into a new cell, can act as a seed that recruits endogenous α-synuclein, leading to formation of larger aggregates. This model suggests that strategies aimed at prevention of cell-to-cell transfer of α-synuclein could retard progression of symptoms in Parkinson's disease and other synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Humans; Lewy Bodies; Lewy Body Disease; Prion Diseases; Prions

The two most frequent synucleinopathies, Parkinson disease (PD) or brainstem predominant type of Lewy body disease, and dementia with Lewy bodies (DLB), are neurodegenerative multisystem disorders with widespread occurrence of alpha-synuclein containing deposits in the central, peripheral, and autonomic systems. For both Lewy body-related disorders staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of alpha-synuclein pathology are used that are considered to be linked to clinical dysfunctions. In PD a six-stage system is suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages related to incidental Lewy body disease, stages 3 and 4 presenting with motor symptoms and the last two (cortical) stages frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of alpha-synuclein pathology (Lewy body density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitory/limbic and diffuse cortical), also considering concomitant Alzheimer-related pathology. Recent retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of cases did not follow the proposed caudo-rostral progression pattern of alpha-synuclein pathology. In 7 to 8.3% of clinically manifested PD cases with synuclein inclusions in midbrain and cortex corresponding to LB stages 4-5 the medullary nuclei were spared, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of Lewy body pathology, but is related to concomitant Alzheimer lesions or mixed pathologies. There is no relationship between Braak LB stages and clinical severity of PD. Therefore, the predictive validity of this concept is doubtful, since in large unselected autopsy series 30 to 55% of elderly subjects with widespread alpha-synuclein pathology (Braak stages 5-6) revealed no definite neuropsychiatric symptoms or were not classifiable, indicating comp

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease

Topics: Acetylcholine; Aged; alpha-Synuclein; Alzheimer Disease; Apolipoprotein E4; Brain; Dementia; Diagnosis, Differential; Dopamine; Humans; Lewy Body Disease; Parkinson Disease; Phenotype

Lewy body diseases are characterized by the presence of Lewy bodies, alpha-synuclein(AS)-positive inclusions in the brain. Since their main component is conformationally modified AS, aggregation of the latter is thought to be a key pathogenic event in these diseases. The analysis of inclusion body constituents gives additional information about pathways also involved in the pathology of synucleinopathies. Widespread mitochondrial dysfunction is very closely related to disease development. The impairment of protein degradation pathways, including both the ubiquitin-proteasome system and the autophagy-lysosome pathway also play an important role during the development of Lewy body diseases. Finally, differential expression changes of isoforms corresponding to genes primarily involved in Lewy body formation point to alternative splicing as another important mechanism in the development of Parkinson's disease, as well as dementia with Lewy bodies. The present paper attempts to give an overview of recent molecular findings related to the pathogenesis of Lewy body diseases.

Topics: alpha-Synuclein; Alternative Splicing; Humans; Lewy Bodies; Lewy Body Disease; Mitochondria; Presenilins; Proteasome Endopeptidase Complex; Protein Isoforms; Ubiquitin

Genetic analysis has identified many loci designated as PARK loci (OMIM #168600). Many of these loci do not refer to idiopathic Parkinson's disease which is characterized by Lewy body pathology, but rather to clinical parkinsonisms. In this review, besides reviewing the genetic of the disorder, we argue that this designation is misleading and that if we seek to understand the pathogenesis, we should study the genetics of Lewy body diseases: these include not only idiopathic Parkinson's disease, but also such disparate syndromes as Hallevorden-Spatz disease and Niemann-Pick Type C.

Topics: alpha-Synuclein; F-Box Proteins; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Mutation; Parkinson Disease; Protein Serine-Threonine Kinases; Syndrome; Ubiquitin-Protein Ligases

A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson's disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism.

Topics: Adult; Aged; alpha-Synuclein; Child; DNA Mutational Analysis; Enzyme Replacement Therapy; Ethnicity; Female; Gaucher Disease; Genetic Counseling; Genetic Predisposition to Disease; Glucosylceramidase; Hippocampus; Humans; Lewy Body Disease; Lysosomes; Male; Middle Aged; Mutation; Parkinsonian Disorders; Risk Factors; Substantia Nigra

Neurodegenerative diseases constitute a set of pathological conditions originating from the slow, irreversible and systematic cell loss within the various regions of the brain and/or the spinal cord. Neurodegenerative diseases are proteinopathies associated with misbehavior and disarrangement of a specific protein, affecting its processing, functioning, and/or folding. Many proteins associated with human neurodegenerative diseases are intrinsically disordered; i.e., they lack stable tertiary and/or secondary structure under physiological conditions in vitro. Intrinsically disordered proteins (IDPs) have broad presentation in nature. Functionally, they complement ordered proteins, being typically involved in regulation, signaling and control. Structures and functions of IDPs are intensively modulated by alternative splicing and posttranslational modifications. It is recognized now that nanoimaging offers a set of tools to analyze protein misfolding and self-assembly via monitoring the aggregation process, to visualize protein aggregates, and to analyze properties of these aggregates. The major goals of this review are to show the interconnections between intrinsic disorder and human neurodegenerative diseases and to overview a recent progress in development of novel nanoimaging tools to follow protein aggregation.

Topics: alpha-Synuclein; Alzheimer Disease; Amino Acid Sequence; Amyloid; Amyloidosis; Computational Biology; Down Syndrome; Humans; Lewy Body Disease; Models, Molecular; Nerve Tissue Proteins; Neurodegenerative Diseases; Parkinson Disease; Prion Diseases; Protein Conformation

Filamentous protein inclusions in neurons (Lewy bodies, LB) and dystrophic neurites containing pathologic alpha-synuclein (alpha Syn) are the morphologic hallmarks of sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), but are also found in aged subjects and in a variety of neurogenerative disorders. They occur in the central, peripheral, and autonomic nervous system as an essential or coincident feature. Their formation runs through several phases from initial dust-like particles cross-linked with alpha Syn to aggregation of ubiquitinated dense filaments, formation of LBs, finally degradation and death of the afflicted neurons. Pathologic accumulation of alpha Syn/LBs proposed by Braak et al. (Neurobiol Aging 24:197-211, 2003), following a predictable sequence of lesions in six stages with ascending progression from medullary and olfactory nuclei to the cortex, has been considered to be linked to clinical dysfunctions. The consensus pathologic guidelines of DLB (Neurology 65:1863-1872, 2005), by semiquantitative scoring to alpha Syn pathology (LB density and distribution) in specific brain regions, distinguish three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), and also consider concomitant Alzheimer-related pathology. alpha Syn pathology in the amygdala is often associated with Alzheimer disease. Although some retrospective clinico-pathologic studies have largely confirmed the Braak LB staging system, it shows neither correlation to the clinical severity and duration of parkinsonism nor to nigral alpha Syn burden and cell loss which significantly correlates with resulting striatal loss of dopamine, dopamine transporter and tyrosine hydroxylase, duration and severity of motor dysfunction. Between 6.3 and 43% of clinically manifested PD cases did not follow this pattern, and in 7-8.3% of those with alpha Syn-positive inclusions in midbrain and cortex the medullary nuclei were spared. On the other hand, 30-55% of elderly subjects with widespread Lewy pathology revealed no neuropsychiatric symptoms or were not classifiable. Therefore, detection and staging of Lewy pathology without assessment of neuronal loss in specific areas may not have clinical impact and its predictive validity is questionable. For demented patients, modified criteria for categorization of Lewy pathology were proposed. If robust correlations between clinical course and Lewy/alpha Syn pathology are to be confirmed by future studies, the currently

Topics: alpha-Synuclein; Biomarkers; Brain; Disease Progression; Humans; Lewy Bodies; Lewy Body Disease; Neurons; Parkinson Disease

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are second only to Alzheimer's disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated alpha-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson's-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of alpha-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce alpha-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Receptor, Serotonin, 5-HT1A; Serotonin

Many groups have generated alpha-synuclein (alpha-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as alpha-syn deposits, compromised function of dopaminergic neurons, fibrillization of alpha-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of alpha-syn tg mice may be required. We predict that beta-synuclein (beta-syn), the homologue of alpha-syn, might be a key molecule for this purpose. Although beta-syn is a neuroprotective molecule counteracting the alpha-syn pathology in tg mice, it was previously shown that both beta-syn and gamma-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson's disease and DLB. Furthermore, two missense mutations (P123H and V70M) of beta-syn were recently identified in DLB. These mutants of beta-syn were prone to aggregate in vitro and overexpression of these mutant beta-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of beta-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant beta-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional alpha-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant beta-syn/alpha-syn might be characterized by a more accelerated phenotype of synucleinopathies.

Topics: alpha-Synuclein; Animals; beta-Synuclein; Brain; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Lewy Bodies; Lewy Body Disease; Mice; Mutation, Missense; Parkinson Disease

Depositions of proteins in form of amyloid and non-amyloid plaques are common pathogenic signs of more than 20 degenerative diseases affecting the central nervous system or a variety of peripheral tissues. Among the neuropathological conditions, Alzheimer's, Parkinson's and the prion diseases, such as Creutzfeldt-Jakob disease (CJD), present ambiguities as regarding their differential diagnosis. At present, their diagnosis must be confirmed by post-mortem examination of the brain. Currently the ante-mortem diagnosis is still based on the integration of multiple data (clinical, paraclinical and biological analyses) because no unique marker exists for such diseases. The detection of specific biomarkers would be useful to develop a differential diagnostic, distinguishing not only different neurodegenerative diseases but also the disease from the non-pathological effects of aging. Several neurodegenerative biomarkers are present at very low levels during the early stages of the disease development and their ultra-low detection is needed for early diagnosis, which should permit more effective therapeutic interventions, before the disease concerned can progress to a stage where considerable damage to the brain has already occurred. In the case of prion diseases, there are concerns regarding not only patient care, but the wider community too, with regard to the risk of transmission of prions, especially during blood transfusion, for which, four cases of variant CJD infection associated with transfusion of non-leukocyte-depleted blood components have been confirmed. Therefore the development of techniques with high sensitivity and specificity represent the major challenge in the field of the protein misfolding diseases. In this paper we review the current analytical and/or biochemical diagnostic technologies used mainly in prion, but also in Alzheimer and Parkinson diseases and emphasizing work on the protein detection as a surrogates and specific biomarker in the body fluid of patients (urine, CSF and blood). This review highlights the urgency of the development of early and sensitive diagnostics in terms of therapeutic challenge.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Animals; Biomarkers; Blood Transfusion; Brain; Creutzfeldt-Jakob Syndrome; Donor Selection; Electroencephalography; Humans; Lewy Body Disease; Nerve Tissue Proteins; Palatine Tonsil; Parkinson Disease; Prion Diseases; Prions; Proteostasis Deficiencies; PrPSc Proteins; Sensitivity and Specificity; Sheep; tau Proteins

In the past few years, mutations have been identified in the genes encoding alpha-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in some patients with dementia with Lewy bodies (DLB). Furthermore, a novel locus for familial DLB has been mapped to chromosome 2q35-q36. Collectively, these discoveries highlight a substantial overlap between the known genetic determinants of Parkinson's disease and DLB, as well as the presence of profound etiologic heterogeneity in Lewy body disorders.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Mutation; Protein Serine-Threonine Kinases

Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.

Topics: alpha-Synuclein; Amino Acid Sequence; Humans; Lewy Body Disease; Molecular Sequence Data; Protein Binding

Heterozygous loss-of-function mutations at the glucosecerebrosidase locus have recently been shown to be a potent risk factor for Lewy body disease. Based on this observation, we have re-evaluated the likelihood that the different PARK loci (defined using clinical criteria for disease) may be misleading attempts to find common pathways to pathogenesis. Rather, we suggest, grouping the different loci which lead to different Lewy body disease may be more revealing. Doing this, we suggest that several of the genes involved in disparate Lewy body diseases impinge on ceramide metabolism and we suggest that this may be a common theme for pathogenesis.

Topics: alpha-Synuclein; Carrier Proteins; Ceramides; Humans; Intracellular Signaling Peptides and Proteins; Lewy Bodies; Lewy Body Disease; Membrane Glycoproteins; Niemann-Pick C1 Protein; Parkinson Disease; Phosphotransferases; Serine C-Palmitoyltransferase; Signal Transduction

Cardiac uptake of meta-iodobenzylguanidine (MIBG) is specifically reduced in Lewy body disease (LBD). To see pathological basis of the reduced cardiac uptake of MIBG in LBD, we immunohistichemically examined cardiac tissues from patients with LBD, related movement disorders and Alzheimer's disease (AD). In LBD, cardiac sympathetic denervation occurs, which accounts for the reduced cardiac uptake of MIBG. Patients with LBD have Lewy bodies (LBs) in the nervous system, whereas patients with the other neurodegenerative parkinsonism, parkin-associated Parkinson's disease (PD) and AD and have no LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. We further investigate how a-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. Accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that it heralds centripetal degeneration of the cardiac sympathetic nerve in PD. This chronological and dynamic relationship between alpha-synuclein aggregates and degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.

Topics: 3-Iodobenzylguanidine; alpha-Synuclein; Biomarkers; Diagnosis, Differential; Early Diagnosis; Heart; Humans; Iodine Radioisotopes; Lewy Body Disease; Nerve Degeneration; Parkinson Disease; Radionuclide Imaging; Radiopharmaceuticals; Sympathetic Nervous System

The clinical diagnostic criteria for dementia with Lewy bodies (DLB) have a low sensitivity, and there are no generally accepted biomarkers to distinguish DLB from other dementias. Our aim was to identify biomarkers that may differentiate DLB from Alzheimer's disease (AD).. We performed a systematic literature search for studies of EEG, imaging techniques and genetic and CSF markers that provide sensitivity and specificity in the identification of DLB.. The best evidence was for scintigraphy of the striatal dopamine transporter system using FP-CIT SPECT. Several small scintigraphy studies of cardiovascular autonomic function using metaiodobenzylguanidine SPECT have reported promising results. Studies exploring innovative techniques based on CSF have reported interesting findings for the combination of amyloid beta (abeta) isoforms as well as alpha-synuclein, and there are interesting results emerging from preliminary studies applying proteomic techniques. Data from studies using structural MRI, perfusion SPECT, genetics and EEG studies show differences between DLB and AD but only at a group level.. Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown good diagnostic accuracy in the research setting. Data from large multicentre studies and from studies with autopsy confirmation exist for scintigraphy of the dopamine transporter system. Future studies should explore its value in possible DLB and for clinical management and health economics.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cognition Disorders; Diagnosis, Differential; Dopamine Plasma Membrane Transport Proteins; Early Diagnosis; Electroencephalography; Humans; Iodine Radioisotopes; Lewy Body Disease; Neuropsychological Tests; Phosphorylation; Positron-Emission Tomography; Severity of Illness Index; Tomography, Emission-Computed, Single-Photon; Tropanes; Ubiquitin

[123I] Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy has been used to evaluate postganglionic cardiac sympathetic innervation in heart diseases and some neurological disorders. To see clinical usefulness of MIBG myocardial scintigraphy to differentiate Parkinson's disease (PD) and dementia with Lewy bodies (DLB) from related movement disorders and Alzheimer disease (AD), we performed MIBG myocardial scintigraphy in patients with these disorders. Cardiac uptake of MIBG is specifically reduced in PD and DLB, and this imaging approach is a sensitive diagnostic tool that possibly differentiates PD and DLB from related movement disorders and AD. To see pathological basis of the reduced cardiac uptake of MIBG in Lewy body disease, we immunohistochemically examined cardiac tissues from patients with PD, DLB, related movement disorders and AD using antibodies against tyrosine hydroxylase (TH) and phosphorylated neurofilament (NF). Not only TH- but also NF-immunoreactive (ir) axons in the epicardial nerve fascicles were markedly decreased in Lewy body disease, namely cardiac sympathetic denervation, which accounts for the reduced cardiac uptake of MIBG in Lewy body disease. Patients with PD and DLB have Lewy bodies (LBs) in the nervous system, whereas patients with multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration, parkin-associated PD and AD have no LBs in the nervous system. Even in patients with MSA, cardiac sympathetic denervation was associated with the presence of LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. Taken together, we conclude that the reduced cardiac uptake of MIBG is a potential biomarker for the presence of LBs. Because alpha-synuclein is one of the key molecules in the pathogenesis of PD, we further investigate how alpha-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. We immunohistochemically examined cardiac tissues from patients with incidental Lewy body disease (ILBD) and PD using antibodies against TH and phosphorylated alpha-synuclein. We found that (1) alpha-synuclein aggregates in the epicardial nerve fascicles, namely the distal axons of the cardiac sympathetic nerve, were much more abundant in ILBD with preserved TH-ir axons than in ILBD with decreased TH-ir axons and PD; (2) alpha-synuclein aggregates in the epicardial nerve fascicles were closely related

Topics: 3-Iodobenzylguanidine; alpha-Synuclein; Diagnosis, Differential; Early Diagnosis; Heart; Humans; Iodine Radioisotopes; Lewy Body Disease; Myocardium; Nerve Degeneration; Parkinson Disease; Radionuclide Imaging; Radiopharmaceuticals; Sympathetic Nervous System

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Ataxia; Caenorhabditis elegans; Dementia; Disease Models, Animal; Drosophila melanogaster; Gene Targeting; Genes, Recessive; Heredodegenerative Disorders, Nervous System; Humans; Lewy Body Disease; Mice; Mice, Knockout; Mice, Neurologic Mutants; Minisatellite Repeats; Neurodegenerative Diseases; Neurotoxins; Parkinsonian Disorders; Prion Diseases; Reelin Protein; Species Specificity; tau Proteins

Pathological studies have prompted the idea that Parkinson disease (PD) is a multisystem disorder, which starts far away from the nigrostriatal dopamine system and it goes through a long pre-clinical period. Evidence from epidemiological research, functional imaging, olfaction and sleep studies provides support to this hypothesis. Accordingly, PD is seen as an homogeneous disease which sequentially affects different neural structures leading to a well-defined clinical picture. This concept, recently named PD complex, has deep theoretical and practical implications which raise some concerns. This report shows the concept of classical PD as opposed to PD complex. Although the relevance of the central argument concerning the PD complex concept is admitted, it needs to be fully proved before premature conclusions are drawn. In contrast, the notion of classical and clinically significant PD can explain many of the well-characterized pathological and clinical features of the disease and it gives support to the idea that the magic word in PD is variability.

Topics: Aged; alpha-Synuclein; Brain; Brain Chemistry; Cell Death; Cerebral Cortex; Corpus Striatum; Disease Progression; Dopamine; Enteric Nervous System; Humans; Lewy Bodies; Lewy Body Disease; Male; Medulla Oblongata; Models, Neurological; Neurodegenerative Diseases; Olfaction Disorders; Parkinson Disease; Proteasome Endopeptidase Complex; REM Sleep Behavior Disorder; Risk; Substantia Nigra; Ubiquitin; Vagus Nerve

Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Animals, Genetically Modified; Disease Models, Animal; Humans; Lewy Body Disease; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; tau Proteins

We provide an overview of synaptic pathology in dementia with Lewy bodies (DLB) and related neurodegenerative disorders that are characterised by intraneuronal accumulation of alpha-synuclein aggregates. The review addresses the clinico-neuropathological correlates of synaptic pathology in Lewy body disease, and concentrates on: altered alpha-synuclein metabolism, mechanisms leading to alpha-synuclein fibril formation (self-polymerisation, alpha-synuclein mutations and post-translational modifications) and how these influence the axonal transport and synaptic network in ageing and disease process. Understanding the mechanisms leading to intraneuronal alpha-synuclein accumulation are crucial for the development of novel therapies for treatment of Lewy body disease.

Topics: Aging; alpha-Synuclein; Axons; Biological Transport; Humans; Lewy Body Disease; Multiprotein Complexes; Synapses

The health and socioeconomic impacts of dementia with Lewy bodies and dementia associated with Parkinson's disease have become increasingly recognized. Whilst the nosological status of dementia with Lewy bodies has been better classified as 'Lewy body dementias', both conditions are now believed to represent a disease spectrum, characterized pathologically by synuclein protein and clinically by a variable admixture of cognitive, neuropsychiatric and extrapyramidal features.. Recent epidemiological studies are described and clinical and pathological similarities emphasized between dementia with Lewy bodies and Parkinson's disease. A number of investigational techniques are highlighted which have helped to better characterize dementia with Lewy bodies and discriminate it from Alzheimer's disease, whilst also shedding light upon the pathophysiology of both conditions. Finally, the therapeutic aspects of the Lewy body dementias will be considered, concentrating upon studies of the cholinesterase inhibitors.. The pathology underlying dementia with Lewy bodies and Parkinson's disease is heterogeneous, and is neither stereotyped in its topography nor its composition. Cholinesterase inhibitor drugs improve cognition and neuropsychiatric symptoms but the clinical response is unpredictable. Major future challenges are to better understand the pathophysiological basis underpinning the diseases, what determines clinical phenotypic expression and how disease-modifying therapies may best be developed and deployed.

Topics: alpha-Synuclein; Cerebral Cortex; Cholinesterase Inhibitors; Diagnosis, Differential; Diagnostic Imaging; Dopamine Agents; Humans; Lewy Body Disease; Parkinson Disease; Plaque, Amyloid

REM sleep behavior disorder (RBD) is a parasomnia characterized by a lack of motor inhibition during REM sleep leading to potentially harmful dream-enacting behaviors. RBD affects mainly older men and its prevalence in the general population is estimated to be around 0.5%. RBD may be idiopathic or associated with other neurologic disorders. A strong association between RBD and alpha-synucleinopathies has been recently observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of patients with RBD. Small clinical follow-up studies revealed that a proportion of these patients will eventually develop a parkinsonian syndrome or a dementia of Lewy bodies type in the years following the RBD diagnosis, while some patients will never show other neurologic signs within several decades from the RBD onset. Recent studies have looked at neurophysiologic and neuropsychological functions in idiopathic RBD and have found evidences of CNS dysfunction during both wakefulness and sleep. An impairment of the cortical activity, specific neuropsychological deficits, and signs of autonomic dysfunction have been observed in a variable proportion of these patients, challenging the concept of idiopathic RBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies.

Topics: alpha-Synuclein; Brain; Brain Stem; Cerebral Cortex; Corpus Striatum; Disease Progression; Dopamine; Humans; Lewy Body Disease; REM Sleep Behavior Disorder

Twenty years ago Parkinson's disease (PD) was thought of as an environmentally determined neurodegenerative disease. It is now known that there are two autosomal dominant disease genes, alpha-synuclein and dardarin, and three genes responsible for autosomal recessive PD, parkin, DJ-1 and PINK-1. Although these gene mutations are not common, their identification has led to a new understanding of the pathogenesis of PD, and to a development in the understanding of the clinical and pathological definitions of PD and Lewy body disease. Ultimately, these advances may lead to the development of new disease-modifying therapies, but more immediately these discoveries have led to a more coherent view of the spectrum of PD and Lewy body diseases and to accurate genetic diagnosis and counselling for some families.

Topics: alpha-Synuclein; Genetic Predisposition to Disease; Heterozygote; Humans; Intracellular Signaling Peptides and Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Mutation; Nerve Tissue Proteins; Oncogene Proteins; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; Synucleins; Ubiquitin-Protein Ligases

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people that has only been recognized in the past decade and that remains widely underdiagnosed. At postmortem examination, affected patients show numerous alpha-synuclein-positive Lewy bodies (LB) in many parts of the cerebral cortex, particularly neocortical and limbic areas in addition to the nigral LB degeneration characteristic of Parkinson's disease (PD). Clinical presentation, unlike PD, is with progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function accompanied by usually only mildly to moderately severe parkinsonism, which is often akineto-rigid without the classical parkinsonian rest-tremor. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance. The two main differential diagnoses are Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). To improve the differential diagnosis of DLB, consensus criteria have been developed that establish possible and probable levels of clinical diagnostic accuracy. Generally, their sensitivity is variable and low but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. Using operationalized criteria, DLB can be diagnosed clinically with an accuracy similar to that achieved for AD or PD. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. We review the present state of the best practice in the clinical diagnosis of DLB. Future modifications of diagnostic criteria would ideally include the full range of clinical presentations that can be associated with LB disease.

Topics: Accidental Falls; Age Factors; Aged; alpha-Synuclein; Alzheimer Disease; Brain; Cerebral Cortex; Cognition Disorders; Diagnosis, Differential; Dysarthria; Electromyography; Hallucinations; Humans; Hypotension, Orthostatic; Lewy Bodies; Lewy Body Disease; Limbic System; Magnetic Resonance Imaging; Parkinson Disease; Substantia Nigra; Urinary Incontinence

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Topics: alpha-Synuclein; Brain; Corpus Striatum; Diagnosis, Differential; Dopamine Plasma Membrane Transport Proteins; Drug Tolerance; Humans; Lewy Bodies; Lewy Body Disease; REM Sleep Behavior Disorder

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are members of a family of disorders characterized by the presence of inclusion bodies, or Lewy bodies (LBs), filled with aggregates of alpha-synuclein. These diseases are a leading cause of movement disorders and dementia in the aging population, and it is crucial to understand the factors leading to the accumulation and assembly of these alpha-synuclein aggregates. Previous studies have uncovered much about the factors leading to aggregation and the mechanisms causing neurotoxicity of these inclusion bodies; however, little is known about factors that promote the degradation and prevent the aggregation of alpha-synuclein. The present article provides a review of recent efforts in the investigation of factors involved in alpha-synuclein metabolism and the mechanisms involved in preventing accumulation of alpha-synuclein and degrading this molecule. Understanding these processes might provide targets for the development of novel therapies for disorders such as DLB and PD.

Topics: alpha-Synuclein; Animals; Brain; Humans; Lewy Bodies; Lewy Body Disease; Models, Neurological; Nerve Tissue Proteins; Oxidative Stress; Proteasome Endopeptidase Complex; Signal Transduction; Synucleins; Ubiquitin

Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of various neurodegenerative diseases. Missense mutations in the alpha-synuclein gene are linked to familial cases of Parkinson's disease (PD), and it has further been shown that alpha-synuclein is a major constituent of the Lewy bodies in sporadic PD and dementia with Lewy body (DLB). The contribution of alpha-synuclein to the pathological changes in Alzheimer's disease (AD) has been currently a matter of scientific debate. Some reports hypothesized that alpha-synuclein may play a role in amyloid beta/A4 protein (Abeta) aggregation in senile plaques, whereas recent reports challenged this finding by showing a lack of alpha-synuclein-immunoreactivity in Abeta plaques. In this review, we report on recent findings on the physiological and pathological role of alpha-synuclein and try to elucidate its possible contribution to AD pathology.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Lewy Bodies; Lewy Body Disease; Mutation, Missense; Nerve Tissue Proteins; Phosphoproteins; Plaque, Amyloid; Synucleins

Alpha-synuclein (alphaSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer's disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as alpha-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of alphaSN. This molecular form of alphaSN contrasts sharply with normal alphaSN, which is an abundant soluble presynaptic protein in brain neurons. alphaSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an alphaSN gene. Implicated in neurotoxicity are two alphaSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, alphaSN fibrils and protofibrils, soluble protein complexes of alphaSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated alphaSN species. Unlike rare forms of fPD caused by mutations in alphaSN, disease mechanisms in most alpha-synucleinopathies implicate wildtype alphaSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve alphaSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic alphaSN forms damage neurons. Here, we summarize the main structural features of alphaSN and its functions, and discuss the molecular alphaSN species implicated in human disease and transgenic animal models of alpha-synucleinopathy in fly and rodents.

Topics: alpha-Synuclein; Alzheimer Disease; Amino Acid Sequence; Animals; Humans; Lewy Body Disease; Molecular Sequence Data; Nerve Tissue Proteins; Neurodegenerative Diseases; Parkinson Disease; Synucleins

Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroglia; Neurons; Synucleins

The Lewy body, an eosinophilic inclusion around 10 microns in diameter, is localised in the neuronal perikaryon. Its dense core is surrounded by a clear halo, which is lacking in the so-called "cortical Lewy bodies". Numerous proteins have been identified in Lewy bodies, among which the three neurofilament isoforms, ubiquitin and proteasome subunits. More recently, alpha-synuclein--a pre-synaptic protein--has been found to be the essential constituent of the Lewy body. Alpha-synuclein antibody has greatly increased the sensitivity of the neuropathological examination: it has emphasized the frequency of "Lewy neurites" (accumulation of alpha--synuclein in neuronal processes) and has shown the importance of extra-nigral pathology. Lewy bodies and neurites are indeed to be found in many areas of the central and peripheral nervous system: stellate ganglia, cardiac and enteric plexus, pigmented nuclei of the brainstem, basal nucleus of Meynert, amygdala, limbic nuclei of the thalamus, parahippocampal and cingulate gyri, insula and isocortex. Lewy body diseases include at least three clinical syndromes: 1) idiopathic Parkinson disease in which the brainstem bears the brunt of the pathology 2) Parkinson disease dementia in which Lewy lesions are found in the brainstem and are also abundant in the isocortex. A large number of senile plaques is frequently associated. 3) In dementia with Lewy bodies, the same lesions are observed but the cognitive deficit occurs first or shortly (less than one year) after the motor symptoms.

Topics: Aging; alpha-Synuclein; Alzheimer Disease; Brain Stem; Diagnosis, Differential; Humans; Lewy Bodies; Lewy Body Disease; Locus Coeruleus; Nerve Degeneration; Nerve Tissue Proteins; Parkinson Disease; Synucleins; Ubiquitin

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders that share progressive dementia as the common major clinical symptom. Damages to memory-related brain structures are the likely pathological correlate, and in both illnesses deposition of amyloidogenic proteins are present mainly within these limbic structures. Amyloid-beta-positive plaques and phospho-tau-positive neurofibrillary tangles are the main feature of AD and alpha-synuclein-positive Lewy bodies and Lewy neurites are found in DLB. Interestingly the associated proteins also interfere with synaptic function and synaptic plasticity. Here, we propose that the same neuronal circuits are disturbed within the hippocampal formation in AD and DLB and that in both diseases the associated proteins might lead to changes in synaptic plasticity and function. Thus both classic neuropathological changes and cellular dysfunctions might contribute to the cognitive impairments in AD and DLB.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Lewy Body Disease; Memory Disorders; Nerve Degeneration; Nerve Tissue Proteins; Neural Pathways; Neurites; Neuronal Plasticity; Synaptic Transmission; Synucleins

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative disorders affecting the elderly. The cognitive and motor deficits in these diseases are associated with the disruption of neuritic substructure, loss of synaptic contacts in selectively vulnerable circuitries, and aberrant sprouting. Where as in AD, accumulation of misfolded forms of Abeta triggers neurodegeneration, in DLB accumulation of alpha-synuclein might play a central role. The mechanisms by which oligomeric forms of these proteins might lead to cycles of synapse loss and aberrant sprouting are currently under investigation. Several possibilities are being considered, including mitochondrial damage, caspase activation, lysosomal leakage, fragmentation of the Golgi apparatus, interference with synaptic vesicle transport and function, and interference with gene transcription and signaling. Among them, recent lines of research support the possibility that alterations in signaling pathways such extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 relevant to synaptic plasticity and cell survival might play a pivotal role. A wide range of cellular functions are affected by the accumulation of misfolded Abeta and alpha-synuclein; thus it is possible that a more fundamental cellular alteration may underlie the mechanisms of synaptic pathology in these disorders. Among them, one possibility is that scaffold proteins, such as caveolin and JNK-interacting protein (JIP), which are necessary to integrate signaling pathways, are affected, leading to cycles of synapse loss and aberrant sprouting. This is significant because both caveolar dysfunction and altered axonal plasticity might be universally important in the pathogenesis of various neurodegenerative disorders, and therefore these signaling pathways might be common therapeutic targets for these devastating diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Lewy Body Disease; Memory Disorders; Nerve Degeneration; Nerve Tissue Proteins; Neural Pathways; Neurites; Neuronal Plasticity; Synaptic Transmission; Synucleins

Topics: alpha-Synuclein; Amino Acid Sequence; Animals; Brain; Humans; Lewy Bodies; Lewy Body Disease; Molecular Sequence Data; Mutation, Missense; Nerve Tissue Proteins; Parkinsonian Disorders; Phosphorylation; Protein Processing, Post-Translational; Synucleins

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Lewy Bodies; Lewy Body Disease; Macromolecular Substances; Nerve Tissue Proteins; Parkinson Disease; Protein Binding; Protein Structure, Tertiary; Synucleins

Parkinson's disease (PD) was noted to have a familial component as early as 1880 (Leroux, 1880). More recently, the discovery of several genetic factors influencing parkinsonism has emphasized the importance of heredity in PD. The clinical spectrum of familial parkinsonism is wide; it includes not only PD, but also dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), essential tremor, and other disorders. In the general population, it is likely that PD results from combined genetic and environmental factors, most of which are not yet known. The discovery of causal mutations in the gene for alpha-synuclein, parkin, and of genetic linkages to chromosomes 2p4, 4p5, and three loci on 1q6-8 have revolutionized PD research. This review focuses on recent progress in the Mendelian genetics of PD and those diseases in which parkinsonism is a prominent feature, and considers how these discoveries modify our beliefs regarding the etiology and pathogenesis of these disorders.

Topics: alpha-Synuclein; Chromosome Mapping; Essential Tremor; Humans; Lewy Body Disease; Ligases; Nerve Tissue Proteins; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive; Synucleins; Ubiquitin-Protein Ligases

Lewy body disease includes clinically and pathologically defined disorders in which Lewy bodies occur in the nervous system. In recent years, the molecular features of these disorders have been emerging. Several genetic loci have been identified in association with familial Lewy body disease; however, the genetic risks underlying most cases of familial Lewy body disease remain to be discovered. The fact that Lewy bodies stain strongly with antibodies to asynuclein and that mutations in the alpha-synuclein gene lead to syndromes in which parkinsonism and dementia occur gives us important clues regarding the biologic processes leading to disease. Pursuit of additional mendelian causes of familial Lewy body disease and study of the factors contributing to the complex phenotypes associated with Lewy body disorders will elucidate underlying disease pathways and, thus, possible targets for therapeutic intervention.

Topics: Aged; alpha-Synuclein; Brain; Chromosomes, Human, Pair 4; Genetic Predisposition to Disease; Humans; Lewy Bodies; Lewy Body Disease; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Synucleins

The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.

Topics: alpha-Synuclein; Animals; Humans; Lewy Body Disease; Multiple System Atrophy; Nerve Tissue Proteins; Neurodegenerative Diseases; Parkinson Disease; Synucleins

The term alpha-synucleinopathy is used to name a group of disorders having in common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or glial cells, as well as in extracellular deposits of amyloid. In Parkinson's disease and Lewy body dementia, alpha-synuclein is the main component of Lewy bodies and dystrophic neurites; alpha-synuclein also accumulates in the cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95 amino acids of alpha-synuclein is the non-Abeta component of senile plaque amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these disorders have in common a fibrilar configuration, but they differ in the binding of alpha-synuclein to distinct proteins with the exception of ubiquitin whose binding to alpha-synuclein is common to all alpha-synuclein inclusions. The mechanisms leading to alpha-synuclein fragmentation and aggegation into extracellular amyloid are not known, although alpha-synuclein fragment and betaA4 aggregates are the result of abnormal cleavage of large precursors. On the other hand, several studies have shown that alpha-synuclein may adopt a fibrilar conformation and give rise to insoluble forms and high molecular weight aggregates in vitro. Similar complexes have also been observed in alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic effects of alpha-synuclein, the consequence of alpha-synuclein deposition on cell survival in alpha-synucleinopathies is not known.

Topics: alpha-Synuclein; Alzheimer Disease; Cell Death; Cytoplasm; Humans; Lewy Body Disease; Multiple System Atrophy; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroglia; Neurons; Parkinson Disease; Synucleins

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopamine; Humans; Lewy Bodies; Lewy Body Disease; Multigene Family; Multiple System Atrophy; Nerve Tissue Proteins; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Sequence Homology, Amino Acid; Synucleins

alpha-Synuclein has risen to prominence during the past 5 years because of its association with several neurodegenerative diseases that have come to be known as the synucleinopathies. The clinical phenotype of the synucleinopathies is variable, with the most common being parkinsonism, autonomic dysfunction, and dementia. Progress has been made in clinical, neuropathologic and biochemical characterization of the synucleinopathies and their differentiation from other neurodegenerative disorders. At the molecular level, the synucleinopathies have conformational and post-translational modifications of synuclein that favor its fibrillization and aggregation in inclusions in neurons and glia. Whether inclusion body formation is an adaptive response or is directly related to degeneration of neuronal and glial cells is a topic of current research.

Topics: alpha-Synuclein; Diagnosis, Differential; Humans; Inclusion Bodies; Lewy Body Disease; Nerve Tissue Proteins; Neuroglia; Neurons; Phenotype; Synucleins

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Neuropathologically, it is characterized by the degeneration of populations of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that the filamentous inclusions of Parkinson's disease are made of the protein alpha-synuclein and that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene. Besides Parkinson's disease, the filamentous inclusions of two additional neurodegenerative diseases, namely, dementia with Lewy bodies and multiple system atrophy, have also been found to be made of alpha-synuclein. Recombinant alpha-synuclein has been shown to assemble into filaments with similar morphologies to those found in the human diseases and with a cross-beta fiber diffraction pattern. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Mutation, Missense; Nerve Tissue Proteins; Parkinson Disease; Synucleins

Topics: alpha-Synuclein; Amino Acid Substitution; Humans; Lewy Body Disease; Mutation, Missense; Nerve Tissue Proteins; Parkinson Disease; Synucleins

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are increasingly recognized as alpha-synucleinopathies, i.e. neurodegenerative disorders that share a common subcellular pathology characterized by alpha-synuclein abnormal aggregation. In the present review we focus on depression in alpha-synucleinopathies, discussing epidemiological, pathophysiological and treatment aspects of this frequently disabling clinical feature which may occur in PD, DLB and MSA alike.

Topics: alpha-Synuclein; Animals; Antidepressive Agents; Brain; Depressive Disorder; Diagnosis, Differential; Humans; Lewy Body Disease; Multiple System Atrophy; Nerve Tissue Proteins; Parkinson Disease; Prevalence; Synucleins

Alzheimer's disease (AD) and Lewy body disease (LBD) are the most common causes of dementia in the elderly population. Previous studies have shown that cognitive alterations in these disorders are associated with synaptic loss. Injury and loss of synapses might be associated with altered function of synaptic proteins. Among them, recent studies have shown that abnormal aggregation and accumulation of synaptic proteins, such as alpha-synuclein, might be associated with plaque formation in AD and Lewy body formation in LBD. Further reinforcing the hypothesis that alpha-synuclein plays a major role in the pathogenesis of these disorders, recent work has shown that mutations that alter the conformation of this molecule are associated with familial forms of Parkinson's disease. The mechanisms by which altered function or aggregation of alpha-synuclein might lead to neurodegeneration are not completely clear; however, new evidence points to a potential role for this molecule in synaptic damage and neurotoxicity via amyloid-like fibril formation and mitochondrial dysfunction. In this manuscript we review the data linking alpha-synuclein to the pathogenesis of AD and LBD.

Topics: alpha-Synuclein; Alzheimer Disease; Humans; Lewy Body Disease; Nerve Tissue Proteins; Synucleins

In a previous proteomic study, we identified the neurosecretory protein VGF (VGF) as a potential biomarker for dementia with Lewy bodies (DLB). Here, we extended the study of VGF by comparing levels in cerebrospinal fluid (CSF) from 44 DLB patients, 20 Alzheimer's disease (AD) patients, and 22 cognitively normal controls selected from the Amsterdam Dementia Cohort. CSF was analyzed using two orthogonal analytical methods: (1) In-house-developed quantitative ELISA and (2) selected reaction monitoring (SRM). We further addressed associations of VGF with other CSF biomarkers and cognition. VGF levels were lower in CSF from patients with DLB compared to either AD patients or controls. VGF was positively correlated with CSF tau and α-synuclein (0.55 <

Topics: Aged; alpha-Synuclein; Amyloid beta-Peptides; Female; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Growth Factors; Peptide Fragments; tau Proteins

Assessment of a series of 279 cases with Lewy body disease revealed 14 families having a family history consistent with autosomal dominant inheritance, eight of these with dominant Parkinsonism and six with dominant dementia. Analysis of the age at onset and genetic features in these families revealed significant anticipation only in a subset of parkinsonian families, with no pathological alleles for spinocerebellar ataxias or the common alpha-synuclein or LRRK2 point mutations.

Topics: Age of Onset; Aged; alpha-Synuclein; DNA Mutational Analysis; Female; Genetic Testing; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Penetrance; Predictive Value of Tests; Prospective Studies; Protein Serine-Threonine Kinases; Spinocerebellar Ataxias; Trinucleotide Repeats

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Cross-Sectional Studies; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Schwann Cells

Topics: alpha-Synuclein; Humans; Lewy Body Disease

Although alpha-synuclein-related pathology is the hallmark of dementia with Lewy bodies (DLB), cerebrovascular and Alzheimer disease pathologies are common in patients with DLB. Little is known about the contribution of these pathologies to neurodegeneration in DLB. We investigated associations of cerebrovascular, β-amyloid, and tau biomarkers with gray matter (GM) volume in patients with probable DLB.. We assessed patients with probable DLB and cognitively unimpaired (CU) controls with. We included 30 patients with DLB (69.3 ± 10.2 years, 87% men) and 100 CU controls balanced on age and sex. Compared with CU controls, patients with DLB showed a lower GM volume across all cortical and subcortical regions except for the cuneus, putamen, and pallidum. A larger WMH volume was associated with a lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in patients with DLB. A higher PiB SUVr was associated with a lower volume in the inferior temporal cortex, while flortaucipir SUVr did not correlate with GM volume. SEMs showed that a higher age and absence of the. Patients with probable DLB have widespread cortical atrophy, most of which is likely influenced by alpha-synuclein-related pathology. Although cerebrovascular, β-amyloid, and tau pathologies often coexist in probable DLB, their contributions to neurodegeneration seem to be region specific.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Cross-Sectional Studies; Female; Humans; Lewy Body Disease; Male; Positron-Emission Tomography; tau Proteins

Topics: alpha-Synuclein; Alzheimer Disease; Brain; DNA Methylation; Humans; Lewy Bodies; Lewy Body Disease

Epidemiological studies show correlations between constipation and development of Parkinson's disease (PD); however, few studies have explored the association between constipation and dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and multiple system atrophy (MSA). We sought to explore the lifelong association of constipation and PD, DLB, PDD, and MSA (α-Synucleinopathies), compared to age- and sex-matched controls.. Using the Rochester Epidemiology Project (REP), we established an incident cohort of clinically defined α-synucleinopathies. A movement-disorder specialist reviewed all medical charts to establish clinical diagnoses.. We identified 453 incident cases of clinically diagnosed α-synucleinopathies and an identical number of age- and sex-matched controls in Olmsted County (MN), 1991-2010. There were 303 cases of PD; 80, DLB; 54, PDD; and 16, MSA. Approximately 50% of α-synucleinopathies of all types reported constipation, compared to 27% in controls. The earliest pre-motor onset constipation was in DLB (median, 3.76 years prior to α-synucleinopathies motor-symptom onset); latest onset post-motor constipation was in PD (median, 5.15 years after motor-symptom onset). PD also had the highest longstanding constipation rate (18.2%). All α-synucleinopathies had higher odds of constipation compared to controls, except for MSA (p = 0.09), likely due to a limited sample size.. PD, DLB, and PDD had higher odds of constipation compared to controls; PD had the most widespread onset of lifelong constipation, both longstanding and pre- or post-motor onset symptoms. Our results indicate that constipation rates do not differ among α-synucleinopathies but do differ in terms of temporal onset compared to disease onset.

Topics: alpha-Synuclein; Chronic Disease; Constipation; Dementia; Humans; Lewy Body Disease; Minnesota; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Topics: alpha-Synuclein; Biopsy; Humans; Lewy Body Disease; Parkinson Disease; Synucleinopathies

Aggregation of misfolded α-synuclein (α-syn) protein in the periphery and central nervous system (CNS) gives rise to a group of disorders, which are labeled collectively as synucleinopathies. These clinically distinct disorders are known as pure autonomic failure, Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). In the case of PD, it has been demonstrated that toxic aggregates of α-syn protein not only cause apoptosis of dopamine neurons but its accumulation in the neocortex and limbic area principally contributes to dementia. In our multifunctional drug discovery research for PD, we converted one of our catechol-containing lead dopamine agonist molecules

Topics: alpha-Synuclein; Animals; Dementia; Disease Models, Animal; Humans; Lewy Body Disease; Mice; Parkinson Disease; Prodrugs

Within Lewy body spectrum disorders (LBSD) with α-synuclein pathology (αSyn), concomitant Alzheimer's disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p-tau. In autopsy-confirmed αSyn-positive LBSD, we tested how plasma p-tau. Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β = 0.31, 95% CI = 0.065-0.56, and P = 0.015), after covarying for age at plasma, plasma-to-death interval, and sex; plasma p-tau. Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β-amyloid plaques.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Glial Fibrillary Acidic Protein; Humans; Lewy Body Disease; Plaque, Amyloid; tau Proteins

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 (95% CI 0.84-1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49-0.79)/AUC: 0.73 (95% CI 0.49-0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74-0.99)) and MSA (AUC: 0.80 (95% CI 0.65-0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

α-synuclein (αS) is an abundant, neuronal protein that assembles into fibrillar pathological inclusions in a spectrum of neurodegenerative diseases that include Lewy body diseases (LBD) and Multiple System Atrophy (MSA). The cellular and regional distributions of pathological inclusions vary widely between different synucleinopathies contributing to the spectrum of clinical presentations. Extensive cleavage within the carboxy (C)-terminal region of αS is associated with inclusion formation, although the events leading to these modifications and the implications for pathobiology are of ongoing study. αS preformed fibrils can induce prion-like spread of αS pathology in both in vitro and animal models of disease. Using C truncation-specific antibodies, we demonstrated here that prion-like cellular uptake and processing of αS preformed fibrils resulted in two major cleavages at residues 103 and 114. A third cleavage product (122 αS) accumulated upon application of lysosomal protease inhibitors. In vitro, both 1-103 and 1-114 αS polymerized rapidly and extensively in isolation and in the presence of full-length αS. 1-103 αS also demonstrated more extensive aggregation when expressed in cultured cells. Furthermore, we used novel antibodies to αS cleaved at residue Glu114, to assess x-114 αS pathology in postmortem brain tissue from patients with LBD and MSA, as well as three different transgenic αS mouse models of prion-like induction. The distribution of x-114 αS pathology was distinct from that of overall αS pathology. These studies reveal the cellular formation and behavior of αS C-truncated at residues 114 and 103 as well as the disease dependent distribution of x-114 αS pathology.

Topics: alpha-Synuclein; Animals; Autopsy; Glutamic Acid; Humans; Lewy Body Disease; Lysosomes; Mice; Mice, Transgenic; Multiple System Atrophy; Prions; Protease Inhibitors

Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein

Topics: alpha-Synuclein; Animals; Female; Lewy Body Disease; Male; Mice; Parkinson Disease; Synucleinopathies

Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.. To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.. Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively.. Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load.. In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Corpus Striatum; Dopamine; Humans; Lewy Body Disease; Parkinson Disease; Putamen; Substantia Nigra

Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option to frozen tissues, we developed a streamlined protein extraction protocol for evaluating disease-specific seeding in FFPE human brain. We evaluated the protein extraction efficiency of different tissue preparations, deparaffinizations, and protein extraction buffers using formaldehyde-fixed and FFPE tissue of a single Lewy body disease (LBD) subject. Alternatively, we incorporated heat-induced antigen retrieval and dissociation using a commercially available kit. Our novel protein extraction protocol has been optimized to work with 10 sections of 4.5-µm-thickness or 2-mm-diameter micro-punch of FFPE tissue that can be used to seed SAAs. We demonstrated that extracted proteins from FFPE still preserve seeding potential and further show disease-specific seeding in LBD and multiple system atrophy. To the best of our knowledge, our study is the first to recapitulate disease-specific αSyn seeding behaviour in FFPE human brain. Our findings open new perspectives in re-evaluating archived human brain tissue, extending the disease-specific seeding assays to larger cohorts to facilitate molecular subtyping of synucleinopathies.

Topics: alpha-Synuclein; Brain; Formaldehyde; Humans; Lewy Body Disease; Multiple System Atrophy; Paraffin; Paraffin Embedding; Synucleinopathies

Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA-containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α-synuclein-containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post-mortem samples from the parietal cortex of 25 DLB patients and 17 age-matched controls were processed for phospholipidomics analyses using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA-phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA-phospholipid species were subsequently validated with further LC-MS/MS measurements. Of the DHA-containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta-amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α-synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Chromatography, Liquid; Docosahexaenoic Acids; Fatty Acid-Binding Proteins; Humans; Lewy Body Disease; Neocortex; Phospholipids; Tandem Mass Spectrometry

α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic) individuals, either as isolated pathology or coexisting with Alzheimer's disease (AD) pathology (β-amyloid (Aβ) and tau). We examined the effects of LB pathology using a cerebrospinal fluid α-synuclein-seed amplification assay in 1,182 cognitively and neurologically unimpaired participants from the BioFINDER study: 8% were LB positive, 26% Aβ positive (13% of those were LB positive) and 16% tau positive. LB positivity occurred more often in the presence of Aβ positivity but not tau positivity. LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention/executive function. Tau had cognitive effects of a similar magnitude, but these were less pronounced for Aβ. Participants with both LB and AD (Aβ and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell. Only LB-positive participants progressed to clinical LB disease over 10 years. These results are important for individualized prognosis, recruitment and choice of outcome measures in preclinical LB disease trials, but also for the design of early AD trials because >10% of individuals with preclinical AD have coexisting LB pathology.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition; Cognitive Dysfunction; Cross-Sectional Studies; Humans; Lewy Bodies; Lewy Body Disease; Positron-Emission Tomography; tau Proteins

Development of radiopharmaceuticals for in vivo positron emission tomography imaging of alpha-synuclein aggregates has the potential to revolutionize Lewy body disease diagnosis and treatment. Reporting in this issue of Cell, Xiang et al. developed a high-affinity positron emission tomography tracer for alpha-synuclein.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Positron-Emission Tomography; Radiopharmaceuticals

Topics: alpha-Synuclein; Animals; Humans; Lewy Body Disease; Mice; Parkinson Disease; Rats

Inflammatory processes and mechanisms are of central importance in neurodegenerative diseases. In the brain, α-synucleinopathies such as Parkinson's disease (PD) and Lewy body dementia (LBD) show immune cytokine network activation and increased toll like receptor 3 (TLR3) levels for viral double-stranded RNA (dsRNA). Brain inflammatory reactions caused by TLR3 activation are also relevant to understand pathogenic cascades by viral SARS-CoV-2 infection causing post- COVID-19 brain-related syndromes. In the current study, following regional brain TLR3 activation induced by dsRNA in mice, an acute complement C3 response was seen at 2 days. A C3 splice-switching antisense oligonucleotide (ASO) that promotes the splicing of a non-productive C3 mRNA, prevented downstream cytokines, such as IL-6, and α-synuclein changes. This report is the first demonstration that α-synuclein increases occur downstream of complement C3 activation. Relevant to brain dysfunction, post-COVID-19 syndromes and pathological changes leading to PD and LBD, viral dsRNA TLR3 activation in the presence of C3 complement blockade further revealed significant interactions between complement systems, inflammatory cytokine networks and α-synuclein changes.

Topics: alpha-Synuclein; Animals; Brain; Complement C3; COVID-19; Cytokines; Lewy Body Disease; Mice; Parkinson Disease; RNA, Double-Stranded; SARS-CoV-2; Syndrome; Toll-Like Receptor 3

Misfolded α-synuclein in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can be detected using the real-time quaking-induced conversion (RT-QuIC) technique in cerebrospinal fluid (CSF).. The objectives are (1) to examine misfolded CSF α-synuclein incidence, and (2) to compare clinical presentation, sports history, brain volumes, and RT-QuIC α-synuclein positivity in former athletes.. Thirty former athletes with magnetic resonance imaging, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-β 42 (Aβ42), and neurofilament light chain (NfL). CSF α-synuclein was detected using RT-QuIC.. Six (20%) former athletes were α-synuclein positive. α-Synuclein positive athletes were similar to α-synuclein negative athletes on demographics, sports history, clinical features, CSF p-tau, t-tau, Aβ42, and NfL; however, had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula and right olfactory cortices.. α-Synuclein RT-QuIC analysis of CSF may be useful as a prodromal biofluid marker of PD and DLB. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Athletes; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease; tau Proteins

The alpha-synuclein (aSyn) seed amplification assay (SAA) can identify aSyn aggregates as indicator for Lewy body pathology in biomaterials of living patients and help in diagnosing Parkinson´s disease and dementia syndromes. Our objective was to confirm that qualitative results of aSyn SAA are reproducible across laboratories and to determine whether quantitative findings correlate with patient clinical characteristics. Therefore cerebrospinal fluid samples were re-analysed by aSyn SAA in a second laboratory with four technical replicates for each sample. Kinetic parameters derived from each aggregation curve were summarized and correlated with patient characteristics. We found that qualitative findings were identical between the two laboratories for 54 of 55 patient samples. The number of positive replicates for each sample also showed good agreement between laboratories. Moreover, specific kinetic parameters of the SAA showed a strong correlation with clinical parameters, notably with cognitive performance evaluated by the Montreal Cognitive Assessment. We concluded that SAA findings are highly reproducible across laboratories following the same protocol. SAA reports not only the presence of Lewy pathology but is also associated with clinical characteristics. Thus, aSyn SAA can potentially be used for patient stratification and determining the target engagement of aSyn targeting treatments.

Topics: alpha-Synuclein; Cognitive Dysfunction; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder underlying dementia in the geriatric population. AD manifests by two pathological hallmarks: extracellular amyloid-β (Aβ) peptide-containing senile plaques and intraneuronal neurofibrillary tangles comprised of aggregated hyperphosphorylated tau protein (p-tau). However, more than half of AD cases also display the presence of aggregated α-synuclein (α-syn)-containing Lewy bodies. Conversely, Lewy bodies disorders have been reported to have concomitant Aβ plaques and neurofibrillary tangles. Our drug discovery program focuses on the synthesis of multitarget-directed ligands to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to slow the progression of AD and related dementias. To this end, we synthesized 11 compounds with a triazine-linker and evaluated their effectiveness in reducing α-syn, tau isoform 2N4R, and p-tau isoform 1N4R aggregation. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), and M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. We also performed disaggregation assays with isolated Aβ-plaques from human AD brains. Our results demonstrated that compound

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Lewy Body Disease; Protein Isoforms; tau Proteins

Fibrils of the protein α-synuclein (Asyn) are implicated in the pathogenesis of Parkinson Disease, Lewy Body Dementia, and Multiple System Atrophy. Numerous forms of Asyn fibrils have been studied by solid-state NMR and resonance assignments have been reported. Here, we report a new set of

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease

Misfolded α-synuclein (α-syn) is believed to contribute to neurodegeneration in Lewy body disease (LBD) based on considerable evidence including a gene-dosage effect observed in relation to point mutations and multiplication of SNCA in familial Parkinson's disease. A contradictory concept proposes early loss of the physiological α-syn as the major driver of neurodegeneration. There is a paucity of data on SNCA transcripts in various α-syn immunoreactive cytopathologies. Here, the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD (n = 5) were evaluated using RNAscope combined with immunofluorescence for disease-associated α-syn. Single-nucleus RNA sequencing was performed to elucidate cell-type specific SNCA expression in non-diseased frontal cortex (n = 3). SNCA transcripts were observed in the neuronal nucleus and cytoplasm in neurons without α-syn, those containing punctate α-syn immunoreactivity, irregular-shaped compact inclusion, and brainstem-type and cortical-type LBs. However, SNCA transcripts were only rarely found in the α-syn immunoreactive LB areas. The total cell body SNCA transcript area densities in neurons with punctate α-syn immunoreactivity were preserved but were significantly reduced in neurons with compact α-syn inclusions both in the substantia nigra and amygdala. This reduction was also observed in the cytoplasm but not in the nucleus. Only single SNCA transcripts were detected in astrocytes with or without disease-associated α-syn immunoreactivity in the amygdala. Single-nucleus RNA sequencing revealed that excitatory and inhibitory neurons, oligodendrocyte progenitor cells, oligodendrocytes, and homeostatic microglia expressed SNCA transcripts, while expression was largely absent in astrocytes and microglia. The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies might provide a pool for local protein production that can aggregate and serve as a seed for misfolded α-syn. Successful segregation of disease-associated α-syn is associated with the exhaustion of SNCA production in the terminal cytopathology, the Lewy body. Our observations inform therapy development focusing on targeting SNCA transcription in LBD.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Neurons; Parkinson Disease

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are major neurodegenerative disorders that share commonalities in their pathology involving the formation of Lewy bodies, the main component of which is α-synuclein protein. Aberrancy and dysfunction in lysosomes have been suggested to play critical roles in the pathogenesis of Lewy body diseases. We recently identified a novel lysosomal degradation pathway in which various macromolecules, including α-synuclein protein, are directly imported into lysosomes and degraded. In this study, we analyzed the levels and localization of the lysosomal membrane protein SIDT2, a key factor in this pathway, in the postmortem brains of patients with PD and DLB. The levels of SIDT2 protein were significantly higher in the anterior cingulate cortex (ACC) of both PD and DLB cases than in age-matched control subjects, but this difference was not observed in the inferior frontal gyrus. The levels of SIDT2 also showed a strong correlation with α-synuclein levels in the ACC of all subjects, including controls. SIDT2 was colocalized with aggregates positive for phosphorylated α-synuclein protein, which is a hallmark of Lewy bodies, in all examined cases of both PD and DLB. These observations suggest that changes in the levels and localization of SIDT2 occur at the lesion site of Lewy body diseases in accordance with the progression of Lewy body pathology. Our findings provide mechanistic insights into the pathogenesis of Lewy body diseases, as well as other neurodegenerative disorders, and may provide clues for improved diagnosis, prevention, and therapeutic intervention for such diseases.

Topics: alpha-Synuclein; Animals; Autopsy; Brain; Humans; Lewy Body Disease; Mice; Nucleotide Transport Proteins; Parkinson Disease

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Norepinephrine; Parkinson Disease

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.

Topics: alpha-Synuclein; Brain; Humans; Leukodystrophy, Globoid Cell; Lewy Body Disease; Prions; Sphingolipids; Synucleinopathies

Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions.. We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs.. We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case.. LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Brain; Humans; Lewy Body Disease; Neocortex; tau Proteins

The synucleinopathies are a group of neurodegenerative diseases characterized by the oligomerization of alpha-synuclein protein in neurons or glial cells. Recent studies provide data that ceramide metabolism impairment may play a role in the pathogenesis of synucleinopathies due to its influence on alpha-synuclein accumulation. The aim of the current study was to assess changes in activities of enzymes involved in ceramide metabolism in patients with different synucleinopathies (Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)). The study enrolled 163 PD, 44 DLB, and 30 MSA patients as well as 159 controls. Glucocerebrosidase, alpha-galactosidase, acid sphingomyelinase enzyme activities, and concentrations of the corresponding substrates (hexosylsphingosine, globotriaosylsphingosine, lysosphingomyelin) were measured by liquid chromatography tandem-mass spectrometry in blood. Expression levels of GBA, GLA, and SMPD1 genes encoding glucoceresobridase, alpha-galactosidase, and acid sphingomyelinase enzymes, correspondently, were analyzed by real-time PCR with TaqMan assay in CD45 + blood cells. Increased hexosylsphingosine concentration was observed in DLB and MSA patients in comparison to PD and controls (p < 0.001) and it was associated with earlier age at onset (AAO) of DLB (p = 0.0008). SMPD1 expression was decreased in MSA compared to controls (p = 0.015). Acid sphingomyelinase activity was decreased in DLB, MSA patients compared to PD patients (p < 0.0001, p < 0.0001, respectively), and in MSA compared to controls (p < 0.0001). Lower acid sphingomyelinase activity was associated with earlier AAO of PD (p = 0.012). Our data support the role of lysosomal dysfunction in the pathogenesis of synucleinopathies, namely, the pronounced alterations of lysosomal activities involved in ceramide metabolism in patients with MSA and DLB.

Topics: alpha-Galactosidase; alpha-Synuclein; Ceramides; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Sphingolipids; Sphingomyelin Phosphodiesterase; Synucleinopathies

The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.

Topics: Aged; alpha-Synuclein; Cell Line; Dementia; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Prions; Synucleinopathies

The protein α-synuclein, a key player in Parkinson's disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible "prion-like" propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a "prion-like" aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and "prion-like" aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Prions; Synucleinopathies

α-Synuclein aggregates abnormally into intracellular inclusions in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and many other neurological disorders, closely connecting with their pathogenesis. The accurate tracking of α-synuclein by targeting probes is of great significance for early diagnosis, disease monitoring, and drug development. However, there have been no promising α-synuclein targeting probes for clinical application reported so far. This overview focuses on various potential α-synuclein targeting probes reported in the past two decades, including small-molecule fluorescent probes and radiolabeled probes. We provide the current status of the development of the small molecular α-synuclein imaging probes, including properties of promising imaging molecules, strategies of processing new probes, limited progress, and growth prospects in this field, expecting to help in the further development of α-synuclein targeting probes.

Topics: alpha-Synuclein; Early Diagnosis; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system.

Topics: alpha-Synuclein; Animals; Autophagy; Female; Humans; Induced Pluripotent Stem Cells; Lewy Body Disease; Male; Mice; Mice, Transgenic; Neurons; Parkinson Disease; Protein S; RNA-Binding Proteins

Lewy body-related α-synucleinopathy (Lewy pathology) has been reported in patients with myotonic dystrophy (DM) type 1 (DM1), but no detailed report has described the prevalence and extent of its occurrence. We studied consecutive full autopsy cases of DM1 at the National Center of Neurology and Psychiatry (NCNP) Brain Bank for intractable psychiatric and neurological disorders. Thirty-two cases, genetically determined to be DM1 (59.0 ± 8.7 years), obtained from the NCNP Brain Bank, were compared with control cases obtained from the Brain Bank for Aging Research (BBAR) in Japan. The investigated anatomical sites followed the Dementia with Lewy Bodies Consensus Guideline, expanding to the peripheral autonomic nervous system, temporal pole, and occipital cortex, in addition to the olfactory epithelium and spinal cord. Of the 32 patients, 11 (34.4%) had Lewy pathology, with a significantly higher prevalence than that in the control cases from the BBAR (20.1%). Lewy pathology detected in DM1 was widespread, but no macroscopic depigmentation of the substantia nigra was observed in any DM1 case; this was commensurate with the microscopic paucity of Lewy pathology in the substantia nigra and amygdala. Lewy pathology in DM1 does not appear to follow either Braak's ascending paradigm or the olfactory-amygdala extension. Lewy neurites and dots in DM1 were very sparse in the cerebral cortex and distinct from those observed in BBAR control cases. This study was the first demonstration of unique Lewy pathology in DM1 and may contribute to the understanding of the protein propagation hypothesis of Lewy pathology.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Myotonic Dystrophy; Parkinson Disease

Lewy body disease is a clinicopathological entity that includes Parkinson's disease, dementia with Lewy bodies, and pure autonomic failure with Lewy bodies, all of which are characterized by varied degrees of autonomic dysfunction. Research in animal models has shown transmission of α-synuclein from peripheral autonomic nerves to the central nervous system via the autonomic nervous system, and the autonomic nervous system plays an important role in the study of Lewy body disease. This paper outlines the pathophysiology, characteristics, and treatment of typical autonomic dysfunction in patients with Lewy body disease.

Topics: alpha-Synuclein; Autonomic Nervous System Diseases; Central Nervous System; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Alpha-synucleinopathies (AS) are characterized by pathologic aggregations of alpha-synuclein (α-syn) in the central nervous system, and comprise dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. Previous studies on AS have reported findings of α-syn pathology in the peripheral nervous system of multiple organs, including the heart.. The aim of this study was to further investigate and confirm the presence of cardiac α-syn in AS compared to other major neurocognitive disorders in a neuropathologically confirmed cohort.. All deceased patients with performed autopsy and with neuropathologically confirmed AS at the Clinical Department of Pathology in Lund 2010-May 2021 were evaluated for inclusion. Cases with insufficiently sampled cardiac tissue or only limited neuropathological investigation were excluded. An age-matched group of individuals with other neurodegenerative diseases, having no α-syn in the CNS, served as controls. In total, 68 AS and 32 control cases were included in the study. Immunohistochemistry for detection of cardiac α-syn aggregates was performed.. The AS group had a significantly higher prevalence of cardiac α-syn pathology (p≤0.001) than the control group, 82% and 0%, respectively.. This study confirms the association between AS and the presence of cardiac α-syn in a neuropathologically confirmed cohort. This motivates further research on potential pathophysiological effects on cardiac function in AS patients.

Topics: alpha-Synuclein; Cadaver; Case-Control Studies; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Synucleinopathies encompass several neurodegenerative diseases, which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. These diseases are characterized by the deposit of α-synuclein aggregates in intracellular inclusions in neurons and glial cells. Unlike Parkinson's disease and dementia with Lewy bodies, where aggregates are predominantly neuronal, multiple system atrophy is associated with α-synuclein cytoplasmic inclusions in oligodendrocytes. Glial cytoplasmic inclusions are the pathological hallmark of multiple system atrophy and are associated with neuroinflammation, modest demyelination and, ultimately, neurodegeneration. To evaluate the possible pathogenic role of glial cytoplasmic inclusions, we inoculated glial cytoplasmic inclusion-containing brain fractions obtained from multiple system atrophy patients into the striatum of non-human primates. After a 2-year in vivo phase, extensive histochemical and biochemical analyses were performed on the whole brain. We found loss of both nigral dopamine neurons and striatal medium spiny neurons, as well as loss of oligodendrocytes in the same regions, which are characteristics of multiple system atrophy. Furthermore, demyelination, neuroinflammation and α-synuclein pathology were also observed. These results show that the α-synuclein species in multiple system atrophy-derived glial cytoplasmic inclusions can induce a pathological process in non-human primates, including nigrostriatal and striatofugal neurodegeneration, oligodendroglial cell loss, synucleinopathy and gliosis. The present data pave the way for using this experimental model for MSA research and therapeutic development.

Topics: alpha-Synuclein; Animals; Brain; Demyelinating Diseases; Humans; Inclusion Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

The cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration pattern of the hippocampus differs between AD and DLB with the CA1 subfield being more severely affected in AD. The activation of microglia, the brain immune cells, could play a role in its selective volume loss. How subregional microglia populations vary within AD or DLB and across these conditions remains poorly understood. Furthermore, how the nature of the hippocampal local pathological imprint is associated with microglia responses needs to be elucidated. To this purpose, we employed an automated pipeline for analysis of 3D confocal microscopy images to assess CA1, CA3 and DG/CA4 subfields microglia responses in post-mortem hippocampal samples from late-onset AD (n = 10), DLB (n = 8) and age-matched control (CTL) (n = 11) individuals. In parallel, we performed volumetric analyses of hyperphosphorylated tau (pTau), amyloid-β (Aβ) and phosphorylated α-synuclein (pSyn) loads. For each of the 32,447 extracted microglia, 16 morphological features were measured to classify them into seven distinct morphological clusters. Our results show similar alterations of microglial morphological features and clusters in AD and DLB, but with more prominent changes in AD. We identified two distinct microglia clusters enriched in disease conditions and particularly increased in CA1 and DG/CA4 of AD and CA3 of DLB. Our study confirms frequent concomitance of pTau, Aβ and pSyn loads across AD and DLB but reveals a specific subregional pattern for each type of pathology, along with a generally increased severity in AD. Furthermore, pTau and pSyn loads were highly correlated across subregions and conditions. We uncovered tight associations between microglial changes and the subfield pathological imprint. Our findings suggest that combinations and severity of subregional pTau, Aβ and pSyn pathologies transform local microglia phenotypic composition in the hippocampus. The high burdens of pTau and pSyn associated with increased microglial alterations could be a factor in CA1 vulnerability in AD.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Hippocampus; Humans; Lewy Body Disease; Microglia; Phenotype; tau Proteins

α-Synuclein (α-syn) phosphorylation at serine 129 (pS129–α-syn) is substantially increased in Lewy body disease, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129–α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129–α-syn inhibits α-syn fibril formation and seeded aggregation. We also identified lower seeding propensity of pS129–α-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129–α-syn (WT–α-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of α-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with α-syn preformed fibrils, and we observed aggregation of nonphosphorylated α-syn followed by later pS129–α-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated α-syn and disease duration. These findings suggest that pS129–α-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129–α-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129–α-syn as a measure of efficacy in clinical trials.

Topics: alpha-Synuclein; Amyloid; Humans; Lewy Body Disease; Parkinson Disease; Phosphorylation; Protein Aggregates; Protein Aggregation, Pathological; Serine

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Apolipoprotein E4; Genome-Wide Association Study; Humans; Lewy Body Disease

The hallmark alteration in α-synucleinopathies, α-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of α-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for α-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing α-synucleinopathy. Seventy-four subjects with cerebral α-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, α-synuclein was seen in the mucosal/submucosal GI biopsies. Two subjects with severe cerebral α-synucleinopathy and a long delay between biopsy and death displayed no α-synuclein pathology in the gut, and 11 subjects with sparse cerebral α-synucleinopathy displayed GI α-synuclein up to 36 years prior to death. The finding that there was no GI α-synuclein in 19% of the subjects with cerebral α-synucleinopathy, and α-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral α-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of α-synuclein in the peripheral tissue for confirmation of an ongoing cerebral α-synucleinopathy.

Topics: alpha-Synuclein; Biomarkers; Biopsy; Early Detection of Cancer; Humans; Lewy Body Disease; Neoplasms; Synucleinopathies

Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that α-synuclein (α-SYN) aggregation is a regulated event in the pathogenesis of AD. Genome-wide association studies revealed that the ε4 allele of the apolipoprotein E (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-β (Aβ) and α-SYN pathogenesis. How APOE4 modulates α-SYN aggregation in AD is unclear. In this study, we aimed to determine how α-SYN is associated with AD-related pathology and how APOE4 impacts α-SYN seeding and toxicity. We measured α-SYN levels and their association with other established AD-related markers in brain samples from autopsy-confirmed AD patients (N = 469), where 54% had concomitant LB pathology (AD + LB). We found significant correlations between the levels of α-SYN and those of Aβ40, Aβ42, tau and APOE, particularly in insoluble fractions of AD + LB. Using a real-time quaking-induced conversion (RT-QuIC) assay, we measured the seeding activity of soluble α-SYN and found that α-SYN seeding was exacerbated by APOE4 in the AD cohort, as well as a small cohort of autopsy-confirmed LBD brains with minimal Alzheimer type pathology. We further fractionated the soluble AD brain lysates by size exclusion chromatography (SEC) ran on fast protein liquid chromatography (FPLC) and identified the α-SYN species (~ 96 kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates α-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects α-SYN pathogenesis in AD.

Topics: alpha-Synuclein; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Genome-Wide Association Study; Humans; Induced Pluripotent Stem Cells; Lewy Bodies; Lewy Body Disease; Neurotoxicity Syndromes; tau Proteins

Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia after Alzheimer's disease (AD). Neuroinflammation plays an important role in neurodegenerative diseases. It is urgent to unravel the pathogenesis of DLB and find potential therapeutic drugs. Here, we investigated the pharmacological effects of the NLRP3 inflammasome inhibitor MCC950 in A53T α-synuclein transgenic line M83 mice aged 4 months. The behavioral tests including Y-maze, Barnes maze, nest building and Rotarod showed that MCC950 significantly improved the cognitive dysfunction symptom without affecting the motor coordination after consecutive intragastric administration every day for 5 weeks. Furthermore, immunostaining or immunoblotting experiments on the hippocampal tissue were performed, and the results suggested that MCC950 not only inhibited the expression of NLRP3, and suppressed the activation of astrocytes and microglia, but also promoted the mTOR-mediated autophagy pathway to reduce human α-synuclein accumulation. Our findings further demonstrate that line M83 mice may be used as an animal model for DLB research, and can provide preclinical evidences for the development of MCC950 as a promising therapeutic drug.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Disease Models, Animal; Furans; Hippocampus; Indenes; Lewy Body Disease; Mice; Mice, Transgenic; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfonamides

Topics: alpha-Synuclein; COVID-19; Humans; Lewy Body Disease; Parkinson Disease; Post-Acute COVID-19 Syndrome

Based on immunostainings and biochemical analyses, certain post-translationally modified alpha-synuclein (aSyn) variants, including C-terminally truncated (CTT) and Serine-129 phosphorylated (pSer129) aSyn, are proposed to be involved in the pathogenesis of synucleinopathies such as Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, quantitative information about aSyn proteoforms in the human brain in physiological and different pathological conditions is still limited. To address this, we generated sequential biochemical extracts of the substantia nigra, putamen and hippocampus from 28 donors diagnosed and neuropathologically-confirmed with different synucleinopathies (PD/PDD/DLB/MSA), as well as Alzheimer's disease, progressive supranuclear palsy, and aged normal subjects. The tissue extracts were used to build a reverse phase array including 65 aSyn antibodies for detection. In this multiplex approach, we observed increased immunoreactivity in donors with synucleinopathies compared to controls in detergent-insoluble fractions, mainly for antibodies against CT aSyn and pSer129 aSyn. In addition, despite of the restricted sample size, clustering analysis suggested disease-specific immunoreactivity signatures in patient groups with different synucleinopathies. We aimed to validate and quantify these findings using newly developed immunoassays towards total, 119 and 122 CTT, and pSer129 aSyn. In line with previous studies, we found that synucleinopathies shared an enrichment of post-translationally modified aSyn in detergent-insoluble fractions compared to the other analyzed groups. Our measurements allowed for a quantitative separation of PDD/DLB patients from other synucleinopathies based on higher detergent-insoluble pSer129 aSyn concentrations in the hippocampus. In addition, we found that MSA stood out due to enrichment of CTT and pSer129 aSyn also in the detergent-soluble fraction of the SN and putamen. Together, our results achieved by multiplexed and quantitative immunoassay-based approaches in human brain extracts of a limited sample set point to disease-specific biochemical aSyn proteoform profiles in distinct neurodegenerative disorders.

Topics: Aged; alpha-Synuclein; Brain; Detergents; Humans; Lewy Body Disease; Multiple System Atrophy; Synucleinopathies

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by the aberrant accumulation of intracytoplasmic misfolded and aggregated α-synuclein (α-Syn), resulting in neurodegeneration associated with inflammation. The propagation of α-Syn aggregates from cell to cell is implicated in the spreading of pathological α-Syn in the brain and disease progression. We and others demonstrated that antibodies generated after active and passive vaccinations could inhibit the propagation of pathological α-Syn in the extracellular space and prevent/inhibit disease/s in the relevant animal models. We recently tested the immunogenicity and efficacy of four DNA vaccines on the basis of the universal MultiTEP platform technology in the DLB/PD mouse model. The antibodies generated by these vaccines efficiently reduced/inhibited the accumulation of pathological α-Syn in the different brain regions and improved the motor deficit of immunized female mice. The most immunogenic and preclinically effective vaccine, PV-1950D, targeting three B-cell epitopes of pathological α-Syn simultaneously, has been selected for future IND-enabling studies. However, to ensure therapeutically potent concentrations of α-Syn antibodies in the periphery of the vaccinated elderly, we developed a recombinant protein-based MultiTEP vaccine, PV-1950R/A, and tested its immunogenicity in young and aged D-line mice. Antibody responses induced by immunizations with the PV-1950R/A vaccine and its homologous DNA counterpart, PV-1950D, in a mouse model of PD/DLB have been compared.

Topics: alpha-Synuclein; Animals; Antibodies; Disease Models, Animal; Epitopes, B-Lymphocyte; Female; Lewy Body Disease; Mice; Parkinson Disease; Recombinant Proteins; Vaccines, DNA

Lewy body disorders are characterized by oxidative damage to DNA and inclusions rich in aggregated forms of α-synuclein. Among other roles, apurinic/apyrimidinic endonuclease 1 (APE1) repairs oxidative DNA damage, and APE1 polymorphisms have been linked to cases of Lewy body disorders. However, the link between APE1 and α-synuclein is unexplored. We report that knockdown or inhibition of APE1 amplified inclusion formation in primary hippocampal cultures challenged with preformed α-synuclein fibrils. Fibril infusions into the mouse olfactory bulb/anterior olfactory nucleus (OB/AON) elicited a modest decrease in APE1 expression in the brains of male mice but an increase in females. Similarly, men with Lewy body disorders displayed lower APE1 expression in the OB and amygdala compared to women. Preformed fibril infusions of the mouse OB/AON induced more robust base excision repair of DNA lesions in females than males. No fibril-mediated loss of APE1 expression was observed in male mice when the antioxidant N-acetylcysteine was added to their diet. These findings reveal a potential sex-biased link between α-synucleinopathy and APE1 in mice and humans. Further studies are warranted to determine how this multifunctional protein modifies α-synuclein inclusions and, conversely, how α-synucleinopathy and biological sex interact to modify APE1.

Topics: alpha-Synuclein; Animals; DNA; DNA Repair; Endonucleases; Female; Humans; Lewy Body Disease; Male; Mice; Oxidation-Reduction; Synucleinopathies

Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). α-synuclein (αSyn) RT-QuIC has emerged as a promising assay to detect misfolded αSyn in clinically or neuropathologically established patients with various synucleinopathies. In this study, αSyn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFINDER study and postmortem ventricular CSF in a neuropathological cohort from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (AZSAND/BBDP). The BioFINDER cohort included 64 PD/PDD, 15 MSA, 15 PSP, 47 controls and two controls who later converted to PD/DLB. The neuropathological cohort included 101 cases with different brain disorders, including LBD and controls. In the BioFINDER cohort αSyn RT-QuIC identified LBD (i.e. PD, PDD and converters) vs. controls with a sensitivity of 95% and a specificity of 83%. The two controls that converted to LBD were αSyn RT-QuIC positive. Within the AZSAND/BBDP cohort, αSyn RT-QuIC identified neuropathologically verified "standard LBD" (i.e. PD, PD with AD and DLB; n = 25) vs. no LB pathology (n = 53) with high sensitivity (100%) and specificity (94%). Only 57% were αSyn RT-QuIC positive in the subgroup with "non-standard" LBD (i.e., AD with Lewy Bodies not meeting criteria for DLB or PD, and incidental LBD, n = 23). Furthermore, αSyn RT-QuIC reliably identified cases with LB pathology in the cortex (97% sensitivity) vs. cases with no LBs or LBs present only in the olfactory bulb (93% specificity). However, the sensitivity was low, only 50%, for cases with LB pathology restricted to the brainstem or amygdala, not affecting the allocortex or neocortex. In conclusion, αSyn RT-QuIC of CSF samples is highly sensitive and specific for identifying cases with clinicopathologically-defined Lewy body disorders and shows a lower sensitivity for non-standard LBD or asymptomatic LBD or in cases with modest LB pathology not affecting the cortex.

Topics: alpha-Synuclein; Brain; Brain Chemistry; Humans; Lewy Bodies; Lewy Body Disease; Synucleinopathies

Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. Although the distribution of α-Syn correlates with the predominant clinical features, the burden of pathology does not fully explain the observed variability in clinical presentation and rate of disease progression. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding in 8 brain regions from 30 LBD patients with different clinical phenotypes and disease durations. Comparing seeding across the clinical phenotypes revealed that hippocampal α-Syn from patients with a cognitive-predominant phenotype had significantly higher seeding capacity than that derived from patients with a motor-predominant phenotype, whose nigral-derived α-Syn in turn had higher seeding capacity than that from cognitive-predominant patients. Interestingly, α-Syn from patients with rapid disease progression (< 3 years to development of advanced disease) had the highest nigral seeding capacity of all the patients included. To validate these findings and explore factors underlying seeding heterogeneity, we performed in vitro toxicity assays, and detailed neuropathological and biochemical examinations. Furthermore, and for the first time, we performed a proteomic-wide profiling of the substantia nigra from 5 high seeder and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders. These observations suggest that distinct molecular populations of α-Syn may contribute to heterogeneity in phenotypes and progression rates in LBD and imply that effective therapeutic strategies might need to be directed at an ensemble of differently misfolded α-Syn species, with the relative contribution of their differing impacts accounting for heterogeneity in the neurodegenerative process.

Topics: alpha-Synuclein; Disease Progression; Humans; Lewy Bodies; Lewy Body Disease; Proteomics; Substantia Nigra

Dementia with Lewy bodies (DLB) is pathologically defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neurons in the brain. Predominately pre-synaptic, aSyn has been reported in various subcellular compartments in experimental models. Indeed, nuclear alpha-synuclein (aSyn

Topics: Aged; alpha-Synuclein; Brain; Cell Nucleus; Humans; Lewy Bodies; Lewy Body Disease

Pathogenic α-synuclein (α-syn) is a prion-like protein that drives the pathogenesis of Lewy Body Dementia (LBD) and Parkinson's Disease (PD). To target pathogenic α-syn preformed fibrils (PFF), here we designed extracellular disulfide bond-free synthetic nanobody libraries in yeast. Following selection, we identified a nanobody, PFFNB2, that can specifically recognize α-syn PFF over α-syn monomers. PFFNB2 cannot inhibit the aggregation of α-syn monomer, but can significantly dissociate α-syn fibrils. Furthermore, adeno-associated virus (AAV)-encoding EGFP fused to PFFNB2 (AAV-EGFP-PFFNB2) can inhibit PFF-induced α-syn serine 129 phosphorylation (pS129) in mouse primary cortical neurons, and prevent α-syn pathology spreading to the cortex in the transgenic mice expressing human wild type (WT) α-syn by intrastriatal-PFF injection. The pS129 immunoreactivity is negatively correlated with the expression of AAV-EGFP-PFFNB2. In conclusion, PFFNB2 holds a promise for mechanistic exploration and therapeutic development in α-syn-related pathogenesis.

Topics: alpha-Synuclein; Animals; Humans; Lewy Body Disease; Mice; Parkinson Disease; Prions; Synucleinopathies

Loss of activity of the lysosomal glycosidase β-glucocerebrosidase (GCase) causes the lysosomal storage disease Gaucher disease (GD) and has emerged as the greatest genetic risk factor for the development of both Parkinson disease (PD) and dementia with Lewy bodies. There is significant interest into how GCase dysfunction contributes to these diseases, however, progress toward a full understanding is complicated by presence of endogenous cellular factors that influence lysosomal GCase activity. Indeed, such factors are thought to contribute to the high degree of variable penetrance of

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Humans; Lewy Bodies; Lewy Body Disease; Lysosomes; Mutation; Parkinson Disease; Substrate Specificity

The present paper investigated the association of Parkinson's disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson's disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson's disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson's disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson's disease. Sarcopenia and cancer in Parkinson's disease patients are also associated with phosphate toxicity. Additionally, Parkinson's disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson's disease.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Mitochondrial Permeability Transition Pore; Parkinson Disease; Phosphates; Tauopathies

Dysregulation of autophagy, one of the major processes through which abnormal proteins are degraded, is a cardinal feature of synucleinopathies, including Lewy body diseases [Parkinson's disease (PD) and dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA), which are characterized by the presence of abnormal α-synuclein in neurons and glial cells. Although several research groups have reported that Rubicon family proteins can regulate autophagosome-lysosome fusion or positioning, little is known about their involvement in synucleinopathies. In the present study, by studying patients with PD (N = 8), DLB (N = 13), and MSA (N = 5) and controls (N = 16), we explored the involvement of Rubicon family proteins [Rubicon, Pacer and differentially expressed in FDCP8 (DEF8)] in synucleinopathies. Immunohistochemical analysis showed that not only brainstem-type Lewy bodies but also cortical Lewy bodies were immunoreactive for DEF8 in Lewy body diseases, whereas Rubicon and Pacer were detectable in only a few brainstem-type Lewy bodies in PD. Glial cytoplasmic inclusions in patients with MSA were not immunoreactive for Rubicon, Pacer or DEF8. Immunoblotting showed significantly increased protein levels of DEF8 in the substantia nigra and putamen of patients with PD and the temporal cortex of patients with DLB. In addition, the smear band of DEF8 appeared in the insoluble fraction where that of phosphorylated α-synuclein was detected. These findings indicate the involvement of DEF8 in the formation of Lewy bodies. Quantitative and qualitative alterations in DEF8 may reflect the dysregulation of autophagy in Lewy body diseases.

Topics: alpha-Synuclein; Autophagy; Brain; Humans; Intracellular Signaling Peptides and Proteins; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and β-amyloid (Aβ). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10 μg/10 μL) and Aβ (5 μg/2.5 μL) into the left ventricle and prefrontal cortex, respectively. AMI (10 mg/kg/day, i.p.), RIVA (2 mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.

Topics: alpha-Synuclein; Amitriptyline; Animals; Cognition; Glutamates; Lewy Body Disease; Male; Rats; Rats, Wistar

α-Synuclein (α-Syn) binds to vesicle-associated membrane protein-binding protein B (VAPB) in the endoplasmic reticulum membrane. Recent studies have shown that α-Syn-immunoreactive Lewy pathology is characterized by membrane crowding, including vesicular structures. To elucidate the role of VAPB and vesicular structures in Parkinson's disease (PD) and in dementia with Lewy bodies (DLB), the relationships among VAPB, vesicular structures, and Lewy pathology were investigated by immunohistochemistry and immunoelectron microscopy in 8 PD and 4 DLB autopsy cases. The proportions of VAPB-negative neurons in the substantia nigra in PD and in the temporal cortex in DLB were significantly higher than those in 5 controls. In PD, the incidence of α-Syn inclusions in VAPB-negative neurons was significantly higher (77.4%) than in VAPB-positive neurons (1.6%) in the substantia nigra. In DLB, the incidence of α-Syn inclusions in VAPB-negative neurons was also significantly higher (65.3%) than in VAPB-positive neurons (2.8%) in the temporal cortex. Immunoelectron microscopy revealed that α-Syn and VAPB were localized to filamentous structures of Lewy bodies (LBs). However, only a few vesicular structures labeled with anti-α-Syn were observed within LBs. These findings suggest that reduction of VAPB is involved in the disease processes of PD and DLB, although vesicular structures may not directly contribute to the formation of LBs.

Topics: alpha-Synuclein; Carrier Proteins; Humans; Lewy Body Disease; Parkinson Disease; R-SNARE Proteins; Receptors, Fc; Vesicular Transport Proteins

We present a case report on an older woman with unspecific symptoms and predominant long-term gastrointestinal disturbances, acute overall health deterioration with loss of autonomy for daily activities, and cognitive impairment. Autopsy revealed the presence of alpha-synuclein deposits spread into intestinal mucosa lesions, enteric plexuses, pelvic and retroperitoneal nerves and ganglia, and other organs as well as Lewy pathology in the central nervous system (CNS). Moreover, we isolated norovirus from the patient, indicating active infection in the colon and detected colocalization of norovirus and alpha-synuclein in different regions of the patient's brain. In view of this, we report a concomitant norovirus infection with synthesis of alpha-synuclein in the gastrointestinal mucosa and Lewy pathology in the CNS, which might support Braak's hypothesis about the pathogenic mechanisms underlying synucleinopathies.

Topics: Aged; alpha-Synuclein; Brain; Caliciviridae Infections; Cognitive Dysfunction; Female; Humans; Lewy Body Disease; Norovirus

An estimated 50% of patients with Lewy body dementias (LBD), including Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB), have co-occurring Alzheimer's disease (AD) that is associated with worse prognosis. This study tests an automated analysis of natural speech as an inexpensive, non-invasive screening tool for AD co-pathology in biologically-confirmed cohorts of LBD patients with AD co-pathology (SYN + AD) and without (SYN-AD).. We analyzed lexical-semantic and acoustic features of picture descriptions using automated methods in 22 SYN + AD and 38 SYN-AD patients stratified using AD CSF biomarkers or autopsy diagnosis. Speech markers of AD co-pathology were identified using best subset regression, and their diagnostic discrimination was tested using receiver operating characteristic. ANCOVAs compared measures between groups covarying for demographic differences and cognitive disease severity. We tested relations with CSF tau levels, and compared speech measures between PDD and DLB clinical disorders in the same cohort.. Age of acquisition of nouns (p = 0.034, |d| = 0.77) and lexical density (p = 0.0064, |d| = 0.72) were reduced in SYN + AD, and together showed excellent discrimination for SYN + AD vs. SYN-AD (95% sensitivity, 66% specificity; AUC = 0.82). Lower lexical density was related to higher CSF t-Tau levels (R = -0.41, p = 0.0021). Clinically-diagnosed PDD vs. DLB did not differ on any speech features.. AD co-pathology may result in a deviant natural speech profile in LBD characterized by specific lexical-semantic impairments, not detectable by clinical disorder diagnosis. Our study demonstrates the potential of automated digital speech analytics as a screening tool for underlying AD co-pathology in LBD.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Humans; Lewy Body Disease; Parkinson Disease; Speech; tau Proteins

Lewy body diseases (LBDs), which are pathologically defined as the presence of intraneuronal α-synuclein (α-Syn) inclusions called Lewy bodies, encompass Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Autopsy studies have shown that the olfactory bulb (OB) is one of the regions where Lewy pathology develops and initiates its spread in the brain.. This study aims to clarify how Lewy pathology spreads from the OB and affects brain functions using nonhuman primates.. We inoculated α-Syn preformed fibrils into the unilateral OBs of common marmosets (Callithrix jacchus) and performed pathological analyses, manganese-enhanced magnetic resonance imaging, and. Severe α-Syn pathology was observed within the olfactory pathway and limbic system, while mild α-Syn pathology was seen in a wide range of brain regions, including the substantia nigra pars compacta, locus coeruleus, and even dorsal motor nucleus of the vagus nerve. The brain imaging analyses showed reduction in volume of the OB and progressive glucose hypometabolism in widespread brain regions, including the occipital lobe, and extended beyond the pathologically affected regions.. We generated a novel nonhuman primate LBD model with α-Syn propagation from the OB. This model suggests that α-Syn propagation from the OB is related to OB atrophy and cerebral glucose hypometabolism in LBDs. © 2022 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Callithrix; Deoxyglucose; Glucose; Lewy Body Disease; Manganese; Olfactory Bulb; Parkinson Disease

Recent high-resolution structures of alpha-synuclein (aSyn) fibrils offer promise for rational approaches to drug discovery for Parkinson's disease and Lewy body dementia. Harnessing the first such structures, we previously used molecular dynamics and free energy calculations to suggest that threonines 72 and 75─which line water-filled cavities within the fibril stacks─may be of central importance in stabilizing fibrils. Here, we used experimental mutagenesis of both wild-type and A53T aSyn to show that both threonine residues play important but surprisingly disparate roles in fibril nucleation and elongation. The T72A mutant, but not T75A, resulted in a large increase in the extent of fibrillization during primary nucleation, leading us to posit that T72 acts as a "brake" on run-away aggregation. An expanded set of simulations of five recent high-resolution fibril structures suggests that confinement of cavity waters around T72 correlates with this finding. In contrast, the T75A mutation led to a modest decrease in the extent of fibrillization. Furthermore, both T72A and T75A completely blocked the initial fibril elongation in seeded fibrillization. To test whether these threonine-lined cavities are druggable targets, we used computational docking to identify potential small-molecule binders. We show that the top-scoring hit, aprepitant, strongly promotes fibril growth while specifically interacting with aSyn fibrils and not monomer, and we offer speculation as to how such compounds could be used therapeutically.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Mutation; Parkinson Disease; Threonine

Patients with dementia with Lewy bodies perform worse than those with Alzheimer disease (AD) on tests of visual perception, but the clinical utility of these tests remains unknown because studies often had clinically diagnosed groups that may inadvertently cross-contaminate Lewy body disease (LBD) with pure AD pathology, used experimental tests not easily adaptable for clinical use, and had no way to examine relationships between the severity of LBD pathology and degree of cognitive impairment. Therefore, we sought to determine whether performance on a widely used clinical test of visuoperceptual ability effectively differentiates between patients with autopsy-confirmed LBD or AD and correlates with the severity of LBD pathology.. Patients with mild to moderate dementia (n = 42) and cognitively healthy controls (n = 22) performed a Fragmented Letters Test in which they identified letters of the alphabet that were randomly visually degraded by 70% and additional visuospatial and episodic memory tests. At autopsy, dementia cases were confirmed to have LBD (n = 19), all with concomitant AD, or only AD (n = 23). Severity of α-synuclein pathology in the hippocampus and neocortex was rated on an ordinal scale.. Patients with LBD performed worse than those with AD (B = -2.80 ± 0.91,. Fragmented Letters Test performance can effectively differentiate patients with LBD pathology from those with only AD pathology at a mild to moderate stage of dementia, even when LBD occurs with significant concomitant AD pathology, and may also be useful for gauging the severity of cortical α-synuclein pathology in those with LBD.

Topics: alpha-Synuclein; Alzheimer Disease; Humans; Lewy Bodies; Lewy Body Disease; Visual Perception

Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms

Topics: alpha-Synuclein; Brain; Brain Chemistry; Cryoelectron Microscopy; Dementia; Humans; Lewy Body Disease; Parkinson Disease

The development of specific disease-associated PET tracers is one of the major challenges, the realization of which in neurodegenerative diseases would enable not only the efficiency of diagnosis but also support the development of disease-modifying therapeutics. Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by neuronal fibrillary inclusions composed of aggregated α-synuclein (α-syn). However, these deposits are not only found in PD, but also in other related diseases such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), which are grouped under the term synucleinopathies. In this study, we used NGS-guided phage display selection to identify short peptides that bind aggregated α-syn. By surface plasmon resonance (SPR)-based affinity screening, we identified the peptide SVLfib-5 that recognizes aggregated α-syn with high complex stability and sequence specificity. Further analysis SPR showed that SVLfib-5 is not only specific for aggregated α-syn, but in particular recognizes fibrillary and oligomeric structures. Moreover, fluorescence microscopy of human brain tissue sections from PD, MSA, and DLB patients with SVLfib-5 allowed specific recognition of α-syn and a clear discrimination between diseased and non-diseased samples. These findings provide the basis for the further development of an α-syn PET tracer for early diagnosis and monitoring of disease progression and therapy progress.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

The synucleinopathies are neurodegenerative disease caused by abnormal accumulation of the 140-amino acid-containing protein α-synuclein (αSyn), including Parkinson's disease (PD), diffuse Lewy body dementia (DLBD), and multiple system atrophy (MSA). In patients with PD and DLBD, αSyn is misfolded in neurons, and its aggregation forms Lewy bodies (LB) and Lewy neurites (LN). On the other hand, in patients with MSA, αSyn accumulates primarily in oligodendrocytes (OLGs) and forms glial inclusion bodies (GCIs), a typical pathological feature of MSA. We recently demonstrated a making complex between αSyn and fatty acid-binding proteins (FABPs) in synucleinopathies and received wide attention. Fatty acid-binding protein 3 (FABP3) in dopamine nerves, and fatty acid-binding protein 7 (FABP7) in glial cells promoted αSyn accumulation and aggregation, respectively and caused cell death. Here, we introduced the current studies about the role of αSyn and FABP7 in MSA and novel therapeutic approach targeting for FABP7.

Topics: alpha-Synuclein; Fatty Acid-Binding Protein 7; Humans; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease; Synucleinopathies

With the advent of a super-aging society, overcoming age-related neurological diseases and developing fundamental therapeutic agents are urgent issues. In Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies, the accumulation and aggregation of α-synuclein in the neuronal cells, called Lewy bodies, are known as pathological features. Intracellular accumulation of the causative protein α-synuclein in the central nervous system requires an uptake process into neurons. Type 3 fatty acid-binding protein (FABP3) is highly expressed in dopaminergic neurons and has the ability to bind dopamine receptors, particularly dopamine D2 long type (D2L) receptors, which are abundantly localized on caveolae structures in the plasma membrane. We found that dopaminergic neurons do not take up α-synuclein in FABP3 knockout or D2L receptor-selective knockout mice. Next, we found that the C-terminal deletion of α-synuclein reduces the uptake ability. α-Synuclein has a FABP3 binding site in its C-terminal region. On this point, exposure to the C-terminal peptide reduced α-synuclein uptake into dopaminergic neurons. Based on these findings, this article describes the unique mechanism of the propagation and uptake process of α-synuclein, focusing on the physiological significance of FABP3 and dopamine D2 receptors. Additionally, we will review the development status of therapeutic peptide candidates for Lewy body diseases, and then discuss the novel pathogenic mechanism of Lewy body disease as well as the potential of fundamental therapeutics targeting the uptake process of α-synuclein.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Lewy Bodies; Lewy Body Disease; Mice; Mice, Knockout; Peptides

Neuropathologically, Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of insoluble aggregates of α-synuclein (α-syn) in the Lewy bodies (LBs). In addition to full-length α-syn fibrils, C-terminally truncated α-syn is also abundant in the LBs that acts as seeds and facilitates the aggregation of the full-length α-syn

Topics: alpha-Synuclein; Aptamers, Nucleotide; DNA, Single-Stranded; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer’s disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Humans; Lewy Body Disease; Male; Middle Aged; Retrospective Studies; tau Proteins

Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties and topographical distribution of astrocytic aSyn have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology using an expanded antibody toolset covering the entire sequence and key post-translational modifications (PTMs) of aSyn in Lewy body disorders (LBDs) and in MSA. Astrocytic aSyn was detected in the limbic cortical regions of LBDs but were absent in main pathological regions of MSA. The astrocytic aSyn was revealed only with antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34-99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations represent a major part of aSyn pathology in LBDs and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. This is the first description that aSyn accumulations are made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn is a mixture of Y39 phosphorylated and nitrated species. These observations underscore the importance of systematic characterization of aSyn accumulations in different cell types to capture the aSyn pathological diversity in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LBDs can pave the way towards identifying novel disease mechanisms and therapeutic targets.

Topics: alpha-Synuclein; Astrocytes; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Processing, Post-Translational; Synucleinopathies

Parkinson's disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of α-synuclein (α-syn) aggregates. Central to disease progression is the gradual spread of pathological α-syn. α-syn aggregation is closely linked to progressive neuron loss. As such, clearance of α-syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence is increasing that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy. Our previous work has shown that pericytes-vascular mural cells that regulate the blood-brain barrier-contain α-syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar α-syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes cleave fibrillar α-syn aggregates (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110), with cleaved α-syn remaining present for up to 21 days. The number of α-syn aggregates/cell and average aggregate size depends on the type of strain, but differences disappear within 5 five hours of treatment. Our results highlight the role brain vasculature may play in reducing α-syn aggregate burden in PD.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Neurons; Parkinson Disease; Pericytes

Cortical synucleinopathies, including dementia with Lewy bodies and Parkinson's disease dementia, collectively known as Lewy body dementia, are characterized by the aberrant aggregation of misfolded α-synuclein (α-syn) protein into large inclusions in cortical tissue, leading to impairments in proteostasis and synaptic connectivity and eventually resulting in neurodegeneration. Here, we show that male and female rat cortical neurons exposed to exogenous α-syn preformed fibrils accumulate large, detergent-insoluble, PS129-labeled deposits at synaptic terminals. Live-cell imaging of calcium dynamics coupled with assessment of network activity reveals that aberrant intracellular accumulation of α-syn inhibits synaptic response to glutamate through NMDARs, although deficits manifest slowly over a 7 d period. Impairments in NMDAR activity temporally correlated with increased nitric oxide synthesis and S-nitrosylation of the dendritic scaffold protein, microtubule-associated protein 1A. Inhibition of nitric oxide synthesis via the nitric oxide synthase inhibitor l-NG-nitroarginine methyl ester blocked microtubule-associated protein 1A S-nitrosylation and normalized NMDAR-dependent inward calcium transients and overall network activity. Collectively, these data suggest that loss of synaptic function in Lewy body dementia may result from synucleinopathy-evoked nitrosative stress and subsequent NMDAR dysfunction.

Topics: alpha-Synuclein; Animals; Calcium; Dementia; Female; Glutamates; Lewy Body Disease; Male; Microtubule-Associated Proteins; Nitric Oxide; Parkinson Disease; Rats; Receptors, N-Methyl-D-Aspartate; Synucleinopathies

Neuromelanin granules (NMGs) are organelle-like structures present in the human

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Proteome; Proteomics

Axons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB.. α-Synuclein, phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insular (agranular and dysgranular) subregions of post-mortem human brains (n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.. Compared to PD and PDD, DLB showed significantly higher α-synuclein and p-tau pathology load, argyrophilic grains, and  more severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significantly higher load of amyloid-β pathology and its axonal density correlated with cognitive performance. p-Tau contributed most to axonal loss in the DLB group, was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit.. Our results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies, leading to impaired axonal integrity in PD, PDD and DLB, disrupting their functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.

Topics: alpha-Synuclein; Alzheimer Disease; Humans; Insular Cortex; Lewy Body Disease; Parkinson Disease

Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear. We used a mouse model that develops aggregated aSyn nuclear inclusions. Using aSyn preformed fibril injections in GFP-tagged aSyn transgenic mice, we were able to induce the formation of nuclear aSyn inclusions and study their properties in fixed tissue and in vivo using multiphoton microscopy. In addition, we analyzed human synucleinopathy patient tissue to better understand this pathology. Our data demonstrate that nuclear aSyn inclusions may form through the transmission of aSyn between neurons, and these intranuclear aggregates bear the hallmarks of cytoplasmic Lewy pathology. Neuronal nuclear aSyn inclusions can form rod-like structures that do not contain actin, excluding them from being previously described nuclear actin rods. Longitudinal, in vivo multiphoton imaging indicates that certain morphologies of neuronal nuclear aSyn inclusions predict cell death within 14 days. Human multiple system atrophy cases contain neurons and glia with similar nuclear inclusions, but we were unable to detect such inclusions in Lewy body dementia cases. This study suggests that the dysregulation of a nuclear aSyn function associated with nuclear inclusion formation could play a role in the forms of neurodegeneration associated with synucleinopathy.

Topics: Actins; alpha-Synuclein; Animals; Cell Death; Disease Models, Animal; Humans; Lewy Body Disease; Mice; Mice, Transgenic; Multiple System Atrophy; Synucleinopathies

Topics: alpha-Synuclein; Alzheimer Disease; Amyloidosis; Brain; Humans; Lewy Bodies; Lewy Body Disease

The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Lewy body dementia. A current area of intense study is the way in which the pathological deposition of these proteins might influence each other, as various combinations of co-pathology between prion-capable proteins are associated with exacerbation of disease. A spectrum of pathological, genetic and biochemical evidence provides credence to the notion that amyloid β (Aβ) accumulation can induce and promote α-synuclein pathology, driving neurodegeneration.. To assess the interplay between α-synuclein and Aβ on protein aggregation kinetics, we crossed mice expressing human α-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected α-synuclein preformed fibrils (PFFs) unilaterally into the hippocampus of 6-month-old mice, harvesting 2 or 4 months later.. Immunohistochemical analysis of M20/L85 mice revealed that pre-existing Aβ plaques exacerbate the spread and deposition of induced α-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of α-synuclein PFFs in L85 mice enhanced the deposition of Aβ; whereas the level of Aβ deposition in M20/L85 bigenic mice, injected with α-synuclein PFFs, did not differ from that of mice injected with PBS.. These studies reveal novel and unexpected interplays between α-synuclein pathology, Aβ and neuroinflammation in mice that recapitulate the pathology of Alzheimer's disease and Lewy body dementia.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Cerebral Cortex; Crosses, Genetic; Dementia; Disease Models, Animal; Gliosis; Hippocampus; Humans; Injections; Lewy Body Disease; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neuroinflammatory Diseases; Parkinson Disease; Prions; Protein Aggregates; Protein Aggregation, Pathological; Recombinant Proteins

Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase the association between TLR2 and MyD88, resulting in microglial activation. The TLR2-interaction domain of MyD88 (wtTIDM) peptide-mediated selective inhibition of TLR2 reduces PFF-induced microglial inflammation in vitro. In PFF-seeded A53T mice, the nasal administration of the wtTIDM peptide, NEMO-binding domain (wtNBD) peptide, or genetic deletion of TLR2 reduces glial inflammation, decreases α-syn spreading, and protects dopaminergic neurons by inhibiting NF-κB. In summary, α-syn spreading depends on the TLR2/MyD88/NF-κB pathway and it can be reduced by nasal delivery of wtTIDM and wtNBD peptides.

Topics: alpha-Synuclein; Animals; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Humans; Lewy Body Disease; Mice; Mice, Knockout; Microglia; Multiple System Atrophy; Mutagenesis, Site-Directed; Mutation; Myeloid Differentiation Factor 88; NF-kappa B; Parkinson Disease; Primary Cell Culture; Promoter Regions, Genetic; Signal Transduction; Toll-Like Receptor 2

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Cross-Sectional Studies; Humans; Lewy Body Disease

Recent studies indicate that the adaptive immune system plays a role in Lewy body dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic neurons in postmortem LBD brains. Single-cell RNA sequencing of cerebrospinal fluid (CSF) identified up-regulated expression of

Topics: alpha-Synuclein; Animals; Brain; CD4-Positive T-Lymphocytes; Cerebrospinal Fluid; Chemokine CXCL12; Female; Humans; Lewy Body Disease; Lymphocyte Activation; Male; Meninges; Mice; Mice, Inbred C57BL; Nerve Degeneration; Receptors, CXCR4; Signal Transduction; T-Lymphocyte Subsets; Th17 Cells; Up-Regulation

Accumulation of phosphorylated α-synuclein in the central and peripheral nervous systems is a histological hallmark of Lewy body disease (LBD), including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and LB-related pure autonomic failure. The submandibular gland is employed as a biopsy site for detecting Lewy pathology; however, the incidence of Lewy pathology in this region in autopsy-proven LBD cases at all stages from an aged Japanese cohort remains unclear. To validate the utility of Lewy pathology of the submandibular gland as a diagnostic biomarker for LBD, we investigated the submandibular gland Lewy pathology in autopsied patients. To determine the specificity, we prospectively evaluated the submandibular gland in 64 consecutive autopsied patients. To determine the sensitivity, we retrospectively assessed the submandibular gland in 168 consecutive autopsied patients who had prodromal or clinical LBD. In the prospective study, Lewy pathology was found in 21 of 64 patients, and nine of those 21 patients had the submandibular gland Lewy pathology. No Lewy pathology was found in 43 patients without CNS Lewy pathology, giving a specificity of 100%. In the retrospective study, Lewy pathology of the submandibular gland was detected in 126 of 168 patients. The sensitivity was 89.1% in PD and 75.4% in DLB. The sensitivity increased with disease progression. These findings support the utility of the submandibular gland biopsy for the pathological diagnosis of LBD.

Topics: Aged; alpha-Synuclein; Autopsy; Humans; Lewy Body Disease; Prospective Studies; Retrospective Studies; Submandibular Gland

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease

Serine 129 (S129) phosphorylation of α-synuclein (αSyn) is a central feature of Lewy body (LB) disease pathology. Although the neighboring tyrosine residues Y125, Y133, and Y136 are also phosphorylation sites, little is known regarding potential roles of phosphorylation cross-talk between these sites and its involvement in the pathogenesis of LB disease. Here, we found that αSyn aggregates are predominantly phosphorylated at Y136 in the Lewy body dementia brain, which is mediated by unexpected kinase activity of Casein kinase 2 (CK2). Aggregate formation with S129 and Y136 phosphorylation of recombinant αSyn (r-αSyn) were induced by CK2 but abolished by replacement of S129 with alanine (S129A) in vitro. Mutation of Y136 to alanine (Y136A) promoted aggregate formation and S129 phosphorylation of r-αSyn by CK2 in vitro. Introduction of Y136A r-αSyn oligomers into cultured cells exhibited increased levels of aggregates with S129 phosphorylation compared to wild-type r-αSyn oligomers. In addition, aggregate formation with S129 phosphorylation induced by introduction of wild-type r-αSyn oligomers was significantly attenuated by CK2 inhibition, which resulted in an unexpected increase in Y136 phosphorylation in cultured cells. Our findings suggest the involvement of CK2-related αSyn Y136 phosphorylation in the pathogenesis of LB disease and its potential as a therapeutic target.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amino Acid Substitution; Autopsy; Brain; Casein Kinase II; Cells, Cultured; Female; Humans; Lewy Body Disease; Male; Mutation; Phosphorylation; Serine; Tyrosine

The accumulation of aggregated α-synuclein (αSyn) is known as one of the critical reasons to exhibit their variable molecular pathologies and phenotypes in synucleinopathies. Recent studies suggested that the real-time quaking-induced conversion (RT-QuIC) assay is one of the potential methods to detect these αSyn aggregates and could detect the aggregated αSyn in the brain tissue and cerebrospinal fluid (CSF) using the propensity of the prion-like oligomerization.. We tried to optimize the αSyn RT-QuIC assay based on the aggregation of αSyn in brain samples of synucleinopathies by comparing the conditions of the recently reported αSyn RTQuIC assays.. This study applied a highly sensitive RT-QuIC assay using recombinant αSyn (rαSyn) to detect aggregated αSyn in the brain tissue from dementia with Lewy bodies (DLB).. This study compared αSyn RT-QuIC assays under conditions such as beads, rαSyn as a substrate, reaction buffers, and fluorescence detectors. We observed that the addition of beads and the use of 6x His-tagged rαSyn as a substrate help to obtain higher positive responses from αSyn RT-QuIC assay seeding with brain homogenate (BH) of DLB and phosphate buffer-based reaction showed higher positive responses than HEPES buffer-based reaction on both fluorescent microplate readers. We also observed that the DLB BHs gave positive responses within 15-25h, which is faster high positive responses than recently reported assays.. This established αSyn RT-QuIC assay will be able to apply to the early clinical diagnosis of αSyn aggregates-related diseases in various biofluids such as CSF.

Topics: alpha-Synuclein; Biological Assay; Brain; Female; Humans; Lewy Body Disease; Male; Protein Aggregates

Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of novel high-resolution imaging approaches is a current challenge in neuroscience.. To this end, we used a recent super-resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases.. This approach allowed us to perform 2D-, 3D- and two-colour-STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer's disease, Parkinson's disease, Lewy body dementia and fronto-temporal lobar degeneration. Aggregated Aβ branches appeared reticulated and cross-linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP-43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α-synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy.. STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super-resolution imaging of the human brain, with promising avenues to current challenges in neuroscience.

Topics: alpha-Synuclein; Alzheimer Disease; Brain; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Microscopy; Neurons; Parkinson Disease; tau Proteins

The olfactory bulb (OB) seems to be the first affected structure in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Lewy body dementia (LBD). Deposits of protein aggregates, increased dopaminergic neurons, and decreased cholinergic inputs have all been described in the OB of these diseases. We investigated here the contribution of the activated microglial cells to the increased deposits of protein aggregates. We quantified the number of activated microglial cells and astrocytes in the OB of patients with histological diagnosis of PD (n = 5), AD (n = 13), and LBD (n = 7) and aged-matched controls (n = 8). Specific consensus diagnostic criteria were applied for AD, LBD, and PD. Protein aggregates were scored in the OB as grade 0, none; grade 1, mild; grade 2, moderate; and grade 3, severe. OB sections from the 33 subjects were stained with specific antibodies markers for reactive astrocytes (GFAP) and microglial cells (Iba1 and HLA-DR). The total number of Iba1-ir (Iba-immunoreactive) and HLAD-DR cells was estimated by stereological analysis, while quantification of astrocytes was performed by GFAP optical density. Statistical analysis was done using the Stata 12.0 software. The number of microglia and activated microglia cells (HLA-RD-ir) was increased in patients with neurodegenerative diseases (p < 0.05). Moreover, the density of GFAP-ir cells was higher in the OB of patients. Neither the number of microglia cells nor the density of astrocytes correlated with the number of b-amyloid and alpha-synuclein deposits, but the density of Iba1-ir cells correlated with the number of p-Tau aggregates. Activated microglial cells and reactive astrocytes are present in the OB of patients with neurodegenerative diseases. The lack of correlation between the number of activated microglia cells and protein deposits indicate that they might independently contribute to the degenerative process. The presence of microglia is related to phosphorylated Tau deposits in neurodegenerative diseases.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Humans; Lewy Body Disease; Microglia; Neurodegenerative Diseases; Olfactory Bulb

Lewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson's disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach's plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner's plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Biological Specimen Banks; Central Nervous System; Cohort Studies; Esophagus; Female; Humans; Immunohistochemistry; Japan; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Myenteric Plexus; Peripheral Nervous System; Prevalence

Recent studies reported abnormal alpha-synuclein deposition in biopsy-accessible sites of the peripheral nervous system in Parkinson's disease (PD). This has considerable implications for clinical diagnosis. Moreover, if deposition occurs early, it may enable tissue diagnosis of prodromal PD.. The aim of this study was to develop and test an automated bright-field immunohistochemical assay of cutaneous pathological alpha-synuclein deposition in patients with idiopathic rapid eye movement sleep behavior disorder, PD, and atypical parkinsonism and in control subjects.. For assay development, postmortem skin biopsies were taken from 28 patients with autopsy-confirmed Lewy body disease and 23 control subjects. Biopsies were stained for pathological alpha-synuclein in automated stainers using a novel dual-immunohistochemical assay for serine 129-phosphorylated alpha-synuclein and pan-neuronal marker protein gene product 9.5. After validation, single 3-mm punch skin biopsies were taken from the cervical 8 paravertebral area from 79 subjects (28 idiopathic rapid eye movement sleep behavior disorder, 20 PD, 10 atypical parkinsonism, and 21 control subjects). Raters blinded to clinical diagnosis assessed the biopsies.. The immunohistochemistry assay differentiated alpha-synuclein pathology from nonpathological-appearing alpha-synuclein using combined phosphatase and protease treatments. Among autopsy samples, 26 of 28 Lewy body samples and none of the 23 controls were positive. Among living subjects, punch biopsies were positive in 23 (82%) subjects with idiopathic rapid eye movement sleep behavior disorder, 14 (70%) subjects with PD, 2 (20%) subjects with atypical parkinsonism, and none (0%) of the control subjects. After a 3-year follow-up, eight idiopathic rapid eye movement sleep behavior disorder subjects phenoconverted to defined neurodegenerative syndromes, in accordance with baseline biopsy results.. Even with a single 3-mm punch biopsy, there is considerable promise for using pathological alpha-synuclein deposition in skin to diagnose both clinical and prodromal PD. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Parkinson Disease; REM Sleep Behavior Disorder; Skin

Parkinson's disease (PD) is a neurodegenerative disorder caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Lewy bodies (LBs), another histological hallmark of PD, are observed in patients with familial or sporadic PD. The therapeutic potential of reducing the accumulation of α-synuclein, a major LB component, has been investigated, but it remains unknown whether the formation of LBs results in the loss of DA neurons. PARK4 patients exhibit multiplication of the α-synuclein gene (SNCA) without any pathological mutations, but their symptoms develop relatively early. Therefore, study of PARK4 might help elucidate the mechanism of α-synuclein aggregation. In this study, we investigated the dynamics of α-synuclein during the early stage of immature DA neurons, which were differentiated from human-induced pluripotent stem cells (hiPSCs) derived from either a PARK4 patient with SNCA triplication or a healthy donor. We observed increased α-synuclein accumulation in PARK4 hiPSC-derived DA neurons relative to those derived from healthy donor hiPSCs. Interestingly, α-synuclein accumulation disappeared over time in the PARK4 patient-derived DA neurons. Moreover, an SNCA-specific antisense oligonucleotide could reduce α-synuclein levels during the accumulation stage. These observations may help reveal the mechanisms that regulate α-synuclein levels, which may consequently be useful in the development of new therapies for patients with sporadic or familial PD.

Topics: alpha-Synuclein; Cell Differentiation; Cells, Cultured; DNA Copy Number Variations; Dopaminergic Neurons; Gene Duplication; Healthy Volunteers; Humans; Induced Pluripotent Stem Cells; Lewy Body Disease; Parkinson Disease; Primary Cell Culture

Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases.. Specificity and selectivity of [. [. MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties.

Topics: alpha-Synuclein; Animals; Carbon Radioisotopes; Lewy Body Disease; Mice; Neurodegenerative Diseases; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Tissue Distribution

We investigated α-synuclein's (αSyn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic αSyn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson's disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant αSyn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson's disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric αSyn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients ≥80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic αSyn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic αSyn in a particular region at a given neuropathological stage.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Brain Stem; Enteric Nervous System; Female; Formaldehyde; Humans; Lewy Body Disease; Male; Middle Aged; Neurites; Olfactory Bulb; Parkinson Disease; Protein Folding; Proteolysis; Tissue Fixation

Topics: alpha-Synuclein; Alzheimer Disease; Hippocampus; Humans; Lewy Body Disease; tau Proteins

Topics: alpha-Synuclein; Autonomic Nervous System; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy

Lewy-related pathology (LRP), primarily comprised of α-synuclein, is a typical neuropathological change that has been identified in many neurodegenerative disorders such as Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies.. To investigate the distribution of LRP in the China Human Brain Bank, the co-occurrence of neuropathologic features of Alzheimer's disease (AD) in LRP cases, and LRP-related cognitive dysfunction.. LRP neuropathological diagnosis was performed in 180 postmortem brains. AD neuropathological diagnosis was then performed in the 21 neuropathologically-diagnosed LRP cases. Antemortem cognitive functioning evaluation (Everyday Cognitive, ECog) was assessed for brain donors by the immediate kin of the donor within 24 hours after death.. 12% (21 in 180) postmortem brains were neuropathologically diagnosed as LRP cases. 86% (18 in 21) aged above 80, 81% (17 in 21) LRP cases combined with AD neuropathology, and 62% (13 in 21) combined with both the intermediate or high-level amyloid-β and phospho-tau pathologies. ECog scores showed significant differences between the groups of LRP brainstem-predominant type and LRP diffuse neocortical type, and between groups of AD and the combined LRP (diffuse neocortical type)-AD.. The overlap of neocortical α-synuclein, amyloid-β, phospho-tau, and neuritic plaques in LRP suggested the potential interplay among the common characteristics of proteinopathies in the late stage of neuropathological development of LRP in human brains. The anatomic progression of LRP, the process of α-synuclein spreading from the brainstem to limbic and neocortical regions, might aggravate the deterioration of cognitive function in addition to that effect of AD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Biological Specimen Banks; Brain Stem; China; Cognition; Disease Progression; Female; Humans; Lewy Body Disease; Limbic System; Male; Neocortex; Plaque, Amyloid; tau Proteins

Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration.. The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1-42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer's disease (AD) patients compared to healthy controls (HC).. By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1-42, tau, and their heteroaggregates (α-syn/Aβ1-42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson's disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60).. The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aβ1-42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80).. RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aβ1-42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Erythrocytes; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Parkinson Disease; tau Proteins

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Alzheimer Disease; Case-Control Studies; Gene Expression Profiling; Genetic Predisposition to Disease; Genome-Wide Association Study; Genome, Human; Glucosylceramidase; Humans; Lewy Body Disease; Nuclear Proteins; Parkinson Disease; Polymorphism, Single Nucleotide; Tumor Suppressor Proteins

Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy.. In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations.. 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177).. In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein.. Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.

Topics: Aged; alpha-Synuclein; Computer Systems; Disease Progression; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lewy Body Disease; Longitudinal Studies; Male; Middle Aged; Parkinson Disease; Polysomnography; Prodromal Symptoms; REM Sleep Behavior Disorder; Risk Assessment; Sensitivity and Specificity; Spinal Puncture

Many neurodegenerative diseases are associated with neuronal misfolded protein accumulation, indicating a need for proteostasis-promoting strategies. Here we show that de-repressing the transcription factor Nrf2, epigenetically shut-off in early neuronal development, can prevent protein aggregate accumulation. Using a paradigm of α-synuclein accumulation and clearance, we find that the classical electrophilic Nrf2 activator tBHQ promotes endogenous Nrf2-dependent α-synuclein clearance in astrocytes, but not cortical neurons, which mount no Nrf2-dependent transcriptional response. Moreover, due to neuronal Nrf2 shut-off and consequent weak antioxidant defences, electrophilic tBHQ actually induces oxidative neurotoxicity, via Nrf2-independent Jun induction. However, we find that epigenetic de-repression of neuronal Nrf2 enables them to respond to Nrf2 activators to drive α-synuclein clearance. Moreover, activation of neuronal Nrf2 expression using gRNA-targeted dCas9-based transcriptional activation complexes is sufficient to trigger Nrf2-dependent α-synuclein clearance. Thus, targeting reversal of the developmental shut-off of Nrf2 in forebrain neurons may alter neurodegenerative disease trajectory by boosting proteostasis.

Topics: alpha-Synuclein; Animals; Astrocytes; Cell Death; Cells, Cultured; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Epigenetic Repression; Female; Gene Targeting; Hydroquinones; Lewy Body Disease; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Prosencephalon; Proteostasis

α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations. Here, we develop a quantitative real-time quaking-induced conversion (qRT-QuIC) assay to measure permissive α-synuclein fibril-templating activity in tissues and cerebrospinal fluid (CSF). The assay is anchored through reference panels of stabilized ultra-short fibril particles. In humanized α-synuclein transgenic mice, qRT-QuIC identifies differential levels of fibril activity across the brain months before the deposition of phosphorylated α-synuclein in susceptible neurons. α-Synuclein fibril activity in cortical brain extracts from dementia with Lewy bodies (DLB) correlates with activity in matched ventricular CSF. Elevated α-synuclein fibril activity in CSF corresponds to reduced survival in DLB. α-Synuclein fibril particles amplified from cases with high fibril activity show superior templating in the formation of new inclusions in neurons relative to the same number of fibril particles amplified from DLB cases with low fibril activity. Our results highlight a previously unknown broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes. We predict that quantitative assessments of fibril activities in CSF that correlate to fibril activities in brain tissue will help stratify patient populations as well as measure therapeutic responses to facilitate the development of α-synuclein-targeted therapeutics.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Chemistry Techniques, Analytical; Female; Humans; Lewy Body Disease; Male; Mice; Middle Aged; Phenotype

As an established treatment for movement disorders, deep brain stimulation (DBS) has been adapted for the treatment of Alzheimer's disease (AD) by modulating fornix activity. Although it is generally regarded as a safe intervention in patients over 65 years of age, the complex neurophysiology and interconnection within circuits connected to the fornix warrants a careful ongoing evaluation of the true benefit and risk potential of DBS on slowing cognitive decline in AD patients. Here we report on a patient who died long after being implanted with a DBS device who donated her brain for neuropathologic study. The autopsy confirmed multiple proteinopathies including AD-related change, diffuse neocortical Lewy body disease, TDP-43 proteinopathy, and a nonspecific tauopathy. We discuss the possible mechanisms of these overlapping neurodegenerative disorders and caution that future studies of DBS for AD will need to take these findings into consideration.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Deep Brain Stimulation; Female; Humans; Lewy Body Disease; Tauopathies; TDP-43 Proteinopathies

Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson's disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Brain; Disease Models, Animal; Female; Humans; Lewy Body Disease; Liver; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Parkinson Disease; Synucleinopathies

Definitive diagnosis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSyn

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; High-Throughput Screening Assays; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Sensitivity and Specificity

To determine whether (1) immunofluorescence is a reproducible technique in detecting misfolded α-synuclein in skin nerves and subsequently whether (2) immunofluorescence and real-time quaking-induced conversion (RT-QuIC) (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguishing synucleinopathies from non-synucleinopathies in a large cohort of patients.. We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all synucleinopathies variants and non-synucleinopathies (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for immunofluorescence and RT-QuIC; CSF was examined in patients who underwent lumbar puncture for diagnostic purposes. Immunofluorescence and RT-QuIC analysis were made blinded to the clinical diagnosis.. Immunofluorescence showed reproducible results between 2 pairs of neighboring skin samples. Both immunofluorescence and RT-QuIC showed high sensitivity and specificity in discriminating synucleinopathies from non-synucleinopathies and controls but immunofluorescence presented higher diagnostic accuracy. Immunofluorescence presented a good level of agreement with RT-QuIC in both skin and CSF in synucleinopathies.. Both immunofluorescence and RT-QuIC showed high diagnostic accuracy, although immunofluorescence displayed the better value as well as optimal reproducibility; they presented a good level of agreement in synucleinopathies, supporting the use of less invasive tests such as skin immunofluorescence or RT-QuIC instead of CSF RT-QuIC as a diagnostic tool for synucleinopathies.. This study provides Class III evidence that immunofluorescence or RT-QuIC accurately distinguish synucleinopathies from non-synucleinopathies.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Female; Fluorescent Antibody Technique; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Parkinson Disease, Secondary; Peripheral Nerves; Protein Aggregates; Reproducibility of Results; Sensitivity and Specificity; Skin; Supranuclear Palsy, Progressive; Synucleinopathies; Tauopathies; TDP-43 Proteinopathies

To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA).. Well-characterized patients with PAF (n = 32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline.. Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters. ASyn-PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA.. αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212-1220.

Topics: Aged; alpha-Synuclein; Biomarkers; Disease Progression; Female; Humans; Lewy Body Disease; Longitudinal Studies; Male; Middle Aged; Multiple System Atrophy; Neurofilament Proteins; Parkinson Disease; Prospective Studies; Pure Autonomic Failure

Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017.. Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients.. Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Topics: Aged; alpha-Synuclein; Disease Progression; Female; Follow-Up Studies; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Peripheral Nerves; Prodromal Symptoms; REM Sleep Behavior Disorder; Skin

Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases.. We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer's disease (AD) and cognitively healthy people.. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-β (Aβ)42, Aβ40, Aβ38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOEɛ4 carrier status.. Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOEɛ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOEɛ4 carriers) and 27 controls (78.48±8.7 years old, four APOEɛ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOEɛ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis.. Biomarker ratios were superior to Aβ and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOEɛ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognition; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Peptide Fragments; Phosphorylation; tau Proteins

Growing evidence suggests a shared pathogenesis between Parkinson's disease and diabetes although the underlying mechanisms remain unknown. The aim of this study was to evaluate the effect of type 2 diabetes on Parkinson's disease progression and to correlate neuropathological findings to elucidate pathogenic mechanisms.. In this cohort study, medical records were retrospectively reviewed of cases with pathologically confirmed Parkinson's disease with and without pre-existing type 2 diabetes. Time to disability milestones (recurrent falls, wheelchair dependence, dementia and care home placement) and survival were compared to assess disease progression and their risk estimated using Cox hazard regression models. Correlation with pathological data was performed, including quantification of α-synuclein in key brain regions and staging of vascular, Lewy and Alzheimer's pathologies.. Patients with PD and diabetes (male 76%; age at death 78.6 ± 6.2 years) developed earlier falls (p < 0.001), wheelchair dependence (p = 0.004), dementia (p < 0.001), care home admission (p < 0.001) and had reduced survival (p < 0.001). Predating diabetes was independently associated with a two to three-fold increase in the risk of disability and death. Neuropathological assessment did not show any differences in global or regional vascular pathology, α-synuclein load in key brain areas, staging of Lewy pathology or Alzheimer's disease pathology.. Pre-existing type 2 diabetes contributes to faster disease progression and reduced survival in Parkinson's disease which is not driven by increased vascular, Lewy or Alzheimer's pathologies. Additional non-specific neurodegeneration related to chronic brain insulin resistance may be involved.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Diabetes Mellitus, Type 2; Humans; Lewy Body Disease; Male; Parkinson Disease; tau Proteins

Evidence suggests that skin represents a suitable matrix for demonstrating α-synuclein oligomers as a diagnostic biomarker for Lewy body disease.. The objective of this study was to evaluate the diagnostic performance of skin α-syn real-time quaking-induced conversion assay in patients with Lewy body disease.. We analyzed skin punches taken in vitam (n = 69) or postmortem (n = 49) from patients with PD, dementia with Lew bodies (DLB), incidental Lewy body pathology, and neurological controls. Seventy-nine patients underwent both CSF and skin α-synuclein real-time quaking-induced conversion assay.. Overall, the skin α-synuclein real-time quaking-induced conversion assay distinguished Lewy body disease patients with 94.1% accuracy (sensitivity, 89.2%; specificity, 96.3%). Assay sensitivity reached 94.1% in the 17 Lewy body disease patients analyzed in the cervical region. In patients with both CSF and skin samples, the 2 real-time quaking-induced conversion assay protocols yielded similar diagnostic accuracy (skin, 97.5%; CSF, 98.7%).. Skin punch biopsies might represent a valid and convenient alternative to CSF analysis to demonstrate Lew body-related α-synuclein deposition in patients with Lewy body disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Autopsy; Biomarkers; Humans; Lewy Body Disease; Skin

Extrapyramidal symptoms (EP) are not uncommon in Alzheimer's Disease (AD); when present, they negatively influence the course of the disorder. A large proportion of AD patients shows concomitant Lewy bodies' pathology post mortem. Total α Synuclein (αSyn) concentrations are frequently increased in the cerebrospinal fluid (CSF) of AD patients, but are decreased in Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn CSF concentrations in AD patients with EP (EP+) have not been reported so far. αSyn and the four Neurochemical Dementia Diagnostics (NDD) CSF biomarkers, (Aβ1-42, Aβ42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm, were measured in patients with positive NDD results and presence of extrapyramidal symptoms (NDD + / EP+; n = 26), in patients with positive NDD results and absence of extrapyramidal symptoms (NDD+ / EP-; n = 54), and in subjects with negative NDD results (NDD-; n = 34). Compared to the NDD- controls (379.8 ± 125.2 pg/mL), NDD+ patients showed, on average, highly significantly increased CSF αSyn (519 ± 141.3 pg/mL, p < 0.01), but without differences between NDD+ / EP+ and NDD+ / EP- subgroups (p = 0. 38). Moderate but highly significant association was observed between concentrations of αSyn and Tau (r = 0.47, p < 0.01) and pTau181 (r = 0.65, p < 0.01). Adjusted for diagnoses, age, and sex, subjects with more advanced neurodegeneration on neuroimaging showed significantly lower αSyn concentrations (p < 0.02). In the setting AD versus controls, the area under the receiver operating characteristic (ROC) curve was 0.804 [0.712; 0.896] with the sensitivity and the specificity of 0.863 and 0.618, respectively. αSyn in AD patients does not differentiate between subjects with- and without EP. Its increased average concentration reflects probably neurodegenerative process, and is not specific for any pathophysiologic mechanisms. Further studies are necessary to explain the role of CSF αSyn as a potential biomarker.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease; Peptide Fragments; tau Proteins

Aggregated α-synuclein (αSyn) protein is a core pathological feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Both PD and DLB demonstrate the presence of diverse intracellular α-synuclein (αSyn) species, including C-terminally truncated αSyn (C-αSyn), although it is unknown how C-αSyn species contribute to disease progression. Using recombinant C-αSyn and PD and DLB brain lysates as seeds in the real-time quaking-induced conversion (RT-QuIC) assay, we explored how C-αSyn may be involved in disease stratification. Comparing the seeding activity of aqueous-soluble fractions to detergent-soluble fractions, and using αSyn 1-130 as substrate for the RT-QuIC assay, the temporal cortex seeds differentiated PD and DLB from healthy controls. In contrast to the temporal cortex, where PD and DLB could not be distinguished, αSyn 1-130 seeded by the detergent-soluble fractions from the PD frontal cortex demonstrated greater seeding efficiency compared to the DLB frontal cortex. Moreover, proteinase K-resistant (PK

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; Protein Aggregates

Amyloid β (Aβ), a product of APP, and SNCA (α-synuclein (α-syn)) are two of the key proteins found in lesions associated with the age-related neurodegenerative disorders Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. Previous clinical studies uncovered Aβ and α-syn co-expression in the brains of patients, which lead to Lewy body dementia (LBD), a disease encompassing Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). To explore the pathogenesis and define the relationship between Aβ and α-syn for LBD, we established a C. elegans model which co-expresses human Aβ and α-syn with alanine 53 to threonine mutant (α-syn(A53T)) in pan-neurons. Compared to α-syn(A53T) single transgenic animals, pan-neuronal Aβ and α-syn(A53T) co-expression further enhanced the thrashing, egg laying, serotonin and cholinergic signaling deficits, and dopaminergic neuron damage in C. elegans. In addition, Aβ increased α-syn expression in transgenic animals. Transcriptome analysis of both Aβ;α-syn(A53T) strains and DLB patients showed common downregulation in lipid metabolism and lysosome function genes, suggesting that a decrease of lysosome function may reduce the clearance ability in DLB, and this may lead to the further pathogenic protein accumulation. These findings suggest that our model can recapitulate some features in LBD and provides a mechanism by which Aβ may exacerbate α-syn pathogenesis.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Brain; Caenorhabditis elegans; Humans; Lewy Body Disease; Lipid Metabolism; Lysosomes; Middle Aged; Neurons; Parkinson Disease; Transcriptome

Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson's disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla.. We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD.. Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology.. Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive.. As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.

Topics: Aged; alpha-Synuclein; Humans; Lewy Body Disease; Parkinson Disease; Stomach; Synucleinopathies; Vagus Nerve

Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids.. The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis.. We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories.. (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile.. CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Autophagy; Biomarkers; Glucosylceramidase; Humans; Lewy Body Disease; Neuronal Plasticity; Neurotransmitter Agents; Parkinson Disease

To investigate whether the CSF α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment (MCI) due to probable Lewy body (LB) disease.. We applied α-syn RT-QuIC to 289 CSF samples obtained from 2 independent cohorts, including 81 patients with probable MCI-LB (age 70.7 ± 6.6 years, 13.6% female, Mini-Mental State Examination [MMSE] score 26.1 ± 2.4), 120 with probable MCI due to Alzheimer disease (AD) (age 68.6 ± 7.4 years, 45.8% female, MMSE score 25.5 ± 2.8), and 30 with unspecified MCI (age 65.4 ± 9.3 years, 30.0% female, MMSE score 27.0 ± 3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathologic examination were used as controls.. RT-QuIC identified patients with MCI-LB against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy and showed 98% specificity in neuropathologic controls. The accuracy of the test for MCI-LB was consistent between the 2 cohorts (97.3% vs 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed 1 core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB copathology.. These findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB.. This study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI-LB.

Topics: Aged; alpha-Synuclein; Biomarkers; Cognitive Dysfunction; Early Diagnosis; Female; Fluorescent Antibody Technique; Humans; Lewy Body Disease; Male; Middle Aged

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain Cortical Thickness; CA1 Region, Hippocampal; Case-Control Studies; DNA-Binding Proteins; Entorhinal Cortex; Female; Frontotemporal Lobar Degeneration; Hippocampus; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neurodegenerative Diseases; Neurofibrillary Tangles; Parahippocampal Gyrus; Pick Disease of the Brain; Plaque, Amyloid; Supranuclear Palsy, Progressive; tau Proteins; Temporal Lobe

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may-in analogy to pGlu-Aβ peptides in Alzheimer's disease-act as a seed for pathogenic protein aggregation.

Topics: alpha-Synuclein; Aminoacyltransferases; Animals; Brain; Cell Survival; Chromatography, Gel; Dopaminergic Neurons; Glutamine; Humans; Kinetics; Lewy Body Disease; Mice; Mice, Transgenic; Parkinson Disease; Protein Processing, Post-Translational; Sambucus nigra; Synucleinopathies

α-Synuclein oligomers are thought to play an important role in the pathogenesis of dementia with Lewy bodies (DLB). There is no effective cure for DLB at present. Previously, we demonstrated that in APP- and tau-transgenic mice, oral or intranasal rifampicin reduced brain Aβ and tau oligomers and improved mouse cognition. In the present study, we expanded our research to DLB. Rifampicin was intranasally administered to 6-month-old A53T-mutant α-synuclein-transgenic mice at 0.1 mg/day for 1 month. The mice displayed memory impairment but no motor deficit at this age, indicating a suitable model of DLB. α-Synuclein pathologies were examined by the immunohistochemical/biochemical analyses of brain tissues. Cognitive function was evaluated by the Morris water maze test. Intranasal rifampicin significantly reduced the levels of [pSer129] α-synuclein in the hippocampus and α-synuclein oligomers in the visual cortex and hippocampus. The level of the presynaptic marker synaptophysin in the hippocampus was recovered to the level in non-transgenic littermates. In the Morris water maze, a significant improvement in spatial reference memory was observed in rifampicin-treated mice. Taken together with our previous findings, these results suggest that intranasal rifampicin is a promising remedy for the prevention of neurodegenerative dementia, including Alzheimer's disease, frontotemporal dementia, and DLB.

Topics: Administration, Intranasal; alpha-Synuclein; Animals; Cognition; Dementia; Disease Models, Animal; Female; Lewy Bodies; Lewy Body Disease; Male; Mice, Transgenic; Protein Multimerization; Rifampin

Synucleinopathies, including Parkinson's disease (PD), Lewy body dementia (LBD), Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB), and multiple system atrophy (MSA) comprise a spectrum of neurodegenerative disorders characterized by the presence of distinct pathological α-synuclein (αSyn) inclusions. Experimental and pathological studies support the notion that αSyn aggregates contribute to cellular demise and dysfunction with disease progression associated with a prion-like spread of αSyn aggregates via conformational templating. The initiating event(s) and factors that contribute to diverse forms of synucleinopathies remain poorly understood. A major post-translational modification of αSyn associated with pathological inclusions is a diverse array of specific truncations within the carboxy terminal region. While these modifications have been shown experimentally to induce and promote αSyn aggregation, little is known about their disease-, region- and cell type specific distribution. To this end, we generated a series of monoclonal antibodies specific to neo-epitopes in αSyn truncated after residues 103, 115, 119, 122, 125, and 129. Immunocytochemical investigations using these new tools revealed striking differences in the αSyn truncation pattern between different synucleinopathies, brain regions and specific cellular populations. In LBD, neuronal inclusions in the substantia nigra and amygdala were positive for αSyn cleaved after residues 103, 119, 122, and 125, but not 115. In contrast, in the same patients' brain αSyn cleaved at residue 115, as well as 103, 119 and 122 were abundant in the dorsal motor nucleus of the vagus. In patients with AD/ALB, these modifications were only weakly or not detected in amygdala αSyn inclusions. αSyn truncated at residues 103, 115, 119, and 125 was readily present in MSA glial cytoplasmic inclusions, but 122 cleaved αSyn was only weakly or not present. Conversely, MSA neuronal pathology in the pontine nuclei was strongly reactive to the αSyn x-122 neo-epitope but did not display any reactivity for αSyn 103 cleavage. These studies demonstrate significant disease-, region- and cell type specific differences in carboxy terminal αSyn processing associated with pathological inclusions that likely contributes to their distinct strain-like prion properties and promotes the diversity displayed in the degrees of these insidious diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amygdala; Antibodies, Monoclonal; Epitopes; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Synucleinopathies; Temporal Lobe

Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstra

Topics: Age of Onset; alpha-Synuclein; Case-Control Studies; Cathepsin B; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Glucosylceramidase; Humans; Induced Pluripotent Stem Cells; Lewy Body Disease; Neurogenesis; Neurons; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide; Risk Factors; RNA, Messenger; Whole Genome Sequencing

Identification of a peripheral biomarker is a major roadblock in the diagnosis of PD. Immunohistological identification of p-serine 129 α-synuclein in the submandibular gland tissues of PD patients has been recently reported.. We report on a proof-of-principle study for using an ultra-sensitive and specific, real-time quaking-induced conversion assay to detect pathological α-synuclein in the submandibular gland tissues of PD patients.. The α-synuclein real-time quaking-induced conversion assay was used to detect and quantify pathological α-synuclein levels in PD, incidental Lewy body disease, and control submandibular gland tissues as well as in formalin-fixed paraffin-embedded sections.. We determined the quantitative seeding kinetics of pathological α-synuclein present in submandibular gland tissues from autopsied subjects using the α-synuclein real-time quaking-induced conversion assay. A total of 32 cases comprising 13 PD, 3 incidental Lewy body disease, and 16 controls showed 100% sensitivity and 94% specificity. Interestingly, both PD and incidental Lewy body disease tissues showed 100% concordance for elevated levels of pathological α-synuclein seeding activity compared to control tissues. End-point dilution kinetic analyses revealed that the submandibular gland had a wide dynamic range of pathological α-synuclein seeding activity.. Our results are the first to demonstrate the utility of using the real-time quaking-induced conversion assay on peripherally accessible submandibular gland tissues and formalin-fixed paraffin-embedded tissue sections to detect PD-related pathological changes with high sensitivity and specificity. Additionally, the detection of seeding activity from incidental Lewy body disease cases containing immunohistochemically undetected pathological α-synuclein demonstrates the α-synuclein real-time quaking-induced conversion assay's potential utility for identifying prodromal PD in submandibular gland tissues. © 2019 International Parkinson and Movement Disorder Society.

Topics: Aged; alpha-Synuclein; Autopsy; Biomarkers; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Parkinsonian Disorders; Submandibular Gland

Studies have shown an overlap of Aβ plaques, tau tangles, and α-synuclein (α-syn) pathologies in the brains of Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia (PDD) patients, with increased pathological burden correlating with severity of cognitive and motor symptoms. Despite the observed co-pathology and concomitance of motor and cognitive phenotypes, the consequences of the primary amyloidogenic protein on the secondary pathologies remain poorly understood. To better define the relationship between α-syn and Aβ plaques, we injected α-syn preformed fibrils (α-syn mpffs) into mice with abundant Aβ plaques. Aβ deposits dramatically accelerated α-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected 5xFAD mice. Finally, α-syn mpff-injected 5xFAD mice showed neuron loss that correlated with the progressive decline of cognitive and motor performance. Our findings suggest a "feed-forward" mechanism whereby Aβ plaques enhance endogenous α-syn seeding and spreading over time post-injection with mpffs.

Topics: alpha-Synuclein; Animals; Brain; Cell Count; Cognitive Dysfunction; Humans; Lewy Body Disease; Mice; Motor Activity; Neurons; Phosphorylation; Plaque, Amyloid; tau Proteins

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic α-synuclein and show potent inhibition of pathology seeding in a neuronal model of α-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of α-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of α-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of α-synuclein antibodies to identify those with preferred properties.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Cells, Cultured; Dose-Response Relationship, Immunologic; Female; Humans; Immunotherapy; Lewy Body Disease; Male; Mice; Mice, Inbred BALB C; Parkinson Disease

Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.

Topics: alpha-Synuclein; Animals; Astrocytes; Cerebral Cortex; Disease Susceptibility; Genetic Predisposition to Disease; Glucosylceramidase; HEK293 Cells; Hippocampus; Humans; Lewy Body Disease; Mesencephalon; Mice; Mice, Transgenic; Neurons; Parkinson Disease; Parkinsonian Disorders; Primary Cell Culture; Protein Aggregation, Pathological; Synucleinopathies

The pathological hallmark of synucleinopathies, including Lewy body dementia and Parkinson's disease (PD), is the presence of Lewy bodies, which are primarily composed of intracellular inclusions of misfolded α-synuclein (α-syn) among other proteins. α-Syn is found in extracellular biological fluids in PD patients and has been implicated in modulating immune responses in the central nervous system (CNS) and the periphery. Natural killer (NK) cells are innate effector lymphocytes that are present in the CNS in homeostatic and pathological conditions. NK cell numbers are increased in the blood of PD patients and their activity is associated with disease severity; however, the role of NK cells in the context of α-synucleinopathies has never been explored. Here, we show that human NK cells can efficiently internalize and degrade α-syn aggregates via the endosomal/lysosomal pathway. We demonstrate that α-syn aggregates attenuate NK cell cytotoxicity in a dose-dependent manner and decrease the release of the proinflammatory cytokine, IFN-γ. To address the role of NK cells in PD pathogenesis, NK cell function was investigated in a preformed fibril α-syn-induced mouse PD model. Our studies demonstrate that in vivo depletion of NK cells in a preclinical mouse PD model resulted in exacerbated motor deficits and increased phosphorylated α-syn deposits. Collectively, our data provide a role of NK cells in modulating synuclein pathology and motor symptoms in a preclinical mouse model of PD, which could be developed into a therapeutic for PD and other synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Central Nervous System; Cytokines; Disease Models, Animal; Female; Killer Cells, Natural; Lewy Bodies; Lewy Body Disease; Lysosomes; Male; Mice; Mice, Transgenic; Parkinson Disease; Synucleinopathies; Synucleins

Neurodegenerative diseases like Alzheimer's disease and Parkinson's disease are characterized pathologically by aberrant protein accumulation, such as Aβ or α-synuclein deposition. In this issue of Neuron, Bassil et al. (2020) observed an exacerbation of α-syn pathology in the presence of Aβ plaques in vivo, with comorbid pathologies associated with greater neurodegeneration.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Lewy Bodies; Lewy Body Disease; Mice; Plaque, Amyloid

Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.. Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.. A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.. There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

Topics: Adult; Aged; alpha-Synuclein; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Lewy Body Disease; Logistic Models; Male; Middle Aged; Odds Ratio; Parkinson Disease; Polymorphism, Single Nucleotide; Prodromal Symptoms; REM Sleep Behavior Disorder; Synucleinopathies

Aggregation of α-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson's disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

Topics: alpha-Synuclein; Amino Acid Motifs; Cryoelectron Microscopy; Humans; Lewy Body Disease; Mutation, Missense; Parkinson Disease; Protein Folding

Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cognitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, α-synuclein, collagen IV) and neuropathological staging were performed on 100-µm sections. Tissue from the enteric or peripheral nervous system was unavailable. As controls, a second cognitively unimpaired 50-year-old male FD patient without LP or motor symptoms and 3 age-matched individuals were examined. Inclusion body pathology was semiquantitatively evaluated. Although Lewy neurites/bodies were not present in the 50-year-old individual or in controls, severe neuronal loss in the substantia nigra pars compacta and LP corresponding to neuropathological stage 4 of Parkinson disease was seen in the 58-year-old FD patient. Major cerebrovascular lesions and/or additional pathologies were absent in this individual. We conclude that Lewy body disease with parkinsonism can occur within the context of FD. Further studies determining the frequencies of both inclusion pathologies in large autopsy-controlled FD cohorts could help clarify the implications of both lesions for disease pathogenesis, potential spreading mechanisms, and therapeutic interventions.

Topics: alpha-Synuclein; Astrocytes; Brain; Fabry Disease; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurons; Trihexosylceramides

The apolipoprotein E (

Topics: alpha-Synuclein; Amyloid beta-Peptides; Animals; Apolipoprotein E4; Lewy Body Disease; Mice; Mice, Knockout, ApoE; Synucleinopathies

REM sleep behavior disorder (RBD) can progress to Parkinson's disease, Lewy body dementia, or multiple system atrophy within 20 years of onset. Accurate diagnosis of RBD is therefore important for early intervention. The development of markers that can more sensitively evaluate the effects of high-risk groups or candidate therapies that develop α-synucleinopathy in the short term is the key to a successful clinical trial. Clinical protocols for early diagnosis of α-synucleinopathy are currently being developed. The next stage will be to conduct clinical trials for candidate therapies.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; REM Sleep Behavior Disorder; Synucleinopathies

Although α-synuclein protein (αS) undergoes aggregation from a monomer to assemblies, such as oligomers, protofibrils, and mature fibrils, the early intermediate aggregates, that is, oligomers, are considered to be the most toxic species in the pathogenesis of α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While it has been reported that the αS concentration in cerebrospinal fluid (CSF) is decreased significantly in patients with PD and DLB, there have been reports of the αS oligomer concentration being elevated in the CSF of patients with PD. Moreover, it is supposed that the αS oligomer concentration is also elevated in the blood of patients with PD. Recently, it has been reported that lower cerebrospinal β-amyloid (Aβ)1-40, Aβ1-42, and αS levels are associated with cognitive decline in PD. Further combination studies of the CSF and blood may lead to the establishment of the candidate αS as a biomarker for α-synucleinopathies, including PD and DLB.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease

RT-QuIC is a shaking-based cyclic amplification technique originally developed in the prion field to detect minute amounts of scrapie prion protein (PrP

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Biological Assay; Brain; Disease Models, Animal; Humans; Lewy Body Disease; Mice, Transgenic; Middle Aged; Mutation; Synucleinopathies

Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.

Topics: Acetates; alpha-Synuclein; Animals; Cyclopropanes; Disease Models, Animal; Female; Humans; Leukotriene Antagonists; Lewy Body Disease; Memory; Memory Disorders; Mice; Mice, Transgenic; Quinolines; Receptors, Leukotriene; Sulfides

This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD).. We included 61 patients [49 with idiopathic Parkinson's disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls. All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student's t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue.. Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test. Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes, systolic blood pressure during the Valsalva maneuver predicting apathy and depression. The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory).. Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.

Topics: Aged; alpha-Synuclein; Apathy; Autonomic Nervous System Diseases; Blood Pressure; Cognitive Dysfunction; Depression; Fatigue; Female; Heart Rate; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease

α-Synuclein is a naturally unfolded protein which easily aggregates and forms toxic inclusions and deposits. It is associated with several neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). These diseases, called synucleinopathies, have overlapping symptoms but require different methods of treatment. There are no reliable approaches for early diagnoses of these diseases, and as a result, the treatment begins late, and the disorders are often misdiagnosed. Recent studies revealed that α-synuclein forms distinctive spatial structures or strains at the early steps of these diseases, which may be used for early diagnosis. One of these early diagnostic methods called PMCA (protein misfolding cyclic amplification) allows identification of the distinct α-synuclein strains specific for different human diseases. The method is successfully used for differential diagnosis of patients with PD and MSA.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Early Diagnosis; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Conformation; Protein Folding; Synucleinopathies

Aggregation of the protein α-synuclein (α-syn) into insoluble intracellular assemblies termed Lewy bodies (LBs) is thought to be a critical pathogenic event in LB diseases such as Parkinson's disease and dementia with LBs. In LB diseases, the majority of α-syn is phosphorylated at serine 129 (pS129), suggesting that this is an important disease-related post-translational modification (PTM). However, PTMs do not typically occur in isolation and phosphorylation at the proximal tyrosine 125 (pY125) residue has received considerable attention and has been inconsistently reported to be present in LBs. Furthermore, the proximity of Y125 to S129 means that some pS129 antibodies may have epitopes that include Y125, in which case phosphorylation of Y125 will impede recognition of α-syn. This would potentially lead to underestimating LB pathology burdens if pY125 occurs alongside pS129. To address the apparent controversy in the literature regarding the detection of pY125, we investigated its presence in the LB pathology. We generated pS129 antibodies whose epitope includes or does not include Y125 and compared the extent of α-syn pathology recognized in mouse models of α-synucleinopathies, human brain tissue lysates and fixed post-mortem brain tissues. Our study demonstrated no difference in α-syn pathology recognized between pS129 antibodies, irrespective of whether Y125 was part of the epitope or not. Furthermore, evaluation with pY125 antibodies whose epitope does not include S129 demonstrated no labeling of LB pathology. This study reconciles disparate results in the literature and demonstrates pY125 is not a key component of LB pathology in murine models or human tissues in idiopathic LB diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Female; Humans; Lewy Body Disease; Male; Mice; Phosphorylation; Protein Processing, Post-Translational; Serine; Tyrosine

The clinical diagnosis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Sensitivity and Specificity; Spectrometry, Fluorescence; Synucleinopathies

Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Dementia; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease

Synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibody-based immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative disease-relevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; Protein Aggregates; Protein Binding; Single-Chain Antibodies

α-Synuclein (α-syn) is a major component of Lewy bodies, a pathologic marker of Parkinson's disease (PD) in post-mortem studies. The use of α-syn as a practical PD biomarker has been investigated by numerous researchers. However, reports of differences in α-syn levels in biofluids, such as cerebrospinal fluid, plasma, and saliva, between PD patients and controls are inconsistent. Recently, the measurement of α-syn oligomer levels has emerged as a novel approach to diagnose PD.. Lysates and culture media from two different types of dopaminergic neuronal cells or urine samples from 11 non-PD and 21 PD patients were collected and analyzed.. We developed and performed an enzyme-linked immuno-absorbent assay (ELISA) to detect various oligomeric α-syn using distinct pairs of antibodies.. We validated our ELISA using rotenone-induced alterations of α-syn levels in human dopaminergic neurons. Total urinary α-syn levels, measured using our ELISA method, showed no difference between PD and non-PD individuals, but a higher level of α-syn oligomer recognized by MJFR-14-6-5-2 in PD urine samples was observed. Levels of distinct oligomeric α-syn detected by ASyO5 were lower in PD urine samples. Three different α-syn ELISA results were analyzed with respect to the severity of PD, but only the correlation between total α-syn levels and PD index was significant.. Our findings suggest that detection of distinct oligomeric formations of α-syn and measurement of their levels in urine might be feasible for use in PD diagnostics.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease; Saliva; Sensitivity and Specificity

Several studies have proposed a role for infections to induce an inflammatory response triggering Parkinson's disease. This remains controversial and the influence of severe infections on other α-synucleinopathies (Dementia with Lewy Bodies, Parkinson's disease dementia, and Multiple System Atrophy) has not been adequately investigated.. To assess the association between hospitalization-required infections or sepsis and risk of clinically diagnosed α-synucleinopathies.. Using the medical records-linkage system (Rochester Epidemiology Project), we identified all α-synucleinopathy cases of in Olmsted County (1991-2010). Cases were matched by symptom-onset age and sex to controls. We reviewed complete medical records to detect hospital-required infections or sepsis preceding clinical-motor onset of α-synucleinopathies. We used conditional logistic regression to calculate the odds ratio of all α-synucleinopathies, adjusting for medications, coffee, and smoking.. There was no association between infection-related hospitalization (odds ratio: 1.05; 95% confidence interval: 0.78-1.40; P = 0.76) or sepsis (odds ratio: 0.86; 95% confidence interval: 0.40-1.85; P = 0.70) and all α-synucleinopathies in multivariable analyses. We did not identify any associations after stratifying for type of α-synucleinopathy, sex, and age at clinical-motor onset. We analyzed sepsis separately with similar results.. We did not observe any associations between infections leading to hospitalization or sepsis and development of any α-synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Case-Control Studies; Humans; Lewy Body Disease; Minnesota; Sepsis; Synucleinopathies

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Disease Models, Animal; DNA-Binding Proteins; Dopaminergic Neurons; Gene Knockout Techniques; Humans; Lewy Body Disease; Locomotion; Longevity; Protein Aggregation, Pathological; RNA-Binding Proteins

To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as markers of early multiple system atrophy (MSA) and to contrast findings with Lewy body synucleinopathies.. In a discovery cohort of well-characterized early MSA patients (n = 24) and matched healthy controls (CON, n = 14), we utilized enzyme-linked immunosorbent assay to measure NFL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF. We confirmed findings in a separate prospectively enrolled cohort of patients with early MSA (n = 38), Parkinson disease (PD, n = 16), and dementia with Lewy bodies (DLB, n = 13), and CON subjects (n = 15).. In the discovery cohort, NFL was markedly elevated in MSA patients, with perfect separation from CON. αSyn-PMCA was nonreactive in all CON, whereas all MSA samples were positive. In the confirmatory cohort, NFL again perfectly separated MSA from CON, and was significantly lower in PD and DLB compared to MSA. PMCA was again nonreactive in all CON, and positive in all but 2 MSA cases. All PD and all but 2 DLB samples were also positive for αSyn aggregates but with markedly different reaction kinetics from MSA; aggregation occurred later, but maximum fluorescence was higher, allowing for perfect separation of reactive samples between MSA and Lewy body synucleinopathies.. NFL and αSyn oligomers in CSF faithfully differentiate early MSA not only from CON but also from Lewy body synucleinopathies. The findings support the role of these markers as diagnostic biomarkers, and have important implications for understanding pathophysiologic mechanisms underlying the synucleinopathies. ANN NEUROL 2020;88:503-512.

Topics: Aged; alpha-Synuclein; Biomarkers; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Neurofilament Proteins; Parkinson Disease

To determine whether Lewy body disease subgroups have different clinical profiles.. Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder.. In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles.. The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.

Topics: Age of Onset; Aged; Aged, 80 and over; alpha-Synuclein; Attention; Cognition; Disease Progression; Female; Humans; Lewy Body Disease; Male; Memory; Middle Aged; Neocortex; Neurofibrillary Tangles; Psychomotor Performance; Sensitivity and Specificity; tau Proteins

α-Synuclein (α-syn) is a pre-synaptic protein which progressively accumulates in neuronal and non-neuronal cells in neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Recent evidence suggests that aberrant immune activation may be involved in neurodegeneration in PD/DLB. While previous studies have often focused on the microglial responses, less is known about the role of the peripheral immune system in these disorders.. To understand the involvement of the peripheral immune system in PD/DLB, we evaluated T cell populations in the brains of α-syn transgenic (tg) mice (e.g., Thy1 promoter line 61) and DLB patients.. Immunohistochemical analysis showed perivascular and parenchymal infiltration by CD3+/CD4+ helper T cells, but not cytotoxic T cells (CD3+/CD8+) or B cells (CD20+), in the neocortex, hippocampus, and striatum of α-syn tg mice. CD3+ cells were found in close proximity to the processes of activated astroglia, particularly in areas of the brain with significant astrogliosis, microgliosis, and expression of pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells in the brains of α-syn tg mice revealed that CD1d-tet+ T cells were also increased in the brains of α-syn tg mice suggestive of natural killer T cells. In post-mortem DLB brains, we similarly detected increased numbers of infiltrating CD3+/CD4+ T cells in close proximity with blood vessels.. These results suggest that infiltrating adaptive immune cells play an important role in neuroinflammation and neurodegeneration in synucleinopathies and that modulating peripheral T cells may be a viable therapeutic strategy for PD/DLB.

Topics: Adaptive Immunity; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Brain; Female; Humans; Inflammation; Lewy Body Disease; Male; Mice; Mice, Transgenic; T-Lymphocytes

Genetic and biochemical evidence attributes neuronal loss in Parkinson's disease (PD) and related brain diseases to dyshomeostasis of the 14 kDa protein α-synuclein (αS). There is no consensus on how αS exerts toxicity. Explanations range from disturbed vesicle biology to proteotoxicity caused by fibrillar aggregates. To probe these mechanisms further, robust cellular toxicity models are needed, but their availability is limited. We previously reported that a shift from dynamic multimers to monomers is an early event in αS dyshomeostasis, as caused by familial PD (fPD)-linked mutants such as E46K. Excess monomers accumulate in round, lipid-rich inclusions. Engineered αS '3K' (E35K+E46K+E61K) amplifies E46K, causing a PD-like, L-DOPA-responsive motor phenotype in transgenic mice. Here, we present a cellular model of αS neurotoxicity after transducing human neuroblastoma cells to express yellow fluorescent protein (YFP)-tagged αS 3K in a doxycycline-dependent manner. αS-3K::YFP induction causes pronounced growth defects that accord with cell death. We tested candidate compounds for their ability to restore growth, and stearoyl-CoA desaturase (SCD) inhibitors emerged as a molecule class with growth-restoring capacity, but the therapeutic window varied among compounds. The SCD inhibitor MF-438 fully restored growth while exerting no apparent cytotoxicity. Our αS bioassay will be useful for elucidating compound mechanisms, for pharmacokinetic studies, and for compound/genetic screens.

Topics: alpha-Synuclein; Bacterial Proteins; Cell Death; Cell Line, Tumor; Cell Proliferation; Humans; Lewy Body Disease; Luminescent Proteins; Mutation; Neuroblastoma; Neurons; Parkinson Disease; Pyridazines; Stearoyl-CoA Desaturase; Thiadiazoles

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Discoidin Domain Receptor 1; Disease Models, Animal; Humans; Inflammation; Lewy Body Disease; Mice; MicroRNAs; Neurodegenerative Diseases; Parkinson Disease; Pyrimidines

In this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of "Pick's disease" in the proband's father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.

Topics: alpha-Synuclein; Brain; Female; Frontotemporal Lobar Degeneration; Humans; Lewy Body Disease; Middle Aged; Mutation; Mutation, Missense

Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing.. Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing.. LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aβ severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009).. Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Entorhinal Cortex; Female; Hippocampus; Humans; Lewy Body Disease; Male; Parkinson Disease; tau Proteins

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease

Sleep disorders as a preclinical symptom of synucleinopathies become more prevalent in older adults. Synucleinopathies might be caused by the abnormal aggregation of alpha-synuclein in the brain, which was indicated by alpha-synuclein levels in cerebrospinal fluid (CSF). We aimed to investigate associations of sleep characteristics with CSF alpha-synuclein in older adults.. Our study recruited 536 cognitively intact individuals (aged between 40 and 90 years old) from the Chinese Alzheimer's Biomarker and Lifestyle study. Sleep behaviors were assessed by Pittsburgh Sleep Quality Index and total alpha-synuclein in CSF was measured by enzyme-linked immune-sorbent assay. We used multiple linear and non-linear regression models for research.. Significant non-linear associations of CSF alpha-synuclein with sleep time and duration were revealed. Individuals who went to bed and fell asleep too early or late tended to have lower CSF alpha-synuclein (reflection point for time to bed and fall asleep were 10:26 p.m. and 10:40 p.m.). Lower CSF alpha-synuclein was also observed in individuals with either excessive or insufficient sleep duration (reflection point: 7.24 hours). Besides, overall poor sleep quality (β = -0.0621; P = 0.0242), longer sleep latency (β = -0.0415; P = 0.0174) and lower sleep efficiency (β = 0.0036; P = 0.0017) showed linear associations with lower CSF alpha-synuclein. Sleep disturbances and daytime dysfunction were not significantly associated with CSF alpha-synuclein.. Poor sleep was associated with lower levels of CSF alpha-synuclein in older adults, which may provide new insight into the prevention of synucleinopathies.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Humans; Lewy Body Disease; Male; Parkinson Disease; Peptide Fragments; Sleep; tau Proteins

An unmet clinical need in Parkinson's disease (PD) is to identify biomarkers for diagnosis, preferably in peripherally accessible tissues such as skin. Immunohistochemical studies have detected pathological α-synuclein (αSyn) in skin biopsies from PD patients albeit sensitivity needs to be improved.. Our study provides the ultrasensitive detection of pathological αSyn present in the skin of PD patients, and thus, pathological αSyn in skin could be a potential biomarker for PD.. The real-time quaking-induced conversion assay was used to detect pathological αSyn present in human skin tissues. Further, we optimized this ultra-sensitive and specific assay for both frozen and formalin-fixed paraffin-embedded sections of skin tissues. We determined the seeding kinetics of the αSyn present in the skin from autopsied subjects consisting of frozen skin tissues from 25 PD and 25 controls and formalin-fixed paraffin-embedded skin sections from 12 PD and 12 controls.. In a blinded study of skin tissues from autopsied subjects, we correctly identified 24/25 PD and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 PD and 10/12 controls using formalin-fixed paraffin-embedded skin sections (75% sensitivity and 83% specificity).. Our blinded study results clearly demonstrate the feasibility of using skin tissues for clinical diagnosis of PD by detecting pathological αSyn. Moreover, this peripheral biomarker discovery study may have broader translational value in detecting misfolded proteins in skin samples as a longitudinal progression marker. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Autopsy; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease

Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved in α-syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinson's disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify α-syn oligomers has become increasingly crucial for mechanistic studies to understand their role in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of α-syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse α-syn species is tested and validated. Herein, we describe an antibody characterization and validation pipeline that allows a systematic investigation of the specificity of α-syn antibodies using well-defined and well-characterized preparations of various α-syn species, including monomers, fibrils, and different oligomer preparations that are characterized by distinct morphological, chemical and secondary structure properties. This pipeline was used to characterize 18 α-syn antibodies, 16 of which have been reported as conformation- or oligomer-specific antibodies, using an array of techniques, including immunoblot analysis (slot blot and Western blot), a digital ELISA assay using single molecule array technology and surface plasmon resonance. Our results show that i) none of the antibodies tested are specific for one particular type of α-syn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar α-syn; and iii) a few antibodies showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that the great majority of α-syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic tools or therapeutic agents. This will not only improve

Topics: alpha-Synuclein; Amyloid; Antibodies; Brain; Humans; Lewy Body Disease; Parkinson Disease

Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.. All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d), and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer's biomarkers (t-Tau, P-Tau, Aβ42, and Aβ40) were also measured.. The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB.. The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer's biomarker does not improve the differential diagnosis between AD and DLB.. ClinicalTrials.gov, NCT01876459 (AlphaLewyMa).

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Diagnosis, Differential; France; Humans; Lewy Body Disease; Prodromal Symptoms; tau Proteins

Topics: alpha-Synuclein; Animals; Axons; Brain; Dopamine; Dopaminergic Neurons; Humans; Lewy Body Disease; Mice; Nerve Degeneration; Neurons; Synucleinopathies

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Asian People; Female; Gene Duplication; Humans; Hypotension, Orthostatic; Japan; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Pedigree; Penetrance

Cardiac [123I]metaiodobenzylguanidine scintigraphy (123I-MIBG) is considered a useful test in differentiating multiple system atrophy (MSA) and Lewy body disorders (LBD), including idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). The detection of skin nerve phosphorylated α-synuclein (p-α-syn) deposits could be an alternative marker in vivo. We sought to compare 123I-MIBG scintigraphy and skin biopsy findings in α-synucleinopathies.. We studied 54 patients (7 DLB, 21 IPD, 13 PAF, 13 MSA) who underwent 123I-MIBG scintigraphy and skin biopsy to evaluate cardiac innervation and skin p-α-syn deposition, respectively.. Cardiac denervation was observed in 90.5% IPD, 100% DLB and PAF and in none of the MSA patients (P < 0.0001) whereas p-α-syn deposits were detected in all DLB and PAF, in 95.2% of IPD and 69.2% of MSA patients (P = 0.02). However, the analysis of skin structures disclosed a different distribution of the deposits in somatic subepidermal plexus and autonomic fibers among groups, showing that p-α-syn deposits rarely affected the autonomic fibers in MSA as opposed to LBD. Studying the p-α-syn deposition in autonomic nerves, concordance among I123-MIBG scintigraphy and skin biopsy results was observed in 100% of DLB and PAF, 95.2% IPD and 92.3% MSA patients. I123-MIBG scintigraphy and autonomic p-α-syn deposits analysis both showed a sensitivity of 97.5% and a specificity of 100% and 92.3%, respectively, in distinguishing LBD and MSA.. Skin biopsy and 123-MIBG scintigraphy can be considered alternative tests for the differential diagnosis of IPD, PAF and DLB versus MSA.

Topics: 3-Iodobenzylguanidine; Aged; alpha-Synuclein; Female; Heart; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Myocardium; Parkinson Disease; Peripheral Nerves; Phosphorylation; Pure Autonomic Failure; Radionuclide Imaging; Radiopharmaceuticals; Skin

There is no consensus on the exact role of the adaptive immune system in Parkinson's disease pathogenesis, although there is increasing evidence that it is somehow involved. Moreover, T cell infiltration in the brain has not been thoroughly studied in Parkinson's disease and no study has assessed the infiltration in incidental Lewy body diseases cases that are considered to be early presymptomatic stages of the disease. In this study, we performed an immunohistochemistry/immunofluorescence quantitative and phenotypic assessment of T cell infiltration in human substantia nigra pars compacta and analysed the correlations with neuronal death and synucleinopathy throughout different stages of the disease. We included two groups of incidental Lewy disease in the study. One of the groups, which is believed to be the earliest stage of the disease, showed α-synuclein aggregates only in the olfactory bulb. The second group also presented α-synuclein aggregates in the substantia nigra. We also assessed the formation of different α-synuclein aggregates throughout the different stages of the unified staging system for Lewy body disorders (I to IV). We found that CD8 T cells were increased in diagnosed Parkinson's disease cases compared to the control group and their density positively correlated with neuronal death. Some of the infiltrating CD8 T cells were indeed contacting dopaminergic neurons. No differences were found regarding CD4 T cells. In the earliest stage of the disease, when substantia nigra α-synuclein aggregation is absent, we found a robust CD8 T cell infiltration and no dopaminergic neuronal death yet. Conversely, in the next stage we found neuronal loss and a milder CD8 T cell infiltration. CD8 T cell infiltration paralleled that of α-synuclein accumulation and neuronal death throughout stages II to IV. We also confirmed that CD8 T cells in charge of immune surveillance and involved in the aetiopathogenesis of the disease are equipped with cytolytic enzymes (granzyme A, B and K) and/or proinflammatory cytokines (interferon gamma), and that phenotypic differences were observed between early and late stages of the disease. We also demonstrate that a high proportion of nigral CD8 T cells are tissue resident memory T cells. Our results show that nigral cytotoxic CD8 T cell infiltration is an earlier pathogenic event than α-synuclein aggregation and neuronal death and that it parallels the progression of neuronal death and synucleinopathy in Parkinson's d

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; CD8-Positive T-Lymphocytes; Cell Death; Cytokines; Cytotoxins; Disease Progression; Dopaminergic Neurons; Female; Granzymes; Humans; Immunohistochemistry; Immunologic Surveillance; Lewy Body Disease; Male; Neurons; Parkinson Disease; Substantia Nigra; Synucleinopathies

While the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach.. We collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data.. We found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD.. Synucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.

Topics: Acetylcholine; Aged; alpha-Synuclein; Brain; Cerebral Cortex; Corpus Striatum; Female; Humans; Lewy Body Disease; Male; Metabolic Networks and Pathways; Middle Aged; Nerve Net; Norepinephrine; Parkinson Disease; REM Sleep Behavior Disorder; Substantia Nigra

Alpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies.. Guinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available α-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with α-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases.. Vaccine-generated antibodies detected more α-Syn pathology compared to NOV. The levels of α-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of α-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar α-Syn. Higher levels of α-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional α-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study.. These vaccines induce antibodies that bind α-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Guinea Pigs; Immunotherapy; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Topics: Aged; alpha-Synuclein; Biomarkers; C-Reactive Protein; Case-Control Studies; Cognitive Dysfunction; Cohort Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Growth Factors; Nerve Tissue Proteins

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are three of the most common neurodegenerative disorders. Up to 20% of these patients have the wrong diagnosis, due to overlapping symptoms and shared pathologies. A cerebrospinal fluid (CSF) biomarker panel for AD is making its way into the clinic, but an equivalent panel for PD and DLB and for improved differential diagnoses is still lacking. Using well-defined, community-based cohorts and validated analytical methods, the diagnostic value of CSF total-α-synuclein (t-α-syn) alone and in combination with total tau (t-tau) in newly diagnosed patients with PD, DLB and AD was determined.. Cerebrospinal fluid concentrations of t-α-syn were assessed using our validated in-house enzyme-linked immunosorbent assay in 78 PD patients, 20 AD patients, 19 DLB patients and 32 controls. t-tau was measured using a commercial assay. Diagnostic performance was assessed by receiver operating characteristic curve analysis.. Compared to controls (mean 517 pg/ml), significantly lower levels of CSF t-α-syn in patients with PD (434 pg/ml, 16% reduction, P = 0.036), DLB (398 pg/ml, 23% reduction, P = 0.009) and AD (383 pg/ml, 26% reduction, P = 0.014) were found. t-α-syn levels did not differ significantly between PD, DLB and AD. The t-tau/t-α-syn ratio showed an improved performance compared to the single markers.. This is the first study to compare patients with PD, DLB and AD at the time of diagnosis. It was found that t-α-syn can contribute as a teammate with tau in a CSF biomarker panel for PD and DLB, and strengthen the existing biomarker panel for AD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; tau Proteins

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD-DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α-synuclein pathology. We found moderate-severe vascular changes and high-vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub-set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α-synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging-related neurodegenerative disorders and characterize their end-stage clinical syndromes.

Topics: Aging; alpha-Synuclein; Alzheimer Disease; Autonomic Nervous System Diseases; Dementia; Dementia, Vascular; Lewy Body Disease; Magnetic Resonance Imaging; Microvessels; Neocortex; Parkinson Disease; Primary Dysautonomias; White Matter

Discovering biomarkers for dementia is a pivotal step toward successful early diagnosis and treatment. Although plasma biomarkers have been explored, no consensus has been reached. Alpha-synuclein (AS), a 14 kDa synaptic protein associated with several neurodegenerative diseases, exists natively within erythrocytes (ERC). This protein is characteristic of Lewy body diseases, in which it aggregates into toxic Lewy bodies. As ERC are implicated in dementia, they are a potential target for future biomarkers.. The aims of this study were to assess AS levels within ERC and whether AS can be used as a peripheral biomarker to differentiate between dementia and aged matched healthy control subjects.. A total of 114 samples (60 aging controls, 36 Alzheimer's disease, 12 vascular dementia (VaD) and 6 dementia with Lewy bodies (DLB) subjects) were analyzed. We used Bradford assay to measure protein concentration, indirect ELISA to detect levels of AS, and immunoblotting to identify AS composition. Data were analyzed with nonparametric tests.. AS oligomers were present in dementia blood samples, whereas in controls, AS was largely monomeric. There was a significant increase in AS levels in DLB whole blood (p = 0.005; Kruskal-Wallis test), with a sensitivity and specificity of 100.0% and 93.9%. Protein concentrations in ERC isolated at pH 5.7 were significantly increased in dementia patients compared to controls (17.58 versus 40.33μg/ml; p≤0.005; Mann-Whitney test). In the VaD group, the protein concentration in the pH5.7 ERC fraction had sensitivity and specificity of 91.7% and 62.1%.. ERC protein concentration and AS levels have a potential for development of a novel diagnostic dementia blood test.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Blood Proteins; Case-Control Studies; Dementia; Dementia, Vascular; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Female; Humans; Lewy Body Disease; Male

Neuropathologic confirmation of dementia with Lewy bodies (DLB) involves labeling cytoplasmic Lewy body inclusions for α-synuclein in cortical and subcortical neurons. The authors studied the postmortem brain of a 78-year-old man who had a diagnosis of DLB by exclusion. The patient had symptoms ascribed to DLB that included fluctuating cognitive changes in attention and executive function with progression to dementia, visual hallucinations, and parkinsonism. Sections from the olfactory bulbs and cortical and subcortical regions were stained with periodic acid-Schiff, as well as immunolabeled with antibodies specific for α-synuclein, tau protein, β-amyloid 1-42, and Chlamydia pneumoniae. Most regions demonstrated mixed neuropathologic features, and α-synuclein was notable in Lewy bodies in the amygdala and hippocampus. Periodic acid-Schiff-positive staining was noted in bodies in the amygdala and olfactory bulbs. In this case of DLB, neuropathologic inclusions were consistent with the disease diagnosis, but also with Alzheimer disease and other neurodegenerative diseases, such as polyglucosan body disease.

Topics: Aged; alpha-Synuclein; Autopsy; Brain; Dementia; Humans; Lewy Body Disease; Male

Cortical α-synuclein pathology plays a role in the development of cognitive dysfunction in both Parkinson's disease and dementia with Lewy bodies, although the causative cellular lesions have remained unclear. We aimed to address causal links between α-synuclein-driven pathology in the cerebral cortex and the development of cognitive impairments using new experimental models.. Neuronal overexpression of human α-synuclein was induced in the rat medial prefrontal cortex using viral vectors. This was combined with inoculations of preformed fibrils of human α-synuclein in some animals. Rats were evaluated with tests probing prefrontal cognitive functions (delayed matching/nonmatching to position and 5-choice serial reaction time task). Patterns of neuropathology were characterized immunohistochemically.. Neither α-synuclein overexpression nor the fibril seeds alone yielded any behavioral phenotype. In contrast, combining the 2 approaches produced significant impairments in working memory, attention, and inhibitory control. All animals injected with α-synuclein vectors exhibited high immunoreactivity for human α-synuclein in the medial prefrontal cortex and its primary projection targets. However, only when this overexpression was combined with fibril inoculations did animals exhibit large, proteinase K-resistant and Ser. Cortical overexpression of human α-synuclein is not sufficient to produce cognitive dysfunction, whereas combining this overexpression with fibril seeds yields both cognitive and histopathological phenotypes that are relevant to human Lewy body disease. © 2019 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Cognitive Dysfunction; Disease Models, Animal; Lewy Bodies; Lewy Body Disease; Neurons; Parkinson Disease; Parkinsonian Disorders; Protein Aggregates; Rats; Synaptic Transmission

The protein α-synuclein (αsyn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson's disease (PD). It is unclear why diseases such as LBD may develop widespread αsyn pathology, while in Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB) the αsyn aggregates remain localized. The amygdala contains αsyn aggregates in both LBD and in AD/ALB; to understand why αsyn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized αsyn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil αsyn aggregates, astrocytic αsyn, and αsyn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of αsyn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of αsyn pathology. Similar to carboxy-truncated αsyn, it was demonstrated herein that the presence of aggregation prone A53T αsyn is sufficient to drive misfolding of wild-type αsyn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in αsyn pathology that may be a determinant of disease progression.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amygdala; Animals; Brain; Disease Progression; Humans; Inclusion Bodies; Lewy Body Disease; Mice, Transgenic; Middle Aged; Neurons

This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I-olfactory bulb only; 15.4% IIa-brainstem predominant; 13.6% IIb-limbic predominant; 31.8% III-brainstem and limbic; and 30.7% IV-neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Cognitive Dysfunction; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Severity of Illness Index

Tau and α-synuclein are central in several neurodegenerative diseases, including Alzheimer Disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson Disease (PD). New analytical methods for precise quantification of cerebrospinal fluid (CSF) levels of both tau and α-synuclein are required to differentiate between dementias or monitor therapeutic responses. Notably, levels of total α-synuclein reported by ELISA are inconsistent among studies, impacted by antibody specificity or lack of standardization. Here, we report on the development and validation of a sensitive and robust mass spectrometry-based assay for the simultaneous quantification of tau and α-synuclein in CSF. The optimized workflow avoided any affinity reagents, and involved the combination of two enzymes, Glu-C and trypsin for optimal sequence coverage of α-synuclein acidic C-terminus. Up to 7 α-synuclein peptides were quantified, including the C-terminal peptide (132-140), resulting in a sequence coverage of 54% in CSF. The lower limits of quantification (LLOQ) ranged from 0.1 ng mL-1 to 1 ng mL-1 depending on the peptide. Regarding CSF tau, 4 peptides common to all isoforms were monitored, and LLOQ ranged from 0.5 ng mL-1 to 0.75 ng mL-1. The multiplex method was successfully applied to CSF samples from AD and DLB patients, two clinically overlapping neurodegenerative diseases. CSF α-synuclein levels were significantly lower in DLB patients compared to AD and controls. Moreover, tau and α-synuclein concentrations showed opposite trends in AD and DLB patients, suggesting the benefit of combining the two biomarkers for differentiation of DLB from AD and controls.

Topics: alpha-Synuclein; Alzheimer Disease; Amino Acid Sequence; Biomarkers; Chromatography, Liquid; Diagnosis, Differential; Humans; Lewy Body Disease; Peptide Fragments; Proteolysis; Serine Endopeptidases; Tandem Mass Spectrometry; tau Proteins; Trypsin

We applied RT-QuIC assay to detect α-synuclein aggregates in cerebrospinal fluid (CSF) of patients with suspected Creutzfeldt-Jakob disease who had a neuropathological diagnosis of dementia with Lewy bodies (DLB) (n = 7), other neurodegenerative diseases with α-synuclein mixed pathology (n = 20), or without Lewy-related pathology (n = 49). The test had a sensitivity of 92.9% and specificity of 95.9% in distinguishing α-synucleinopathies from non-α-synucleinopathies. When performed in the CSF of patients with DLB (n = 36), RT-QuIC was positive in 17/20 with probable DLB, 0/6 with possible DLB, and 0/10 with Alzheimer disease. These results indicate that RT-QuIC for α-synuclein is an accurate test for DLB diagnosis.

Topics: alpha-Synuclein; Alzheimer Disease; Biological Assay; Creutzfeldt-Jakob Syndrome; Diagnosis, Differential; Humans; Lewy Body Disease; Sensitivity and Specificity

Impulsive compulsive behaviours in Parkinson's disease have been linked to increased dopaminergic release in the ventral striatum and excessive stimulation of dopamine D3 receptors. Thirty-one patients with impulsive compulsive behaviours and Parkinson's disease who donated their brains to the Queen Square Brain Bank for Neurological Disorders were assessed for α-synuclein neuropathological load and tyrosine hydroxylase levels in the nucleus accumbens, dorsal putamen and caudate using immunohistochemistry. Dopamine D2 and dopamine D3 receptors protein levels in the nucleus accumbens, frontal cortex and putamen were determined using western blotting. Results were compared to 29 Parkinson's disease cases without impulsive compulsive behaviours matched by age, sex, disease duration, age at Parkinson's disease onset and disease duration. The majority of patients with impulsive compulsive behaviours had dopamine dysregulation syndrome. Patients with Parkinson's disease and impulsive compulsive behaviours had lower α-synuclein load and dopamine D3 receptor levels in the nucleus accumbens. No differences were seen between groups in the other brain areas and in the analysis of tyrosine hydroxylase and dopamine D2 receptor levels. Lower α-synuclein load in the nucleus accumbens of individuals with Parkinson's disease and impulsive compulsive behaviours was confirmed on western blotting. Downregulation of the dopamine D3 receptor levels may have occurred either as a consequence of the degenerative process or of a pre-morbid trait. The lower levels of α-synuclein may have contributed to an excessive stimulation of the ventral striatum resulting in impulsive compulsive behaviours.

Topics: alpha-Synuclein; Alzheimer Disease; Autopsy; Compulsive Behavior; Female; Humans; Impulsive Behavior; Lewy Body Disease; Male; Middle Aged; Nucleus Accumbens; Parkinson Disease; Receptors, Dopamine D2; Receptors, Tumor Necrosis Factor, Member 25; Tyrosine 3-Monooxygenase

The group of neurodegenerative diseases, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) all exhibit inclusions containing amyloid-type α-synuclein (α-syn) aggregates within degenerating brain cells. α-syn also exists as soluble oligomeric species that are hypothesized to represent intermediates between its native and aggregated states. These oligomers are present in brain extracts from patients suffering from synucleinopathies and hold great potential as biomarkers. Although easily prepared in vitro, oligomers are metastable and dissociate over time, thereby complicating α-syn oligomer research. Using the small amine-reactive cross-linker, formaldehyde (FA), we successfully stabilized α-syn oligomers without affecting their size, overall structure or antigenicity towards aggregate-conformation specific α-syn antibodies FILA and MJFR-14-6-4-2. Further, cross-linked α-syn oligomers show resistance towards denaturant like urea and SDS treatment and remain fully functional as internal standard in an aggregation-specific enzyme-linked immunosorbent assay (ELISA) despite prior incubation with urea. We propose that FA cross-linked α-syn oligomers could serve as important calibrators to facilitate comparative and standardized α-syn biomarker studies going forward.

Topics: alpha-Synuclein; Amyloid; Formaldehyde; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Multimerization; Protein Stability

Emerging evidence implicates α-synuclein oligomers as potential culprits in the pathogenesis of Lewy body disease (LBD). Soluble oligomeric α-synuclein accumulation in cytoplasm is believed to modify neuronal activities and intraneural Ca

Topics: alpha-Synuclein; Animals; Calcium; Calcium Channels; Calcium-Binding Proteins; Inositol 1,4,5-Trisphosphate Receptors; Intracellular Space; Lewy Bodies; Lewy Body Disease; Mice; Models, Biological; Neurons; Protein Multimerization; Small-Conductance Calcium-Activated Potassium Channels

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lewy Body Disease; Mutation; Synucleinopathies

The insular cortex consists of a heterogenous cytoarchitecture and diverse connections and is thought to integrate autonomic, cognitive, emotional and interoceptive functions to guide behaviour. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), it reveals α-synuclein pathology in advanced stages. The aim of this study is to assess the insular cortex cellular and subregional vulnerability to α-synuclein pathology in well-characterized PD and DLB subjects.. We analysed postmortem insular tissue from 24 donors with incidental Lewy body disease, PD, PD with dementia (PDD), DLB and age-matched controls. The load and distribution of α-synuclein pathology and tyrosine hydroxylase (TH) cells were studied throughout the insular subregions. The selective involvement of von Economo neurons (VENs) in the anterior insula and astroglia was assessed in all groups.. A decreasing gradient of α-synuclein pathology load from the anterior periallocortical agranular towards the intermediate dysgranular and posterior isocortical granular insular subregions was found. Few VENs revealed α-synuclein inclusions while astroglial synucleinopathy was a predominant feature in PDD and DLB. TH neurons were predominant in the agranular and dysgranular subregions but did not reveal α-synuclein inclusions or significant reduction in density in patient groups.. Our study highlights the vulnerability of the anterior agranular insula to α-synuclein pathology in PD, PDD and DLB. Whereas VENs and astrocytes were affected in advanced disease stages, insular TH neurons were spared. Owing to the anterior insula's affective, cognitive and autonomic functions, its greater vulnerability to pathology indicates a potential contribution to nonmotor deficits in PD and DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cerebral Cortex; Female; Humans; Lewy Body Disease; Male; Parkinson Disease; Tissue Banks

Alzheimer's disease (AD) is characterized by accumulation of β-amyloid plaques (AP) and neurofibrillary tangles (NFT) in the cortex, together with synaptic loss and amyloid angiopathy. Perturbations in the brain lysosomal system, including the cathepsin family of proteases, have been implicated in AD where they may be involved in proteolytic clearance of misfolded and abnormally aggregated peptides. However, the status of cathepsin D (catD) is unclear in Lewy body dementia, the second most common form of neurodegenerative dementia after AD, and characterized by Lewy bodies (LB) containing aggregated α-synuclein. Furthermore, earlier reports of catD changes in AD have not been entirely consistent. We measured CatD immunoreactivities in the temporal (Brodmann area BA21) and parietal (BA40) cortices of well characterized AD brains as well as two clinical subtypes of Lewy body dementia, namely Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), known to show varying degrees of concomitant AD pathology. Increased catD immunoreactivities in AD were found for both neocortical regions measured, where they also correlated with neuropathological NFT scores and phosphorylated pSer396 tau burden, and appeared to co-localize at least partly to NFT-containing neurons. In contrast, catD was increased only in BA40 in DLB and not at all in PDD, did not correlate with LB scores, and did not appreciably co-localize with α-synuclein inclusions. Our study suggests that catD upregulation may be an adaptive response to AD-related processes leading to neurofibrillary degeneration, but may not be directly associated with formation of α-synuclein inclusions in Lewy body dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cathepsin D; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Neocortex; Neurodegenerative Diseases; Neurofibrillary Tangles; Neurons; Parietal Lobe; Plaque, Amyloid; tau Proteins; Temporal Lobe

α-Synuclein is the major component of Lewy bodies and a candidate biomarker for neurodegenerative diseases in which Lewy bodies are common, including Parkinson's disease and dementia with Lewy bodies. A large body of literature suggests that these disorders are characterized by reduced concentrations of α-synuclein in cerebrospinal fluid (CSF), with overlapping concentrations compared to healthy controls and variability across studies. Several reasons can account for this variability, including technical ones, such as inter-assay and inter-laboratory variation (reproducibility). We compared four immunochemical methods for the quantification of α-synuclein concentration in 50 unique CSF samples. All methods were designed to capture most of the existing α-synuclein forms in CSF ('total' α-synuclein). Each of the four methods showed high analytical precision, excellent correlation between laboratories (R

Topics: alpha-Synuclein; Biomarkers; Female; Humans; Immunoassay; Lewy Body Disease; Male; Multiple System Atrophy; Parkinson Disease; Reference Values; Reproducibility of Results

Synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal α-synuclein in intraneuronal inclusions, named Lewy bodies. Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase, have been identified as the most common genetic risk factor for PD and DLB. However, despite extensive research, the mechanism by which glucocerebrosidase dysfunction increases the risk for PD or DLB still remains elusive. In our study we expand the toolbox for PD-DLB post-mortem studies by introducing new quantitative biochemical assays for glucocerebrosidase and α-synuclein. Applying causal modelling, we determine how these parameters are interrelated and ultimately impact disease manifestation. We developed quantitative immuno-based assays for glucocerebrosidase and α-synuclein (total and phosphorylated at Serine 129) protein levels, as well as a liquid chromatography-mass spectrometry method for the detection of the glucocerebrosidase lipid substrate glucosylsphingosine. These assays were applied on tissue samples from frontal cortex, putamen and substantia nigra of PD (n = 15) and DLB (n = 15) patients and age-matched non-demented controls (n = 15). Our results confirm elevated p-129 over total α-synuclein levels in the insoluble fraction of PD and DLB post-mortem brain tissue and we found significantly increased α-synuclein levels in the soluble fractions in PD and DLB. Furthermore, we identified an inverse correlation between reduced glucocerebrosidase enzyme activity and protein levels with increased glucosylsphingosine levels. In the substantia nigra, a brain region particularly vulnerable in Parkinson's disease, we found a significant correlation between glucocerebrosidase protein reduction and increased p129/total α-synuclein ratios. We assessed the direction and strength of the interrelation between all measured parameters by confirmatory path analysis. Interestingly, we found that glucocerebrosidase dysfunction impacts the PD-DLB status by increasing α-synuclein ratios in the substantia nigra, which was partly mediated by increasing glucosylsphingosine levels. In conclusion, we show that the introduced immuno-based assays enable the quantitative assessment of glucocerebrosidase and α-synuclein parameters in post-mortem brain. In the substantia nigra, reduced glucocerebrosidase levels contribute to the increase in α-synuclein levels and to PD-DLB disease manifestation

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Chromatography, Liquid; Data Interpretation, Statistical; Female; Glucosylceramidase; Humans; Immunoassay; Lewy Body Disease; Male; Mass Spectrometry; Parkinson Disease

We previously reported up-regulation of tigarb (the zebrafish orthologue of human TIGAR, TP53 - Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1. TIGAR Immunohistochemistry, using a range of antibodies, was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n = 10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA)) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n = 4 control, 4 PD, and 4 dementia with Lewy bodies).. TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections and double staining confirmed the presence of TIGAR alongside alpha-synuclein in these LB and neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I.. TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Apoptosis Regulatory Proteins; Brain; Dementia; Female; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Motor Neuron Disease; Multiple System Atrophy; Neurites; Neurons; Parkinson Disease; Phosphoric Monoester Hydrolases; Substantia Nigra

Lewy body diseases are neuropathologically characterized by the abnormal accumulation of α-synuclein (α-syn) protein within vulnerable neurons. Although studies have evaluated α-syn in post mortem brain tissue, previous findings have been limited by typically employing pan-α-syn antibodies that may not recognize disease-relevant forms of protein. We investigated the presence of α-syn species present in post mortem brain tissues from Lewy body disease and Alzheimer's disease.. Soluble and insoluble/aggregated α-syn from frontal cortex of post mortem brain tissues form Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and aged control cases were sequentially extracted using buffers with increasing detergent concentrations. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the levels of total-, oligomeric- and phosphorylated-Ser129-α-syn (t-, o- and pS129-α-syn). ELISA data were validated by western blot and compared to histological data from the same region of the contralateral hemisphere.. There was no difference in t-α-syn levels between groups in the aqueous-soluble, detergent-soluble or urea-soluble tissue fractions. However, aqueous-soluble non-phosphorylated o-α-syn was increased not only in PD and DLB but also in AD without neocortical Lewy bodies. In PD and AD, pS129-α-syn was increased in the detergent-soluble tissue fragment and, in AD, this was positively correlated with the burden of tau pathology. Increased levels of urea-soluble pS129-α-syn were demonstrated only in DLB tissue lysates but this did not correlate with Lewy body pathological burden.. Taken together, these findings suggest that DLB have elevated levels of insoluble pS129-α-syn, but that increased levels of aqueous-soluble o-α-syn and detergent-soluble pS129-α-syn are also observed in PD and AD, suggesting different changes to α-syn across the spectrum of neurodegenerative proteopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Cerebral Cortex; Female; Humans; Lewy Body Disease; Male; Phosphorylation; tau Proteins

Epidemiologic studies have demonstrated that depression is a risk factor for dementia. In particular, dementia with Lewy bodies (DLB) has been noted to be highly relevant to depression. It has been suggested that α-synuclein (α-syn), a major component of Lewy bodies, is related to the onset and progression of DLB. To investigate the relationship between depression and DLB, we compared serum α-syn levels of patients with depression to those of healthy subjects.. The subjects were 103 inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or DSM-5 major depressive disorder (MDD) and 132 healthy comparisons. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between June 2010 and November 2016. Serum α-syn levels were measured using an enzyme-linked immunosorbent assay kit. Serum α-syn levels were compared using a 2 (age group [<60 years versus ≥60 years]) × 2 (diagnosis [MDD versus comparison]) analysis of variance.. There was no significant main effect of age (F = 1.167, df = 1, 231, p = 0.281). There was a significant main effect of diagnosis (F = 44.657, df = 1, 231, p <0.001), with higher α-syn levels in the MDD group versus the healthy comparison group, regardless of age.. The present results suggest that depression may affect the metabolism of α-syn; there is a possibility that depression is not only a prodromal symptom of DLB but also a causal risk factor for DLB.

Topics: Adult; Aged; alpha-Synuclein; Analysis of Variance; Case-Control Studies; Depressive Disorder, Major; Female; Humans; Japan; Lewy Body Disease; Male; Middle Aged; Risk Factors

Topics: alpha-Synuclein; Alzheimer Disease; Depression; Depressive Disorder, Major; Humans; Lewy Body Disease

To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.. Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing.. SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F. LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Brain; Entorhinal Cortex; Female; Humans; Lewy Body Disease; Male; Mental Status and Dementia Tests; Neocortex; Parkinson Disease; Plaque, Amyloid; Putamen; tau Proteins

Depression is commonly observed even in prodromal stages of Lewy body disorders (LBD), and is associated with cognitive impairment and a faster rate of cognitive decline. Given the role of dopamine in the development of movement disorders, but also in motivation and reward, we investigated neurodegenerative pathology in dopaminergic circuitry in Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) patients in relation to depressive symptoms.. α-synuclein, hyperphosphorylated tau and amyloid-beta pathology was assessed in 17 DLB, 14 PDD and 8 PD cases within striatal and midbrain subregions, with neuronal cell density assessed in substantia nigra and ventral tegmental area. Additionally, we used a structural equation modeling (SEM) approach to investigate the extent to which brain connectivity might influence the deposition of pathological proteins within dopaminergic pathways.. A significantly higher α-synuclein burden was observed in the substantia nigra (P = 0.006), ventral tegmental area (P = 0.011) and nucleus accumbens (P = 0.031) in LBD patients with depression. Significant negative correlations were observed between cell density in substantia nigra with Lewy body (LB) Braak stage (P = 0.013), whereas cell density in ventral tegmental area showed negative correlations with LB Braak stage (P = 0.026) and neurofibrillary tangle Braak stage (P = 0.007).. Dopaminergic α-synuclein pathology appears to drive depression. Selective targeting of dopaminergic pathways may therefore provide symptomatic relief for depressive symptoms in LBD patients.

Topics: Aged; alpha-Synuclein; Amyloid beta-Peptides; Brain; Dementia; Depression; Dopaminergic Neurons; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Neurofibrillary Tangles; Neurons; Parkinson Disease; tau Proteins

Adult-onset neurodegenerative disorders, like Parkinson's disease (PD) and dementia with Lewy bodies (DLB), that share the accumulation of aggregated α-synuclein (αSyn

Topics: Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Animals; Benzothiazoles; Biomarkers; Brain Chemistry; Case-Control Studies; Computer Systems; Fluorescent Dyes; Fluorometry; High-Throughput Screening Assays; Humans; Lewy Body Disease; Mice; Microglia; Middle Aged; Neuroglia; Parkinsonian Disorders; Protein Aggregates; Recombinant Proteins; Reproducibility of Results; Sensitivity and Specificity; Single-Blind Method; Synucleinopathies

Sleep dysfunction is frequent in Dementia with Lewy Bodies (DLB), but polysomnographic (PSG) data is scarce. Our objectives were to: (1) compare PSG data between DLB patients and age normative values (NV), Parkinson's Disease (PD) and idiopathic REM sleep behavior disorder (iRBD) patients; (2) evaluate the relation between of OSA, Fluctuations and Hypersomnolence and PSG data.. We selected all consecutive patients with DLB, PD and iRBD that underwent video-PSG during a two year period. Clinical data was collected by file review. Video-PSG data included sleep structure, Apnea-Hypopnea Index (AHI), REM sleep atonia indexes and video file inspection of motor events (ME) during REM sleep.. Subjects: In this study, 19 DLB, 51 PD and 20 iRBD patients participated. Of those, nine DLB (DLB-RBD) and 23 PD (PD-RBD) patients had RBD. Compared to NV, DLB patients had significantly lower sleep efficiency, total sleep time, and REM sleep duration and higher sleep latency, wake after sleep onset and N2 duration. There were no significant relations between PSG data and OSA, hypersomnolence or fluctuations. Sleep latency and AHI were significantly higher and lower, respectively, in DLB compared to PD patients. ME frequency was higher in iRBD.. DLB patients present significant sleep fragmentation and shortened total and REM sleep time. These changes were not related with OSA, fluctuations or hypersomnolence, suggesting a different pathophysiology. PSG data was similar in the three RBD groups, in accordance with a common neuropathological origin, except for an increase in RBD severity in patients with iRBD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Data Interpretation, Statistical; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Polysomnography; Sleep Wake Disorders; Sleep, REM; Synucleinopathies

The disease course of dementia with Lewy bodies (DLB) can be rapidly progressive, clinically resembling Creutzfeldt-Jakob's disease (CJD). To better understand factors contributing to this rapidly progressive disease course, we describe load and distribution of neuropathology, and the presence of possible disease-associated genetic defects in a post-mortem series of DLB cases clinically suspected of CJD.. We included pathologically confirmed DLB cases with a disease duration of 3.5 years or less from the Dutch Surveillance Center for Prion Diseases, collected between 1998 and 2014. Lewy body disease (LBD) and Alzheimer's disease (AD)-related pathology were staged and semi-quantitatively scored in selected brain regions. Whole exome sequencing analysis of known disease-associated genes, copy number analysis, APOE ε genotyping and C9orf72 repeat expansion analysis were performed to identify defects in genes with a well-established involvement in Parkinson's disease or AD.. Diffuse LBD was present in nine cases, transitional LBD in six cases and brainstem-predominant LBD in one case. Neocortical alpha-synuclein load was significantly higher in cases with intermediate-to-high than in cases with low-to-none AD-related pathology (p = 0.007). We found two GBA variants (p.D140H and p.E326K) in one patient and two heterozygous rare variants of unknown significance in SORL1 in two patients.. A high load of neocortical alpha-synuclein pathology was present in most, but not all DLB cases. Additional burden from presence of concomitant pathologies, synergistic effects and specific genetic defects in the known disease-associated genes may have contributed to the rapid disease progression.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Creutzfeldt-Jakob Syndrome; Diagnosis; Disease Progression; Exome Sequencing; Female; Glucosylceramidase; Humans; LDL-Receptor Related Proteins; Lewy Body Disease; Male; Membrane Transport Proteins; Neocortex

Proteinaceous α-synuclein-containing inclusions are found in affected brain regions in patients with Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). These appear in neurons as Lewy bodies in both PD and DLB and as glial cytoplasmic inclusions (GCIs) in oligodendrocytes in MSA. The role they play in the pathology of the diseases is unknown, and relatively little is still known about their composition. By purifying the inclusions from the surrounding tissue and comprehensively analysing their protein composition, vital clues to the formation mechanism and role in the disease process may be found. In this study, Lewy bodies were purified from postmortem brain tissue from DLB cases (n = 2) and GCIs were purified from MSA cases (n = 5) using a recently improved purification method, and the purified inclusions were analysed by mass spectrometry. Twenty-one percent of the proteins found consistently in the GCIs and LBs were synaptic-vesicle related. Identified proteins included those associated with exosomes (CD9), clathrin-mediated endocytosis (clathrin, AP-2 complex, dynamin), retrograde transport (dynein, dynactin, spectrin) and synaptic vesicle fusion (synaptosomal-associated protein 25, vesicle-associated membrane protein 2, syntaxin-1). This suggests that the misfolded or excess α-synuclein may be targeted to inclusions via vesicle-mediated transport, which also explains the presence of the neuronal protein α-synuclein within GCIs.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Oligodendroglia; Protein Aggregation, Pathological; Synaptic Vesicles

Excessive sleep during the night and for >2 hours during the day is part of the fluctuating wakefulness criterion of dementia with Lewy bodies (DLB). The phenomenon 'sleep days' is not uncommon in nursing homes. Here, we describe a woman who, for months, slept for 3 days and nights in a row and thereafter was awake for 3 days and nights. Electroencephalogram (EEG) showed slow background activity and increased delta activity. No epileptiform activity was detected. Polysomnography showed a severely disturbed, markedly fragmented sleep pattern. On her death, neuropathology revealed degeneration and loss of neurons along with α-synuclein-containing Lewy body inclusions and neurites in the substantia nigra, locus coeruleus, hypothalamus, and neocortex, thus fulfilling the criteria of DLB, cortical type. We propose that the hypothalamic degeneration contributed significantly to the clinical profile in this case. We suggest that patients with sleep days should be investigated for other DLB signs.

Topics: Aged, 80 and over; alpha-Synuclein; Biological Clocks; Female; Humans; Hypothalamus; Lewy Bodies; Lewy Body Disease; Neurons; Parkinson Disease; Sleep Wake Disorders

At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α-synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α-synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α-synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex-one of the earliest and most frequently affected brain regions in Lewy body disorders-in 3-month-old female and male mice and in 11-month-old male mice. After 6 months, we observed that α-synucleinopathy did not expand significantly beyond the limbic connectome in the 9-month-old male and female mice or in the 17-month-old male mice. However, the 9-month-old male mice had developed greater α-synucleinopathy, smell impairment and cell loss than age-matched females. By 10.5 months post-infusion, fibril treatment hastened mortality in the 21.5-month-old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post-infusion, this was not attributable to true cell death. Furthermore, mesencephalic α-synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson's disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α-synucleinopathy.

Topics: alpha-Synuclein; Animals; Brain; Female; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Limbic System; Male; Mice; Olfactory Bulb; Olfactory Cortex; Sex Factors; Substantia Nigra; Synucleinopathies

Topics: alpha-Synuclein; Diagnosis, Differential; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Polysomnography; REM Sleep Behavior Disorder; Sleep Apnea, Obstructive; Sleep, REM; Video Recording

Topics: 3-Iodobenzylguanidine; alpha-Synuclein; Diagnosis, Differential; Heart; Humans; Lewy Body Disease; Male; Middle Aged; Myocardial Perfusion Imaging; Polysomnography; Radiopharmaceuticals; REM Sleep Behavior Disorder; Severity of Illness Index; Sleep Apnea, Obstructive; Video Recording

Posttranslational modifications by phosphorylation, ubiquitination, neddylation and other pathways have emerged as major regulators of cellular functions. NEDD8 ultimate buster 1, NUB1, is an adaptor protein, which negatively regulates the levels of the ubiquitin-like protein NEDD8 as well as neddylated proteins through proteasomal degradation. We previously reported that NUB1 is highly involved in the pathogenesis of synucleinopathy including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In general, since phosphorylation is strongly related to the alteration of protein propensity, we examined if the fundamental function of NUB1 can be modulated by its phosphorylation. We created a series of phosphomimic mutants of NUB1. Among them, we found that phosphorylation of NUB1 at S46 (P-NUB46) efficiently degrades aggregates using a cell-based assay. Immunohistochemical studies have shown that specific antibodies against P-NUB46 reacted with Lewy bodies in PD and DLB but not with glial cytoplasmic inclusions in MSA. Moreover, P-NUB46 levels were significantly higher in the brains of patients with DLB than in control brains, and P-NUB46 was extracted in an insoluble fraction of DLB. These findings suggest that the phosphorylation of NUB1 is modulated during the pathological process of Lewy body disease.

Topics: Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Multiple System Atrophy; NEDD8 Protein; Neuroglia; Parkinson Disease; Phosphorylation

To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features.. All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined.. MSA pathology was not identified in this series. Of the FTLD cohort, 9 cases had coexisting LBD ≥ Braak stage IV and were associated with different FTLD subtypes including Pick disease (n = 2), corticobasal degeneration (n = 2), progressive supranuclear palsy (n = 2), and TDP type A (n = 3). All FTLD-TDP cases with coexisting LBD had mutations in. Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; C9orf72 Protein; DNA-Binding Proteins; Female; Frontotemporal Lobar Degeneration; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinsonian Disorders; Prevalence; Progranulins; tau Proteins

Previous studies have indicated the potential of cerebrospinal fluid (CSF) α-synuclein (α-syn) to be an additional biomarker for improving differential diagnosis of Alzheimer's disease (AD). We evaluated α-syn diagnostic performance across a well-characterized patient cohort with long-term follow-up. For this purpose, CSF α-syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI-AD; n = 32), 24 MCI cases due to Lewy body disease (MCI-LBD; n = 24) and control subjects (Ctrl; n = 18). CSF α-syn levels discriminate between the four groups. There were higher α-syn levels in MCI-AD patients and lower levels in MCI-LBD patients. The combination of α-syn and P-tau resulted in a specificity of 99% and a sensitivity of 97% for MCI-AD. MCI-AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P-tau and α-syn compared to the MCI-AD patients without psychotic symptoms (n = 23). We conclude that adding CSF α-syn to central core AD biomarkers improves an early differential diagnosis of MCI-AD from other forms of MCI. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Diagnosis, Differential; Early Diagnosis; Female; Humans; Lewy Body Disease; Male; Middle Aged; tau Proteins

Retinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease.. Patients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the α-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis.. When compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease.. Our findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cross-Sectional Studies; Female; Fovea Centralis; Humans; Lewy Body Disease; Macula Lutea; Male; Middle Aged; Parkinson Disease; Reference Values; Retina; Retinal Ganglion Cells; Tomography, Optical Coherence; Treatment Outcome; Vision Disorders; Visual Perception

Patients with dementia with Lewy bodies reveal a variable pathology including alpha-synuclein, amyloid-beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha-synuclein.. Whether GBA1 mutations are associated with a CSF alpha-synuclein profile in dementia with Lewy bodies.. Screening of the GBA1 gene and single-nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha-synuclein, amyloid-beta. Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha-synuclein were lowest in DLB. Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha-synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha-synuclein-lowering compounds. © 2019 International Parkinson and Movement Disorder Society.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Gene Expression; Glucosylceramidase; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Mutation; tau Proteins

Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.

Topics: alpha-Synuclein; Alzheimer Disease; Exome Sequencing; Hippocampus; Humans; Imaging, Three-Dimensional; Intracellular Membranes; Lewy Bodies; Lewy Body Disease; Membrane Lipids; Mesencephalon; Microscopy, Confocal; Microscopy, Electron; Microscopy, Fluorescence; Organelles; Parkinson Disease; Substantia Nigra

The percentage of verbal forgetting (VF%) measure of the Rey Auditory Verbal Learning Test (RAVLT) has been proposed to differentiate patients diagnosed clinically with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB).. To determine if VF% aligns with gold-standard biomarker and autopsy evidence of AD and DLB neuropathology.. Clinical, cognitive, sociodemographic, and biomarker data were collected from 315 patients with baseline cognitive impairment and 485 normal controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). AD markers included reduced cerebrospinal fluid (CSF) amyloid-β, elevated total-tau and phosphorylated-tau, hippocampal atrophy, and the presence of amyloid plaques and neurofibrillary tangles at autopsy. DLB markers included reduced CSF α-synuclein, preserved hippocampus, atrophied putamen, occipital glucose metabolism, and the presence of Lewy bodies at autopsy. Cognitively impaired participants were classified as ADVF% (n = 190) or DLBVF% (n = 125) based on their RAVLT VF% scores using a 75% cut-off (≥75%  = ADVF%, <75%  = DLBVF%). Postmortem data were available for 13 ADVF% participants, 13 DLBVF% patients, and six healthy controls.. ADVF% and DLBVF% participants did not differ on CSF or neuroimaging biomarkers, with the exception of total tau levels which were higher in ADVF%. In the subset of participants with autopsy data, comorbid AD and DLB pathology was most frequent in ADVF% participants, and pure DLB pathology was most frequent in DLBVF% participants, however, these differences were not statistically significant.. The RAVLT VF% measure does not reliably align with AD and DLB neuropathology in ADNI participants.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Biomarkers; Diagnosis, Differential; Female; Hippocampus; Humans; Lewy Body Disease; Male; Memory and Learning Tests; Neuroimaging; Neuropathology; Reproducibility of Results; tau Proteins; Verbal Learning

Alpha-synuclein is a presynaptic protein that forms abnormal cytoplasmic aggregates in Lewy body disorders. Although nuclear alpha-synuclein localization has been described, its function in the nucleus is not well understood. We demonstrate that alpha-synuclein modulates DNA repair. First, alpha-synuclein colocalizes with DNA damage response components within discrete foci in human cells and mouse brain. Removal of alpha-synuclein in human cells leads to increased DNA double-strand break (DSB) levels after bleomycin treatment and a reduced ability to repair these DSBs. Similarly, alpha-synuclein knock-out mice show increased neuronal DSBs that can be rescued by transgenic reintroduction of human alpha-synuclein. Alpha-synuclein binds double-stranded DNA and helps to facilitate the non-homologous end-joining reaction. Using a new, in vivo imaging approach that we developed, we find that serine-129-phosphorylated alpha-synuclein is rapidly recruited to DNA damage sites in living mouse cortex. We find that Lewy inclusion-containing neurons in both mouse model and human-derived patient tissue demonstrate increased DSB levels. Based on these data, we propose a model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs, and may contribute to programmed cell death via nuclear loss-of-function. This model could inform development of new treatments for Lewy body disorders by targeting alpha-synuclein-mediated DNA repair mechanisms.

Topics: alpha-Synuclein; Animals; Brain; Cells, Cultured; DNA Breaks, Double-Stranded; DNA End-Joining Repair; Humans; Lewy Bodies; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Parkinson Disease

Immunotherapeutic approaches targeting amyloid β (Aβ) protein and tau in Alzheimer's disease and α-synuclein (α-syn) in Parkinson's disease are being developed for treating dementia with Lewy bodies. However, it is unknown if single or combined immunotherapies targeting Aβ and/or α-syn may be effective.. Amyloid precursor protein/α-syn tg mice were immunized with AFFITOPEs® (AFF) peptides specific to Aβ (AD02) or α-syn (PD-AFF1) and the combination.. AD02 more effectively reduced Aβ and pTau burden; however, the combination exhibited some additive effects. Both AD02 and PD-AFF1 effectively reduced α-syn, ameliorated degeneration of pyramidal neurons, and reduced neuroinflammation. PD-AFF1 more effectively ameliorated cholinergic and dopaminergic fiber loss; the combined immunization displayed additive effects. AD02 more effectively improved buried pellet test behavior, whereas PD-AFF1 more effectively improved horizontal beam test; the combined immunization displayed additive effects.. Specific active immunotherapy targeting Aβ and/or α-syn may be of potential interest for the treatment of dementia with Lewy bodies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Immunologic Factors; Immunotherapy; Lewy Body Disease; Mice; Parkinson Disease

Intracellular aggregates of α-synuclein are the pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), being linked to neurotoxicity. Multiple triggers of α-synuclein aggregation have been implicated, including raised copper. The potential protective role of the endogenous copper-/zinc-binding proteins, metallothioneins (MT), has been explored in relation to copper-induced α-synuclein aggregation. Up-regulated endogenous expression of MT was induced in SHSY-5Y cells by the synthetic glucocorticoid analogue, dexamethasone. After treatment to induce endogenous MT expression, immunofluorescence confocal microscopy was used to quantify protein aggregates in cells with/without copper treatment. MT induction resulted in significant (p < 0.01), dose-dependent up-regulation of MT expression and significant reduction in Cu-dependent α-synuclein intracellular aggregates (p < 0.01) that could be suppressed by MT-specific siRNA. Ubiquitous (MT-2) and brain-specific (MT-3) isoforms were investigated by transient transfection of the GFP-fusion proteins, observing equivalent α-synuclein aggregate suppression by each. These studies indicate MT induction could have potential in PD/DLB neuroprotective therapy by suppressing α-synuclein aggregation.

Topics: alpha-Synuclein; Brain; Cell Line, Tumor; Copper; Dexamethasone; Humans; Lewy Body Disease; Metallothionein; Parkinson Disease

We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid β (Aβ) to duration of illness in dementia with Lewy bodies (DLB).. Quantitative digital pathology of limbic and neocortical α-synuclein, tau, and Aβ was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration.. Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and Aβ. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and Aβ. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein.. In DLB, α-synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aβ.

Topics: Aged; alpha-Synuclein; Amyloid beta-Peptides; Disease Progression; Female; Humans; Lewy Body Disease; Limbic System; Male; Neocortex; Prospective Studies; tau Proteins; Time Factors

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Gene Expression; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Tissue Fixation

The autophagy-lysosome pathway (ALP) regulates intracellular homeostasis of the cytosolic protein SNCA/alpha-synuclein and is impaired in synucleinopathies, including Parkinson disease and dementia with Lewy bodies (DLB). Emerging evidence suggests that ALP influences SNCA release, but the underlying cellular mechanisms are not well understood. Several studies identified SNCA in exosome/extracellular vesicle (EV) fractions. EVs are generated in the multivesicular body compartment and either released upon its fusion with the plasma membrane, or cleared via the ALP. We therefore hypothesized that inhibiting ALP clearance 1) enhances SNCA release via EVs by increasing extracellular shuttling of multivesicular body contents, 2) alters EV biochemical profile, and 3) promotes SNCA cell-to-cell transfer. Indeed, ALP inhibition increased the ratio of extra- to intracellular SNCA and upregulated SNCA association with EVs in neuronal cells. Ultrastructural analysis revealed a widespread, fused multivesicular body-autophagosome compartment. Biochemical characterization revealed the presence of autophagosome-related proteins, such as LC3-II and SQSTM1. This distinct "autophagosome-exosome-like" profile was also identified in human cerebrospinal fluid (CSF) EVs. After a single intracortical injection of SNCA-containing EVs derived from CSF into mice, human SNCA colocalized with endosome and neuronal markers. Prominent SNCA immunoreactivity and a higher number of neuronal SNCA inclusions were observed after DLB patient CSF EV injections. In summary, this study provides compelling evidence that a) ALP inhibition increases SNCA in neuronal EVs, b) distinct ALP components are present in EVs, and c) CSF EVs transfer SNCA from cell to cell in vivo. Thus, macroautophagy/autophagy may regulate EV protein composition and consequently progression in synucleinopathies.

Topics: alpha-Synuclein; Animals; Autophagosomes; Autophagy; Biomarkers; Cells, Cultured; Chloroquine; Exosomes; Humans; Lewy Body Disease; Lysosomes; Macrolides; Mice; Neurons; Parkinson Disease; Protein Transport; Rats, Sprague-Dawley

α-Synuclein (α-SYN), a presynaptic protein with the tendency to aggregate, is linked to α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). α-SYN is the main component of round intracytoplasmic inclusions called Lewy bodies (LBs), which are the hallmark of PD and DLB. In addition, accumulation of amyloid-β and neurofibrillary tangles as in the pathology of Alzheimer's disease has been found in the DLB brain. Glial cytoplasmic inclusions are an MSA-specific type of inclusion found in oligodendrocytes and mainly comprise α-SYN. FK506-binding protein (FKBP) 12 is a member of the immunophilin family with peptidyl-prolyl isomerase activity that promotes protein folding and is believed to act as a chaperone protein. Previous in vitro work indicated that FKBP12 accelerated α-SYN aggregation more than other peptidyl-prolyl isomerases. The enzymatic activity of FKBP12 increases the formation of α-SYN fibrils at subnanomolar concentrations. In this study, we found that FKBP12 colocalized with α-SYN in LBs and neurites in PD and DLB brains. Furthermore, FKBP12-immunopositive neurofibrillary tangles colocalized with phosphorylated tau in DLB and FKBP12-immunopositive glial cytoplasmic inclusions colocalized with α-SYN in MSA. These findings suggest that FKBP12 is linked to the accumulation of α-SYN and phosphorylated tau protein in α-synucleinopathies. FKBP12 may play important roles in the pathogenesis of α-synucleinopathies through its strong aggregation function. Thus, FKBP12 could be an important drug target for α-synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Neurites; Neurofibrillary Tangles; Parkinson Disease; Tacrolimus Binding Protein 1A

Genetics and neuropathology strongly link α-synuclein aggregation and neurotoxicity to the pathogenesis of Parkinson's disease and related α-synucleinopathies. Here we describe a new Drosophila model of α-synucleinopathy based on widespread expression of wild-type human α-synuclein, which shows robust neurodegeneration, early-onset locomotor deficits, and abundant α-synuclein aggregation. We use results of forward genetic screening and genetic analysis in our new model to demonstrate that α-synuclein expression promotes reorganization of the actin filament network and consequent mitochondrial dysfunction through altered Drp1 localization. Similar changes are present in a mouse α-synucleinopathy model and in postmortem brain tissue from patients with α-synucleinopathy. Importantly, we provide evidence that the interaction of α-synuclein with spectrin initiates pathological alteration of the actin cytoskeleton and downstream neurotoxicity. These findings suggest new therapeutic approaches for α-synuclein induced neurodegeneration.

Topics: Actin Cytoskeleton; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Cytoskeletal Proteins; Disease Models, Animal; Drosophila melanogaster; Female; GTP-Binding Proteins; Humans; Lewy Body Disease; Male; Middle Aged; Mitochondria; Nerve Degeneration; Spectrin

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia, where an accumulation of aggregated fibrillar alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to visual hallucination, cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances. Beta-synuclein counteracts aggregation of alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human Lewy body dementia (LBD) diseases. Here we examine expression of alpha-, beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age-matched controls. We provide evidence for neuronal upregulation of beta-synuclein within the frontal cortex and its decrease in occipital cortex of DLB patients. While beta-synuclein-containing neurons were consistently devoid of oligomeric alpha-synuclein in the frontal cortex, we did not observe an overall correlation between total beta-synuclein and 5G4 levels (marker of oligomeric alpha-synuclein). The autophagy markers LC3-II and p62 were increased in the areas of beta-synuclein upregulation in DLB brains, and we show attenuation of autophagy flux when beta-synuclein is overexpressed in vitro. Altogether, this data suggests that beta-synuclein changes in DLB may exacerbate neuronal dysfunction caused by accumulation of alpha-synuclein by influencing protein degradation pathways; this should be taken into consideration when designing therapeutic strategies aimed to decrease alpha-synuclein burden in Lewy body diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autophagy; beta-Synuclein; Female; Frontal Lobe; Humans; Lewy Body Disease; Male; Neurons; Occipital Lobe; Up-Regulation

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Female; Humans; Lewy Body Disease; Male; Olfactory Bulb; tau Proteins

Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson's disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients.. Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA).. MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH.. Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.

Topics: alpha-Synuclein; Chronic Disease; Ganglia, Sympathetic; Humans; Lewy Body Disease; Parkinson Disease; Pure Autonomic Failure; Tyrosine 3-Monooxygenase

The diagnosis and treatment of synucleinopathies such as Parkinson disease and dementia with Lewy bodies would be aided by the availability of assays for the pathogenic disease-associated forms of α-synuclein (αSyn

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Brain Chemistry; Clinical Laboratory Techniques; Female; Follow-Up Studies; Humans; Lewy Body Disease; Longitudinal Studies; Male; Parkinson Disease; Recombinant Proteins; Sensitivity and Specificity; Time Factors

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Humans; Lewy Bodies; Lewy Body Disease

Dementia due to Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the two most common neurodegenerative causes of dementia. They commonly occur together, especially in older people, but clinical identification of these diseases in dementia is difficult in such circumstances. We therefore conducted a study using cases with both comprehensive prospective clinical assessments and complete neuropathological examination to determine if it is possible to identify such mixed cases clinically and to determine features which may identify DLB in the presence of AD dementia.. At Newcastle Brain Bank we identified subjects who had a clinical diagnosis of dementia and who also had autopsy diagnoses of pure AD, pure DLB, or mixed AD+DLB. All subjects had undergone prospective longitudinal clinical assessments. Mixed AD+DLB patients met neuropathological criteria for both DLB (limbic/neocortical Lewy body disease) and AD (Braak stage V/VI and CERAD B/C). The records of these subjects were carefully reviewed by two specialists in old-age psychiatry blind to autopsy findings to determine baseline and final clinical diagnoses based on these detailed records. The presence of characteristic Lewy body symptoms and other clinical information was also recorded.. Of 59 subjects included, 19 were AD, 18 DLB, and 22 mixed AD+DLB. At baseline no subjects were correctly identified as having mixed AD+DLB and by final diagnosis only 23% were identified. The only symptom which helped in identifying the presence of Lewy body disease in the context of a mixed AD+DLB dementia was complex visual hallucinations.. Whilst the identification of DLB in the context of a dementia with an AD pattern is difficult, the emergence of complex visual hallucinations in the context of such a degenerative dementia suggests the presence of Lewy body disease and should encourage a careful assessment. Biomarkers appear likely to be necessary to help improve identification of different disease subtypes underlying dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Brain; Cohort Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; tau Proteins

Topics: alpha-Synuclein; Biomarkers; Dementia; Humans; Lewy Bodies; Lewy Body Disease

Topics: alpha-Synuclein; Biomarkers; Dementia; Humans; Lewy Bodies; Lewy Body Disease

Parkinson's disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Pre-existing diabetes mellitus might be a risk factor for developing Parkinson's disease, and indeed, nearly 60% of Parkinson's disease patients are insulin resistant. Thus, we have investigated whether phosphorylated α-synuclein is deposited in pancreatic tissue of subjects with synucleinopathies. We studied pancreatic tissue from 39 subjects diagnosed with Parkinson's disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 subjects with diabetes mellitus and a normal neuropathological examination, and 52 subjects with a normal neuropathological examination. We examined the pancreatic accumulation of phosphorylated α-synuclein and of the islet amyloid polypeptide precursor (IAPP), an amyloidogenic protein that plays an unknown role in diabetes mellitus, but that can promote α-synuclein amyloid deposition in vitro. Moreover, we performed proximity ligation assays to assess whether these two proteins interact in the pancreas of these subjects. Cytoplasmic phosphorylated α-synuclein deposits were found in the pancreatic β cells of 14 subjects with Parkinson's disease (93%), in 11 subjects with Lewy body Dementia (85%) and in 8 subjects with incidental Lewy body disease (73%). Furthermore, we found similar phosphorylated α-synuclein inclusions in 23 subjects with a normal neuropathological examination but with diabetes mellitus (68%) and in 9 control subjects (17%). In addition, IAPP/α-synuclein interactions appear to occur in patients with pancreatic inclusions of phosphorylated α-synuclein. The presence of phosphorylated α-synuclein inclusions in pancreatic β cells provides a new evidence of a mechanism that is potentially common to the pathogenesis of diabetes mellitus, PD and DLB. Moreover, the interaction of IAPP and α-synuclein in the pancreatic β cells of patients may represent a novel target for the development of strategies to treat these diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloidogenic Proteins; Brain; Cytoplasm; Diabetes Mellitus; Female; Fluorescent Antibody Technique; Humans; Insulin-Secreting Cells; Lewy Body Disease; Male; Parkinson Disease; Phosphorylation; Retrospective Studies

α-Synuclein shares structural homology with 14-3-3 proteins. Seven 14-3-3 protein isoforms have been identified in mammals. Among them, the 14-3-3 sigma isoform was initially considered absent in the mammalian brain. However, we previously identified immunohistochemical association of 14-3-3 sigma with Pick bodies. Because 14-3-3 isoforms other than sigma isoform have been identified in Lewy bodies, we were prompted to look for this 14-3-3 sigma-like immunoreactivity (IR) in Lewy bodies in the brainstem, cerebral cortex, and Lewy neurites in seven patients with Lewy body disease. Unexpectedly, 14-3-3 sigma-like IR was consistently found in various types of Lewy pathologies in all cases examined. Double labeling studies confirmed its colocalization with alpha-synuclein. In general, 14-3-3 proteins can trap and hold some phosphorylated proteins in the cytoplasm and they can prevent or mediate apoptosis and survival of some cells. More precisely, the 14-3-3 sigma isoform is unique in its multiple cellular functions such as facilitating cell cycle arrest in the G2 phase, positively regulating p53, and suppressing tumor growth. Although the precise role of 14-3-3 sigma in the development of Lewy pathology remains elusive, its consistent association to Lewy pathology may expand our understanding of Lewy pathogenesis.

Topics: 14-3-3 Proteins; Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers, Tumor; Brain Stem; Cerebral Cortex; Exoribonucleases; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Neurites; Phosphorylation; Protein Isoforms

Dementia with Lewy bodies is characterized by transient clinical features, including fluctuating cognition and visual hallucinations, implicating dysfunction of cerebral hub regions, such as the pulvinar nuclei of the thalamus. However, the pulvinar is typically only mildly affected by Lewy body pathology in dementia with Lewy bodies, suggesting additional factors may account for its proposed dysfunction.. We conducted a comprehensive analysis of postmortem pulvinar tissue using whole-transcriptome RNA sequencing, protein expression analysis, and histological evaluation.. We identified 321 transcripts as significantly different between dementia with Lewy bodies cases and neurologically normal controls, with gene ontology pathway analysis suggesting the enrichment of transcripts related to synapses and positive regulation of immune functioning. At the protein level, proteins related to synaptic efficiency were decreased, and general synaptic markers remained intact. Analysis of glial subpopulations revealed astrogliosis without activated microglia, which was associated with synaptic changes but not neurodegenerative pathology.. These results indicate that the pulvinar, a region with relatively low Lewy body pathological burden, manifests changes at the molecular level that differ from previous reports in a more severely affected region. We speculate that these alterations result from neurodegenerative changes in regions connected to the pulvinar and likely contribute to a variety of cognitive changes resulting from decreased cortical synchrony in dementia with Lewy bodies. © 2018 International Parkinson and Movement Disorder Society.

Topics: Acetyltransferases; alpha-Synuclein; Chitinase-3-Like Protein 1; Cohort Studies; Diagnosis; Dynamins; Female; Gene Expression; Gene Ontology; Glial Fibrillary Acidic Protein; Glutamate Decarboxylase; Hallucinations; HSP70 Heat-Shock Proteins; Humans; Lewy Body Disease; Male; N-Ethylmaleimide-Sensitive Proteins; Pulvinar; RNA, Messenger; Synaptophysin; Syntaxin 1

GBA1 encodes the lysosomal enzyme β-glucocerebrosidase (GCase) which converts glucosylceramide into ceramide and glucose. Mutations in GBA1 lead to Gaucher's disease and are a major risk factor for Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), synucleinopathies characterized by accumulation of intracellular α-synuclein. In this study, we examined whether decreased ceramide that is observed in GCase-deficient cells contributes to α-synuclein accumulation. We demonstrated that deficiency of GCase leads to a reduction of C18-ceramide species and altered intracellular localization of Rab8a, a small GTPase implicated in secretory autophagy, that contributed to impaired secretion of α-synuclein and accumulation of intracellular α-synuclein. This secretory defect was rescued by exogenous C18-ceramide or chemical inhibition of lysosomal enzyme acid ceramidase that converts lysosomal ceramide into sphingosine. Inhibition of acid ceramidase by carmofur resulted in increased ceramide levels and decreased glucosylsphingosine levels in GCase-deficient cells, and also reduced oxidized α-synuclein and levels of ubiquitinated proteins in GBA1-PD patient-derived dopaminergic neurons. Together, these results suggest that decreased ceramide generation via the catabolic lysosomal salvage pathway in GCase mutant cells contributes to α-synuclein accumulation, potentially due to impaired secretory autophagy. We thus propose that acid ceramidase inhibition which restores ceramide levels may be a potential therapeutic strategy to target synucleinopathies linked to GBA1 mutations including PD and DLB.

Topics: alpha-Synuclein; Autophagy; Cell Line; Ceramides; CRISPR-Cas Systems; Dopaminergic Neurons; Gene Editing; Gene Expression; Glucosylceramidase; Humans; Lewy Body Disease; Lysosomes; Parkinson Disease; Protein Isoforms; rab GTP-Binding Proteins

The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis.. CSF total α-syn, phosphorylated α-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases.. CSF total α-syn, when combined with amyloid β peptide 1-42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ∼0.9) and was largely validated in neuropathologically confirmed cases.. Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid; Biomarkers; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Phosphorylation; tau Proteins

The concept that abnormal protein aggregates show prion-like propagation between cells has been considered to explain the onset and progression of many neurodegenerative diseases. Indeed, both synthetic amyloid-like fibrils and pathogenic proteins extracted from patients' brains induce self-templated amplification and cell-to-cell transmission in vitro and in vivo. However, it is unclear whether exposure to exogenous prion-like proteins can potentially cause these diseases in humans. Here, we investigated in detail the prion-like seeding activities of several kinds of pathogenic α-synuclein (α-syn), including synthetic fibrils and detergent-insoluble fractions extracted from brains of patients with α-synucleinopathies. Exposure to synthetic α-syn fibrils at concentrations above 100 pg/mL caused seeded aggregation of α-syn in SH-SY5Y cells, and seeded aggregation was also observed in C57BL/6 J mice after intracerebral inoculation of at least 0.1 μg/animal. α-Syn aggregates extracted from brains of multiple system atrophy (MSA) patients showed higher seeding activity than those extracted from patients with dementia with Lewy bodies (DLB), and their potency was similar to that of synthetic α-syn fibrils. We also examined the effects of various methods that have been reported to inactivate abnormal prion proteins (PrP

Topics: alpha-Synuclein; Amyloid; Animals; Brain; Cell Line, Tumor; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Lewy Body Disease; Mice; Mice, Inbred C57BL; Microscopy, Immunoelectron; Multiple System Atrophy; Neuroblastoma; Peptide Fragments; Prion Diseases; Transfection

PD patients often have visual alterations, for example, loss of visual acuity, contrast sensitivity or motion perception, and diminished electroretinogram responses. PD pathology is mainly characterized by the accumulation of pathological α-synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina.. To study the correlation between α-synuclein deposits in the retina and brain of autopsied subjects with PD and incidental Lewy body disease.. We evaluated the presence of phosphorylated α-synuclein in the retina of autopsied subjects with PD (9 subjects), incidental Lewy body disease (4 subjects), and controls (6 subjects) by immunohistochemistry and compared the retinal synucleinopathy with brain disease severity indicators.. Whereas controls did not show any phosphorylated α-synuclein immunoreactivity in their retina, all PD subjects and 3 of 4 incidental Lewy body disease subjects had phosphorylated α-synuclein deposits in ganglion cell perikarya, dendrites, and axons, some of them resembling brain Lewy bodies and Lewy neurites. The Lewy-type synucleinopathy density in the retina significantly correlated with Lewy-type synucleinopathy density in the brain, with the Unified Parkinson's disease pathology stage and with the motor UPDRS.. These data suggest that phosphorylated α-synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia. Therefore, the retina may provide an in vivo indicator of brain pathology severity, and its detection could help in the diagnosis and monitoring of disease progression. © 2018 International Parkinson and Movement Disorder Society.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Brain; Correlation of Data; Female; Humans; Lewy Body Disease; Male; Parkinson Disease; Phosphorylation; Retina

In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology

Topics: alpha-Synuclein; Animals; Cytoplasm; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Mice; Mice, Inbred C57BL; Neurons; Oligodendroglia; Organ Specificity; Protein Folding

In Parkinson's disease and dementia with Lewy bodies, neuronal α-synuclein aggregates (Lewy bodies and Lewy neurites) are distributed throughout the nervous system, including the brain, spinal cord, sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla, and skin. Lewy bodies also occur in 10-20% of neurologically asymptomatic individuals older than 60 years. These cases are called incidental Lewy body disease (ILBD). In ILBD, Lewy bodies can be found in the brain, spinal cord, sympathetic ganglia, visceral autonomic nervous system and skin. In addition, neuronal loss in the substantia nigra is observed in ILBD. Thus, ILBD represents pre-symptomatic Parkinson's disease and/or dementia with Lewy bodies. The pathological process of Lewy body disease may affect the peripheral and central nervous systems at the same time.

Topics: alpha-Synuclein; Dementia; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the Arizona Study of Aging and Neurodegenerative Disorders had clinician assessment for PRBD (298 with, 304 without support of the MSQ), completed cognitive and movement examinations, and had neuropathological assessment. Mean age at death was 84.8 years. Histological evidence of LTS was found in 80/101(79.2%) cases with PRBD and 198/501 (39.5%) without PRBD (p < 0.001). Overall sensitivity for predicting LTS by PRBD diagnosis was 28.8%, specificity 93.5%, positive predictive value (PPV) 79.2%, negative predictive value (NPV) 60.5%. Diagnosis of PRBD was less frequently present in subjects without LTS [4/105 (3.8%) of healthy controls, 42/255 (16.5%) AD, 2/33 (6.1%) progressive supranuclear palsy (PSP) without LTS] than in subjects with LTS [11/46 (23.9%) DLB, 58/104 (55.8%) PD, and 4/16 (25.0%) PSP with LTS.] PRBD was not present in any of 46 subjects with incidental Lewy body disease (ILBD). MSQ-supported diagnosis of PRBD appears useful for predicting LTS in manifest neurodegenerative disease, but not necessarily ILBD. Additional prospective autopsy research, including well-characterized polysomnogram-confirmed RBD subjects, is needed to elucidate the earliest tissue abnormalities in the "idiopathic" (premotor/pre-dementia) stage of RBD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Lewy Body Disease; Male; REM Sleep Behavior Disorder; Statistics, Nonparametric; Supranuclear Palsy, Progressive; Surveys and Questionnaires

To assess whether biopsy of the labial minor salivary glands safely detects phosphorylated α-synuclein (pAS) deposits in idiopathic rapid eye movement sleep behavior disorder (IRBD), a condition that precedes the cardinal manifestations of synuclein disorders associated with Lewy-type pathology, namely, Parkinson's disease (PD) and dementia with Lewy bodies (DLB).. In a prospective study, labial biopsy of the minor salivary glands was performed in 62 patients with IRBD, 13 patients with PD, and 10 patients with DLB who were initially diagnosed with IRBD, and in 33 controls. Aggregates of pAS were assessed by immunohistochemistry using antiserine 129-pAS antibody and the conformation-specific 5G4 antibody.. Sufficient biopsy material containing glandular parenchyma was obtained in all participants. Deposits of pAS were found in 31 of 62 (50%) participants with IRBD, 7 of 13 (54%) with PD, 5 of 10 (50%) with DLB, and in one of the 33 (3%) controls. Participants with IRBD, PD, and DLB with and without pAS immunoreactivity did not differ in demographic and clinical features. Adverse events were lip bruising (9.2%), swelling (6.6%), pain (2.4%), and numbness (1.7%) which were mild and transitory and did not require treatment.. Labial minor salivary glands biopsy proved to be a safe and useful procedure to identify pAS in participants with IRBD, and in participants with PD and DLB initially diagnosed with IRBD. The biopsy provides direct histopathological evidence that IRBD represents a synucleinopathy and that could be useful for histological confirmation of synuclein pathology in PD and DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biopsy; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Phosphorylation; Prospective Studies; REM Sleep Behavior Disorder; Salivary Glands, Minor

Neuropsychiatric symptoms such as agitation and delusions occur frequently in Lewy body dementia and Alzheimer's disease and represent significant burden and unmet treatment need. The underlying aetiology remains poorly understood.. We used a multidimensional linear model to look for associations between measurements of agitation, delusions, amyloid, tau and α-synuclein pathology, and synaptic proteins (ZnT3, PSD95, synaptophysin, and β-III-tubulin) across multiple brain regions in post-mortem tissue from a cohort of 130 Lewy body dementia and Alzheimer's disease patients and non-demented controls.. We found both agitations and delusions to be significantly associated with increased tau pathology and decreased levels of ZnT3. ZnT3 packages Zn. Our finding adds to the evidence that zinc modulating compounds are of interest for treatment or symptomatic relief in these dementias.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid; Biomarkers; Blotting, Western; Brain; Cation Transport Proteins; Cohort Studies; Delusions; Female; Humans; Lewy Body Disease; Linear Models; Male; Middle Aged; Psychomotor Agitation; tau Proteins

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Apolipoprotein E4; DNA-Binding Proteins; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Pick Disease of the Brain; Prevalence; Supranuclear Palsy, Progressive; tau Proteins; Tauopathies; TDP-43 Proteinopathies

Topics: alpha-Synuclein; Dementia; Genetic Linkage; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Lewy body disease (LBD) is characterized by accumulation of aggregated α-synuclein in the central nervous system as eosinophilic cytoplasmic inclusions called Lewy bodies. According to their distribution pattern, it is classified into brainstem LBD, limbic LBD and diffuse neocortical LBD. It has been reported that α-synuclein affects various points in the MAPK cascade but its relationship with FGF receptors, which are the most upstream of the pathway, has not been previously investigated. We discovered that among the four FGFRs, FGFR3 showed neuronal upregulation in LBD brains histopathologically. Further examination using neuron-specific methylome analysis revealed that the gene body of FGFR3 was hypermethylated in LBD, suggesting its increased transcription. Altered methylation was not observed in the non-neuronal genome. Altered methylation status was associated with the severity of α-synuclein pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; DNA Methylation; Epigenesis, Genetic; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Neurons; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 3

Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease.. BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Biomarkers; Brain; Cohort Studies; Female; HeLa Cells; Humans; Lewy Body Disease; Male; Middle Aged; Mitophagy; Mutation; Phosphorylation; Phosphoserine; Protein Binding; tau Proteins; Ubiquitin

Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; beta-Synuclein; Brain; Correlation of Data; Female; Genotype; Haplotypes; Humans; INDEL Mutation; Lewy Body Disease; Male; Middle Aged; Regulatory Elements, Transcriptional; Statistics, Nonparametric

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Apolipoproteins E; Brain; Chronic Traumatic Encephalopathy; Cohort Studies; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Polymorphism, Single Nucleotide; Sports; tau Proteins; Trauma Severity Indices; Young Adult

Neuropathological hallmarks of Lewy body disease including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are Lewy bodies in not only the central nervous system but also the peripheral autonomic nervous system. α-synuclein is a presynaptic protein, and is a major constituent of Lewy bodies. The peripheral autonomic nervous system innervates various organs such as the gastrointestinal tract, the heart, the bladder, and the skin. Severe autonomic dysfunction is one of the supportive clinical features of DLB, and reduced cardiac MIBG uptake is an indicative biomarkers of DLB according to the revised criteria for the clinical diagnosis of DLB in 2017. Recently, it was reported that α-synuclein deposits in various biopsied tissue samples, particularly in the skin, can act as a possible biomarker to diagnose PD. Above approach was conducted by using skin biopsies from patients with DLB. Phosphorylated α-synuclein deposits in the skin were found in all patients with DLB, but not in patients with non-synucleinopathy dementia or controls, suggesting that phosphorylated α-synuclein can potentially act as a diagnostic biomarker in DLB.

Topics: alpha-Synuclein; Biomarkers; Biopsy; Dementia; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Skin

Given the overlapping of neuropathological, neurochemical and neuropsychiatric profiles of Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), their differential diagnosis is challenging. Specific neuropsychiatric features or biomarkers, such as cerebrospinal fluid (CSF) α-Synuclein (α-Syn), may aid in differential diagnosis. This study aims to compare the neuropsychiatric and CSF α-Syn profiles in these conditions, and to investigate the possible association between CSF α-Syn levels and neuropsychiatric symptoms.. We conducted a prospective cross-sectional study, between January 2013 and January 2015, with 16 PDD, 28 DLB and 19 AD patients. All participants underwent a detailed clinical, neuropsychological, neuropsychiatric [Neuropsychiatric Inventory (NPI)] and CSF α-Syn analysis.. Significantly greater NPI Hallucinations Subitem score was found in the PDD and DLB groups compared to AD (both p < 0.001). NPI Agitation score was greater in the DLB compared to PDD group (p = 0.012). NPI Sleep score was greater in the DLB compared to AD group (p = 0.001). Total NPI score was greater in the DLB compared to AD and PDD groups. To discriminate between the DLB and AD and between DLB and PDD groups, logistic regression analysis showed that both NPI scores and α-Syn levels were independently associated. There was no correlation between NPI scores and α-Syn levels. Increased NPI scores and α-Syn levels are associated with greater likelihood for being in DLB than in PDD or AD groups. ROC analysis showed that the combination of NPI and α-Syn increases the discriminative ability of each marker alone (p < 0.001) with AUC equal to 0.95 (95% CI 0.91-0.99).. NPI scores and CSF α-Syn levels were useful as independent variables to differentiate DLB from PDD and AD.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cross-Sectional Studies; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Neuropsychological Tests; Parkinson Disease; Prospective Studies

Synucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. For this purpose, herein, we targeted TLR2 using a functional inhibitory antibody (anti-TLR2).. Two different human α-synuclein overexpressing transgenic mice were used in this study. α-synuclein low expresser mouse (α-syn-tg, under the PDGFβ promoter, D line) was stereotaxically injected with TLR2 overexpressing lentivirus to demonstrate that increment of TLR2 expression triggers neurotoxicity and neuroinflammation. α-synuclein high expresser mouse (α-Syn-tg; under mThy1 promoter, Line 61) was administrated with anti-TLR2 to examine that functional inhibition of TLR2 ameliorates neuropathology and behavioral defect in the synucleinopathy animal model. In vitro α-synuclein transmission live cell monitoring system was used to evaluate the role of TLR2 in α-synuclein cell-to-cell transmission.. We demonstrated that administration of anti-TLR2 alleviated α-synuclein accumulation in neuronal and astroglial cells, neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein tg mouse model of PD/DLB. Moreover, in vitro studies with neuronal and astroglial cells showed that the neuroprotective effects of anti-TLR2 antibody were mediated by blocking the neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission which otherwise promotes NFκB dependent pro-inflammatory responses.. This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Humans; Immunotherapy; Lewy Body Disease; Mice; Mice, Transgenic; Nerve Degeneration; Parkinsonian Disorders; Toll-Like Receptor 2

α-Synuclein (αsyn) is the key protein that forms neuronal aggregates in the neurodegenerative disorders Parkinson's disease (PD) and dementia with Lewy bodies. Recent evidence points to the prion-like spread of αsyn from one brain region to another. Propagation of αsyn is likely dependent on release, uptake, and misfolding. Under normal circumstances, this highly expressed brain protein functions normally without promoting pathology, yet the underlying endogenous mechanisms that prevent αsyn spread are not understood. 14-3-3 proteins are highly expressed brain proteins that have chaperone function and regulate protein trafficking. In this study, we investigated the potential role of the 14-3-3 proteins in the regulation of αsyn spread using two models of αsyn spread. In a paracrine αsyn model, 14-3-3θ promoted release of αsyn complexed with 14-3-3θ. Despite higher amounts of released αsyn, extracellular αsyn showed reduced oligomerization and seeding capability, reduced internalization, and reduced toxicity in primary mixed-gender mouse neurons. 14-3-3 inhibition reduced the amount of αsyn released, yet released αsyn was more toxic and demonstrated increased oligomerization, seeding capability, and internalization. In the preformed fibril model, 14-3-3 θ reduced αsyn aggregation and neuronal death, whereas 14-3-3 inhibition enhanced αsyn aggregation and neuronal death in primary mouse neurons. 14-3-3s blocked αsyn spread to distal chamber neurons not exposed directly to fibrils in multichamber, microfluidic devices. These findings point to 14-3-3s as a direct regulator of αsyn propagation, and suggest that dysfunction of 14-3-3 function may promote αsyn pathology in PD and related synucleinopathies.

Topics: 14-3-3 Proteins; alpha-Synuclein; Animals; Brain; Lewy Bodies; Lewy Body Disease; Mice; Neurons; Parkinson Disease; Protein Transport

Dementia with Lewy bodies (DLB) is characterized by neuronal deficits and

Topics: alpha-Synuclein; Animals; Brain; Ceftriaxone; China; Dementia; Disease Models, Animal; Hippocampus; Lewy Bodies; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neurodegenerative Diseases; Neurons; Rats; Rats, Wistar

We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers.. 1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid; Brain; Female; Humans; Lewy Body Disease; Male; Multiple System Atrophy; Nerve Fibers; Parkinson Disease; Protein Aggregation, Pathological; Pure Autonomic Failure; Skin; Skin Diseases

Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.

Topics: alpha-Synuclein; Animals; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lewy Body Disease; Mice; Mice, Transgenic; Multiple System Atrophy; Neurons; Parkinson Disease; Piperidines; Protein Aggregation, Pathological; Protein Folding; Pyrazines; Pyrimidines; Retina

The objective of this study was to investigate the discriminating value of a range of CSF α-synuclein species for dementia with Lewy bodies compared with Alzheimer's disease, PD, and cognitively normal controls.. We applied our recently published enzyme-linked immunosorbent assays to measure the CSF levels of total α-synuclein, oligomeric α-synuclein, and phosphorylated α-synuclein in dementia with Lewy bodies (n = 42), Alzheimer's disease (n = 39), PD (n = 46), and controls (n = 78). General linear models corrected for age and sex were performed to assess differences in α-synuclein levels between groups. We used backward-elimination logistic regression analysis to investigate the combined discriminating value of the different CSF α-synuclein species and Alzheimer's disease biomarkers.. CSF levels of total α-synuclein were lower in dementia with Lewy bodies and PD compared with Alzheimer's disease as well as controls (P < 0.001). In contrast, CSF levels of oligomeric α-synuclein were higher in dementia with Lewy bodies and PD compared with Alzheimer's disease (P < 0.05) and controls (P < 0.001). No group differences were found for phosphorylated α-synuclein. In dementia with Lewy bodies and PD, CSF total α-synuclein levels positively correlated with tau and phosphorylated tau (both r > 0.40, P < 0.01), but not with amyloid-β. CSF α-synuclein species could be useful as part of a biomarker panel for dementia with Lewy bodies. Evaluating both oligomeric α-synuclein and total α-synuclein in CSF helps in the diagnosis of dementia with Lewy bodies. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Electroencephalography; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Psychiatric Status Rating Scales; Retrospective Studies; tau Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes

Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (Syn

Topics: alpha-Synuclein; Animals; Brain; Caffeine; Coffee; Disease Models, Animal; Fatty Acids; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuroprotection; Parkinson Disease; Phosphorylation; Protein Phosphatase 2; Serotonin

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-syn by proteases such as calpain may have a role. Therefore, inhibition of calpain may be of value. The main objective of this study was to evaluate the effects of systemically administered novel low molecular weight calpain inhibitors on α-syn pathology in a transgenic mouse model. For this purpose, non-tg and α-syn tg mice received the calpain inhibitors - Gabadur, Neurodur or a vehicle, twice a day for 30 days. Immunocytochemical analysis showed a 60% reduction in α-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus α-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in α-spectrin breakdown products (SBDPs) SBDPs with Gabadur and 63% reduction using Neurodur. There was a 65% reduction in the active calpain form with Gabadur and a 45% reduction with Neurodur. Moreover, treatment with calpain inhibitors improved activity performance of the α-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies.

Topics: alpha-Synuclein; Animals; Astrocytes; Calpain; Disease Models, Animal; Glycoproteins; Immunohistochemistry; Lewy Body Disease; Mice; Mice, Transgenic; Neuroglia; Neurons; Parkinson Disease

Enhanced inflammation has been associated with Alzheimer's disease (AD) and diseases with Lewy body (LB) pathology, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). One issue is whether amyloid and tangle pathology, features of AD, or α-synuclein LB pathology have similar or different effects on brain inflammation. An aim of this study was to examine if certain features of inflammation changed in brains with increasing LB pathology. To assess this, we measured levels of the anti-inflammatory protein CD200 and the pro-inflammatory protein intercellular adhesion molecule-1 (ICAM-1) in cingulate and temporal cortex from a total of 143 cases classified according to the Unified Staging System for LB disorders. Changes in CD200 and ICAM-1 levels did not correlate with LB pathology, but with AD pathology. CD200 negatively correlated with density of neurofibrillary tangles, phosphorylated tau, and amyloid plaque density. ICAM-1 positively correlated with these AD pathology measures. Double immunohistochemistry for phosphorylated α-synuclein and markers for microglia showed limited association of microglia with LB pathology, but microglia strongly associated with amyloid plaques or phosphorylated tau. These results suggest that there are different features of inflammatory pathology in diseases associated with abnormal α-synuclein compared with AD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Antigens, CD; Female; Gyrus Cinguli; Humans; Intercellular Adhesion Molecule-1; Lewy Body Disease; Male; Microglia; Neurofibrillary Tangles; Plaque, Amyloid; tau Proteins; Temporal Lobe

Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, β-amyloid and α-synuclein pathologies were increased in cases with dementia. Aβ score was the best correlate of the time to dementia in PD. In addition, β-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; tau Proteins

The α-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB).. A computational analysis of SNCA 3' untranslated region to identify potential microRNA (miRNA) binding sites and quantitative real-time polymerase chain reaction (PCR) to determine their expression in isogenic induced pluripotent stem cell-derived dopaminergic and cholinergic neurons as a model of PD and DLB, respectively, were performed. In addition, we performed a deep sequencing analysis of the SNCA 3' untranslated region of autopsy-confirmed cases of PD, DLB, and normal controls, followed by genetic association analysis of the identified variants.. We identified four miRNA binding sites and observed a neuronal-type-specific expression profile for each miRNA in the different isogenic induced pluripotent stem cell-derived dopaminergic and cholinergic neurons. Furthermore, we found that the short structural variant rs777296100-polyT was moderately associated with DLB but not with PD.. We suggest that the regulation of SNCA expression through miRNAs is neuronal-type-specific and possibly plays a part in the phenotypic heterogeneity of synucleinopathies. Furthermore, genetic variability in the SNCA gene may contribute to synucleinopathies in a pathology-specific manner.

Topics: 3' Untranslated Regions; Aged; Aged, 80 and over; alpha-Synuclein; Binding Sites; Cells, Cultured; Cohort Studies; Female; Flow Cytometry; Gene Expression; Gene Expression Regulation; Humans; Lewy Body Disease; Male; MicroRNAs; Nerve Tissue Proteins; Neurons; Parkinson Disease; Polymorphism, Single Nucleotide; RNA, Messenger; Stem Cells

Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha-synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait, and impaired balance, which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, whereas lobules were mildly affected. Cerebellar aggregation pathology may suggest a prionlike spread originating from affected precerebellar structures, and the high homogeneity between patients with dementia with Lewy bodies and Parkinson disease shows that both diseases likely belong to the same neuropathological spectrum. Ann Neurol 2017;81:898-903.

Topics: alpha-Synuclein; Cerebellar Diseases; Humans; Lewy Body Disease; Parkinson Disease

The tau PET ligand 2-((1E,3E)-4-(6-([. Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α-synuclein severity based on the quantitative analysis of α-synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α-synuclein and phospho-tau, Prussian blue staining, and in vitro autoradiography with [. PBB3 fluorescence labeled various α-synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [. Given that the maximum concentration of [

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amygdala; Autoradiography; Basal Ganglia; Benzothiazoles; Female; Hippocampus; Humans; Lewy Body Disease; Male; Microscopy, Fluorescence; Middle Aged; Multiple System Atrophy; Positron-Emission Tomography; tau Proteins; Tissue Banks

Topics: alpha-Synuclein; Antibodies; Brain; Humans; Lewy Body Disease; Parkinson Disease

We investigated the frequency of Lewy-related pathology (LRP) in the amygdala among the population-based Vantaa 85+ study. Data of amygdala samples (N = 304) immunostained with two α-synuclein antibodies (clone 42 and clone 5G4) was compared with the previously analyzed LRP and AD pathologies from other brain regions. The amygdala LRP was present in one third (33%) of subjects. Only 5% of pure AD subjects, but 85% of pure DLB subjects had LRP in the amygdala. The amygdala LRP was associated with dementia; however, the association was dependent on LRP on other brain regions, and thus was not an independent risk factor. The amygdala-predominant category was a rare (4%) and heterogeneous group.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amygdala; Female; Finland; Follow-Up Studies; Humans; Lewy Body Disease; Logistic Models; Male; Prevalence

To our knowledge, a comprehensive study of the survival and causes of death of persons with synucleinopathies compared with the general population has not been conducted. Understanding the long-term outcomes of these conditions may inform patients and caregivers of the expected disease duration and may help with care planning.. To compare survival rates and causes of death among patients with incident, clinically diagnosed synucleinopathies and age- and sex-matched referent participants.. This population-based study used the Rochester Epidemiology Project medical records-linkage system to identify all residents in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from 1991 through 2010. A movement-disorders specialist reviewed the medical records of each individual to confirm the presence of parkinsonism and determine the type of synucleinopathy. For each confirmed patient, an age- and sex-matched Olmsted County resident without parkinsonism was also identified.. We determined the age- and sex-adjusted risk of death for each type of synucleinopathy, the median time from diagnosis to death, and the causes of death.. Of the 461 patients with synucleinopathies, 279 (60.5%) were men, and of the 452 referent participants, 272 (60.2%) were men. From 1991 through 2010, 461 individuals received a diagnosis of a synucleinopathy (309 [67%] of Parkinson disease, 81 [17.6%] of dementia with Lewy bodies, 55 [11.9%] of Parkinson disease dementia, and 16 [3.5%] of multiple system atrophy with parkinsonism). During follow-up, 68.6% (n = 316) of the patients with synucleinopathies and 48.7% (n = 220) of the referent participants died. Patients with any synucleinopathy died a median of 2 years earlier than referent participants. Patients with multiple system atrophy with parkinsonism (hazard ratio, 10.51; 95% CI, 2.92-37.82) had the highest risk of death compared with referent participants, followed by those with dementia with Lewy bodies (hazard ratio, 3.94; 95% CI, 2.61-5.94), Parkinson disease with dementia (hazard ratio, 3.86; 95% CI, 2.36-6.30), and Parkinson disease (hazard ratio, 1.75; 95% CI, 1.39-2.21). Neurodegenerative disease was the most frequent cause of death listed on the death certificate for patients, and cardiovascular disease was the most frequent cause of death among referent participants.. Individuals with multiple system atrophy with parkinsonism, dementia with Lewy bodies, and Parkinson disease dementia have increased mortality compared with the general population. The mortality among persons with Parkinson disease is only moderately increased compared with the general population.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cause of Death; Comorbidity; Dementia; Female; Follow-Up Studies; Humans; Lewy Body Disease; Male; Middle Aged; Minnesota; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders

Proteins implicated in neurodegenerative conditions such as Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have been identified in bodily fluids encased in extracellular vesicles called exosomes. Whether exosomes found in DLB patients can transmit pathology is not clear. In this study, exosomes were successfully harvested through ultracentrifugation from brain tissue from DLB and AD patients as well as non-diseased brain tissue. Exosomes extracted from brains diagnosed with either AD or DLB contained aggregate-prone proteins. Furthermore, injection of brain-derived exosomes from DLB patients into the brains of wild type mice induced α-synuclein (α-syn) aggregation. As assessed through immunofluorescent double labeling, α-syn aggregation was observed in MAP2

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Animals; Astrocytes; Brain; Cell Line, Tumor; Endocytosis; Exosomes; Humans; Lewy Body Disease; Male; Mice, Inbred C57BL; Mice, Inbred DBA; Neurons; Protein Aggregation, Pathological; Rats

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Skin

To investigate whether (1) phosphorylated α-synuclein (p-syn) deposits in skin nerves could be useful in differentiating dementia with Lewy bodies (DLB) from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB.. We studied 18 well-characterized patients with DLB (11 with autonomic dysfunction), 23 patients with nonsynucleinopathy dementia (NSD; 13 with young-onset Alzheimer disease dementia, 6 frontotemporal dementia, and 4 vascular dementia), and 25 healthy controls. All participants underwent skin biopsies from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of p-syn, considered the pathologic form of α-synuclein.. No p-syn was detected in any skin sample in patients with NSD and controls but was found in all patients with DLB. SFN was found in patients with DLB and the autonomic denervation of skin was more severe in patients with autonomic dysfunctions.. (1) In autonomic skin nerves, p-syn is a sensitive biomarker for DLB diagnosis, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger, more representative sample; and (2) skin autonomic neuropathy is part of the DLB pathology and may contribute to autonomic symptoms.. This study provides Class III evidence that p-syn in skin nerve fibers on skin biopsy accurately distinguishes DLB from other forms of dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Autonomic Pathways; Biomarkers; Dementia, Vascular; Diagnosis, Differential; Female; Frontotemporal Dementia; Humans; Leg; Lewy Body Disease; Male; Microscopy, Confocal; Middle Aged; Phosphorylation; Skin

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Dementia; Humans; Lewy Body Disease

Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB) share clinical and molecular features. Cerebrospinal fluid (CSF) biomarkers may help the characterization of these diseases, improving the differential diagnosis. We evaluated the diagnostic performance of five CSF biomarkers across a well-characterized cohort of patients diagnosed with AD, DLB, PDD, and Parkinson's disease (PD).. A total of 208 patients were enrolled in 3 European centers. The diagnostic groups (AD, n = 48; DLB, n = 40; PDD, n = 20; PD, n = 54) were compared with cognitively healthy neurological control subjects (patients with other neurological diseases [OND], n = 46). CSF levels of fatty acid binding protein 3, heart type (FABP3), α-synuclein (α-syn), amyloid-β peptide 1-42, total tau (t-tau), and phosphorylated tau 181 (p-tau) were assessed with immunoassays. Univariate and multivariate statistical analyses were applied to calculate the diagnostic value of the biomarkers as well as their association with clinical scores.. FABP3 levels were significantly increased in patients with AD and DLB compared with those with PD and OND (p < 0.001). CSF t-tau, p-tau, and α-syn were significantly higher in patients with AD than in patients with PDD, DLB, PD, and OND. Combination of FABP3 with p-tau showed high accuracy for the differential diagnosis between AD and DLB (AUC 0.92), whereas patients with AD were separated from those with PDD using a combination of p-tau, FABP3, and α-syn (AUC 0.96). CSF FABP3 was inversely associated with Mini Mental State Examination score in the whole cohort (r = -0.42, p < 0.001).. The combination of CSF biomarkers linked to different aspects of neurodegeneration, such as FABP3, α-syn, and AD biomarkers, improves the biochemical characterization of AD and Lewy body disorders.

Topics: Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Area Under Curve; Diagnosis, Differential; Europe; Fatty Acid Binding Protein 3; Female; Humans; Immunoassay; Lewy Body Disease; Male; Mental Status and Dementia Tests; Middle Aged; Parkinson Disease; Peptide Fragments; Sex Factors; Statistics as Topic; Supranuclear Palsy, Progressive; tau Proteins

Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the intracellular deposition of the protein α-synuclein leading to multiple outcomes, including dementia and Parkinsonism. Recent findings support the notion that across the spectrum of synucleinopathies there exist diverse but specific biochemical modifications and/or structural conformations of α-synuclein, which would give rise to protein strain specific prion-like intercellular transmission, a proposed model that could explain synucleinopathies disease progression. Herein, we characterized a panel of antibodies with epitopes within both the C- and N- termini of α-synuclein. A comprehensive analysis of human pathological tissue and mouse models of synucleinopathy with these antibodies support the notion that α-synuclein exists in distinct modified forms and/or structural variants. Furthermore, these well-characterized and specific tools allow the investigation of biochemical changes associated with α-synuclein inclusion formation. We have identified several antibodies of interest with diverse staining and epitope properties that will prove useful in future investigations of strain specific disease progression and the development of targeted immunotherapeutic approaches to synucleinopathies.

Topics: alpha-Synuclein; Animals; Antibodies; Disease Models, Animal; Epitopes; Humans; Lewy Body Disease; Mice; Mice, Inbred BALB C; Mice, Transgenic

α-Synuclein (αS) forms round cytoplasmic inclusions in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence suggests a physiological function of αS in vesicle trafficking and release. In contrast to earlier tenets, recent work indicates that αS normally exists in cells in a dynamic equilibrium between monomers and tetramers/multimers. We engineered αS mutants incapable of multimerization, leading to excess monomers at vesicle membranes. By EM, such mutants induced prominent vesicle clustering, leading to round cytoplasmic inclusions. Immunogold labeling revealed abundant αS intimately associated with vesicles of varied size. Fluorescence microscopy with marker proteins showed that the αS-associated vesicles were of diverse endocytic and secretory origin. An αS '3K' mutant (E35K + E46K + E61K) that amplifies the PD/DLB-causing E46K mutation induced αS-rich vesicle clusters resembling the vesicle-rich areas of Lewy bodies, supporting pathogenic relevance. Mechanistically, E46K can increase αS vesicle binding via membrane-induced amphipathic helix formation, and '3K' further enhances this effect. Another engineered αS variant added hydrophobicity to the hydrophobic half of αS helices, thereby stabilizing αS-membrane interactions. Importantly, substituting charged for uncharged residues within the hydrophobic half of the stabilized helix not only reversed the strong membrane interaction of the multimer-abolishing αS variant but also restored multimerization and prevented the aberrant vesicle interactions. Thus, reversible αS amphipathic helix formation and dynamic multimerization regulate a normal function of αS at vesicles, and abrogating multimers has pathogenic consequences.

Topics: alpha-Synuclein; Amino Acid Sequence; Animals; Cells, Cultured; Conserved Sequence; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Mutation; Neurons; Parkinson Disease; Protein Structure, Secondary

Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Case-Control Studies; Female; Fluorescent Antibody Technique; Gyrus Cinguli; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Neostriatum; Phosphoproteins; Synapses

Neuronal loss in specific brain regions and neurons with intracellular inclusions termed Lewy bodies are the pathologic hallmark in both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Lewy bodies comprise of aggregated intracellular vesicles and proteins and α-synuclein is reported to be a major protein component. Using human brain tissue from control, PD and DLB and light and confocal immunohistochemistry with antibodies to superoxide dismutase 2 as a marker for mitochondria, α-synuclein for Lewy bodies and βIII Tubulin for microtubules we have examined the relationship between Lewy bodies and mitochondrial loss. We have shown microtubule regression and mitochondrial and nuclear degradation in neurons with developing Lewy bodies. In PD, multiple Lewy bodies were often observed with α-synuclein interacting with DNA to cause marked nuclear degradation. In DLB, the mitochondria are drawn into the Lewy body and the mitochondrial integrity is lost. This work suggests that Lewy bodies are cytotoxic. In DLB, we suggest that microtubule regression and mitochondrial loss results in decreased cellular energy and axonal transport that leads to cell death. In PD, α-synuclein aggregations are associated with intact mitochondria but interacts with and causes nuclear degradation which may be the major cause of cell death.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers; Cell Death; Cell Nucleus; Electron Transport Complex IV; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Microtubules; Middle Aged; Mitochondria; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Parkinson Disease; Superoxide Dismutase

Dementia with Lewy bodies is characterized by α-synuclein accumulation and degeneration of dopaminergic and cholinergic pathways. To gain an overview of brain systems affected by neurodegeneration, we characterized the [18F]FDG-PET metabolic connectivity in 42 dementia with Lewy bodies patients, as compared to 42 healthy controls, using sparse inverse covariance estimation method and graph theory. We performed whole-brain and anatomically driven analyses, targeting cholinergic and dopaminergic pathways, and the α-synuclein spreading. The first revealed substantial alterations in connectivity indexes, brain modularity, and hubs configuration. Namely, decreases in local metabolic connectivity within occipital cortex, thalamus, and cerebellum, and increases within frontal, temporal, parietal, and basal ganglia regions. There were also long-range disconnections among these brain regions, all supporting a disruption of the functional hierarchy characterizing the normal brain. The anatomically driven analysis revealed alterations within brain structures early affected by α-synuclein pathology, supporting Braak's early pathological staging in dementia with Lewy bodies. The dopaminergic striato-cortical pathway was severely affected, as well as the cholinergic networks, with an extensive decrease in connectivity in Ch1-Ch2, Ch5-Ch6 networks, and the lateral Ch4 capsular network significantly towards the occipital cortex. These altered patterns of metabolic connectivity unveil a new in vivo scenario for dementia with Lewy bodies underlying pathology in terms of changes in whole-brain metabolic connectivity, spreading of α-synuclein, and neurotransmission impairment.

Topics: Acetylcholine; Aged; alpha-Synuclein; Brain; Connectome; Databases, Factual; Dopamine; Energy Metabolism; Female; Fluorodeoxyglucose F18; Humans; Lewy Body Disease; Male; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies

It is difficult to diagnose dementia with Lewy bodies (DLB) because it exhibits clinical and neuropathological overlap with both Alzheimer's disease and Parkinson's disease. The α-synuclein protein is a major component of Lewy bodies, and accumulation of α-synuclein aggregates causes synaptic dysfunction in DLB. Epigenetic changes at the synuclein alpha ( SNCA ) gene may be involved in DLB pathogenesis.. We examined DNA methylation rates at 10 CpG sites located in intron 1 of SNCA and SNCA mRNA expression in peripheral leukocytes to compare DLB patients (n = 20; nine men, 11 women; age = 78.8 ± 7.7 years) with healthy controls (n = 20; eight men, 12 women; age = 77.0 ± 6.9 years).. The methylation rate at CpG 4 ( P  = 0.002) and the overall mean methylation rate at these sites (P < 0.001) were significantly lower in DLB patients than in healthy controls after Bonferroni correction. Although SNCA126 , a partial form of SNCA mRNA expression, was significantly increased in DLB ( P  = 0.017), there was no significant difference in total SNCA mRNA expression between DLB patients and healthy controls ( P  = 0.165). No correlation was observed between SCNA mRNA expression levels and blood DNA methylation rates in either DLB or healthy controls.. Our findings indicated that lower methylation rates may be a biomarker for DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers; CpG Islands; DNA Methylation; Female; Humans; Introns; Lewy Body Disease; Male; RNA, Messenger

Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden.. To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively.. Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42.. TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity.. TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Diagnosis; Female; Humans; Lewy Body Disease; Male; Neocortex; Peptide Fragments; Psychiatric Status Rating Scales; tau Proteins; Transforming Growth Factor beta2

Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases.. To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies.. The strategy evaluated in this proof-of-concept study uses the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of misfolded oligomers by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. The technology was first adapted with synthetic αSyn oligomers prepared in vitro and used to screen in 2 blinded cohorts of CSF samples from German and Japanese patients with PD (n = 76) and individuals serving as controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The kinetics of αSyn aggregation were measured by αSyn-PMCA in the presence of CSF samples from the participants to detect αSyn oligomeric seeds present in this biological fluid. The assays were conducted from November 15, 2013, to August 28, 2015.. Kinetic parameters correlated with disease severity at the time of sample collection, measured by the Hoehn and Yahr scale, with the lowest grade indicating unilateral involvement with minimal or no functional impairment, and the highest grade defining patients with complete confinement to wheelchair or bed.. Studies with synthetic αSyn aggregates showed that αSyn-PMCA enabled to detect as little as 0.1 pg/mL of αSyn oligomers. The αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. A blinded study of CSF samples correctly identified patients affected by PD with an overall sensitivity of 88.5% (95% CI, 79.2%-94.6%) and specificity of 96.9% (95% CI, 89.3%-99.6%). The αSyn-PMCA results for different patients correlated with the severity of the clinical symptoms of PD (Japanese cohort: rs = -0.54, P = .006; German cohort: rs = -0.36, P = .02).. The findings suggest that detection of αSyn oligomers by αSyn-PMCA in the CSF of patients affected by PD may offer a good opportunity for a sensitive and specific biochemical diagnosis of the disease. Further studies are needed to investigate the usefulness of αSyn-PMCA to monitor disease progression and for preclinical identification of patients who may develop PD.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Biochemical Phenomena; Diagnostic Tests, Routine; Female; Humans; In Vitro Techniques; Lewy Body Disease; Male; Multiple System Atrophy; Outcome Assessment, Health Care; Parkinson Disease; Peptide Fragments; Predictive Value of Tests; Protein Aggregation, Pathological; Proteostasis Deficiencies; Retrospective Studies; Sensitivity and Specificity; Severity of Illness Index; tau Proteins

Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.. In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.. On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R. Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology.. US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Autopsy; Cohort Studies; Dementia; Female; Humans; Lewy Bodies; Lewy Body Disease; Linear Models; Male; Mutation; Parkinson Disease; PubMed; ROC Curve

Ample in vitro and in vivo experimental evidence supports the hypothesis that intercellular transmission of α-synuclein (αS) is a mechanism underlying the spread of αS pathology in Parkinson's disease and related disorders. What remains unexplained is where and how initial transmissible αS aggregates form. In a previous study, we demonstrated that αS aggregates rapidly form in neurons with impaired nuclear membrane integrity due to the interaction between nuclear proaggregant factor(s) and αS and that such aggregates may serve as a source for αS seeding. In the present study, we identify histones as a potential nuclear proaggregant factor for αS aggregation in both apoptotic neurons and brains with αS pathology. We further demonstrate that histone-induced aggregates contain a range of αS oligomers, including protofibrils and mature fibrils, and that these αS aggregates can seed additional aggregation. Importantly, we demonstrate transmissibility in mouse brains from stereotaxic injection. This study provides new clues to the mechanism underlying initial pathological aggregation of αS in PD and related disorders, and could lead to novel diagnostic and therapeutic approaches.

Topics: alpha-Synuclein; Animals; Apoptosis; Blotting, Western; Brain; Cell Line, Tumor; Cytoplasm; Fluorescent Antibody Technique; Histones; Humans; Immunoprecipitation; Lewy Body Disease; Mice, Inbred C57BL; Microscopy, Confocal; Microscopy, Electron; Microscopy, Fluorescence; Neurons; Protein Aggregation, Pathological; Recombinant Proteins

Despite considerable research to uncover them, the anatomic and neuropathologic correlates of memory impairment in dementia with Lewy bodies (DLB) remain unclear. While some studies have implicated Lewy bodies in the neocortex, others have pointed to α-synuclein pathology in the hippocampus. We systematically examined hippocampal Lewy pathology and its distribution in hippocampal subfields in 95 clinically and neuropathologically characterized human cases of DLB, finding that α-synuclein pathology was highest in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). While the EC had numerous classic somatic Lewy bodies, CA2 contained mainly Lewy neurites in presumed axon terminals, suggesting the involvement of the EC → CA2 circuitry in the pathogenesis of DLB symptoms. Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing these memory deficits. Lewy pathology in CA1-the main output region for CA2-correlated best with results from memory testing despite a milder pathology. This result indicates that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. These correlations remained significant after controlling for several factors, including concurrent Alzheimer's pathology (neuritic plaques and neurofibrillary tangles) and the interval between time of testing and time of death. Our data suggest that although hippocampal Lewy pathology in DLB is predominant in CA2 and EC, memory performance correlates most strongly with CA1 burden.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Cation Transport Proteins; Female; Hippocampus; Humans; Lewy Body Disease; Male; Memory Disorders; Neuropsychological Tests; Psychiatric Status Rating Scales; Regression Analysis; Synucleins

Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound aSyn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial aSyn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-aSyn-binding S109E variant, interfered with membrane-induced aSyn self-assembly, aSyn-mediated vesicle disruption and aSyn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound aSyn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to aSyn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders.

Topics: Adenoviridae; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Brain; Cell Membrane; Cells, Cultured; Cohort Studies; Dopaminergic Neurons; Escherichia coli; Female; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins; Lewy Body Disease; Male; Middle Aged; Neuroprotective Agents; Peptides; Protein Aggregation, Pathological; Rats, Sprague-Dawley; Recombinant Proteins; Unilamellar Liposomes

Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with

Topics: Adaptor Proteins, Vesicular Transport; alpha-Synuclein; Biomarkers; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Lewy Body Disease; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Real-Time Polymerase Chain Reaction; REM Sleep Behavior Disorder; RNA; RNA, Messenger

We have examined the roles of the endothelin-converting enzyme-1 and -2 (ECE-1 and ECE-2) in the homeostasis of α-synuclein (α-syn) and pathogenesis of Lewy body disease. The ECEs are named for their ability to convert inactive big endothelin to the vasoactive peptide endothelin-1 (EDN1). We have found that ECE-1 and ECE-2 cleave and degrade α-syn in vitro and siRNA-mediated knockdown of ECE-1 and ECE-2 in SH-SY5Y neuroblastoma cells significantly increased α-syn both intracellularly (within the cell lysate) (p < 0.05 for both ECE-1 and -2) and extracellularly (in the surrounding medium) (p < 0.05 for ECE-1 and p = 0.07 for ECE-2). Double immunofluorescent labelling showed co-localization of ECE-1 and ECE-2 with α-syn within the endolysosomal system (confirmed by a proximity ligation assay). To assess the possible relevance of these findings to human Lewy body disease, we measured ECE-1 and ECE-2 levels by sandwich ELISA in post-mortem samples of cingulate cortex (a region with a predilection for Lewy body pathology) in dementia with Lewy bodies (DLB) and age-matched controls. ECE-1 (p < 0.001) and ECE-2 (p < 0.01) levels were significantly reduced in DLB and both enzymes correlated inversely with the severity of Lewy body pathology as indicated by the level of α-syn phosphorylated at Ser129 (r = -0.54, p < 0.01 for ECE-1 and r = -0.49, p < 0.05 for ECE-2). Our novel findings suggest a role for ECEs in the metabolism of α-syn that could contribute to the development and progression of DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Cell Line, Tumor; Endothelin-Converting Enzymes; Female; Humans; Lewy Body Disease; Male

Patients with dementia with Lewy bodies (DLB) often experience visual hallucinations, which are related to decreased quality of life for patients and increased caregiver distress. The pathologic changes that contribute to visual hallucinations are not known, but several hypotheses implicate deficient attentional processing. The superior colliculus has a role in visual attention and planning eye movements and has been directly implicated in several models of visual hallucinations. Therefore, the present study sought to identify neurodegenerative changes that may contribute to hallucinations in DLB.. Postmortem superior colliculus tissue from 13 comparison, 10 DLB, and 10 Alzheimer disease (AD) cases was evaluated using quantitative neuropathologic methods.. α-Synuclein and tau deposition were more severe in deeper layers of the superior colliculus. DLB cases had neuronal density reductions in the stratum griseum intermedium, an important structure in directing attention toward visual targets. In contrast, neuronal density was reduced in all laminae of the superior colliculus in AD.. These findings suggest that regions involved in directing attention toward visual targets are subject to neurodegenerative changes in DLB. Considering several hypotheses of visual hallucinations implicating dysfunctional attention toward external stimuli, these findings may provide evidence of pathologic changes that contribute to the manifestation of visual hallucinations in DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Case-Control Studies; Cell Count; Female; Hallucinations; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Degeneration; Superior Colliculi; Tauopathies

Topics: alpha-Synuclein; Female; Humans; Lewy Body Disease; Locus Coeruleus; Middle Aged; Mutation; Parkinson Disease; Substantia Nigra; Tomography, Emission-Computed, Single-Photon; Tropanes

Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α-synuclein (α-syn) into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of α-syn in cortical, hippocampal, and brainstem neurons, resulting in multiple cellular stressors that particularly impair dopamine and glutamate neurotransmission and related motor and cognitive function. Recent studies show that murine neural stem cell (NSC) transplantation can improve cognitive or motor function in transgenic models of Alzheimer's and Huntington's disease, and DLB. However, examination of clinically relevant human NSCs in these models is hindered by the challenges of xenotransplantation and the confounding effects of immunosuppressant drugs on pathology and behavior. To address this challenge, we developed an immune-deficient transgenic model of DLB that lacks T-, B-, and NK-cells, yet exhibits progressive accumulation of human α-syn (h-α-syn)-laden inclusions and cognitive and motor impairments. We demonstrate that clinically relevant human neural progenitor cells (line CNS10-hNPCs) survive, migrate extensively and begin to differentiate preferentially into astrocytes following striatal transplantation into this DLB model. Critically, grafted CNS10-hNPCs rescue both cognitive and motor deficits after 1 and 3 months and, furthermore, restore striatal dopamine and glutamate systems. These behavioral and neurochemical benefits are likely achieved by reducing α-syn oligomers. Collectively, these results using a new model of DLB demonstrate that hNPC transplantation can impact a broad array of disease mechanisms and phenotypes and suggest a cellular therapeutic strategy that should be pursued. Stem Cells Translational Medicine 2017;6:1477-1490.

Topics: alpha-Synuclein; Animals; Astrocytes; Cells, Cultured; Humans; Lewy Body Disease; Memory; Mice; Neural Stem Cells; Neurogenesis; Stem Cell Transplantation

Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aβ1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was used for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aβ1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas intracerebroventricular injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), which also establish detrimental side effects on memory.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Executive Function; Hippocampus; Injections, Intraventricular; Lewy Body Disease; Male; Memory Disorders; Peptide Fragments; Psychomotor Agitation; Rats; Rats, Sprague-Dawley

A tissue microarray (TMA) has previously been developed for use in assessment of neurodegenerative diseases. We investigated the variation of pathology loads in semi-quantitative score categories and how pathology load related to disease progression. Post-mortem tissue from 146 cases were used; Alzheimer's disease (AD) (n = 36), Lewy body disease (LBD) (n = 56), mixed AD/dementia with Lewy bodies (n = 14) and controls (n = 40). TMA blocks (one per case) were constructed using tissue cores from 15 brain regions including cortical and subcortical regions. TMA tissue sections were stained for hyperphosphorylated tau (HP-

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Neurofibrillary Tangles; Pattern Recognition, Automated; Phosphorylation; Severity of Illness Index; tau Proteins; Tissue Array Analysis

We previously demonstrated that transplantation of murine neural stem cells (NSCs) can improve motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB). These benefits occurred without changes in human α-synuclein pathology and were mediated in part by stem cell-induced elevation of brain-derived neurotrophic factor (BDNF). However, instrastriatal NSC transplantation likely alters the brain microenvironment via multiple mechanisms that may synergize to promote cognitive and motor recovery. The underlying neurobiology that mediates such restoration no doubt involves numerous genes acting in concert to modulate signaling within and between host brain cells and transplanted NSCs. In order to identify functionally connected gene networks and additional mechanisms that may contribute to stem cell-induced benefits, we performed weighted gene co-expression network analysis (WGCNA) on striatal tissue isolated from NSC- and vehicle-injected wild-type and DLB mice. Combining continuous behavioral and biochemical data with genome wide expression via network analysis proved to be a powerful approach; revealing significant alterations in immune response, neurotransmission, and mitochondria function. Taken together, these data shed further light on the gene network and biological processes that underlie the therapeutic effects of NSC transplantation on α-synuclein induced cognitive and motor impairments, thereby highlighting additional therapeutic targets for synucleinopathies.

Topics: alpha-Synuclein; Animals; Cell Movement; Corpus Striatum; Disease Models, Animal; Gene Expression; Green Fluorescent Proteins; Lewy Body Disease; Lysosomes; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Neural Stem Cells; Neuroimmunomodulation; Phenotype; Recovery of Function; Stem Cell Transplantation; Synaptic Transmission

The unfolded protein response (UPR) is a pro-survival defence mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders.. The level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison with Alzheimer's disease (AD) and age-matched controls using Western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like endoplasmic reticulum (ER) kinase (p-PERK).. GRP78/BiP was increased to a greater extent in DLB and PDD patients compared with AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex.. Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Endoplasmic Reticulum Chaperone BiP; Female; Heat-Shock Proteins; Humans; Lewy Body Disease; Male; Parkinson Disease; Unfolded Protein Response

The histological hallmark of multiple system atrophy (MSA) is accumulation of phosphorylated α-synuclein in oligodendrocytes. However, it is uncertain whether phosphorylated α-synuclein accumulates in astrocytes of MSA patients. We immunohistochemically examined the frontal and temporal lobes, basal ganglia, cerebellum, brainstem and spinal cord of patients with MSA (n = 15) and Lewy body disease (n = 20), and also in control subjects (n = 20). Accumulation of abnormally phosphorylated and aggregated α-synuclein was found in subpial and periventricular astrocytes in six of the 15 patients with MSA (40%). The structures were confined to the subpial surface of the ventro-lateral part of the spinal cord and brainstem, as well as the subependymal region of the lateral ventricles. They were not visualized by Gallyas-Braak staining, and were immunonegative for ubiquitin and p62. Immunoelectron microscopy revealed that the phosphorylated α-synuclein-immunoreactive structures in astrocytes were non-fibrillar and associated with granular and vesicular structures. The extent of phosphorylated α-synuclein-immunoreactive astrocytes was correlated with disease duration. No such structures were found in Lewy body disease or controls. Accumulation of phosphorylated α-synuclein can occur in subpial and periventricular astrocytes in patients with MSA, especially in those with a long disease duration.

Topics: Aged; alpha-Synuclein; Astrocytes; Brain; Female; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Microscopy, Immunoelectron; Middle Aged; Multiple System Atrophy; Phosphorylation; Spinal Cord; Time Factors

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder caused by abnormal accumulation of Lewy bodies, which are intracellular deposits composed primarily of aggregated α-synuclein (αSyn). Although αSyn has been strongly implicated to induce neurotoxicity, overexpression of wild-type αSyn is shown to be insufficient to trigger formation of protein aggregates by itself. Therefore, investigating the possible mechanism underlying αSyn aggregation is essential to understand the pathogenesis of DLB. Previous studies have demonstrated that amyloid β (Aβ), the primary cause of Alzheimer's disease (AD), may promote the formation of αSyn inclusion bodies. However, it remains unclear how Aβ contributes to the deposition and neurotoxicity of αSyn. In the present study, we investigated the cytotoxic effects of Aβ in αSyn-overexpressed neuronal cells. Our results showed that Aβ inhibits autophagy and enhances αSyn aggregation in αSyn-overexpressed cells. Moreover, Aβ also reduced sirtuin 1 (Sirt1) and its downstream signaling, resulting in increased intracellular ROS accumulation and mitochondrial dysfunction. Our in vitro and in vivo studies support that Aβ-inhibition of AMP-activated protein kinase (AMPK) signaling is involved in the neurotoxic effects of αSyn. Taken together, our findings suggest that Aβ plays a synergistic role in αSyn aggregation and cytotoxicity, which may provide a novel understanding for exploring the underlying molecular mechanism of DLB.

Topics: alpha-Synuclein; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Cell Survival; Humans; Lewy Body Disease; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction

Microglial activation (neuroinflammation) is often cited as a pathogenic factor in the development of neurodegenerative diseases. However, there are significant caveats associated with the idea that inflammation directly causes either α-synuclein pathology or neurofibrillary degeneration (NFD). We have performed immunohistochemical studies on microglial cells in five cases of dementia with Lewy bodies (DLB), median age 87, and nine cases of non-demented (ND) controls, median age 74, using tissue samples from the temporal lobe and the superior frontal gyrus. Three different antibodies known to label microglia and macrophages were employed: iba1, anti-CD68, and anti-ferritin. All DLB cases showed both α-synuclein pathology (Lewy bodies and neurites) and NFD ranging from Braak stage II to IV. In contrast, all controls were devoid of α-synuclein pathology but did show NFD ranging from Braak stage I to III. Using iba1 labeling, our current results show a notable absence of activated microglia in all cases with the exception of two controls that showed small focal areas of microglial activation and macrophage formation. Both iba1 and ferritin antibodies revealed a mixture of ramified and dystrophic microglial cells throughout the regions examined, and there were no measurable differences in the prevalence of dystrophic microglial cells between DLB and controls. Double-labeling for α-synuclein and iba1-positive microglia showed that cortical Lewy bodies were surrounded by both ramified and dystrophic microglial cells. We found an increase in CD68 expression in DLB cases relative to controls. Since microglial dystrophy has been linked to NFD and since it did not appear to be worse in DLB cases over controls, our findings support the idea that the additional Lewy body pathology in DLB is not the result of intensified microglial dystrophy. CD68 is likely associated with lipofuscin deposits in microglial cells which may be increased in DLB cases because of impaired proteostasis. Overall, we conclude that neurodegenerative changes in DLB are unlikely to result directly from activated microglia but rather from dysfunctional ones.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Inflammation; Lewy Body Disease; Lipofuscin; Male; Microglia

Accumulation of phosphorylated α-synuclein in neurons and glial cells is a histological hallmark of Lewy body disease (LBD) and multiple system atrophy (MSA). Recently, filamentous aggregations of phosphorylated α-synuclein have been reported in the cytoplasm of Schwann cells, but not in axons, in the peripheral nervous system in MSA, mainly in the cranial and spinal nerve roots. Here we conducted an immunohistochemical investigation of the cranial and spinal nerves and dorsal root ganglia of patients with LBD. Lewy axons were found in the oculomotor, trigeminal and glossopharyngeal-vagus nerves, but not in the hypoglossal nerve. The glossopharyngeal-vagus nerves were most frequently affected, with involvement in all of 20 subjects. In the spinal nerve roots, Lewy axons were found in all of the cases examined. Lewy axons in the anterior nerves were more frequent and numerous in the thoracic and sacral segments than in the cervical and lumbar segments. On the other hand, axonal lesions in the posterior spinal nerve roots appeared to increase along a cervical-to-sacral gradient. Although Schwann cell cytoplasmic inclusions were found in the spinal nerves, they were only minimal. In the dorsal root ganglia, axonal lesions were seldom evident. These findings indicate that α-synuclein pathology in the peripheral nerves is axonal-predominant in LBD, whereas it is restricted to glial cells in MSA.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Axons; Cranial Nerves; Female; Ganglia, Spinal; Humans; Inclusion Bodies; Lewy Body Disease; Male; Phosphorylation; Schwann Cells; Spinal Nerves

Extracellular α-synuclein has been proposed as a crucial mechanism for induction of pathological aggregate formation in previously healthy cells. In vitro, extracellular α-synuclein is partially associated with exosomal vesicles. Recently, we have provided evidence that exosomal α-synuclein is present in the central nervous system in vivo. We hypothesized that exosomal α-synuclein species from patients with α-synuclein related neurodegeneration serve as carriers for interneuronal disease transmission. We isolated exosomes from cerebrospinal fluid from patients with Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy as a non-α-synuclein related disorder that clinically overlaps with Parkinson's disease, and neurological controls. Cerebrospinal fluid exosome numbers, α-synuclein protein content of cerebrospinal fluid exosomes and their potential to induce oligomerization of α-synuclein were analysed. The quantification of cerebrospinal fluid exosomal α-synuclein showed distinct differences between patients with Parkinson's disease and dementia with Lewy bodies. In addition, exosomal α-synuclein levels correlated with the severity of cognitive impairment in cross-sectional samples from patients with dementia with Lewy bodies. Importantly, cerebrospinal fluid exosomes derived from Parkinson's disease and dementia with Lewy bodies induce oligomerization of α-synuclein in a reporter cell line in a dose-dependent manner. Our data suggest that cerebrospinal fluid exosomes from patients with Parkinson's disease and dementia with Lewy bodies contain a pathogenic species of α-synuclein, which could initiate oligomerization of soluble α-synuclein in target cells and confer disease pathology.

Topics: alpha-Synuclein; Cerebrospinal Fluid; Cohort Studies; Cross-Sectional Studies; Exosomes; Female; Follow-Up Studies; Humans; Lewy Body Disease; Longitudinal Studies; Male; Parkinson Disease; Protein Aggregates

We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher's input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen. PD cases with AD pathology showed increased LRP. The cluster with occipital LRP was associated with non-AD type dementia clinical diagnosis in the Dem-AD-LB group and a faster progression to dementia in the PD groups. We found that (1) LRP pathology in Dem-AD-LB shows a distribution that differs from PD, without significant brainstem or extracranial LRP in initial phases; (2) coincident AD pathology is associated with increased LRP in PD indicating an interaction; (3) LRP and coincident AD pathology independently predict progression to dementia in PD, and (4) evaluation of LRP needs to acknowledge different LRP spreading patterns and evaluate substantia nigra integrity in the neuropathological assessment and consider the implications of neuropathological heterogeneity for clinical and biomarker characterization.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Cluster Analysis; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Parkinson Disease

α-Synuclein (α-syn) has been implicated in neurological disorders with parkinsonism, including Parkinson's disease and Dementia with Lewy body. Recent studies have shown α-syn oligomers released from neurons can propagate from cell-to-cell in a prion-like fashion exacerbating neurodegeneration. In this study, we examined the role of the endosomal sorting complex required for transport (ESCRT) pathway on the propagation of α-syn. α-syn, which is transported via the ESCRT pathway through multivesicular bodies for degradation, can also target the degradation of the ESCRT protein-charged multivesicular body protein (CHMP2B), thus generating a roadblock of endocytosed α-syn. Disruption of the ESCRT transport system also resulted in increased exocytosis of α-syn thus potentially increasing cell-to-cell propagation of synuclein. Conversely, delivery of a lentiviral vector overexpressing CHMP2B rescued the neurodegeneration in α-syn transgenic mice. Better understanding of the mechanisms of intracellular trafficking of α-syn might be important for understanding the pathogenesis and developing new treatments for synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Case-Control Studies; Cell Line; Disease Models, Animal; Endosomal Sorting Complexes Required for Transport; Humans; Lewy Bodies; Lewy Body Disease; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neurons; Parkinson Disease; Parkinsonian Disorders

The "dual-hit" and propagation hypotheses of α-synuclein suggests that the olfactory cells of the olfactory epithelium are among the earliest sites of involvement in Parkinson's disease (PD). We investigated the olfactory epithelium in consecutive cases that had been registered with a brain bank.. This study was undertaken to check the presence or absence of Lewy body pathology in olfactory cells.. Thirty-six male and 11 female patients were examined, including eight with PD, two with dementia with Lewy bodies, 11 with incidental Lewy body disease, and 26 with no Lewy-related alpha-synucleinopathy. The olfactory epithelium was sampled by craniotomy followed by resection of the cribriform plate, which was fixed in formalin and decalcified with ethylenediaminetetra-acetate. Coronal paraffin-embedded sections of the plate were stained with hematoxylin and eosin or immunohistochemically stained with antibodies against phosphorylated α-synuclein to detect Lewy body pathology and neuronal markers of protein gene product 9.5, phosphorylated neurofilament, and tyrosine hydroxylase.. Lewy body pathology was detected in the olfactory cells of the olfactory epithelium in a single patient with incidental Lewy body disease and in six patients with PD, but it was not detected in patients who had dementia with Lewy bodies.. We detected Lewy body pathology in the olfactory epithelium in six of the eight patients with Parkinson's disease and in one patient with incidental Lewy body pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Olfactory Mucosa; Parkinson Disease; Sensory Receptor Cells; Ubiquitin Thiolesterase

Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders.. To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders.. Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA).. Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects.. These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Early Diagnosis; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Parkinson Disease; Prevalence; Submandibular Gland Diseases

Abnormal α-synuclein is deposited in neuronal cytoplasmic inclusions and presynapses in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Previously we have shown that NUB1 is accumulated in these specific regions together with abnormal α-synuclein and that NUB1 is able to inhibit α-synuclein aggregation in cultured cells. We therefore created transgenic (Tg) mice expressing both NUB1 and abnormal α-synuclein to investigate the role of NUB1 on degradation of abnormal α-synuclein in vivo. Immunohistochemical and biochemical studies confirmed that NUB1 was over-expressed in neurons of mice expressing NUB1 (NUB1 Tg), and both NUB1 and abnormal α-synuclein (double Tg). NUB1 levels were increased by 4.7-fold in NUB1 Tg mice compared with wild type mice. Unexpectedly, normal and abnormal α-synuclein levels were unchanged between abnormal α-synuclein Tg mice (Lewy body disease model mice) and double Tg mice, and pathological observations were almost similar between them. Finally, we found that the levels of insoluble α-synuclein were lower and those of some chaperone molecules were higher in double Tg mice compared with abnormal α-synuclein Tg mice. These results suggest that increased levels of NUB1 play a potential role in degradation of detergent-insoluble α-synuclein in vivo, although it is insufficient to degrade abnormal α-synuclein in Lewy body disease model mice.

Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Animals; Brain; Disease Models, Animal; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are pathologically characterized by intraneuronal α-synuclein aggregates and thus labelled as Lewy body disorders (LBD). Conjoint cortical α-synuclein, tau and amyloid-β (Aβ), and striatal Aβ aggregates, have been related to dementia in LBD. Interpretation of current and emerging in vivo molecular imaging of these pathologies will need of precise knowledge of their topographic distribution. We aimed to assess these pathologies further down the encephalon across the LBD-spectrum.. Semiquantitative rating of α-synuclein, Aβ and hyperphosphorylated tau aggregates in midbrain (and cerebellum in the case of Aβ as it represents the last β-amyloidosis stage) sections from cases representative of the LBD-spectrum (PD non-dementia, PD-dementia, DLB; n = 10 each) compared to controls (n = 10) and Alzheimer's disease (AD; n = 10).. α-synuclein midbrain scores rose from controls to AD and then LBD irrespective of dementia. Aβ and tau were more prominent in the tectum/tegmentum, increasing from controls to LBD (mostly in dementia cases in the case of Aβ), and then peaking in AD. By contrast, cerebellar Aβ scores were marginal across the LBD-spectrum, as opposed to AD, only showing a trend towards greater involvement in LBD cases with dementia.. Frequency and severity of Aβ and tau pathologies in the midbrain across the LBD-spectrum were midway between controls and AD, with Aβ in the tectum/tegmentum being associated with dementia. These findings might have potential implications in the eventual interpretation of regional uptake of in vivo molecular imaging of these pathologies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Cerebellum; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Mesencephalon; Parkinson Disease; tau Proteins

The relationship between Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) has long been debated. Although PD is primarily considered a motor disorder, cognitive impairment is often present at diagnosis, and only ∼20% of patients remain cognitively intact in the long term. Alpha-synuclein (SNCA) was first implicated in the pathogenesis of the disease when point mutations and locus multiplications were identified in familial parkinsonism with dementia. In worldwide populations, SNCA genetic variability remains the most reproducible risk factor for idiopathic PD. However, few investigators have looked at SNCA variability in terms of cognitive outcomes.. We have used targeted high-throughput sequencing to characterize the 135kb SNCA locus in a large multinational cohort of patients with PD, PDD, and DLB and healthy controls.. An analysis of 43 tagging single nucleotide polymorphisms across the SNCA locus shows 2 distinct association profiles for symptoms of parkinsonism and/or dementia, respectively, toward the 3' or the 5' of the SNCA gene. In addition, we define a specific haplotype in intron 4 that is directly associated with PDD. The PDD risk haplotype has been interrogated at single nucleotide resolution and is uniquely tagged by an expanded TTTCn repeat.. Our data show that PD, PDD, and DLB, rather than a disease continuum, have distinct genetic etiologies albeit within one genomic locus. Such results may serve as prognostic biomarkers to these disorders, to inform physicians and patients, and to assist in the design and stratification of clinical trials aimed at disease modification. Ann Neurol 2016;79:991-999.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Dementia; Female; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Lewy Body Disease; Male; Parkinson Disease; Polymorphism, Single Nucleotide

Alpha-Synuclein (aSyn) misfolding and aggregation is common in several neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies, which are known as synucleinopathies. Accumulating evidence suggests that secretion and cell-to-cell trafficking of pathological forms of aSyn may explain the typical patterns of disease progression. However, the molecular mechanisms controlling aSyn aggregation and spreading of pathology are still elusive. In order to obtain unbiased information about the molecular regulators of aSyn oligomerization, we performed a microscopy-based large-scale RNAi screen in living cells. Interestingly, we identified nine Rab GTPase and kinase genes that modulated aSyn aggregation, toxicity and levels. From those, Rab8b, Rab11a, Rab13 and Slp5 were able to promote the clearance of aSyn inclusions and rescue aSyn induced toxicity. Furthermore, we found that endocytic recycling and secretion of aSyn was enhanced upon Rab11a and Rab13 expression in cells accumulating aSyn inclusions. Overall, our study resulted in the identification of new molecular players involved in the aggregation, toxicity, and secretion of aSyn, opening novel avenues for our understanding of the molecular basis of synucleinopathies.

Topics: alpha-Synuclein; Calcium-Calmodulin-Dependent Protein Kinase Type 1; Carrier Proteins; Cell Line; DNA-Binding Proteins; Dyrk Kinases; Humans; Lewy Body Disease; Membrane Proteins; Oncogene Proteins; Parkinson Disease; Protein Aggregates; Protein Folding; Protein Serine-Threonine Kinases; Protein Transport; Protein-Tyrosine Kinases; rab GTP-Binding Proteins; RNA Interference; RNA, Small Interfering

α-Synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully-automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in α-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed.

Topics: alpha-Synuclein; Analysis of Variance; Brain; Chi-Square Distribution; Dementia; Female; Humans; Image Processing, Computer-Assisted; Italy; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Parkinson Disease; Pilot Projects; Psychiatric Status Rating Scales; Severity of Illness Index

While increasing life expectancy is a major achievement, the global aging of societies raises a number of medical issues, such as the development of age-related disorders, including neurodegenerative diseases. The three main disease groups constituting the majority of neurodegenerative diseases are tauopathies, alpha-synucleinopathies and diseases due to repetitions of glutamine (including Huntington's disease). In each neurodegenerative disease, the accumulation of one or more aggregated proteins has been identified as the molecular signature of the disease (as seen, for example, in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis and frontotemporal dementia). The etiology of neurodegenerative diseases is often multifactorial, and the known risk factors include, in addition to genetic polymorphisms and age, some other possible causes, such as certain immune and metabolic conditions, endocrine pathologies, gender, socioeconomic or professional status, oxidative stress or inflammation, vitamin deficiencies and environmental factors (chemical exposure, metals). However, innovative strategies to elaborate suitable diagnostic and therapeutic approaches (aiming to at least delay or possibly even reverse disease progression) require further knowledge of the genetic and adaptive immunological characteristics of neurodegenerative diseases.

Topics: alpha-Synuclein; Brain; Cytoskeleton; Humans; Inclusion Bodies; Lewy Body Disease; Nerve Degeneration; Neurodegenerative Diseases; Parkinsonian Disorders; Tauopathies

Dementia with Lewy bodies (DLB) patients frequently experience well formed recurrent complex visual hallucinations (RCVH). This is associated with reduced blood flow or hypometabolism on imaging of the primary visual cortex. To understand these associations in DLB we used pathological and biochemical analysis of the primary visual cortex to identify changes that could underpin RCVH. Alpha-synuclein or neurofibrillary tangle pathology in primary visual cortex was essentially absent. Neurone density or volume within the primary visual cortex in DLB was also unchanged using unbiased stereology. Microarray analysis, however, demonstrated changes in neuropeptide gene expression and other markers, indicating altered GABAergic neuronal function. Calcium binding protein and GAD65/67 immunohistochemistry showed preserved interneurone populations indicating possible interneurone dysfunction. This was demonstrated by loss of post synaptic GABA receptor markers including gephyrin, GABARAP, and Kif5A, indicating reduced GABAergic synaptic activity. Glutamatergic neuronal signalling was also altered with vesicular glutamate transporter protein and PSD-95 expression being reduced. Changes to the primary visual cortex in DLB indicate that reduced GABAergic transmission may contribute to RCVH in DLB and treatment using targeted GABAergic modulation or similar approaches using glutamatergic modification may be beneficial.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Enzyme-Linked Immunosorbent Assay; gamma-Aminobutyric Acid; Hallucinations; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Lewy Body Disease; Microarray Analysis; Neurons; Real-Time Polymerase Chain Reaction; RNA, Messenger; tau Proteins; Visual Cortex

Abnormal α-synuclein (α-syn) accumulation in the CNS may underlie neuronal cell and synaptic dysfunction leading to motor and cognitive deficits in synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Multiple groups demonstrated α-syn accumulation in CNS accessory structures, including the eyes and olfactory terminals, as well as in peripheral organs of Parkinsonian patients. Retinal imaging studies of mice overexpressing fused α-syn::GFP were conducted to evaluate the presence and progression of retinal pathology in a PD/DLB transgenic mouse model. Bright-field image retinal maps and fluorescent images were acquired at 1-month intervals for 3 months. Retinal imaging revealed the accumulation of GFP-tagged α-syn in retinal ganglion cell layer and in the edges of arterial blood vessels in the transgenic mice. Double labeling studies confirmed that the α-syn::GFP-positive cells were retinal ganglion cells containing α-syn. Accumulation of α-syn persisted in the same cells and increased with age. Accumulation of α-syn::GFP was reduced by immunization with single chain antibodies against α-syn. In conclusion, longitudinal live imaging of the retina in the PDGF-α-syn::GFP mice might represent a useful, non-invasive tool to monitor the fate of α-syn accumulation in the CNS and to evaluate the therapeutic effects of compounds targeting α-syn.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Disease Progression; Green Fluorescent Proteins; Humans; Immunotherapy; Lewy Body Disease; Male; Mice; Mice, Transgenic; Optical Imaging; Parkinson Disease; Recombinant Fusion Proteins; Retina; Retinal Ganglion Cells; Single-Chain Antibodies

In Parkinson's disease, misfolded α-synuclein accumulates, often in a ubiquitinated form, in neuronal inclusions termed Lewy bodies. An important outstanding question is whether ubiquitination in Lewy bodies is directly relevant to α-synuclein trafficking or turnover and Parkinson's pathogenesis. By comparative analysis in human postmortem brains, we found that ubiquitin immunoreactivity in Lewy bodies is largely due to K63-linked ubiquitin chains and markedly reduced in the substantia nigra compared with the neocortex. The ubiquitin staining in cells with Lewy bodies inversely correlated with the content and pathological localization of the deubiquitinase Usp8. Usp8 interacted and partly colocalized with α-synuclein in endosomal membranes and, both in cells and after purification, it deubiquitinated K63-linked chains on α-synuclein. Knockdown of Usp8 in the Drosophila eye reduced α-synuclein levels and α-synuclein-induced eye toxicity. Accordingly, in human cells, Usp8 knockdown increased the lysosomal degradation of α-synuclein. In the dopaminergic neurons of the Drosophila model, unlike knockdown of other deubiquitinases, Usp8 protected from α-synuclein-induced locomotor deficits and cell loss. These findings strongly suggest that removal of K63-linked ubiquitin chains on α-synuclein by Usp8 is a critical mechanism that reduces its lysosomal degradation in dopaminergic neurons and may contribute to α-synuclein accumulation in Lewy body disease.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Drosophila; Endopeptidases; Endosomal Sorting Complexes Required for Transport; Humans; Lewy Bodies; Lewy Body Disease; Lysosomes; Male; Ubiquitin; Ubiquitin Thiolesterase; Ubiquitination

A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate "strains" with distinct structures. Among the amyloidogenic proteins, α-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive. Here we show that in the presence of bacterial endotoxin, lipopolysaccharide (LPS), α-synuclein generated a self-renewable, structurally distinct fibril strain that consistently induced specific patterns of synucleinopathies in mice. These results suggest that amyloid fibrils with self-renewable structures cause distinct types of proteinopathies despite the identical primary structure and that exposure to exogenous pathogens may contribute to the diversity of synucleinopathies.

Topics: alpha-Synuclein; Amyloid; Animals; Cells, Cultured; Female; Humans; Lewy Body Disease; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Microglia; Multiple System Atrophy; Neurons; Parkinson Disease; Protein Aggregates; Protein Structure, Tertiary; Protein Transport

The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB.. 417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB.. We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061).. LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Genetic Association Studies; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Logistic Models; Male; Middle Aged; Mutation; Retrospective Studies

α-Synuclein (α-syn) aggregates (Lewy bodies) in Dementia with Lewy Bodies (DLB) may be associated with disturbed calcium homeostasis and oxidative stress. We investigated the interplay between α-syn aggregation, expression of the calbindin-D28k (CB) neuronal calcium-buffering protein and oxidative stress, combining immunofluorescence double labelling and Western analysis, and examining DLB and normal human cases and a unilateral oxidative stress lesion model of α-syn disease (rotenone mouse). DLB cases showed a greater proportion of CB+ cells in affected brain regions compared to normal cases with Lewy bodies largely present in CB- neurons and virtually undetected in CB+ neurons. The unilateral rotenone-lesioned mouse model showed a greater proportion of CB+ cells and α-syn aggregates within the lesioned hemisphere than the control hemisphere, especially proximal to the lesion site, and α-syn inclusions occurred primarily in CB- cells and were almost completely absent in CB+ cells. Consistent with the immunofluorescence data, Western analysis showed the total CB level was 25% higher in lesioned compared to control hemisphere in aged animals that are more sensitive to lesion and 20% higher in aged compared to young mice in lesioned hemisphere, but not significantly different between young and aged in the control hemisphere. Taken together, the findings show α-syn aggregation is excluded from CB+ neurons, although the increased sensitivity of aged animals to lesion was not related to differential CB expression.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Calbindin 1; Humans; Lewy Body Disease; Mice; Mice, Inbred C57BL; Neurons; Oxidative Stress; Protein Aggregates; Rotenone

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Parkinson Disease

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are among the human synucleinopathies, which show alpha-synuclein immunoreactive neuronal and/or glial aggregations and progressive neuronal loss in selected brain regions (eg, substantia nigra, ventral tegmental area, pedunculopontine nucleus). Despite several studies about brainstem pathologies in PD and DLB, there is currently no detailed information available regarding the presence of alpha-synuclein immunoreactive inclusions (i) in the cranial nerve, precerebellar, vestibular and oculomotor brainstem nuclei and (ii) in brainstem fiber tracts and oligodendroctyes. Therefore, we analyzed the inclusion pathologies in the brainstem nuclei (Lewy bodies, LB; Lewy neurites, LN; coiled bodies, CB) and fiber tracts (LN, CB) of PD and DLB patients. As reported in previous studies, LB and LN were most prevalent in the substantia nigra, ventral tegmental area, pedunculopontine and raphe nuclei, periaqueductal gray, locus coeruleus, parabrachial nuclei, reticular formation, prepositus hypoglossal, dorsal motor vagal and solitary nuclei. Additionally we were able to demonstrate LB and LN in all cranial nerve nuclei, premotor oculomotor, precerebellar and vestibular brainstem nuclei, as well as LN in all brainstem fiber tracts. CB were present in nearly all brainstem nuclei and brainstem fiber tracts containing LB and/or LN. These findings can contribute to a large variety of less well-explained PD and DLB symptoms (eg, gait and postural instability, impaired balance and postural reflexes, falls, ingestive and oculomotor dysfunctions) and point to the occurrence of disturbances of intra-axonal transport processes and transneuronal spread of the underlying pathological processes of PD and DLB along anatomical pathways.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain Stem; Coiled Bodies; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurons; Oligodendroglia; Parkinson Disease

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Brain; Cognition Disorders; Female; Humans; Lewy Body Disease; Male; Neurofibrillary Tangles; Phosphorylation; Plaque, Amyloid; tau Proteins

Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer's disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD.. Determine associations between CSF α-synuclein and Lewy body-like symptomatology.. We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6-7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration.. Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI).. The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Executive Function; Female; Hallucinations; Humans; Lewy Body Disease; Male; Neuropsychological Tests; tau Proteins

In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regard to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbor of the brca1 gene (NBr1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 affect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.

Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Animals; Brain; Heat-Shock Proteins; Humans; Inclusion Bodies; Intracellular Signaling Peptides and Proteins; Lewy Body Disease; Mice; Mice, Transgenic; Motor Activity; Proteins; Proteolysis; Sequestosome-1 Protein; Stress, Physiological

Accumulation and aggregation of alpha-synuclein in cortical and hippocampal areas is a pathological sign for dementia with Lewy bodies (DLB) and Parkinson's disease with dementia. However the mechanisms of alpha-synuclein triggered cellular dysfunction leading to the development of memory impairment is not clear. We have created a mouse model of DLB, where aggregation-prone human truncated (120 amino acid) alpha-synuclein is expressed in forebrain areas under the calcium/calmodulin-dependent protein kinase II alpha (CamKII-alpha) promoter. We have observed the presence of the transgenic protein in target forebrain areas, with small granular cytoplasmic accumulation of aggregated alpha-synuclein. This was associated with a progressive deficit in cortical-hippocampal memory tests including the Barnes maze and novel object recognition. This data suggests that low levels of aggregation prone alpha-synuclein are sufficient to induce memory deficits in mice and that forebrain regions associated with cognitive function may have an increased sensitivity to the truncated toxic form of alpha-synuclein.

Topics: Age Factors; alpha-Synuclein; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Humans; Lewy Body Disease; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Prosencephalon; RNA, Messenger

An increase in DNA content is associated with neuronal degeneration in Alzheimer's disease but has not been evaluated in Lewy body diseases. Using stereological principles, flow cytometry, and standard histopathologic methods, we evaluated the number and DNA content of neurons and all cells and the severity of Lewy and Alzheimer pathologies, in brain regions affected at different stages in Lewy body diseases compared with controls. An increase in neuronal DNA content was observed in all the affected brain regions examined, although this change was related to different pathologies. In the substantia nigra, increased neuronal DNA content related to neuronal loss, whereas in the cortex and hippocampus, increased neuronal DNA content related to Alzheimer pathologies. Of note, increased neuronal DNA content did not relate to the deposition of Lewy bodies in any region examined. These data support the concept that increased DNA content increases neuronal susceptibility to degeneration and Alzheimer pathologies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Aneuploidy; Cerebral Cortex; DNA; Female; Hippocampus; Humans; Lewy Bodies; Lewy Body Disease; Male; Nerve Degeneration; Neurofibrillary Tangles

Aberrant accumulation of α-synuclein constitutes inclusion bodies that are considered a characteristic feature of a group of neurological disorders described as synucleinopathies. Often, multiple disease-causing proteins overlap within a given disease pathology. An emerging body of research focuses on the oligomeric populations of various pathogenic proteins, considering them as the culprits causing neuronal damage and degeneration. To this end, the use of conformation-specific antibodies has proven to be an effective tool. Previous work from our laboratory and others has shown that oligomeric entities of α-synuclein and tau accumulate in their respective diseases, but their interrelationship at this higher order has yet to be shown in synucleinopathies.. Here, we used two novel conformation-specific antibodies, F8H7 and Syn33, which recognize α-synuclein oligomers and were developed in our laboratory. We investigated brain tissue from five of each Parkinson's disease and dementia with Lewy bodies patients by performing biophysical and biochemical assays using these antibodies, in addition to the previously characterized anti-tau oligomer antibody T22.. We demonstrate that in addition to the deposition of oligomeric α-synuclein, tau oligomers accumulate in these diseased brains compared with control brains. Moreover, we observed that oligomers of tau and α-synuclein exist in the same aggregates, forming hybrid oligomers in these patients' brains.. In addition to the deposition of tau oligomers, our results also provide compelling evidence of co-occurrence of α-synuclein and tau into their most toxic forms, i.e., oligomers suggesting that these species interact and influence each other's aggregation via an interface in synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Antibodies; Enzyme-Linked Immunosorbent Assay; Female; Frontal Lobe; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Neurons; Parkinson Disease; tau Proteins

Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Comorbidity; Dementia; Female; Humans; Lewy Body Disease; Male; Microtubule-Associated Proteins; Parkinson Disease; Phenotype; Protein Aggregates; tau Proteins

Reducing the burden of α-synuclein oligomeric species represents a promising approach for disease-modifying therapies against synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. However, the lack of efficient drug discovery strategies that specifically target α-synuclein oligomers has been a limitation to drug discovery programs.. Here we describe an innovative strategy that harnesses the power of bimolecular protein-fragment complementation to monitor synuclein-synuclein interactions. We have developed two robust models to monitor α-synuclein oligomerization by generating novel stable cell lines expressing α-synuclein fusion proteins for either fluorescent or bioluminescent protein-fragment complementation under the tetracycline-controlled transcriptional activation system.. A pilot screen was performed resulting in the identification of two potential hits, a p38 MAPK inhibitor and a casein kinase 2 inhibitor, thereby demonstrating the suitability of our protein-fragment complementation assay for the measurement of α-synuclein oligomerization in living cells at high throughput.. The application of the strategy described herein to monitor α-synuclein oligomer formation in living cells with high throughput will facilitate drug discovery efforts for disease-modifying therapies against synucleinopathies and other proteinopathies.

Topics: alpha-Synuclein; Casein Kinase II; Cell Line; Drug Design; Drug Discovery; High-Throughput Screening Assays; Humans; Lewy Body Disease; Models, Biological; Molecular Targeted Therapy; p38 Mitogen-Activated Protein Kinases; Parkinson Disease; Pilot Projects; Protein Multimerization

Urinary urgency and frequency are common in α-synucleinopathies such as Parkinson disease, Lewy body dementia, and multiple system atrophy. These symptoms cannot be managed with dopamine therapy, and their underlying pathophysiology is unclear. We show that in individuals with Parkinson disease, Lewy body dementia, or multiple system atrophy, α-synuclein pathology accumulates in the lateral collateral pathway, a region of the sacral spinal dorsal horn important for the relay of pelvic visceral afferents. Deposition of α-synuclein in this region may contribute to impaired micturition and/or constipation in Parkinson disease and other α-synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Female; Humans; Immunohistochemistry; Lewy Body Disease; Lumbar Vertebrae; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Sacrum; Spinal Cord; Spinal Cord Dorsal Horn; Thoracic Vertebrae; Urinary Incontinence; Visceral Afferents

α-Synuclein (α-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that α-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of α-syn. We describe here the generation and characterization of six novel conformation-specific monoclonal antibodies that recognize specifically α-syn aggregates but not the soluble, monomeric form of the protein. The antibodies described herein did not recognize monomers or fibrils generated from other amyloidogenic proteins including β-syn, γ-syn, β-amyloid, tau protein, islet amyloid polypeptide and ABri. Interestingly, the antibodies did not react to overlapping linear peptides spanning the entire sequence of α-syn, confirming further that they only detect α-syn aggregates. In immunohistochemical studies, the new conformation-specific monoclonal antibodies showed underappreciated small micro-aggregates and very thin neurites in PD and DLB cases that were not observed with generic pan antibodies that recognize linear epitope. Furthermore, employing one of our conformation-specific antibodies in a sandwich based ELISA, we observed an increase in levels of α-syn oligomers in brain lysates from DLB compared to Alzheimer's disease and control samples. Therefore, the conformation-specific antibodies portrayed herein represent useful tools for research, biomarkers development, diagnosis and even immunotherapy for PD and related pathologies.

Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; beta-Synuclein; Brain; Escherichia coli; gamma-Synuclein; Islet Amyloid Polypeptide; Lewy Body Disease; Membrane Glycoproteins; Mice; Neoplasm Proteins; Parkinson Disease; Peptide Fragments; Protein Conformation; Protein Multimerization; Recombinant Proteins; tau Proteins

Synucleinopathies, such as Parkinson's disease and diffuse Lewy body disease, are progressive neurodegenerative disorders characterized by selective neuronal death, abnormal accumulation of misfolded α-synuclein, and sustained microglial activation. In addition to inducing neuronal toxicity, higher-ordered oligomeric α-synuclein causes proinflammatory responses in the brain parenchyma by triggering microglial activation, which may exacerbate pathogenic processes by establishing a chronic neuroinflammatory milieu. We found that higher-ordered oligomeric α-synuclein induced a proinflammatory microglial phenotype by directly engaging the heterodimer TLR1/2 (Toll-like receptor 1 and 2) at the cell membrane, leading to the nuclear translocation of NF-κB (nuclear factor κB) and the increased production of the proinflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-1β (interleukin-1β) in a MyD88-dependent manner. Blocking signaling through the TLR1/2 heterodimer with the small-molecule inhibitor CU-CPT22 reduced the nuclear translocation of NF-κB and secretion of TNF-α from cultured primary mouse microglia. Candesartan cilexetil, a drug approved for treating hypertension and that inhibits the expression of TLR2, reversed the activated proinflammatory phenotype of primary microglia exposed to oligomeric α-synuclein, supporting the possibility of repurposing this drug for synucleinopathies.

Topics: alpha-Synuclein; Animals; HEK293 Cells; Humans; Lewy Body Disease; Mice; Myeloid Differentiation Factor 88; Parkinson Disease; Protein Folding; Proteostasis Deficiencies; Signal Transduction; Toll-Like Receptor 1; Toll-Like Receptor 2

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Inclusion Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Neuroglia; Neurons

Topics: alpha-Synuclein; Animals; Female; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.

Topics: alpha-Synuclein; Animals; Blood-Brain Barrier; Brain; Female; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phenotype; Rats; Rats, Wistar; Substantia Nigra; Synapses

We recently showed that tagging single-nucleotide polymorphisms across the SNCA locus were significantly associated with increased risk for Lewy body (LB) pathology in Alzheimer's disease (AD) cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive.. We used a bioinformatics algorithm to catalog structural variants in a region of SNCA intron 4, followed by phased sequencing. We performed a genetic association analysis in autopsy series of LB variant of Alzheimer's disease (LBV/AD) cases compared with AD-only controls. We investigated the biological functions by expression analysis using temporal-cortex samples.. We identified four distinct haplotypes within a highly polymorphic low-complexity cytosine-thymine (CT)-rich region. We showed that a specific haplotype conferred risk to develop LBV/AD. We demonstrated that the CT-rich site acts as an enhancer element, where the risk haplotype was significantly associated with elevated levels of SNCA messenger RNA.. We have discovered a novel haplotype in a CT-rich region in SNCA that contributes to LB pathology in AD patients, possibly via cis-regulation of the gene expression.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Cytosine; Female; Gene Expression Regulation; Haplotypes; Humans; Introns; Lewy Body Disease; Polymorphism, Single Nucleotide; Risk; RNA, Messenger; Thymine

Topics: alpha-Synuclein; Animals; Female; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

The accumulation of mis-folded and/or abnormally modified proteins is a major characteristic of many neurodegenerative diseases. In Lewy body disease (LBD), which includes Parkinson's disease and dementia with Lewy bodies, insoluble α-synuclein is widely deposited in the presynaptic terminals as well as in the neuronal cytoplasm in distinct brain regions. It is well known that the autophagy-lysosome system serves as an efficient degradation pathway for abnormal molecules within cells. To test the possibility that activated autophagy can degrade abnormal molecules, we investigated the effect of trehalose on abnormal aggregation of α-synuclein in a model of LBD. Trehalose is a natural disaccharide composed of two glucose units and functions as an autophagy inducer. Consistent with previous studies, trehalose increased level of the autophagosomal protein LC3, especially a lipidated form LC3-II in cultured cells and mice brain. Also, trehalose increased levels of several chaperon molecules, such as HSP90 and SigmaR1, in the brains of LBD model mice. Further studies revealed that level of detergent-insoluble α-synuclein was suppressed in mice following oral administration of trehalose, despite an apparent alteration was not observed regarding abnormal aggregation of α-synuclein. These results suggest that the oral intake of trehalose modulates propensity of molecules prior to aggregation formation.

Topics: Administration, Oral; alpha-Synuclein; Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Brain; Disease Models, Animal; HeLa Cells; HSP90 Heat-Shock Proteins; Humans; Lewy Body Disease; Maltose; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Molecular Chaperones; Protein Aggregation, Pathological; Receptors, sigma; Sigma-1 Receptor; Solubility; Trehalose

To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.. In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls.. The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution.. Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha-Synuclein; Case-Control Studies; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; tau Proteins; Young Adult

Lewy body-related α-synucleinopathy (LBAS, the abnormal accumulation of pathologic α-synuclein) is found in the central and peripheral nervous systems, including the spinal cord, dorsal root ganglia, and sympathetic ganglia, of Parkinson's disease patients. However, few studies have focused on the distribution of LBAS in the spinal cord, primary sensory neurons, and preganglionic sympathetic nerves.. We analyzed 265 consecutive subjects with LBAS who underwent autopsy at a general geriatric hospital. LBAS in the spinal cord was significantly associated with that in the lower brainstem regions that are directly connected to the spinal cord (i.e., the medullary reticular formation and locus ceruleus), but it was not associated with the olfactory bulb-amygdala system, which is not directly connected to the spinal cord, suggesting that the lower brainstem is a key structure regarding the spread of LBAS to the spinal cord. In the primary sensory neurons, most subjects with LBAS in the dorsal root ganglia had LBAS in the dorsal root, and all subjects with LBAS in the dorsal root also had LBAS in the dorsal horn, suggesting that LBAS spreads retrogradely from the axonal terminals of the dorsal horn to the somata of the dorsal root ganglia via the dorsal root. In the preganglionic sympathetic nerves, the LBAS in the sympathetic ganglia preceded that in the nucleus of the intermediolateral column of the thoracic cord, suggesting that LBAS spreads retrogradely through the preganglionic sympathetic nerves.. LBAS in the spinal cord was associated with the lower regions of the brainstem, but not with the olfactory bulb or amygdala. LBAS may spread centrifugally along the primary sensory neurons, whereas it may spread centripetally along the preganglionic sympathetic nerves.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Autopsy; Brain; Chi-Square Distribution; Cohort Studies; Female; Ganglia, Spinal; Humans; Lewy Body Disease; Male; Neurons; Psychiatric Status Rating Scales; Spinal Cord; Statistics, Nonparametric

Inflammatory processes have previously been shown to influence cognition and progression of dementia. An involvement of interleukin (IL)-6 has in particular been suggested as altered levels of IL-6 in cerebrospinal fluid (CSF) have been found in patients with Alzheimer's disease (AD). Also, an association between cognitive decline and levels of IL-6 in CSF have been reported. The aim of the present study was to investigate whether patients clinically diagnosed with dementia with Lewy bodies (DLB) display altered CSF IL-6 levels in comparison with patients with AD and control subjects without dementia and whether the IL-6 levels are correlated with cognitive status and biomarkers for AD and synucleinopathy.. To analyse CSF of patients with AD (n = 45), patients with DLB (n = 29) and control subjects without dementia (n = 36), we used immunoassays to measure levels of IL-6 (multiplex electrochemiluminescence); AD markers phosphorylated tau, total tau and amyloid-β1-42 (enzyme-linked immunosorbent assay [ELISA]); and α-synuclein (ELISA). Cognitive status was evaluated using the Mini Mental State Examination (MMSE).. Our analysis showed significantly lower levels of IL-6 in CSF from patients with DLB than in CSF from patients with AD and control subjects without dementia. The IL-6 levels were also negatively correlated with MMSE and positively correlated with α-synuclein CSF levels.. Our findings support previous studies by demonstrating a link between inflammatory processes and dementia progression and further strengthen the hypothesis that IL-6 is involved in dementia pathology and cognitive decline.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers; Cognition; Female; Humans; Interleukin-6; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests

Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.

Topics: alpha-Synuclein; Animals; Autophagy; Disease Models, Animal; Genetic Therapy; Interferon-beta; Lewy Body Disease; Mice; Mice, Inbred C57BL; Neurons; Parkinson Disease; Receptor, Interferon alpha-beta; Signal Transduction; Transcriptome

Accumulation of α-synuclein (α-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about α-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson's disease dementia. Here, we show that striatal transplantation of NSCs into aged α-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV-mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cognition; Corpus Striatum; Dopamine; Glutamic Acid; Lewy Body Disease; Locomotion; Mice; Mice, Inbred C57BL; Neural Stem Cells

Topics: alpha-Synuclein; Female; Frontal Lobe; Humans; Lewy Body Disease; Male; Neurons; Parkinson Disease; tau Proteins

The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.

Topics: Adaptation, Ocular; Age Factors; Aged; alpha-Synuclein; Animals; Brain; Calcium-Binding Proteins; Detergents; Disease Models, Animal; Exploratory Behavior; Female; Glial Fibrillary Acidic Protein; Humans; Lewy Body Disease; Male; Maze Learning; Mice; Mice, Transgenic; Microfilament Proteins; Microscopy, Electron; Muscle Strength; Platelet-Derived Growth Factor; Sarcosine

Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that are characterized by the intracellular accumulation of alpha-synuclein containing aggregates. Recent increasing evidence suggests that Parkinson's disease and MSA pathology spread throughout the nervous system in a spatiotemporal fashion, possibly by prion-like propagation of alpha-synuclein positive aggregates between synaptically connected areas. Concurrently, intracerebral injection of pathological alpha-synuclein into transgenic mice overexpressing human wild-type alpha-synuclein, or human alpha-synuclein with the familial A53T mutation, or into wild-type mice causes spreading of alpha-synuclein pathology in the CNS. Considering that wild-type mice naturally also express a threonine at codon 53 of alpha-synuclein, it has remained unclear whether human wild-type alpha-synuclein alone, in the absence of endogenously expressed mouse alpha-synuclein, would support a similar propagation of alpha-synuclein pathology in vivo.. Here we show that brain extracts from two patients with MSA and two patients with probable incidental Lewy body disease (iLBD) but not phosphate-buffered saline induce prion-like spreading of pathological alpha-synuclein after intrastriatal injection into mice expressing human wild-type alpha-synuclein. Mice were sacrificed at 3, 6, and 9 months post injection and analyzed neuropathologically and biochemically. Mice injected with brain extracts from patients with MSA or probable iLBD both accumulated intraneuronal inclusion bodies, which stained positive for phosphorylated alpha-synuclein and appeared predominantly within the injected brain hemisphere after 6 months. After 9 months these intraneuronal inclusion bodies had spread to the contralateral hemisphere and more rostral and caudal areas. Biochemical analysis showed that brains of mice injected with brain extracts from patients with MSA and probable iLBD contained hyperphosphorylated alpha-synuclein that also seeded aggregation of recombinant human wild-type alpha-synuclein in a Thioflavin T binding assay.. Our results indicate that human wild-type alpha-synuclein supports the prion-like spreading of alpha-synuclein pathology in the absence of endogenously expressed mouse alpha-synuclein in vivo.

Topics: Adaptor Proteins, Signal Transducing; Age Factors; alpha-Synuclein; Animals; Brain; Female; Gene Expression Regulation; Heat-Shock Proteins; Humans; Lewy Body Disease; Male; Mice; Mice, Transgenic; Multiple System Atrophy; Mutation; Phosphorylation; Sequestosome-1 Protein; Ubiquitin

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP-TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α-synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti-spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin-positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α-synuclein-containing inclusions suggests that spatacsin may be involved in the pathogenesis of α-synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Brain; Female; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Proteins; Temporal Lobe

Immunotherapeutic approaches reducing α-synuclein deposits may provide therapeutic benefit for Dementia with Lewy Bodies (DLB). Immunization with full-length human α-synuclein (hα-Syn) protein in a Parkinson's disease mouse model decreased the accumulation of the aggregated forms of this protein in neurons and reduced neurodegeneration. To enhance the immunogenicity of candidate vaccines and to avoid the risk of autoreactive anti-hα-Syn T-helper (Th) cell responses, we generated three peptide-based epitope vaccines composed of different B-cell epitopes of hα-Syn fused with a "non-self" Th epitope from tetanus toxin (P30). Immunization of mice with these epitope vaccines produced high titers of anti-hα-Syn antibodies that bound to Lewy bodies (LBs) and Lewy neurites (LNs) in brain tissue from DLB cases and induced robust Th cell responses to P30, but not to hα-Syn. Further development of these first generation epitope vaccines may facilitate induction of anti-hα-Syn immunotherapy without producing potentially harmful autoreactive Th cell responses.

Topics: alpha-Synuclein; Animals; Antibody Formation; Brain; Epitopes, B-Lymphocyte; Feasibility Studies; Female; Humans; Lewy Bodies; Lewy Body Disease; Mice; Neurites; Peptide Fragments; Tetanus Toxin; Vaccination; Vaccines

Lewy body (LB) diseases are characterized by alpha-synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non-LB diseases including atypical parkinsonism and non-LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD.

Topics: Adrenal Glands; Aged; Aged, 80 and over; alpha-Synuclein; Autonomic Nervous System; Central Nervous System; Female; Gastrointestinal Tract; Humans; Lewy Body Disease; Male; Myocardium; Retrospective Studies; Urogenital System

Given the difficult clinical differential diagnosis between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), growing interest resulted in research on α-synuclein as a potential cerebrospinal fluid biomarker (CSF) for synucleinopathies.. CSF α-synuclein-140 concentrations were determined by a prototype xMAP™ bead-based assay (Innogenetics NV, Belgium). In addition, CSF amyloid β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau181P) levels were determined.. CSF α-synuclein levels were higher in AD patients as compared with cognitively healthy controls (P=.019) and patients with synucleinopathies (P<.001). CSF α-synuclein levels were correlated with T-tau (P<.001) and P-tau181P (P<.001) levels in autopsy-confirmed AD patients. A diagnostic algorithm using α-synuclein and P-tau181P discriminated neuropathologically confirmed AD from DLB patients, resulting in sensitivity and specificity values of 85% and 81%, respectively.. Because CSF α-synuclein levels were significantly higher in AD as compared with synucleinopathies, α-synuclein might have a value as a biomarker for differential dementia diagnosis.

Topics: Aged; Algorithms; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Female; Humans; Lewy Body Disease; Male; Peptide Fragments; Phosphorylation; Sensitivity and Specificity; tau Proteins

Topics: alpha-Synuclein; Biopsy, Needle; Brain; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Parkinson Disease; Submandibular Gland

Respiratory dysfunction, including sleep disordered breathing, is characteristic of multiple system atrophy (MSA) and may reflect degeneration of brainstem respiratory nuclei involved in respiratory rhythmogenesis and chemosensitivity, including the pre-Bötzinger complex (preBötC), nucleus raphe pallidus (RPa), and nucleus raphe obscurus (ROb). However, impaired ventilatory responses to hypercapnia have also been reported in dementia with Lewy bodies (DLB), suggesting that these nuclei may also be affected in DLB.. To determine whether there is involvement of the preBötC, RPa, and ROb in DLB.. We applied stereological methods to analyze sections immunostained for neurokinin-1 receptor and tryptophan hydroxylase in neuropathologically confirmed cases of DLB, MSA, and controls.. Reduction of neuronal density occurred in all three nuclei in DLB, as well as in MSA. The magnitude of neuronal depletion in ROb was similar in DLB and MSA (49% versus 56% respectively, compared to controls, P < 0.05), but neuronal loss in the preBötC and RPa was less severe in DLB than in MSA (40% loss in preBötC of DLB, P < 0.05 and 68% loss in MSA, P < 0.0001, compared to controls; 46% loss in RPa of DLB, P < 0.05 and 73% loss in MSA P < 0.0001, compared to controls).. Medullary respiratory nuclei are affected in dementia with Lewy bodies but less severely than in multiple system atrophy. This may help explain differences in the frequency of sleep disordered breathing in these two disorders.

Topics: Aged, 80 and over; alpha-Synuclein; Case-Control Studies; Female; Humans; Lewy Body Disease; Male; Medulla Oblongata; Middle Aged; Multiple System Atrophy; Neurons; Receptors, Neurokinin-1; Sleep Apnea Syndromes; Tryptophan Hydroxylase

In dementia with Lewy bodies (DLB), blood flow tends to be reduced in the occipital cortex. We previously showed elevated activity of the endothelin and angiotensin pathways in Alzheimer's disease (AD). We have measured endothelin-1 (ET-1) level and angiotensin-converting enzyme (ACE) activity in the occipital cortex in DLB and control brains. We also measured vascular endothelial growth factor (VEGF); factor VIII-related antigen (FVIIIRA) to indicate microvessel density; myelin-associated glycoprotein (MAG), a marker of ante-mortem hypoperfusion; total α-synuclein (α-syn) and α-synuclein phosphorylated at Ser129 (α-syn-p129). In contrast to findings in AD, ACE activity and ET-1 level were unchanged in DLB compared with controls. VEGF and FVIIIRA levels were, however, significantly lower in DLB. VEGF correlated positively with MAG concentration (in keeping with a relationship between reduction in VEGF and hypoperfusion), and negatively with α-syn and α-syn-p129 levels. Both α-syn and α-syn-p129 levels increased in human SH-SY5Y neuroblastoma cells after oxygen-glucose deprivation (OGD), and VEGF level was reduced in SH-SY5Y cells overexpressing α-syn. Taken together, our findings suggest that reduced microvessel density rather than vasoconstriction is responsible for lower occipital blood flow in DLB, and that the loss of microvessels may result from VEGF deficiency, possible secondary to the accumulation of α-syn.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Capillaries; Cell Hypoxia; Cell Line, Tumor; Endothelial Growth Factors; Endothelin-1; Female; Glucose; Humans; Lewy Body Disease; Male; Myelin-Associated Glycoprotein; Occipital Lobe; Peptidyl-Dipeptidase A; Phosphorylation; Vascular Endothelial Growth Factor A; von Willebrand Factor

Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs(®) (AFF)- that do not elicit an α-syn-specific T cell response. This approach allows for the production of long term, sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies, such as Parkinson's disease (PD). In this context, we screened a large library of peptides that mimic the C-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic (tg) mouse models of PD and Dementia with Lewy bodies, the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses, accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies.

Topics: alpha-Synuclein; Animals; Antibodies; Axons; Caudate Nucleus; Clinical Trials as Topic; Disease Models, Animal; Humans; Lewy Body Disease; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Motor Activity; Nerve Degeneration; Parkinson Disease; Putamen; Synapses; T-Lymphocytes; Vaccination

The accumulation of misfolded proteins appears as a fundamental pathogenic process in human neurodegenerative diseases. In the case of synucleinopathies such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB), the intraneuronal deposition of aggregated alpha-synuclein (αS) is a major characteristic of the disease, but the molecular basis distinguishing the disease-associated protein (αSD) from its normal counterpart remains poorly understood. However, recent research suggests that a prion-like mechanism could be involved in the inter-cellular and inter-molecular propagation of aggregation of the protein within the nervous system.. Our data confirm our previous observations of disease acceleration in a transgenic mouse line (M83) overexpressing a mutated (A53T) form of human αS, following inoculation of either brain extracts from sick M83 mice or fibrillar recombinant αS. A similar phenomenon is observed following a "second passage" in the M83 mouse model, including after stereotactic inoculations into the hippocampus or cerebellum. For further molecular analyses of αSD, we designed an ELISA test that identifies αSD specifically in sick mice and in the brain regions targeted by the pathological process in this mouse model. αSD distribution, mainly in the caudal brain regions and spinal cord, overall appears remarkably uniform, whatever the conditions of experimental challenge. In addition to specific detection of αSD immunoreactivity using an antibody against Ser129 phosphorylated αS, similar results were observed in ELISA with several other antibodies against the C-terminal part of αS, including an antibody against non phosphorylated αS. This also indicated consistent immunoreactivity of the murine αS protein specifically in the affected brain regions of sick mice.. Prion-like behaviour in propagation of the disease-associated αS was confirmed with the M83 transgenic mouse model, that could be followed by an ELISA test. The ELISA data question their possible relationship with the conformational differences between the disease-associated αS and its normal counterpart.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Lewy Body Disease; Mice; Mice, Transgenic; Mutation; Neurons

Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, α-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of α-synuclein aggregates in autophagosomes. Neuronal toxicity caused by α-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of α-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autophagy; Cell Line, Tumor; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Parkinson Disease; Phagosomes; Phospholipase D; Protein Aggregates

In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Disease Models, Animal; Gene Expression Regulation; Glutamic Acid; Humans; Lewy Body Disease; Lysine; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Synapses; Thy-1 Antigens

Hypocretin (Hcrt) is a neuropeptide synthesized in the lateral hypothalamus (LHT) that plays a key role in maintaining arousal state. In Parkinson's disease (PD), a narcolepsy-like syndrome is commonly seen, and a previous study showed substantial Hcrt neuronal loss in accordance with PD severity. In the present study, we quantitatively examined Hcrt immunoreactivity and α-synuclein and tau pathologies in the LHT and locus coeruleus (LC) in dementia with Lewy bodies (DLB) (n=15), Alzheimer's disease (AD) (n=14), and controls (n=7). In the LHT, substantial Hcrt-positive neurons were detected in controls. In contrast, in DLB and AD, the numbers of both total neurons and Hcrt-positive neurons were significantly reduced. The reduction of the latter was significantly severer in DLB than in AD. In the LC of controls, many Hcrt-positive axonal terminals were found. In contrast, the amount of Hcrt immunoreactivity was significantly reduced both in DLB and AD. In DLB, some Lewy body (LB)-bearing neurons were detected in the LHT, but the Hcrt-positive neurons did not have any LBs. Meanwhile, some tau-positive neurofibrillary tangle (NFT)-bearing neurons were detected in the LHT, and Hcrt-positive neurons occasionally contained NFTs. We observed a significant negative correlation between the number of Hcrt-positive neurons in the LHT and the neurofibrillary stage (r=-0.67, p=0.0067), whereas no significant correlation was found between the number of Hcrt-positive neurons and the Lewy stage (r=-0.47, p=0.077). This is the first report clarifying the substantial loss of Hcrt neurons in the LHT and of Hcrt axonal terminals in the LC in DLB and the correlation between the severity of Hcrt neuronal loss and progression of neurofibrillary pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Axons; Brain; Case-Control Studies; Female; Humans; Intracellular Signaling Peptides and Proteins; Lewy Body Disease; Male; Middle Aged; Neurons; Neuropeptides; Orexins; tau Proteins

Progressive loss of substantia nigra dopamine neurons (SN DA) is a hallmark of aging and of Parkinson's disease (PD). Mutations in PARK genes cause familial PD forms. Increased expression of alpha-synuclein (PARK4) is a disease-triggering event in familial PD and also observed in SN DA neurons in sporadic PD but related transcriptional changes are unknown. With optimized single-cell quantitative real-time polymerase chain reaction analysis, we compared messenger RNA and microRNA levels in SN DA neurons from sporadic PD patients and controls. Non-optimally matched donor ages and RNA integrities are common problems when analyzing human samples. We dissected the influence of distinct ages and RNA integrities of our samples by applying a specifically-optimized, linear-mixed-effects model to quantitative real-time polymerase chain reaction-data. We identified that elevated alpha-synuclein messenger RNA levels in SN DA neurons of human PD brains were positively correlated with corresponding elevated levels of mRNAs for functional compensation of progressive SN DA loss and for enhanced proteasomal (PARK5/UCHL1) and lysosomal (PARK9/ATPase13A2) function, possibly counteracting alpha-synuclein toxicity. In contrast, microRNA miR-133b levels, previously implicated in transcriptional dysregulation in PD, were not altered in SN DA neurons in PD.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Dopamine; Dopaminergic Neurons; Female; Humans; Lewy Body Disease; Lysosomes; Male; MicroRNAs; Middle Aged; Mutation; Parkinson Disease; Proteasome Endopeptidase Complex; RNA, Messenger; Substantia Nigra

Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD.. Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible.. We did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA.. Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations.

Topics: alpha-Synuclein; Brain; DNA; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Lewy Body Disease; Male; Mutation; Parkinson Disease

In Lewy body disease, Lewy pathology (LP: the accumulation of α-synuclein in neuronal perikarya and processes as Lewy bodies and Lewy neurites and dots, respectively) is observed in the central and peripheral nervous systems. Previous autopsy or biopsy studies of individuals with Lewy body diseases (LBDs) indicated that LP could be observed in the peripheral nerves of the gastrointestinal (GI) systems. The aim of this study is to clarify whether examination of GI and biliary surgical specimens would be useful for diagnosing LBD. We analyzed eight patients diagnosed clinically with LBD and with medical histories of GI or biliary surgery at our hospital. LP was identified by using α-synuclein immunohistochemistry in GI and biliary surgical specimens obtained before, at or after the clinical onset of LBD. LP was frequently observed in Auerbach's plexus, Meissner's plexus and the subserosal nerve fascicles within the GI and biliary surgical specimens. LP was observed in the specimens obtained 7 years before the onset of LBD. Our approach does not require any invasive procedures for patients. The immunohistochemical analysis of anti- α-synuclein antibody to archival GI or biliary surgical specimens from patients with clinically suspected LBD may contribute to clinical diagnosis of LBD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biliary Tract; Biomarkers; Biopsy; Female; Gastrointestinal Tract; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Myenteric Plexus; Neurites; Retrospective Studies; Submucous Plexus

A growing number of PSEN1 mutations have been associated with dementia with Lewy bodies and familial Alzheimer's disease with concomitant α-synuclein pathology. The objective of this study was to determine if PSEN1 plays a direct role in the development of α-synuclein pathology in these diseases. Using mass spectrometry, immunoelectron microscopy and fluorescence lifetime image microscopy based on Forster resonance energy transfer (FLIM-FRET) we identified α-synuclein as a novel interactor of PSEN1 in wild-type mouse brain tissue. The interaction of α-synuclein with PSEN1 was detected in post-mortem brain tissue from cognitively normal cases and was significantly increased in tissue from cases with dementia with Lewy bodies and familial Alzheimer's disease associated with known PSEN1 mutations. We confirmed an increased interaction of PSEN1 and α-synuclein in cell lines expressing well characterized familial Alzheimer's disease PSEN1 mutations, L166P and delta exon 9, and demonstrated that PSEN1 mutations associate with increased membrane association and accumulation of α-synuclein. Our data provides evidence of a molecular interaction of PSEN1 and α-synuclein that may explain the clinical and pathophysiological overlap seen in synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and some forms of Alzheimer's disease.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Brain; Cells, Cultured; Cerebral Cortex; CHO Cells; Cricetulus; Female; Glutathione Transferase; Humans; Lewy Body Disease; Male; Mice; Mice, Knockout; Microscopy, Immunoelectron; Mutation; Neurons; Presenilin-1

Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of β-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular-structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for β-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Antibodies; Astrocytes; Brain; Extracellular Space; Female; Gliosis; Humans; Intracellular Space; Lewy Bodies; Lewy Body Disease; Male; Microglia; Middle Aged; Neurons; Parkinson Disease; Protein Structure, Secondary

In dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.. We generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.. Together, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Hippocampus; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Lewy Body Disease; Mice; Mice, Transgenic; Neurons; Rats; Real-Time Polymerase Chain Reaction; Receptor, Metabotropic Glutamate 5

Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Female; Immunotherapy; Lewy Body Disease; Male; Mice; Neurons; Parkinson Disease

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

Topics: alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Case-Control Studies; Cohort Studies; Female; Genetic Association Studies; Genetic Loci; Humans; Lewy Body Disease; Lysosomal Membrane Proteins; Lysosomes; Male; Parkinson Disease; Receptors, Scavenger; Risk Factors

To gain a better understanding of the significance of α-synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α-synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α-synuclein pathological conditions are related to clinical measures of disease progression. Post-mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age-matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α-synuclein aggregates. The progression from Braak α-synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α-synuclein stages but did not vary across consecutive Braak α-synuclein stages. We observed a negative correlation between neuronal density and local α-synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = -0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α-synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α-synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Analysis of Variance; Case-Control Studies; Cell Count; Cell Death; Disease Progression; Female; Humans; Lewy Body Disease; Male; Netherlands; Neurons; Parkinson Disease; Severity of Illness Index; Statistics as Topic; Substantia Nigra

Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB) are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV) vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable to α-synuclein over-expression. This animal model provides a powerful new tool for studies of neuronal degeneration in conditions of widespread cortical α-synuclein pathology, such as DLB, as well an attractive model for the exploration of novel biomarkers.

Topics: alpha-Synuclein; Animals; Animals, Newborn; Axons; Cell Nucleus; Cholinergic Neurons; Dependovirus; Disease Models, Animal; Disease Progression; Dopamine Agonists; Exploratory Behavior; Female; Genetic Vectors; Humans; Interneurons; Lewy Body Disease; Microglia; Motor Activity; Neostriatum; Phenotype; Pregnancy; Prosencephalon; Protein Transport; Rats; Rats, Sprague-Dawley; Synapses

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Female; Lewy Body Disease; Male; Parkinson Disease

Synaptic dysfunction is thought to have an important role in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease (AD) and Lewy body disease (LBD). To improve our understanding of synaptic alterations in health and disease, we investigated synaptosomes prepared from post-mortem human cerebral cortex, putamen (PT), and two regions of the caudate nucleus, dorso-lateral (DL) and ventro-medial (VM), regions commonly affected in AD and LBD. We observed that the fraction of synaptosomal particles with reactivity for dopamine transporter (DAT) was significantly reduced in the PT and VM caudate of patients with neuropathological diagnosis of LBD. As expected, these differences also were reflected in direct measurements of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in caudate and PT of LBD patients. The fraction of synaptosomal particles positive for amyloid β (Aβ) was significantly increased in frontal cortical samples of patients with the neuropathological diagnosis of severe AD, and was positively correlated with disease progression. We also prepared synaptosomes from the striatum of mice with severe loss of DA neurons (Slc6a3-DTR mice) and wild-type littermate controls. We observed markedly reduced levels of DAT-positive synaptosomes in Slc6a3-DTR mice following exposure to diphtheria toxin (DT). Striatal levels of DA and DOPAC in Slc6a3-DTR mice also were reduced significantly following DT exposure. We conclude that flow cytometric analysis of synaptosomes prepared from human or mouse brain provides an opportunity to study expression of pathology-associated proteins and also the specific loss of dopaminergic nerve terminals. Hence, we believe it is a valid method to detect pathological changes at the level of the synapse in LBD as well as AD.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Catecholamines; Dopamine Plasma Membrane Transport Proteins; Female; Flow Cytometry; Humans; Lewy Body Disease; Male; Mice; Synaptosomes; Vesicular Glutamate Transport Protein 1

Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson's disease (PD) patients. Little is known, however, about the different phenotypes of microglia and how they change during disease progression, in the SN or in another brain region, like the hippocampus (HC), which is implicated in dementia and depression, important non-motor symptoms in PD. We studied phenotypes and activation of microglia in the SN and HC of established PD patients (Braak PD stage 4–6), matched controls (Braak PD stage 0) and of incidental Lewy Body disease (iLBD) cases (Braak PD stage 1–3) that are considered a prodromal state of PD. As recent experimental studies suggested that toll-like receptor 2 (TLR2) mediates α-synuclein triggered microglial activation, we also studied whether TLR2 expression is indeed related to pathology in iLBD and PD patients. A clear α-synuclein pathology-related increase in amoeboid microglia was present in the HC and SN in PD. Also, morphologically primed/reactive microglial cells, and a profound increase in microglial TLR2 expression were apparent in iLBD, but not PD, cases, indicative of an early activational response to PD pathology. Moreover, TLR2 was differentially expressed between the SN and HC, consistent with a region-specific pattern of microglial activation. In conclusion, the regional changes in microglial phenotype and TLR2 expression in primed/reactive microglia in the SN and HC of iLBD cases indicate that TLR2 may play a prominent role in the microglial-mediated responses that could be important for PD progression.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain; Female; Hippocampus; Humans; Lewy Body Disease; Male; Microglia; Middle Aged; Neurons; Parkinson Disease; Phenotype; Substantia Nigra; Toll-Like Receptor 2

Calcineurin (CN) is a highly conserved Ca(2+)-calmodulin (CaM)-dependent phosphatase that senses Ca(2+) concentrations and transduces that information into cellular responses. Ca(2+) homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca(2+), thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.

Topics: alpha-Synuclein; Animals; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Calmodulin; Cells, Cultured; Gene Knockdown Techniques; Humans; Lewy Body Disease; Mice; Mice, Transgenic; Models, Neurological; Neurons; NFATC Transcription Factors; Parkinson Disease; Phosphoric Monoester Hydrolases; Rats; Recombinant Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Tacrolimus

Topics: Aged; alpha-Synuclein; Amyloid beta-Peptides; Autoantibodies; Biomarkers; Female; Humans; Lewy Body Disease; Male; Parkinson Disease; Peptide Fragments; Severity of Illness Index; tau Proteins

Neurogranin is a calmodulin binding protein that has been implicated in learning and memory, long-term potentiation and synaptic plasticity. Neurons expressing neurogranin in the cortex degenerate in late stages of Parkinson's disease with widespread α-synuclein pathology. While analyzing neurogranin gene expression levels through rtPCR in brains of mouse models overexpressing human α-synuclein, we found levels were elevated 2.5 times when compared to nontransgenic animals. Immunohistochemistry in the cortex revealed colocalization between α-synuclein and neurogranin in mouse transgenics when compared to control mice. Coimmunoprecipitation studies in the superior temporal cortex in humans confirmed interaction between α-synuclein and neurogranin, and decreased interaction between α-synuclein and neurogranin was noticed in patients diagnosed with Parkinson's disease when compared to normal control brains. Additionally, phosphorylated neurogranin levels were also decreased in the human superior temporal cortex in patients diagnosed with Parkinson's disease and patients diagnosed with dementia with Lewy bodies. Here, we show for the first time that neurogranin binds to α-synuclein in the human cortex, and this interaction decreases in Parkinson's disease along with the phosphorylation of neurogranin, a molecular process thought to be involved in learning and memory.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Cerebral Cortex; Disease Models, Animal; Humans; Lewy Body Disease; Long-Term Potentiation; Mice; Neurogranin; Neurons; Parkinson Disease; Protein Binding; Substantia Nigra

Kallikrein-6 and calpain-1 are amongst a small group of proteases that degrade α-synuclein. We have explored the possibility that reduction in the level or activity of these enzymes contributes to the accumulation of α-synuclein in Lewy body diseases. We measured calpain-1 activity by fluorogenic activity assay, kallikrein-6 level by sandwich ELISA, and levels of α-synuclein and α-synuclein phosphorylated at serine 129 (α-synuclein-P129), in post-mortem brain tissue in pure dementia with Lewy bodies (DLB, n=12), Alzheimer's disease (AD, n=20) and age-matched controls (n=19). Calpain-1 activity was significantly reduced in DLB within the cingulate and parahippocampal cortex, regions with highest α-synuclein and α-synuclein-P129 load, and correlated inversely with the levels of α-synuclein and α-synuclein-P129. Calpain-1 was unaltered in the thalamus and frontal cortex, regions with less α-synuclein pathology. Kallikrein-6 level was reduced in the cingulate cortex in the DLB cohort, and correlated inversely with α-synuclein and α-synuclein-P129. Kallikrein-6 was also reduced in DLB in the thalamus but not in relation to α-synuclein or α-synuclein-P129 load and was unaltered in the frontal and parahippocampal cortex. In SH-SY5Y cells overexpressing wild-type α-synuclein there was partial co-localisation of kallikrein-6 and calpain-1 with α-synuclein, and siRNA-mediated knock-down of kallikrein-6 and calpain-1 increased the amount of α-synuclein in cell lysates. Our results indicate that reductions in kallikrein-6 and calpain-1 may contribute to the accumulation of α-synuclein in DLB.

Topics: alpha-Synuclein; Alzheimer Disease; Brain; Calpain; Case-Control Studies; Cell Line, Tumor; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Kallikreins; Lewy Body Disease; Male; Neuroblastoma; Phosphorylation; RNA, Small Interfering; Serine

Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

Topics: alpha-Synuclein; Animals; Cells, Cultured; Chemokines; Chromatography, Gel; Dopaminergic Neurons; Humans; Immunohistochemistry; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurons; Paracrine Communication; Protein Conformation; Protein Structure, Quaternary; Rats; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 2; Up-Regulation

α-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative α-synucleinopathies. However, the molecular mechanisms underlying α-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble α-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated α-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse α-synuclein efficiently induced similar α-synuclein pathologies in wild-type mice. C57BL/6J mice injected with α-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble α-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse α-synuclein started to accumulate 3 months after inoculation, while injected human α-synuclein fibrils disappeared in about a week. These results indicate that α-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces α-synuclein pathology in vivo. This is a new mouse model of sporadic α-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.

Topics: Administration, Intranasal; alpha-Synuclein; Animals; Behavior, Animal; Brain; Disease Models, Animal; Female; Humans; Injections, Intraventricular; Lewy Body Disease; Mice; Mice, Inbred C57BL; Prions; Recombinant Proteins; Time Factors

We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB).. Patients from an IRBD cohort recruited between 1991 and 2003, and previously assessed in 2005, were followed up during an additional period of 7 years. In this original cohort, we sought to identify the nature and frequency of emerging defined neurodegenerative syndromes diagnosed by standard clinical criteria. We estimated rates of survival free from defined neurodegenerative disease by means of the Kaplan-Meier method. We further characterised individuals who remained diagnosed as having only IRBD, through dopamine transporter (DAT) imaging, transcranial sonography (TCS), and olfactory testing. We did a neuropathological assessment in three patients who died during follow-up and who had the antemortem diagnosis of PD or DLB.. Of the 44 participants from the original cohort, 36 (82%) had developed a defined neurodegenerative syndrome by the 2012 assessment (16 patients were diagnosed with PD, 14 with DLB, one with multiple system atrophy, and five with mild cognitive impairment). The rates of neurological-disease-free survival from time of IRBD diagnosis were 65·2% (95% CI 50·9 to 79·5) at 5 years, 26·6% (12·7 to 40·5) at 10 years, and 7·5% (-1·9 to 16·9) at 14 years. Of the four remaining neurological-disease-free individuals who underwent neuroimaging and olfactory tests, all four had decreased striatal DAT uptake, one had substantia nigra hyperechogenicity on TCS, and two had impaired olfaction. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathological examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one case. In these three patients, neuronal loss and Lewy pathology (α-synuclein-containing Lewy bodies and Lewy neurites) were found in the brainstem nuclei that regulate REM sleep atonia.. Most IRBD individuals from our cohort developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD and DLB in IRBD, such as decreased striatal DAT binding. Our findings indicate that in most patients diagnosed with IRBD this parasomnia represents the prodromal phase of a Lewy body disorder. IRBD is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process.. None.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Cohort Studies; Disease Progression; Disease-Free Survival; Female; Humans; Lewy Body Disease; Male; Nerve Degeneration; Prodromal Symptoms; REM Sleep Behavior Disorder

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Female; Gaucher Disease; Glucosylceramidase; Humans; Lewy Body Disease; Male; Mutation; Parkinson Disease; Parkinsonian Disorders; Residence Characteristics

Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against α-synuclein is not well known. We explored serum IgG levels to monomeric α-synuclein in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-α-synuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against α-synuclein in DLB and AD, which may relate to a disturbed α-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target α-synuclein in neurodegenerative disease.

Topics: Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Autoantibodies; Case-Control Studies; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Lewy Body Disease; Male; Severity of Illness Index

The overlapping clinical features of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) make differentiation difficult in the clinical environment. Evaluating the CSF levels of biomarkers in AD and DLB patients could facilitate clinical diagnosis. CSF Visinin-like protein-1 (VILIP-1), a calcium-mediated neuronal injury biomarker, has been described as a novel biomarker for AD. The aim of this study was to investigate the diagnostic utility of CSF VILIP-1 and VILIP-1/Aβ1-42 ratio to distinguish AD from DLB. Levels of CSF VILIP-1, t-tau, p-tau181P , Aβ1-42 , and α-synuclein were measured in 61 AD patients, 32 DLB patients, and 40 normal controls using commercial ELISA kits. The results showed that the CSF VILIP-1 level had significantly increased in AD patients compared with both normal controls and DLB patients. The CSF VILIP-1 and VILIP-1/Aβ1-42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. Additionally, CSF VILIP-1 levels were positively correlated with t-tau and p-tau181P within each group and with α-synuclein in the AD and control groups. We conclude that CSF VILIP-1 could be a diagnostic marker for AD, differentiating it from DLB. The analysis of biomarkers, representing different neuropathologies, is an important approach reflecting the heterogeneous features of AD and DLB. Neuronal Ca(2+) -sensor protein VILIP-1 has been implicated in the calcium-mediated neuronal injury and pathological change of AD. The CSF VILIP-1 and VILIP-1/Aβ1-42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. CSF VILIP-1 is a useful biomarker for AD. Evaluating the CSF levels of VILIP-1 in AD and DLB patients could facilitate clinical diagnosis.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cerebrospinal Fluid; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neurocalcin; Peptide Fragments; Plaque, Amyloid; ROC Curve; Sensitivity and Specificity; tau Proteins

Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss. We counted the pigmented neurons and quantified mitochondrial respiratory activity, deficiencies in mitochondrial proteins, and the percentage of pathogenic mutations in single neurons. We found evidence of defects of both complex I and complex IV of the respiratory chain in all patients. We found that marked neuronal cell loss was only observed in a few patients with mitochondrial disease and that all these patients had mutations in polymerase gamma (POLG), which leads to the formation of multiple mitochondrial DNA deletions over time, similar to aging and Parkinson's disease. Interestingly, we detected α-synuclein pathology in two mitochondrial patients with POLG mutations. Our observations highlight the complex relationship between mitochondrial dysfunction and the susceptibility of SN neurons to degeneration and α-synuclein pathology. Our finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones.

Topics: Adult; Aging; alpha-Synuclein; Cause of Death; Cell Count; DNA Polymerase gamma; DNA-Directed DNA Polymerase; DNA, Mitochondrial; Extrapyramidal Tracts; Female; Gene Deletion; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Neurons; Point Mutation; Prostaglandin-Endoperoxide Synthases; Real-Time Polymerase Chain Reaction; Substantia Nigra; Tyrosine 3-Monooxygenase; Young Adult

To determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.. Patients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.. pRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.. Presence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Autopsy; Brain; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Lewy Body Disease; Likelihood Functions; Magnetic Resonance Imaging; Male; REM Sleep Behavior Disorder; Retrospective Studies; Severity of Illness Index; tau Proteins

Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson's disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.

Topics: alpha-Synuclein; Brain; Cells, Cultured; Dementia; Down-Regulation; Humans; Lewy Body Disease; Parkinson Disease; Phosphatidylinositol 3-Kinases; Phosphorylation; Poly(A)-Binding Proteins; Protein Serine-Threonine Kinases; RNA, Small Interfering; T-Cell Intracellular Antigen-1; Tumor Suppressor Protein p53

Dementia with Lewy bodies (DLB) is pathologically characterized by α-synuclein aggregates in the brain. Most patients with DLB also show cerebral Alzheimer disease-type pathology (i.e. β-amyloid plaques and hyperphosphorylated tau deposits). It is unclear whether this overlap is coincidental or driven by specific regional or cellular interactions. The aims of this study were to investigate the regional convergence of α-synuclein, tau, and β-amyloid and to identify patterns of cellular co-occurrence of tau and α-synuclein in DLB. The study group consisted of 22 patients who met clinical and neuropathologic criteria for DLB. Protein aggregates were assessed semiquantitatively in 17 brain areas. APOE and MAPT genotypes were determined. Cellular co-occurrence of tau and α-synuclein was evaluated by double immunofluorescence. We found that total β-amyloid pathology scores correlated positively with total α-synuclein pathology scores (ρ = 0.692, p = 0.001). The factors that correlated best with the amount of α-synuclein pathology were the severity of β-amyloid pathology and presence of the MAPT H1 haplotype. Tau and α-synuclein frequently colocalized in limbic areas, but no correlation between total pathology scores was observed. This study confirms and extends the role of β-amyloid deposition and the MAPT H1 haplotype as contributing factors in DLB pathogenesis and demonstrates the confluence of multiple agents in neurodegenerative diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Apolipoproteins E; Brain; DNA-Binding Proteins; Female; Humans; Lewy Body Disease; Male; Middle Aged; Statistics as Topic; tau Proteins

ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson's disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies.. In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition.. Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Blotting, Western; Cerebral Cortex; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Peptide Fragments; Proton-Translocating ATPases

The detection of α-synuclein (α-syn) in the cerebrospinal fluid (CSF) of patients with synucleinopathy has yielded promising but inconclusive results. The aim of the present study was to determine the diagnostic value of α-syn as a biological marker for Dementia with Lewy bodies (DLB) vs. normal subjects and patients with Alzheimer's disease (AD), after strict control of several recognized confounders. Sixteen patients with DLB, 18 patients with AD and 22 age- and sex-matched normal controls (CTRL) were recruited. The levels of total α-syn in CSF were measured using a novel enzyme-linked immunosorbent assay. There was a significant increase of CSF α-syn levels in DLB patients as compared to the CTRL and AD groups (P = 0.049 and 0.01 respectively). ROC analysis revealed that increased α-syn was 81.8% specific for the discrimination of DLB vs. CTRL and 90% vs. AD. However, sensitivity was lower (56.2 % and 50% respectively). These findings provide evidence for a possible diagnostic role of α-syn as a surrogate biomarker for DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Case-Control Studies; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Humans; Lewy Body Disease; Middle Aged; Sensitivity and Specificity; Spinal Puncture

Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase-associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases.. All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations.. All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α-synuclein accumulation was detected in any of our PKAN cases. In one case (20-year-old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case.. These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.

Topics: Adult; alpha-Synuclein; Basal Ganglia; Child; Female; Humans; Lewy Body Disease; Male; Pantothenate Kinase-Associated Neurodegeneration; Phosphotransferases (Alcohol Group Acceptor); tau Proteins; Young Adult

Neurosin is a predominant serine protease in the central nervous system (CNS) and has been shown to play a role in the clearance of α-synuclein (α-syn) which is centrally involved in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although it has been previously shown that neurosin and α-syn colocalize and that neurosin degrades α-syn aggregates in vitro, it is not clear if neurosin is dysregulated in the brains of patients with PD/DLB and to what extent delivery of neurosin into the CNS might ameliorate the deficits associated with α-syn accumulation in vivo. We analyzed the levels of neurosin in the brains of patients with PD/DLB and in α-syn transgenic (tg) models. With increased accumulation of α-syn, we observed decreased neurosin expression. Lentiviral vector (LV) driven expression of neurosin in neuronal cell cultures reduced the accumulation of wild type but not A53T α-syn and prevented α-syn associated toxicity. Neuropathological analysis following delivery of LV-Neurosin to α-syn tg mice resulted in reduced accumulation of α-syn and reversal of neurodegenerative alterations in wild type but not A53T α-syn tg mice. Therefore, viral vector driven expression of neurosin may warrant further investigation as a potential therapeutic tool for DLB.

Topics: alpha-Synuclein; Animals; Base Sequence; Disease Models, Animal; DNA Primers; Humans; Immunohistochemistry; Kallikreins; Lentivirus; Lewy Body Disease; Mice; Mice, Transgenic; Microscopy, Confocal; Neurons

We analyzed the incidence and extent of Lewy-related α-synucleinopathy (LBAS) in the olfactory mucosa, as well as the central and peripheral nervous systems of consecutive autopsy cases from a general geriatric hospital. The brain and olfactory mucosa were immunohistochemically examined using antibodies raised against phosphorylated α-synuclein. Thirty-nine out of 105 patients (37.1%) showed LBAS in the central or peripheral nervous systems. Seven patients presented LBAS (Lewy neurites) in the olfactory lamina propria mucosa. One out of the seven cases also showed a Lewy neurite in a bundle of axons in the cribriform plate, but α-synuclein deposits were not detected in the olfactory receptor neurons. In particular, high incidence of α-synuclein immunopositive LBAS in the olfactory mucosa was present in the individuals with clinically as well as neuropathologically confirmed Parkinson's disease and dementia with Lewy bodies (6/8 cases, 75%). However, this pathologic alteration was rare in the cases with incidental or subclinical Lewy body diseases (LBD) (one out of 31 cases, 3.2%). In the olfactory bulb, the LBAS was usually present in the glomeruli and granular cells of most symptomatic and asymptomatic cases with LBD. Our studies further confirmed importance of the olfactory entry zone in propagation of LBAS in the human aging nervous system.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Olfactory Mucosa; Parkinson Disease

The microtubule-associated protein tau (MAPT) H1 haplotype has been identified as a genetic risk factor for synucleinopathies. However, whether it modulates tau or α-synuclein pathology remains unknown. Our aim was to investigate the relationship between MAPT haplotypes and pathologic aggregates of tau and α-synuclein in pathologically confirmed cases of dementia with Lewy bodies (DLB). Twenty-two cases fulfilling clinical and neuropathological criteria for DLB were included. Clinical and neuropathological data were collected, and APOE and MAPT genotypes were determined. Tau and α-synuclein pathology was assessed semiquantitatively in 17 brain areas and total scores were calculated. DLB H1/H1 (n = 12) and H2 carriers (n = 10) did not differ in demographics, clinical variables, concomitant Alzheimer's pathology, or APOE genotype. Total α-synuclein scores were significantly increased in the H1/H1 group (p = 0.011), largely due to an increase in brainstem regions. This difference was driven by an increase in Lewy bodies and diffuse and punctuate cytoplasmatic α-synuclein aggregates (p = 0.007 and p = 0.025 respectively). These findings provide a mechanistic link for the genetic association between MAPT haplotypes and synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Apolipoprotein E4; Brain; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Lewy Bodies; Lewy Body Disease; Male; tau Proteins

In Parkinson's disease (PD), alpha-synuclein (AS) aggregates occur frequently in peripheral autonomic nervous system (pANS). Their presence in asymptomatic subjects suggests incidental Lewy-body disease (iLBD) that is thought to reflect pre-clinical PD. Cardiac involvement has been detected in post-mortem studies in both, PD and also in iLBD. In vivo documentation of cardiac AS pathology is lacking.. To prospectively assess the presence of AS aggregates in epicardial fat tissue from living subjects without parkinsonism undergoing elective cardiac surgery.. Epicardial fat tissue obtained during cardiac surgery from 91 subjects was studied by histology and immunohistochemistry. Areas more likely to contain pANS elements were selected. PD-related motor and non-motor symptoms (NMS) were assessed immediately before or after surgery.. Small autonomic nerves, ganglia and/or tyrosine-hydroxylase positive fibres were identified in epicardial fat in each of the 91 subjects (62 male/29 female, mean age 67 years). AS aggregates were detected in 7 subjects (7.7%), and were more frequent in those aged above 70 years. In AS-positive subjects constipation and acting dreams were significantly more frequent than in the AS-negative ones.. AS aggregates occur in epicardial pANS in subjects without parkinsonism, suggesting the diagnosis of iLBD. The presence in some of these subjects of non-motor symptoms such as acting dreams and constipation known to occur in premotor PD supports this interpretation. Adequate follow-up of the subjects in this study will indicate the time, if any, to progression to motor PD.

Topics: Adipose Tissue; Aged; Aged, 80 and over; alpha-Synuclein; Autonomic Nervous System; Female; Heart; Humans; Lewy Body Disease; Male; Middle Aged; Parkinsonian Disorders; Prospective Studies; Tyrosine 3-Monooxygenase

Patients exhibiting the classic manifestations of parkinsonism - tremors, rigidity, postural instability, slowed movements and, sometimes, sleep disturbances and depression - may also display severe cognitive disturbances. All of these particular motoric and behavioral symptoms may arise from Parkinson's disease [PD] per se, but they can also characterize Lewy Body dementia [LBD] or concurrent Parkinson's and Alzheimer's diseases [PD & AD]. Abnormalities of both movement and cognition are also observed in numerous other neurologic diseases, for example Huntington's Disease and the frontotemporal dementia. Distinguishing among these diseases in an individual patient is important in "personalizing" his or her mode of treatment, since an agent that is often highly effective in one of the diagnoses (e.g., L-dopa or muscarinic antagonists in PD) might be ineffective or even damaging in one of the others. That such personalization, based on genetic, biochemical, and imaging-based biomarkers, is feasible is suggested by the numerous genetic abnormalities already discovered in patients with parkinsonism, Alzheimer's disease and Huntington's disease (HD) and by the variety of regional and temporal patterns that these diseases can produce, as shown using imaging techniques.

Topics: alpha-Synuclein; Alzheimer Disease; Antiparkinson Agents; Biomarkers; Cognition; Cognition Disorders; Diagnosis, Differential; Diagnostic Imaging; Frontotemporal Dementia; Genetic Markers; Genetic Testing; Glucosylceramidase; Humans; Huntington Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa; Lewy Body Disease; Mutation; Parkinson Disease; Precision Medicine; Protein Serine-Threonine Kinases

In 1817, James Parkinson described the symptoms of the shaking palsy, a disease that was subsequently defined in greater detail, and named after Parkinson, by Jean-Martin Charcot. Parkinson expected that the publication of his monograph would lead to a rapid elucidation of the anatomical substrate of the shaking palsy; in the event, this process took almost a century. In 1912, Fritz Heinrich Lewy identified the protein aggregates that define Parkinson disease (PD) in some brain regions outside the substantia nigra. In 1919, Konstantin Nikolaevich Tretiakoff found similar aggregates in the substantia nigra and named them after Lewy. In the 1990s, α-synuclein was identified as the main constituent of the Lewy pathology, and its aggregation was shown to be central to PD, dementia with Lewy bodies, and multiple system atrophy. In 2003, a staging scheme for idiopathic PD was introduced, according to which α-synuclein pathology originates in the dorsal motor nucleus of the vagal nerve and progresses from there to other brain regions, including the substantia nigra. In this article, we review the relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders.

Topics: alpha-Synuclein; Brain; Germany; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Modifications of α-synuclein resulting in changes in its conformation are considered to be key pathological events for Lewy body diseases (LBD), which include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We have previously described a histopathological Unified Staging System for LBD that classifies the spread of α-synuclein phosphorylated at serine 129 (pS129-α-synuclein) from olfactory bulb to brainstem or limbic regions, and finally neocortex. Lewy bodies and Lewy neurites are highly enriched in pS129-α-synuclein. Increased formation of pS129-α-synuclein changes its solubility properties enhancing its tendency to aggregate and disrupt normal function. As in vitro and animal studies have shown that inhibiting formation of pS129-α-synuclein can prevent toxic consequences, this has become one of the therapeutic targets for LBD. However, detailed biochemical descriptions of the changes in pS129-α-synuclein properties in diseased human brains are needed to further our understanding of how these might contribute to molecular pathogenesis. In this study, we used 130 separate brain samples from cingulate cortex (limbic cortex) and 131 from temporal cortex (neocortex) that had been staged according to our Unified Staging System to examine progressive changes in properties of pS129-α-synuclein with the formation of progressively more severe histological Lewy-type pathology. The brain samples from these staged cases had been separated into cytosol-enriched, membrane-enriched (detergent soluble) and insoluble (ureas/SDS soluble) fractions. We also characterized the nature and appearance of higher molecular weight forms of pS129-α-synuclein. The major species was the 16 kD monomeric form; this accumulated with increasing stage with a large increase in Stage IV samples. By comparing two brain regions, we showed higher accumulation of insoluble pS129-α-synuclein in cingulate cortex, where histological deposits occur first, than in temporal cortex in samples with advanced (stage IV) LB pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Gyrus Cinguli; Humans; Lewy Body Disease; Male; Parkinson Disease; Phosphorylation; Serine; Solubility; Temporal Lobe

Neurosin is a protease that in vitro degrades α-synuclein, the main constituent of Lewy bodies found in brains of patients with synucleinopathy including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several studies have reported reduced cerebrospinal fluid (CSF) levels of α-synuclein in synucleinopathy patients and recent data also proposes a significant role of α-synuclein in the pathophysiology of Alzheimer's disease (AD). To investigate potential links between neurosin and its substrate α-synuclein in vivo we used a commercially available sandwich ELISA and an in-house developed direct ELISA to quantify CSF levels of α-synuclein and neurosin in patients diagnosed with DLB, PD and PD dementia (PDD) versus AD patients and non-demented controls. We found that patients with synucleinopathy displayed lower CSF levels of neurosin and α-synuclein compared to controls and AD patients. In contrast, AD patients demonstrated significantly increased CSF α-synuclein but similar neurosin levels compared to non-demented controls. Further, CSF neurosin and α-synuclein concentrations were positively associated in controls, PD and PDD patients and both proteins were highly correlated to CSF levels of phosphorylated tau in all investigated groups. We observed no effect of gender or presence of the apolipoprotein Eε4 allele on neither neurosin or α-synuclein CSF levels. In concordance with the current literature our study demonstrates decreased CSF levels of α-synuclein in synucleinopathy patients versus AD patients and controls. Importantly, decreased α-synuclein levels in patients with synucleinopathy appear linked to low levels of the α-synuclein cleaving enzyme neurosin. In contrast, elevated levels of α-synuclein in AD patients were not related to any altered CSF neurosin levels. Thus, altered CSF levels of α-synuclein and neurosin in patients with synucleinopathy versus AD may not only mirror disease-specific neuropathological mechanisms but may also serve as fit candidates for future biomarker studies aiming at identifying specific markers of synucleinopathy.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Female; Humans; Kallikreins; Lewy Body Disease; Male; Middle Aged; Parkinson Disease

Progressive accumulation of α-synuclein (α-syn) in limbic and striatonigral systems is associated with the neurodegenerative processes in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). The murine Thy-1 (mThy1)-α-syn transgenic (tg) model recapitulates aspects of degenerative processes associated with α-syn accumulation in these disorders. Given that axonal and synaptic pathologies are important features of DLB and PD, we sought to investigate the extent and characteristics of these alterations in mThy1-α-syn tg mice and to determine the contribution of α-syn c-terminally cleaved at amino acid 122 (CT α-syn) to these abnormalities. We generated a novel polyclonal antibody (SYN105) against the c-terminally truncated sequence (amino acids 121 to 123) of α-syn (CT α-syn) and performed immunocytochemical and ultrastructural analyses in mThy1-α-syn tg mice. We found abundant clusters of dystrophic neurites in layers 2 to 3 of the neocortex, the stratum lacunosum, the dentate gyrus, and cornu ammonis 3 of the hippocampus, striatum, thalamus, midbrain, and pons. Dystrophic neurites displayed intense immunoreactivity detected with the SYN105 antibody. Double-labeling studies with antibodies to phosphorylated neurofilaments confirmed the axonal location of full-length and CT α-syn. α-Syn immunoreactive dystrophic neurites contained numerous electrodense laminated structures. These results show that neuritic dystrophy is a prominent pathologic feature of the mThy1-α-syn tg model and suggest that CT α-syn might play an important role in the process of axonal damage in these mice as well as in DLB and PD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amino Acid Sequence; Animals; Antibodies; Antibody Specificity; Axons; Biomarkers; Demography; Disease Models, Animal; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Mice; Mice, Transgenic; Molecular Sequence Data; Mutant Proteins; Neurites; Protein Transport; Synapses; Thy-1 Antigens

The clinical diagnosis of Parkinson disease (PD) is incorrect in 30% or more of subjects particularly at the time of symptom onset. Because Lewy-type α-synucleinopathy is present in the submandibular glands of PD patients, we assessed the feasibility of submandibular gland biopsy for diagnosing PD. We performed immunohistochemical staining for Lewy-type α-synucleinopathy in sections of large segments (simulating open biopsy) and needle cores of submandibular glands from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 progressive supranuclear palsy (3 with concurrent PD), 3 corticobasal degeneration, 2 multiple system atrophy, 22 Alzheimer disease with Lewy bodies, 16 Alzheimer disease without Lewy bodies, and 50 normal elderly. Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had progressive supranuclear palsy); 3 Alzheimer disease with Lewy bodies subjects were also positive, but none of the other subjects were positive. Cores from frozen submandibular glands taken with 18-gauge needles (total length, 15-38 mm; between 10 and 118 sections per subject examined) were positive for Lewy-type α-synucleinopathy in 17 of 19 PD patients. These results suggest that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy. This would be particularly advantageous for subject selection in early-stage clinical trials for invasive therapies or for verifying other biomarker studies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biopsy; Brain; Female; Humans; Lewy Body Disease; Male; Multiple System Atrophy; Muscle, Smooth; Nerve Fibers; Parkinson Disease; Submandibular Gland; Supranuclear Palsy, Progressive

Inclusions of intraneuronal alpha-synuclein (α-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of α-synuclein is a central feature of the disease pathogenesis. Among the different α-synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large α-synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in α-synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of α-synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of α-synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective α-synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Blotting, Western; Brain; DNA, Complementary; Enzyme-Linked Immunosorbent Assay; Epitopes; Formates; Humans; Immunohistochemistry; Lewy Body Disease; Mice; Mice, Transgenic; Mutation; Subcellular Fractions

We report neuropathologic findings in a patient with homozygous deletions of exons 2 to 4 of parkin.. Although the absence of Lewy bodies has been considered a neuropathologic characteristic of parkin mutation, here we report a pathologic finding with the presence of Lewy bodies.. The patient was a 72-year-old woman with onset of the disease at age 61. Her autopsy revealed marked decrease in melanized neurons in the substantia nigra and the locus coeruleus. Lewy bodies were found in the substantia nigra, the locus coeruleus, the dorsal motor nucleus of the vagus, the basal nucleus of Meynert, the amygdaloid nucleus, and the sympathetic nerve bundles in the myocardium.. Only 3 previous case reports described Lewy body formation in patients carrying parkin mutations. The distribution of Lewy bodies in our patient appeared to be reminiscent of sporadic Parkinson's disease.

Topics: Aged; alpha-Synuclein; Exons; Female; Gene Deletion; Homozygote; Humans; Lewy Bodies; Lewy Body Disease; Magnetic Resonance Imaging; Neurons; Substantia Nigra; Ubiquitin-Protein Ligases

Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC).. This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry.. Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD.. Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain Stem; Catecholamines; Cholinergic Agents; Female; Humans; Lewy Body Disease; Locus Coeruleus; Male; Nervous System Diseases; Neurons; REM Sleep Behavior Disorder; Retrospective Studies

Braak's staging concept of Lewy body disease pathogenesis is based on a spatiotemporal sequence of alpha-synuclein deposition, with autonomic nervous system involvement before synucleinopathy in substantia nigra neurons. A patient with primary chronic autonomic failure underwent biennial brain 6-[(18)F]DOPA and myocardial 6-[(18)F]dopamine scanning over 4 years. Low myocardial radioactivity indicated cardiac noradrenergic denervation that persisted. Striatal 6-[(18)F]DOPA-derived radioactivity initially was normal, 2 years later was decreased subtly, and by 4 years was clearly decreased, accompanied by dementia and parkinsonism. In this case, neuroimaging evidence of cardiac noradrenergic denervation and subsequent progressive striatal dopaminergic denervation fit with Braak staging.

Topics: Aged; alpha-Synuclein; Autonomic Denervation; Dementia; Dihydroxyphenylalanine; Disease Progression; Dopamine; Dopaminergic Neurons; Gait Disorders, Neurologic; Hallucinations; Humans; Lewy Body Disease; Male; Neostriatum; Norepinephrine; Parkinson Disease; Radiopharmaceuticals; Shy-Drager Syndrome; Sympathetic Nervous System

Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers; Brain; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease

We performed a quantitative neuropathological examination of the hypometabolic regions on FDG PET in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and control cases. When the DLB cases were divided into two groups according to concomitant AD pathology (ADP), neuronal loss in the temporo-parietal association area was milder in the DLB groups than in the AD group, although there were no differences between the two DLB groups. Tau and Aβ immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aβ immunoreactivities as well as numbers of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) were more common in the AD group than in the DLB group with ADP. There was no difference in neuronal loss in the occipital area among the three groups. α-Synuclein immunoreactivity was observed in the DLB groups but not in the AD group. There were no differences in α-synuclein immunoreactivity and number of Lewy bodies (LBs) between the two DLB groups. These findings indicate that the neuropathological bases of the hypometabolic regions in the temporo-parietal association and occipital area in DLB may be AD pathology and Lewy pathology, respectively.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Brain; Cell Count; Data Interpretation, Statistical; Disease Progression; Female; Fluorodeoxyglucose F18; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Neurofibrillary Tangles; Neurons; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins

α-synuclein is a key protein in Lewy body diseases (LBDs) and a major component of Lewy bodies and related aberrant cytoplasmic and neuritic inclusions. Regional differences in α-synuclein have been associated with selective neuronal vulnerability to Lewy pathology. Furthermore, phosphorylation at serine 129 (Ser129) and α-synuclein truncation have been considered crucial in the pathogenesis of Lewy inclusions. The present study shows consistent reduction in α-synuclein protein expression levels in the human substantia nigra and nucleus basalis of Meynert compared with other brain regions independently of age and pathology. Phosphorylated α-synuclein at Ser129 is naturally increased in these same regions, thus inversely related with the total amount of α-synuclein. In contrast, truncated α-synuclein is naturally observed in control and diseased brains and correlating with the total amount of α-synuclein. Several truncated variants have been identified where some of these variants are truncated at the C-terminal domain, whereas others are truncated at the N-terminal domain, and all are present in cases with and without Lewy pathology. Although accumulation of truncated α-synuclein variants and phosphorylated α-synuclein occurs in Lewy bodies, α-synuclein phosphorylation and truncation can be considered constitutive in control and diseased brains.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Brain; Cell Line, Tumor; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Mass Spectrometry; Mice; Mice, Transgenic; Microscopy, Confocal; Middle Aged; Mutation; Nerve Tissue Proteins; Neuroblastoma; Neurons; Phosphorylation; Postmortem Changes; Protein Structure, Tertiary; Serine; Subcellular Fractions; Time Factors; Transfection

Parkinson's disease is now recognized as a major form of α-synucleinopathy involving both the central and peripheral nervous systems. However, no research has focused on the posterior pituitary lobe (PPL), despite the fact that this organ also plays an important role in systemic homeostasis. In the present study, we aimed to distinguish phosphorylated α-synuclein (pαSyn)-positive deposits in the PPL, as is observed in Lewy body- and non-Lewy body-related disorders. PαSyn deposits were immunohistochemically analyzed using formalin-fixed, paraffin-embedded PPL specimens obtained from 60 autopsy cases. Among the cases with Lewy body-related disorders, PPL pαSyn deposits were observed in almost all cases of Parkinson's disease (22/23), and in one case of dementia with Lewy bodies (1/1). On the other hand, only 3/36 cases of non-Lewy body-related disorders had pαSyn immunoreactivity in the PPL. The present study confirms the presence of pαSyn-positive deposits, as demonstrated by high specificity (97.1%) and sensitivity (88.5%), in both Parkinson's disease and dementia with Lewy bodies, suggesting that this finding can be a useful hallmark of Lewy body-related disorders.

Topics: Aged; alpha-Synuclein; Biomarkers; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Phosphorylation; Pituitary Gland, Posterior; Sensitivity and Specificity

Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Dementia; Female; Humans; Intracellular Signaling Peptides and Proteins; Lewy Body Disease; Male; Neuropeptides; Orexins

Incidental Lewy body disease (ILBD) represents the early asymptomatic phase of Lewy body diseases (LBD), including idiopathic Parkinson's disease (PD). Although pathological disturbances in the spinal cord, which connects the brain to the peripheral nervous system, plays an important role, the pathology of ILBD has not been adequately examined. Eighteen ILBD and eight age-matched LBD cases were enrolled in the present study. LB-related pathology was immunohistochemically evaluated using anti-phosphorylated α-synuclein (pαSyn) antibodies, revealing LB-related pathology in the spinal cords of 15 (83.3%) of the ILBD cases. Attempts were made to identify the early pattern of pαSyn deposition in the spinal cord by comparing the cervical, thoracic, lumbar and sacral segments in detail. Most pαSyn-positive structures were distributed in and around the autonomic nuclei of the spinal cord. The intermediolateral nuclei in the thoracic segments (Th/IML) were the most frequently and severely affected region, suggesting that Th/IML are the first structures affected. Furthermore, following analysis of the distribution pattern of the pαSyn-positive structures, it is suspected that LB-related pathology progresses toward the caudal vertebrae by involving neurons in the spinal cord that are vulnerable to αSyn. It should be noted that the ILBD cases enrolled in the present study were in an earlier stage than the PD cases enrolled in the previous study, and that the present study provides new, previously undescribed information.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Spinal Cord

Parkinson's disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α-synuclein (α-syn) in the central nervous system. Aggregation of α-syn into oligomers with a ring-like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms and the potential sequence of events involved in the formation of pore-like structures are unclear. We utilized computer modeling and cell-based studies to investigate the process of oligomerization of wild-type and A53T mutant α-syn in membranes. The studies suggest that α-syn penetrates the membrane rapidly, changing its conformation from α-helical towards a coiled structure. This penetration facilitates the incorporation of additional α-syn monomers in the complex, and the subsequent displacement of phospholipids and the formation of oligomers in the membrane. This process occurred more rapidly, and with a more favorable energy of interaction, for mutant A53T compared with wild-type α-syn. After 4 ns of simulation of the protein-membrane model, α-syn had penetrated through two-thirds of the membrane. By 9 ns, the penetration of the annular α-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant α-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) α-syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures, resulting in greater neuronal permeability, as demonstrated with the calcein efflux assay. These studies provide a sequential molecular explanation for the process of α-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD.

Topics: alpha-Synuclein; Animals; Cell Membrane; Lewy Body Disease; Lipid Bilayers; Neurons; Parkinson Disease; Protein Structure, Secondary; Rats; Tumor Cells, Cultured

The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies.. A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented.. MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology.. This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Brain; Female; Haplotypes; Humans; Lewy Bodies; Lewy Body Disease; Male; Organ Size; Parkinson Disease; Polymorphism, Single Nucleotide; tau Proteins

α-synuclein (α-Syn) is a chaperone-like protein that is highly implicated in Parkinson's disease (PD) as well as in dementia with Lewy bodies (DLB). Rare forms of PD occur in individuals with mutations of α-Syn or triplication of wild type α-Syn, and in both PD and DLB the intraneuronal inclusions known as Lewy bodies contain aggregated α-Syn that is highly phosphorylated on serine 129. In neuronal cells and in the brains of α-Syn overexpressing transgenic mice, soluble α-Syn stimulates the activity of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase. Serine 129 phosphorylation of α-Syn attenuates its stimulatory effects on PP2A and also accelerates α-Syn aggregation; however, it is unknown if aggregation of α-Syn into Lewy bodies impairs PP2A activity. To assess for this, we measured the impact of α-Syn aggregation on PP2A activity in vitro and in vivo. In cell-free assays, aggregated α-Syn had ∼50% less PP2A stimulatory effects than soluble recombinant α-Syn. Similarly in DLB and α-Syn triplication brains, which contain robust α-Syn aggregation with high levels of serine 129 phosphorylation, PP2A activity was also ∼50% attenuated. As α-Syn normally stimulates PP2A activity, our data suggest that overexpression of α-Syn or sequestration of α-Syn into Lewy bodies has the potential to alter the phosphorylation state of key PP2A substrates; raising the possibility that all forms of synucleinopathy will benefit from treatments aimed at optimizing PP2A activity.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Down-Regulation; Female; Frontal Lobe; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Protein Phosphatase 2; Substrate Specificity

The neuropeptide oxytocin, produced in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, is now understood to function as a neurotransmitter critical for various aspects of social cognition and pro-social behaviour. While patients with Frontotemporal dementia (FTD) display prominent and progressive deficits in such social behaviours, the integrity of these nuclei in FTD is not known.. We conducted a quantitative neuropathologic examination of the SON and PVN from patients with FTLD with TDP-43 proteinopathy, Alzheimer's disease, Lewy body disease and controls to determine whether significant pathologic changes or neuronal loss may contribute to the striking behavioural symptoms of FTD.. Contrary to predictions, we found both nuclei to be free of significant pathologic change (TDP-43) in FTLD. In contrast, tau related pathology was found in the PVN in Alzheimer's disease, and alpha-synuclein pathology in the SON in patients with Lewy body dementia.. These results indicate that the SON and PVN are resistant to FTLD TDP-43 pathology. They also support prior suggestions that the SON is resistant to Alzheimer's disease (AD) related pathology, and extend this to demonstrate SON susceptibility to alpha-synuclein pathology in patients with Lewy body dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; DNA-Binding Proteins; Female; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Middle Aged; Neurons; Paraventricular Hypothalamic Nucleus; Supraoptic Nucleus; tau Proteins

A key component in Lewy body (LB) pathology in LB disorders is α-synuclein phosphorylated at serine 129 (pαsyn). However, it is not known if increase in the level of biochemically measurable pαsyn precedes the presence of histologically identified Lewy-type synucleinopathy (LTS). To gain sights into possible temporal sequence, we measured levels of pαsyn in cingulate and temporal cortices that develop LTS pathology at later stages of LB disorders. Brain homogenates from 128 autopsy cases including normal controls and subjects classified by Unified LTS histopathology staging system were studied. We found that biochemically measurable pαsyn levels in cingulate and temporal cortices were significantly increased at Unified stages III and IV. When pαsyn levels were compared between LTS density scores instead of Unified stages, significant increases were detected even as LTS density scores increased from 0 to 1 in olfactory bulb and substantia nigra. Therefore, our findings demonstrated that changes of pαsyn levels in cingulate and temporal cortices coincided with the early appearance of the LTS pathology in olfactory bulb and substantia nigra, even though histologically demonstrable LTS was lacking in the cortical region. Therefore, identifying the underlying mechanisms driving these changes could be crucial to understanding the pathogenesis of LB disorders.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Blotting, Western; Brain; Female; Humans; Lewy Body Disease; Male; Phosphorylation

To explore the relationship between α-synuclein pathology and mitochondrial respiratory chain protein levels within single substantia nigra neurons.. We examined α-synuclein and mitochondrial protein expression in substantia nigra neurons of 8 patients with dementia with Lewy bodies, 5 patients with Parkinson disease, and 8 control subjects. Protein expression was determined using immunocytochemistry followed by densometric analysis.. We examined single substantia nigra neurons from 5 patients with idiopathic Parkinson disease (mean age, 81.2 years), 8 patients with dementia with Lewy bodies (mean age, 75 years), and 8 neurologically and pathologically normal control subjects (mean age, 74.5 years). The control cases showed minimal Lewy body pathology and cell loss. Patients with dementia with Lewy bodies and idiopathic Parkinson disease fulfilled the clinical and neuropathologic criteria for these diseases.. Our results showed that mitochondrial density is the same in nigral neurons with and without α-synuclein pathology. However, there are significantly higher levels of the respiratory chain subunits in neurons containing α-synuclein pathology.. The finding of increased levels of respiratory chain complex subunits within neurons containing α-synuclein does not support a direct association between mitochondrial respiratory chain dysfunction and the formation of α-synuclein pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cell Count; Densitometry; Female; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Lewy Body Disease; Male; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Neurons; Paraffin Embedding; Parkinson Disease; Reproducibility of Results; Substantia Nigra; Tissue Fixation

The role of Lewy bodies, Lewy neurites and α-synuclein (αSYN) in the pathophysiology and diagnosis of Parkinson's disease (PD) is unclear. We used postmortem human tissue, a panel of antibodies (Abs) and confocal microscopy to examine the three-dimensional neurochemical anatomy of the nigrostriatal system. Abs were specific to truncated (tαSYN), phosphorylated and full-length αSYN. The findings demonstrate the critical role of tαSYN in initiating aggregation, a role for other forms of αSYN in aggregate expansion, a reason for the wide variety of proteins present in different aggregates, an explanation for the laminar appearance of aggregates described historically using different methods, the existence of proximal greater than distal aggregation in the vulnerable nigrostriatal pathway, the independent transport of different forms of αSYN as cargo along axons and a possible sequence for the formation of Lewy bodies. Findings differed between incidental Lewy body disease and PD only quantitatively. These findings have implications for understanding the pathogenesis and treatment of PD.

Topics: Aged; alpha-Synuclein; Autopsy; Brain; Female; Humans; Immunohistochemistry; Incidental Findings; Lewy Body Disease; Male; Microscopy, Confocal; Parkinson Disease

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of α-Synuclein (α-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson's disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic α-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting α-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological α-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with α-Syn amyloid fibrils assembled from recombinant human α-Syn induced identical consequences. Furthermore, we show for the first time that synthetic α-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell-cell transmission and propagation of misfolded α-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.

Topics: alpha-Synuclein; Amyloid; Animals; Brain; Humans; Immunohistochemistry; Injections; Lewy Body Disease; Male; Mice; Mice, Transgenic

α-Synuclein is a neuronal protein implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Whilst increased α-synuclein expression due to gene duplication or triplication can cause familial PD, previous studies of α-synuclein levels in idiopathic disease have produced conflicting data. We quantified α-synuclein mRNA and soluble protein in five human post-mortem brain regions from four groups of individuals with PD, DLB, Alzheimer's disease (AD) and matched controls. α-Synuclein mRNA levels, measured using quantitative real-time PCR, did not differ significantly between groups in any brain regions examined. In contrast, levels of soluble α-synuclein protein, measured by ELISA, were significantly lower in 4 of the 5 regions for patients with DLB, and in 2 of the 5 regions for patients with PD, compared to controls. Soluble α-synuclein protein levels were not significantly different in the AD patients, compared to controls, in 4 of the 5 regions. This study indicates that although levels of soluble α-synuclein protein are lower in DLB and PD, there is no evidence for a corresponding decrease in α-synuclein mRNA levels. This might result from altered translation, or removal of α-synuclein protein from a soluble detectable state, either by turnover or conversion to an insoluble form.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Lewy Body Disease; Male; Parkinson Disease; Postmortem Changes; RNA, Messenger

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Diagnosis, Differential; Female; Histocytochemistry; Humans; Lewy Body Disease

A dysfunctional ubiquitin proteasome system may be a mediating factor of disease progression in Lewy body dementia (LBD). The effects of proteasome inhibition using lactacystin and epoxomicin in primary neuronal culture were studied to assess the validity of this model to reflect the cortical pathology of LBD. Treatment of primary cortical neurons with 5 μM lactacystin for 24 h led to a 38 % reduction in the levels of β-III-tubulin (p < 0.05), a 48 % reduction in the levels of synaptophysin (p < 0.05) and a 74 % reduction in the levels of drebrin (p < 0.01), when compared to controls. Results for epoxomicin were similar. The loss of neuronal protein occurred prior to any loss of mitochondrial activity or cell death. The results are reflective of the loss of synapses and the synaptic changes observed in LBD, which may be an early event in the neurodegeneration of LBD. The similarities with the pathological changes in LBD highlight the possibility that this model can potentially provide a platform to test novel treatments.

Topics: Acetylcysteine; alpha-Synuclein; Animals; Blotting, Western; Cells, Cultured; Cysteine Proteinase Inhibitors; Immunohistochemistry; Lewy Body Disease; Neurons; Neuropeptides; Oligopeptides; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Synapses; Synaptophysin; Tubulin; Ubiquitination

α-Synuclein is an intrinsically disordered protein of 140 amino acids which is abundant in dopaminergic neurons. Misfolding and aggregation of α-synuclein leads to the formation of Lewy bodies inside the neurons which is the hallmark of Parkinson's disease and related dementias. Here we show by nanopore analysis that the recreational drug, methamphetamine, binds to the N-terminus of α-synuclein and causes a conformational change which cannot be detected by circular dichroism spectroscopy. The results suggest a mechanism for the psychoactivity of methamphetamine as well as an increased incidence of Parkinson's disease amongst users of the drug.

Topics: alpha-Synuclein; Binding Sites; Circular Dichroism; Dopaminergic Neurons; Humans; In Vitro Techniques; Lewy Bodies; Lewy Body Disease; Methamphetamine; Models, Molecular; Nanopores; Parkinson Disease; Protein Binding; Protein Conformation; Protein Folding

Induced pluripotent stem cell (iPSC) technology can be used to model human disorders, create cell-based models of human diseases, including neurodegenerative diseases, and in establishing therapeutic strategies. To detect subtle cellular abnormalities associated with common late-onset disease in iPSCs, valid control iPSCs derived from healthy donors free of serious late-onset diseases are necessary. Here, we report the generation of iPSCs from fibroblasts obtained immediately postmortem from centenarian donors (106- and 109-years-old) who were extremely healthy until an advanced age. The iPSCs were generated using a conventional method involving OCT4, SOX2, KLF4, and c-MYC, and then differentiated into neuronal cells using a neurosphere method. The expression of molecules that play critical roles in late-onset neurodegenerative diseases by neurons differentiated from the centenarian-iPSCs was compared to that of neurons differentiated from iPSCs derived from familial Alzheimer's disease and familial Parkinson's disease (PARK4: triplication of the α synuclein gene) patients. The results indicated that our series of iPSCs would be useful in neurodegeneration research. The iPSCs we describe, which were derived from donors with exceptional longevity who were presumed to have no serious disease risk factors, would be useful in longevity research and as valid super-controls for use in studies of various late-onset diseases.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Cell Differentiation; Cells, Cultured; Female; Humans; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4; Lewy Body Disease; Male; Neurons; Parkinson Disease; Transcription Factors

In this autopsy-based study, α-synuclein immunohistochemistry and lipofuscin pigment-Nissl architectonics in serial sections of 100 μm thickness were used to investigate the spinal cords and brains of 46 individuals: 28 patients with clinically and neuropathologically confirmed Parkinson's disease, 6 cases with incidental Lewy body disease, and 12 age-matched controls. α-Synuclein inclusions (particulate aggregations, Lewy neurites/bodies) in the spinal cord were present between neuropathological stages 2-6 in all cases whose brains were staged for Parkinson's disease-related synucleinopathy. The only individuals who did not have Lewy pathology in the spinal cord were a single stage 1 case (incidental Lewy body disease) and all controls. Because the Parkinson's disease-related lesions were observable in the spinal cord only after Lewy pathology was seen in the brain, it could be concluded that, within the central nervous system, sporadic Parkinson's disease does not begin in the spinal cord. In addition: (1) α-Synuclein-immunoreactive axons clearly predominated over Lewy bodies throughout the spinal cord and were visible in medial and anterior portions of the anterolateral funiculus. Their terminal axons formed dense α-synuclein-immunoreactive networks in the gray matter and were most conspicuous in the lateral portions of layers 1, 7, and in the cellular islands of layer 9. (2) Notably, this axonopathy increased remarkably in density from cervicothoracic segments to lumbosacral segments of the cord. (3) Topographically, it is likely that the spinal cord α-synuclein immunoreactive axonal networks represent descending projections from the supraspinal level setting nuclei (locus coeruleus, lower raphe nuclei, magnocellular portions of the reticular formation). (4) Following the appearance of the spinal cord axonal networks, select types of projection neurons in the spinal cord gray matter displayed α-synuclein-immunoreactive inclusions: chiefly, nociceptive neurons of the dorsal horn in layer 1, sympathetic and parasympathetic preganglionic neurons in layer 7, the cellular pools of α-motoneurons in layer 9, and the smaller motoneurons in Onuf's nucleus in layer 9 (ventral horn). The spinal cord lesions may contribute to clinical symptoms (e.g., pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic Parkinson's disease.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Biopsy; Brain; Case-Control Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neurites; Neurons; Parkinson Disease; Postmortem Changes; Spinal Cord; Spinal Cord Diseases

Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice.. In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules.. Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.

Topics: Aging; alpha-Synuclein; Animals; Axons; beta-Synuclein; Brain; Dementia; Humans; Lewy Body Disease; Lysosomes; Mice; Mice, Transgenic; Mitochondria; Mutant Proteins; Oxidative Stress; Parkinson Disease; Risk Factors

Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against α-synuclein specifically target and aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcγ receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of α-synuclein tg mice prevented neuron-to-astroglia transmission of α-synuclein and led to increased localization of α-synuclein and the antibody in microglia. Furthermore, passive immunization with α-synuclein antibody reduced neuronal and glial accumulation of α-synuclein and ameliorated neurodegeneration and behavioral deficits associated with α-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of α-synuclein as potential therapeutic targets.

Topics: alpha-Synuclein; Amyloid; Analysis of Variance; Animals; Antibodies; Antigens, CD; Astrocytes; Brain; Calcium-Binding Proteins; Cathepsin D; Caveolin 1; Cell Communication; Cell Line; Chromatography, Gel; Culture Media, Conditioned; Cytokines; Disease Models, Animal; Extracellular Space; Humans; Immunization, Passive; Lewy Body Disease; Mice; Mice, Transgenic; Microfilament Proteins; Microscopy, Electron, Transmission; Nerve Degeneration; Neuroglia; Phosphopyruvate Hydratase; Platelet-Derived Growth Factor; Synaptic Transmission

Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.. We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).. Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (χ(2)(1) = 19.3; p = 1.1 × 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.. GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; DNA Mutational Analysis; Female; Frontal Lobe; Glucosylceramidase; Humans; Lewy Body Disease; Logistic Models; Male; Middle Aged; Mutation; Mutation Rate; Risk Factors

α-Synuclein has been reported to be important in modulating brain plasticity and to be a key protein in neurodegenerative diseases, including Lewy body dementia (LBD). We investigated how α-synuclein levels modulate adult neurogenesis and the development of dendritic arborization and spines in the dentate gyrus, in which new neurons are constantly added. In the human hippocampus, levels of endogenous α-synuclein were increased in LBD, and the numbers of SOX2-positive cells were decreased. We investigated whether newly generated neurons were modulated by endogenous α-synuclein, and we found increased adult neurogenesis in α/β-synuclein knock-out mice. In contrast, overexpression of human wild-type α-synuclein (WTS) decreased the survival and dendritic development of newborn neurons. Endogenous α-synuclein expression levels increased the negative impact of WTS on dendrite development, suggesting a toxic effect of increasing amounts of α-synuclein. To attempt a rescue of the dendritic phenotype, we administered rolipram to activate the cAMP response element-binding protein pathway, which led to a partial rescue of neurite development. The current work provides novel insights into the role of α-synuclein in adult hippocampal neurogenesis.

Topics: Aged, 80 and over; alpha-Synuclein; Animals; beta-Synuclein; Cell Count; Dendrites; Dendritic Spines; Dentate Gyrus; Female; Fluorescent Antibody Technique; Genetic Vectors; Green Fluorescent Proteins; Humans; Immunohistochemistry; Lewy Body Disease; Male; Mice; Mice, Knockout; Neurogenesis; Neurons; Phosphodiesterase Inhibitors; Retroviridae; Rolipram

Lewy pathology occurs in 8-17% of neurologically normal people age >60, termed incidental Lewy body disease (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) diffuse cortical and subcortical α-synuclein pathology; (2) no cortical α-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; and (3) intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Dementia; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Retrospective Studies

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. Among many other neuropathological changes in DLB, brain region-specific cellular deficits have been reported. They include decreases in motor neuron and pyramidal cell densities, while neocortical parvalbumin (parv)-containing neurons are thought to be free of Lewy bodies and spared in DLB. However, elevated parv levels are found in the cerebrospinal fluid of patients suffering from dementia with Lewy bodies. We performed an immunohistochemical analysis of hippocampal parv-immunoreactive neurons in well-characterised DLB cases and from controls using a specific antibody against the calcium binding protein. In addition, an analysis of the regional and cellular distribution of alpha-synuclein was carried out. Subfield and laminar distribution of parv-immunoreactive (ir) neurons on the hippocampus in subjects with DLB and controls were present exclusively as non-granule cells of the dentate gyrus (DG)/hilus and non-pyramidal cells of CA1, CA2, CA3 and CA4 areas of the hippocampus. The distribution patterns did not differ qualitatively between DLB and controls. Quantitative estimation of parv-ir neuron density revealed significant decreases in the dentate (DG)/hilus region as well as in the CA1 subfield. Double immunolabelling experiments showed that only 2% of parv expressing interneurons were laden with alpha-synuclein immunoreactive material. No significant changes were found for the total neuron densities in DLB cases. Our results show a partial loss of parv-expressing hippocampal interneurons in DLB, which might be the result of long-lasting calcium overload in combination with a proposed impaired mitochondrial function. It remains to be elucidated if the numerical decrease of this particular subset of hippocampal interneurons has consequences for the gamma (20-80 Hz) frequency activity in DLB patients.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cell Count; Female; Hippocampus; Humans; Immunohistochemistry; Inclusion Bodies; Interneurons; Lewy Body Disease; Male; Parvalbumins

Dementia with Lewy bodies (DLB) is associated with alpha synuclein pathology and slowly progressive dementia. Progenitor abnormalities have previously been reported in the subventricular zone (SVZ) adjacent to the lateral ventricle. To evaluate changes in neural stem cells and progenitors in the hippocampal neurogenic niche, immunohistochemistry (IHC) using the neural stem cell markers Musashi 1, nestin, proliferating cell nuclear antigen (PCNA), doublecortin, and glial fibrillary acidic protein (GFAP) were examined in age-matched control and DLB groups. Staining was quantified in the hippocampal SVZ, subgranular layer (SGL) and ependymal cell layer (EPL). There was a significant loss in DLB of Musashi 1 (P < 0.01) in all areas, an increase in PCNA in hippocampal SVZ (P = 0.01) and SGL (P = 0.05), and an increase in doublecortin in the hippocampal SVZ (P = 0.04) and EPL (P = 0.02). This is the first report of the changes in neurogenic markers in the hippocampal SVZ and EPL in DLB and may offer the potential for understanding disease pathology and in the devising of treatment.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Astrocytes; Cilia; Doublecortin Domain Proteins; Epithelial Cells; Female; Glial Fibrillary Acidic Protein; Hippocampus; Humans; Immunohistochemistry; Intermediate Filament Proteins; Lateral Ventricles; Lewy Bodies; Lewy Body Disease; Male; Microtubule-Associated Proteins; Nerve Tissue Proteins; Nestin; Neural Stem Cells; Neurogenesis; Neurons; Neuropeptides; Proliferating Cell Nuclear Antigen; Retrospective Studies; RNA-Binding Proteins; Tissue Banks

CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3ζ in association with the α-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson's disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; CD3 Complex; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Parkinson Disease

α-synuclein (αS) is a cellular protein mostly known for the association of its aggregated forms with a variety of diseases that include Parkinson's disease and Dementia with Lewy Bodies. While the role of αS in disease is well documented there is currently no agreement on the physiological function of the normal isoform of the protein. Here we provide strong evidence that αS is a cellular ferrireductase, responsible for reducing iron (III) to bio available iron (II). The recombinant form of the protein has a V(Max) of 2.72 nmols/min/mg and K(m) 23 µM. This activity is also evident in lysates from neuronal cell lines overexpressing αS. This activity is dependent on copper bound to αS as a cofactor and NADH as an electron donor. Overexpression of α-synuclein by cells significantly increases the percentage of iron (II) in cells. The common disease mutations associated with increased susceptibility to PD show no [corrected] differences in activity or iron (II) levels. This discovery may well provide new therapeutic targets for PD and Lewy body dementias.

Topics: alpha-Synuclein; Cell Line; Copper; FMN Reductase; Humans; Iron; Kinetics; Lewy Body Disease; NAD; Neurons; Parkinson Disease

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of α-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of α-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and α-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in α-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB.

Topics: Adult; alpha-Synuclein; Animals; Brain; CpG Islands; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Humans; Lewy Body Disease; Mice; Mice, Knockout; Selenoprotein W

Appropriate treatment of dementia requires biomarkers that provide an exact and differential diagnosis. We recently presented differentially expressed amyloid-β (Aβ) peptide patterns in cerebrospinal fluid (CSF) as biomarker candidates for neurochemical diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The objective of the present study was to investigate CSF Aβ peptide patterns in both neuropathologically and clinically defined diagnostic groups of AD and DLB. Using the quantitative Aβ-SDS-PAGE/immunoblot, we analyzed CSF samples of neuropathologically defined patients with AD (definite AD, dAD; n = 11) and DLB (definite, dDLB; n = 12). We compared absolute and relative quantities of CSF Aβ-peptides with a larger cohort of clinically diagnosed patients with probable AD (pAD; n = 71), probable DLB (pDLB; n = 32), and non-demented controls (NDC; n = 71). Each neuropathologically and clinically defined diagnostic group showed a similar relative distribution of CSF Aβ-peptides (Aβ(1-X%)). Aβ(1-42%) was lowered in dAD compared to NDC (p = 1.6 × 10⁻⁷, but did not differ between dAD and pAD. Aβ(1-40ox%) was elevated in dDLB as compared to NDC (p = 1.8 × 10⁻⁵, but did not differ between dDLB and pDLB. Thus, we were able to confirm previous results on Aβ peptide patterns in neuropathologically characterized patients with AD and DLB. Our results underline the usefulness of the CSF Aβ(1-42%) and Aβ(1-40ox%) as diagnostic biomarkers for AD and DLB, respectively.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain Chemistry; Female; Humans; Lewy Body Disease; Male; Mental Status Schedule; Neuropsychological Tests; Prospective Studies; Retrospective Studies; tau Proteins

Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular α-synuclein deposits. We aimed to assess whether reduction of α-synuclein concentrations in CSF was a marker for α-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies.. We assessed potential extracellular-fluid markers of α-synuclein deposition in the brain (total α-synuclein and total tau in CSF, and total α-synuclein in serum) in three cohorts: a cross-sectional training cohort of people with Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders; a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders (CSF specimens were drawn ante mortem during clinical investigations); and a validation cohort of patients who between January, 2003, and December, 2006, were referred to a specialised movement disorder hospital for routine inpatient admission under the working diagnosis of parkinsonism. CSF and serum samples were assessed by ELISA, and clinical diagnoses were made according to internationally established criteria. Mean differences in biomarkers between diagnostic groups were assessed with conventional parametric and non-parametric statistics.. In our training set, people with Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies had lower CSF α-synuclein concentrations than patients with Alzheimer's disease and other neurological disorders. CSF α-synuclein and tau values separated participants with synucleinopathies well from those with other disorders (p<0·0001; area under the receiver operating characteristic curve [AUC]=0·908). In the autopsy-confirmed cases, CSF α-synuclein discriminated between dementia with Lewy bodies and Alzheimer's disease (p=0·0190; AUC=0·687); in the validation cohort, CSF α-synuclein discriminated Parkinson's disease and dementia with Lewy bodies versus progressive supranuclear palsy, normal-pressure hydrocephalus, and other neurological disorders (p<0·0001; AUC=0·711). Other predictor variables tested in this cohort included CSF tau (p=0·0798), serum α-synuclein (p=0·0502), and age (p=0·0335). CSF α-synuclein concentrations of 1·6 pg/μL or lower showed 70·72% sensitivity (95% CI 65·3-76·1%) and 52·83% specificity (39·4-66·3%) for the diagnosis of Parkinson's disease. At this cutoff, the positive predictive value for any synucleinopathy was 90·7% (95% CI 87·3-94·2%) and the negative predictive value was 20·4% (13·7-27·2%).. Mean CSF α-synuclein concentrations as measured by ELISA are significantly lower in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. Although specificity was low, the high positive predictive value of CSF α-synuclein concentrations in patients presenting with synucleinopathy-type parkinsonism might be useful in stratification of patients in future clinical trials.. American Parkinson Disease Association, Stifterverband für die Deutsche Wissenschaft, Michael J Fox Foundation for Parkinson's Research, National Institutes of Health, Parkinson Research Consortium Ottawa, and the Government of Canada.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cohort Studies; Cross-Sectional Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; tau Proteins

Heterozygous mutations in the GBA1 gene elevate the risk of Parkinson disease and dementia with Lewy bodies; both disorders are characterized by misprocessing of α-synuclein (SNCA). A loss in lysosomal acid-β-glucosidase enzyme (GCase) activity due to biallelic GBA1 mutations underlies Gaucher disease. We explored mechanisms for the gene's association with increased synucleinopathy risk.. We analyzed the effects of wild-type (WT) and several GBA mutants on SNCA in cellular and in vivo models using biochemical and immunohistochemical protocols.. We observed that overexpression of all GBA mutants examined (N370S, L444P, D409H, D409V, E235A, and E340A) significantly raised human SNCA levels to 121 to 248% of vector control (p < 0.029) in neural MES23.5 and PC12 cells, but without altering GCase activity. Overexpression of WT GBA in neural and HEK293-SNCA cells increased GCase activity, as expected (ie, to 167% in MES-SNCA, 128% in PC12-SNCA, and 233% in HEK293-SNCA; p < 0.002), but had mixed effects on SNCA. Nevertheless, in HEK293-SNCA cells high GCase activity was associated with SNCA reduction by ≤32% (p = 0.009). Inhibition of cellular GCase activity (to 8-20% of WT; p < 0.0017) did not detectably alter SNCA levels. Mutant GBA-induced SNCA accumulation could be pharmacologically reversed in D409V-expressing PC12-SNCA cells by rapamycin, an autophagy-inducer (≤40%; 10μM; p < 0.02). Isofagomine, a GBA chaperone, showed a related trend. In mice expressing two D409Vgba knockin alleles without signs of Gaucher disease (residual GCase activity, ≥20%), we recorded an age-dependent rise of endogenous Snca in hippocampal membranes (125% vs WT at 52 weeks; p = 0.019). In young Gaucher disease mice (V394Lgba+/+//prosaposin[ps]-null//ps-transgene), which demonstrate neurological dysfunction after age 10 weeks (GCase activity, ≤10%), we recorded no significant change in endogenous Snca levels at 12 weeks of age. However, enhanced neuronal ubiquitin signals and axonal spheroid formation were already present. The latter changes were similar to those seen in three week-old cathepsin D-deficient mice.. Our results demonstrate that GBA mutants promote SNCA accumulation in a dose- and time-dependent manner, thereby identifying a biochemical link between GBA1 mutation carrier status and increased synucleinopathy risk. In cell culture models, this gain of toxic function effect can be mitigated by rapamycin. Loss in GCase activity did not immediately raise SNCA concentrations, but first led to neuronal ubiquitinopathy and axonal spheroids, a phenotype shared with other lysosomal storage disorders.

Topics: alpha-Synuclein; Animals; Cathepsin D; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gaucher Disease; Gene Expression Regulation; Glucosylceramidase; Green Fluorescent Proteins; Humans; Immunosuppressive Agents; Lewy Body Disease; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Mutation; Parkinson Disease; Rats; Sirolimus; Transfection

Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson's disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Case-Control Studies; Corpus Striatum; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Prospective Studies; Severity of Illness Index; Statistics as Topic; Ubiquitin

While the prevalence of Alzheimer disease (AD) increases with age, little is known about the frequency of dementia with Lewy bodies (DLB) in the oldest old. A retrospective hospital-based study compared the relative prevalence of DLB among very old individuals.. 1,100 consecutive autopsy cases of demented patients aged over 70 years (mean age: 83.9 ± 5.4 years) were examined using standardized neuropathological methods and current diagnostic consensus criteria.. Evaluation of three age groups (8th-10th decade) showed a significant increase in the relative prevalence of AD with cerebrovascular lesions including mixed dementia, while AD with Lewy body (LB) pathology showed a mild but insignificant age-related increase. Both 'pure' AD and vascular dementia showed a mild but insignificant decline, while DLB (without severe AD pathology) decreased progressively. While the severity of Lewy pathology in DLB slightly decreased with age, concomitant Alzheimer-like pathology increased progressively.. Whether DLB in the oldest old represents a distinct group is a matter of discussion, but the relative prevalence of AD with LB in our sample remained fairly stable.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain Stem; Dementia; Dementia, Vascular; Female; Humans; Lewy Bodies; Lewy Body Disease; Limbic System; Male; Neocortex; Prevalence; Retrospective Studies

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (α-syn). This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4) against the C-terminus (CT) of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved α-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Behavior, Animal; Cell Line, Tumor; Disease Models, Animal; Immunization, Passive; Immunohistochemistry; Lewy Body Disease; Lysosomes; Maze Learning; Mice; Mice, Transgenic; Nerve Degeneration; Rats

There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimer's disease (AD), 11 frontotemporal dementia (FTD), 11 vascular dementia patients (VaD), and 31 healthy controls). Autoantibody levels against α-synuclein, amyloid-β₄₂ (Aβ₄₂), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against α-synuclein, Aβ₄₂, MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte-derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural-derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Myelin Basic Protein; Myelin Proteins; Myelin-Oligodendrocyte Glycoprotein; Nerve Growth Factors; Peptide Fragments; S100 Calcium Binding Protein beta Subunit; S100 Proteins

The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-β score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Dementia; Female; Humans; Lewy Body Disease; Male; Mental Status Schedule; Parkinson Disease; ROC Curve; Statistics as Topic; tau Proteins

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are characterized pathologically by intraneuronal inclusions called Lewy bodies (LBs) and Lewy neurites. A major component of these inclusions is the protein α-synuclein, which is natively unfolded but forms oligomers and insoluble fibrillar aggregates under pathological conditions. Although α-synuclein is known to undergo several posttranslational modifications, the contribution of SUMOylation to α-synuclein aggregation and the pathogenesis of α-synucleinopathies have not been elucidated. Here, we provide evidence that aggregates and inclusions formed as a result of impaired proteasome activity contain SUMOylated α-synuclein. Additionally, SUMO1 is present in the halo of LBs colocalizing with α-synuclein in the brains of PD and DLB patients. Interestingly, SUMOylation does not affect the ubiquitination of α-synuclein. These findings suggest that proteasomal dysfunction results in the accumulation of SUMOylated α-synuclein and subsequently its aggregation, pointing to the contribution of this posttranslational modification to the pathogenesis of inclusion formation in α-synucleinopathies.

Topics: alpha-Synuclein; Animals; Chlorocebus aethiops; COS Cells; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Macromolecular Substances; Parkinson Disease; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Processing, Post-Translational; SUMO-1 Protein; Sumoylation

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn₁₋₁₄₀) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn₁₋₁₃₉ and Ac-α-syn₁₋₁₀₃) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA).

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amino Acid Sequence; Blotting, Western; Brain Chemistry; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Middle Aged; Nanotechnology; Parkinson Disease; Protein Isoforms; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry

Lewy bodies composed of aggregates of α-synuclein (αS) in the brain are the main histopathological features of Lewy body diseases (LBD) such as Parkinson's disease and dementia with Lewy bodies. Mutations such as E46K, A30P and A53T in the αS gene cause autosomal dominant LBD in a number of kindreds. Although these mutations accelerate fibril formation, their precise effects at early stages of the αS aggregation process remain unknown. To answer this question, we examined the aggregation including monomer conformational dynamics and oligomerization of the E46K, A30P, A53T and A30P/A53T mutations and wild type (WT) using thioflavin S assay, circular dichroism spectroscopy, photo-induced cross-linking of unmodified proteins, electron microscopy, and atomic force microscopy. Relative to WT αS, E46K αS accelerated the kinetics of the secondary structure change and oligomerization, whereas A30P αS decelerated them. These effects were reflected in changes in average oligomer size. The mutant oligomers of E46K αS functioned as fibril seeds significantly more efficiently than those of WT αS, whereas the mutant oligomers of A30P αS were less efficient. Our results that mutations of familial LBD had opposite effects at early stages of αS assembly may provide new insight into the molecular mechanisms of LBD.

Topics: alpha-Synuclein; Amino Acid Sequence; Genes, Dominant; Humans; Lewy Body Disease; Microscopy, Atomic Force; Molecular Sequence Data; Parkinson Disease; Point Mutation; Protein Structure, Tertiary

Abnormally accumulated α-synuclein (α-syn) is a pathological hallmark of Lewy body-related disorders such as Parkinson's disease (PD) and dementia with Lewy body disease (DLB). However, it is not well understood whether and how abnormal accumulation of α-syn leads to cognitive impairment or dementia in PD and DLB. Furthermore, it is not known whether targeted removal of α-syn pathology can reverse cognitive decline. Here, we found that the distribution of α-syn pathology in an inducible α-syn transgenic mouse model recapitulates that in human DLB. Abnormal accumulation of α-syn in the limbic system, particularly in the hippocampus, correlated with memory impairment and led to structural synaptic deficits. Furthermore, when α-syn expression was suppressed, we observed partial clearing of pre-existing α-syn pathology and reversal of structural synaptic defects, resulting in an improvement in memory function.

Topics: Acoustic Stimulation; Age Factors; alpha-Synuclein; Analysis of Variance; Animals; Animals, Newborn; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Conditioning, Classical; Cues; Disease Models, Animal; Disease Progression; Embryo, Mammalian; Fear; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Gliosis; Humans; In Vitro Techniques; Indoles; Lewy Body Disease; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Serine; Synapses

Detection and differentiation of neurodegenerative dementias, such as dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), with blood-based biomarkers would facilitate diagnosis and treatment.. By use of a commercially available ELISA kit, we measured α-synuclein levels in the serum of 40 DLB patients and controls, and of 80 AD patients.. We found significantly reduced α-synuclein serum levels in DLB compared to both AD (p = 0.006) and control subjects (p = 0.001), reaching an area under the curve of >0.70.. Although these results do not justify a definition of serum α-synuclein as a potential single biomarker, results may contribute to a multimarker strategy in DLB diagnosis.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Area Under Curve; Biomarkers; Data Interpretation, Statistical; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Neuropsychological Tests; Reproducibility of Results; ROC Curve

α-Synuclein is a major component of Lewy bodies in Parkinson disease (PD) and dementia with Lewy bodies (DLB). We recently showed that abnormal α-synuclein with resistance to proteinase K (PK) is deposited at presynapses of distinct brain anatomic regions from the early stages of PD and DLB. NUB1, a synphilin-1-binding protein, also accumulates in Lewy bodies, but it is not known whether abnormal α-synuclein is associated with NUB1. Here, we demonstrate that, in the brain of patients with PD and DLB, NUB1 accumulates in the presynapses in the hippocampus, cerebral neocortex, and substantia nigra in which PK-resistant α-synuclein is deposited. Endogenous NUB1 also accumulated with PK-resistant α-synuclein in the presynapses of transgenic mice that express human α-synuclein with an A53T mutation. Immunoelectron microscopy showed that NUB1 is localized to presynaptic nerve terminals where no abnormal filaments are seen. Biochemical analyses showed that NUB1 coexists with abnormal α-synuclein in the brain of DLB patients. These findings suggest that NUB1 along with abnormal α-synuclein is involved in the pathogenesis of Lewy body disease.

Topics: Adaptor Proteins, Signal Transducing; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Animals, Newborn; Brain; Endopeptidase K; Female; Gene Expression Regulation, Developmental; HeLa Cells; Humans; Lewy Body Disease; Male; Mice; Mice, Transgenic; Middle Aged; Mutation; Presynaptic Terminals; Synaptophysin; Transcription Factors; Transfection

The α-synuclein gene (SNCA) plays a major role in the aetiology of Lewy body disease (LBD) including Parkinson's disease (PD). Point mutations and genetic alterations causing elevated gene expression are causally linked to familial PD. To what extent epigenetic changes play a role in the regulation of α-synuclein expression and may contribute to the aetiology of sporadic LBD is a matter of debate. We analysed the methylation state of the promoter region and a CpG-rich region of intron 1 of α-synuclein in several brain regions in sporadic LBD and controls using 454 GS-FLX-based high-resolution bisulphite sequencing. Our results indicate that there are significant differences in the level of methylation between different brain areas. The overall methylation levels in the promoter and intron 1 of α-synuclein are rather low in controls and-in contrast to previously reported findings-are not significantly different from LBD. However, single CpG analysis revealed significant hyper- and hypomethylation at different positions in various brain regions and LBD stages. A slight overall increase in methylation related to LBD patients' age was detected.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Base Sequence; Brain Chemistry; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Humans; Introns; Lewy Body Disease; Male; Middle Aged; Promoter Regions, Genetic; Sequence Analysis, DNA

α-Synuclein is central to the pathogenesis of Parkinson disease (PD). Mutations as well as accumulation of α-synuclein promote the death of dopaminergic neurons and the formation of Lewy bodies. α-Synuclein is monoubiquitinated by SIAH, but the regulation and roles of monoubiquitination in α-synuclein biology are poorly understood. We now report that the deubiquitinase USP9X interacts in vivo with and deubiquitinates α-synuclein. USP9X levels are significantly lower in cytosolic fractions of PD substantia nigra and Diffuse Lewy Body disease (DLBD) cortices compared to controls. This was associated to lower deubiquitinase activity toward monoubiquitinated α-synuclein in DLBD cortical extracts. A fraction of USP9X seems to be aggregated in PD and DLBD, as USP9X immunoreactivity is detected in Lewy bodies. Knockdown of USP9X expression promotes accumulation of monoubiquitinated α-synuclein species and enhances the formation of toxic α-synuclein inclusions upon proteolytic inhibition. On the other hand, by manipulating USP9X expression levels in the absence of proteolytic impairment, we demonstrate that monoubiquitination controls the partition of α-synuclein between different protein degradation systems. Deubiquitinated α-synuclein is mostly degraded by autophagy, while monoubiquitinated α-synuclein is preferentially degraded by the proteasome. Moreover, monoubiquitination promotes the degradation of α-synuclein, whereas deubiquitination leads to its accumulation, suggesting that the degradation of deubiquitinated α-synuclein by the autophagy pathway is less efficient than the proteasomal one. Lower levels of cytosolic USP9X and deubiquitinase activity in α-synucleinopathies may contribute to the accumulation and aggregation of monoubiquitinated α-synuclein in Lewy bodies. Our data indicate that monoubiquitination is a key determinant of α-synuclein fate.

Topics: alpha-Synuclein; Autophagy; Cell Line, Tumor; Cerebral Cortex; Dopaminergic Neurons; Gene Expression Regulation; Humans; Lewy Bodies; Lewy Body Disease; Proteasome Endopeptidase Complex; Proteolysis; RNA, Small Interfering; Ubiquitin; Ubiquitin Thiolesterase

Topics: Aged; alpha-Synuclein; Humans; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Neurites

Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. Accurate diagnosis is essential to avoid harm and optimize clinical management. There is therefore an urgent need to identify reliable biomarkers.. Mass spectrometry was used to determine the specificity of antibody alpha-synuclein (211) for alpha-synuclein. Using gel electrophoresis we measured protein levels detected by alpha-synuclein specific antibodies in the cerebrospinal fluid (CSF) of DLB patients and compared them to age matched controls.. A 24 kDa band was detected using alpha-synuclein specific antibodies which was significantly reduced in the CSF of DLB patients compared to age matched controls (p < 0.05). Further analysis confirmed that even DLB patients with mild dementia showed significant reductions in this protein in comparison to controls.. The current study emphasizes the necessity for further studies of CSF alpha-synuclein as a biomarker of DLB and extends our previous knowledge by establishing a potential relationship between alpha-synuclein and the severity of cognitive impairment. The identification of this 24 kDa protein is the next important step in these studies.

Topics: Aged; alpha-Synuclein; Antibodies; Antibody Specificity; Biomarkers; Blotting, Western; Electrophoresis, Polyacrylamide Gel; Female; Humans; Lewy Body Disease; Male; Mass Spectrometry

Alpha-synuclein (alpha-syn) aggregation is a neuropathological hallmark of many diseases including Dementia with Lewy Bodies (DLB) and Parkinson's Disease (PD), collectively termed the alpha-synucleinopathies. The mechanisms underlying alpha-syn aggregation remain elusive though emerging science has hypothesized that the interaction between cholesterol and alpha-syn may play a role. Cholesterol has been linked to alpha-synucleinopathies by recent work suggesting cholesterol metabolites appear to accelerate alpha-syn fibrillization. Consistent with these findings, cholesterol-lowering agents have been demonstrated to reduce alpha-syn accumulation and the associated neuronal pathology in vitro. In this context, this study sought to investigate the in vivo effects of the cholesterol synthesis inhibitor lovastatin on alpha-syn aggregation in two different transgenic (Tg) mouse models that neuronally overexpress human alpha-syn. Lovastatin-treated mice displayed significantly reduced plasma cholesterol levels and levels of oxidized cholesterol metabolites in the brain in comparison to saline-treated controls. Immunohistochemical analysis demonstrated a significant reduction of neuronal alpha-syn aggregates and alpha-syn immunoreactive neuropil in the temporal cortex of lovastatin-treated Tg mice in comparison to saline-treated alpha-syn Tg controls. Consistently, immunoblot analysis of mouse brain homogenates showed a reduction in levels of total and oxidized alpha-syn in lovastatin-treated alpha-syn Tg mice in comparison to saline-treated alpha-syn Tg controls. The reduced alpha-syn accumulation in lovastatin-treated mice was associated with abrogation of neuronal pathology. The results from this study demonstrate that lovastatin administration can reduce alpha-syn aggregation and associated neuropathology and support the possibility that treatment with cholesterol-lowering agents may be beneficial for patients with PD and/or DLB.

Topics: alpha-Synuclein; Analysis of Variance; Animals; Brain; Cholesterol; Dendrites; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lewy Body Disease; Lovastatin; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Neurons; Oxidation-Reduction; Parkinson Disease; Platelet-Derived Growth Factor; Thy-1 Antigens

TRIM family proteins are involved in a broad range of biological processes, and their alteration results in many diverse pathological conditions found in genetic diseases, viral infections, and cancers. However, the spatial and temporal expression and function of TRIM9, one of TRIM family proteins, remain obscure. Our results here showed that TRIM9 protein is mainly expressed in the cerebral cortex, and functions as an E3 ubiquitin ligase collaborating with an E2 ubiquitin conjugating enzyme UbcH5b. Immunohistochemical examination revealed that TRIM9 is localized to the neurons in the normal mouse and human brain and that TRIM9 immunoreactivity is severely decreased in the affected brain areas in Parkinson's disease and dementia with Lewy bodies. This repressed level of TRIM9 protein was supported by immunoblotting analysis. Intriguingly, cortical and brainstem-type Lewy bodies were immunopositive for TRIM9. These results suggest that TRIM9 plays an important role in the regulation of neuronal functions and participates in pathological process of Lewy body disease through its ligase activity.

Topics: alpha-Synuclein; Analysis of Variance; Animals; Blotting, Western; Brain; Carrier Proteins; Cells, Cultured; Humans; Immunohistochemistry; Lewy Body Disease; Mice; Nerve Tissue Proteins; Neurons; Parkinson Disease; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

Topics: alpha-Synuclein; Brain; Disease Progression; Humans; Lewy Bodies; Lewy Body Disease; Nerve Fibers, Unmyelinated; Parkinson Disease; Pure Autonomic Failure; Rare Diseases

Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by alpha-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in alpha-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in alpha-synuclein transgenic mice.. By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying alpha-synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of alpha-synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of alpha-synuclein in transgenic mice and amelioration of associated neurodegenerative alterations.. This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and alpha-synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Animals; Autophagy; Autophagy-Related Protein 7; Blotting, Western; Brain; Cell Line; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Lewy Body Disease; Male; Mice; Mice, Transgenic; Microscopy, Confocal; Microscopy, Electron; Nerve Degeneration; Pyramidal Cells; RNA Interference; Signal Transduction; Ubiquitin-Activating Enzymes

Recently, Braak and coworkers proposed a pathologic staging scheme for Parkinson disease (PD). In this staging, scheme substantia nigra pathology occurs at midstage disease, while involvement of anterior olfactory nucleus, medulla, and pontine tegmentum occur earlier. In the last stages, Lewy bodies (LBs) involve cortical areas. The general principles of the proposed staging system have been confirmed in several studies of PD, but it does not appear to fit with all LB disorders. We studied the density and distribution of LBs with alpha-synuclein immunohistochemistry in normal elderly with incidental LBs (N = 12); progressive supranuclear palsy (PSP) with incidental LBs (N = 18); Lewy body disease (LBD) with minimal or no Alzheimer type pathology (N = 52); LBD with concomitant Alzheimer disease (AD) (N = 84); and cases of AD with amygdala predominant LBs (N = 64). The proportion of cases that fit the PD staging scheme was 67% for incidental LBs; 86% for PSP with LBs; 86% for pure LBD; and 84% for LBD with AD; but only 6% for AD with amygdala predominant LBs. The PD staging scheme is valid, except in the setting of advanced AD. In this situation, LBs may be unrelated to PD and more likely related to factors inherent to AD and the selective vulnerability of the amygdala to both Alzheimer and alpha-synuclein pathologies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Parkinson Disease; Severity of Illness Index; Supranuclear Palsy, Progressive

Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of alpha-synuclein (alpha-syn) in Parkinson disease. Herein we demonstrate that alpha-syn is phosphorylated at S87 in vivo and within LBs. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer disease (AD), LB disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated alpha-syn (S129-P and S87-P), a significant amount of immunoreactivity was detected in the membrane in the LBD, MSA, and AD cases but not in normal controls. In brain homogenates from diseased human brains and TG animals, the majority of S87-P alpha-syn was detected in the membrane fractions. A battery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, and membrane-binding properties of monomeric alpha-syn. These studies demonstrated that phosphorylation at S87 expands the structure of alpha-syn, increases its conformational flexibility, and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of alpha-syn binding to membranes. Together, our findings provide novel mechanistic insight into the role of phosphorylation at S87 and S129 in the pathogenesis of synucleinopathies and potential roles of phosphorylation in alpha-syn normal biology.

Topics: alpha-Synuclein; Alzheimer Disease; Amino Acid Sequence; Animals; Brain; Cell Membrane; Creatine Kinase; Disease Models, Animal; Humans; Lewy Bodies; Lewy Body Disease; Male; Mice; Mice, Transgenic; Multiple System Atrophy; Neurodegenerative Diseases; Neurons; Parkinson Disease; Phosphorylation; Polymers; Protein Isoforms; Rats; Rats, Wistar; Serine

Aggregation of alpha-synuclein (alpha-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric alpha-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two-dimensional analytical separation and an array of biochemical and cell-based assays to characterize alpha-syn oligomers that are present in the nervous system of A53T alpha-syn transgenic mice. The most prominent species identified were 53 A detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing alpha-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized alpha-syn oligomers, significantly accelerated aggregation of alpha-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of alpha-syn fibrils. These data indicate that specific conformations of alpha-syn oligomers are present in distinct brain regions of A53T alpha-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brain-region-specific intrinsic factors.

Topics: alpha-Synuclein; Amyloid; Animals; Antibodies; Antibody Specificity; Brain; Cells, Cultured; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Weight; Neurodegenerative Diseases; Parkinson Disease; Peptide Fragments; Polymers; Promoter Regions, Genetic; Protein Conformation; PrPC Proteins; Solubility

A retrospective autopsy-based study of the human submandibular gland, one of the three major salivary glands, together with anatomically related peripheral structures (cervical superior ganglion, cervical sympathetic trunk, vagal nerve at the level of the carotid bifurcation), was conducted on a cohort consisting of 33 individuals, including 9 patients with neuropathologically confirmed Parkinson's disease (PD), three individuals with incidental Lewy body disease (iLBD), 2 individuals with neuropathologically confirmed multiple system atrophy (MSA), and 19 controls, using alpha-synuclein immunohistochemistry in 100 mum polyethylene glycol-embedded tissue sections. Lewy pathology (LP) was present in the submandibular glands and cervical superior ganglia in PD (9/9 cases) and iLBD (2/3 cases) but not in MSA or controls. The cervical sympathetic trunk (7/9 PD cases, 2/3 iLBD cases) and peripheral vagal nerves (9/9 PD cases, 2/3 iLBD cases) also displayed LP. The results are discussed within the context of hyposmia as well as autonomic dysfunction in PD (sialorrhea, sialopenia, dysphagia). Potential disease-related changes in salivary volume, contents, and viscosity might make it possible, in combination with other tests, to employ human saliva as a biomarker.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cohort Studies; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Retrospective Studies; Submandibular Gland; Superior Cervical Ganglion; Vagus Nerve

A sensitive immunohistochemical method for phosphorylated alpha-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson's disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer's disease with Lewy bodies (ADLB) and 17 with Alzheimer's disease with no Lewy bodies (ADNLB). The relative densities and frequencies of occurrence of phosphorylated alpha-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Female; Ganglia, Sympathetic; Gastrointestinal Tract; Humans; Immunohistochemistry; Lewy Body Disease; Male; Parkinson Disease; Peripheral Nervous System; Phosphorylation; Spinal Cord

Topics: Aged; alpha-Synuclein; Ataxia; Blindness, Cortical; Electroencephalography; Humans; Lewy Body Disease; Male; Myoclonus; Substantia Nigra; Visual Cortex

Abnormally modified alpha-synuclein is a pathological hallmark of Parkinson's disease and the other alpha-synucleinopathies. Since proteinase K (PK) treatment is known to enhance the immunoreactivity of abnormal alpha-synuclein, we immunohistochemically examined the brain of transgenic (Tg) mice expressing human mutant A53T alpha-synuclein using this retrieval method. PK treatment abolished the immunoreactivity of alpha-synuclein in abnormal inclusions as well as of endogenous alpha-synuclein in Tg mice, whereas PK-resistant alpha-synuclein was found in the presynaptic nerve terminals, especially in the hippocampus and temporal cortex. In human Lewy body disease, PK-resistant alpha-synuclein was deposited in Lewy bodies and Lewy neurites, as well as in the presynapses in distinct brain regions, including the hippocampus, temporal cortex and substantia nigra. Biochemical analysis revealed that PK-resistant alpha-synuclein was detected in the presynaptic fraction in Tg mice and human Lewy body disease. Although PK-resistant alpha-synuclein was found in the presynapse in Tg mice even at 1 week of age, it was not phosphorylated until at least 8 months of age. Moreover, PK-resistant alpha-synuclein in the presynapse was not phosphorylated in human Lewy body disease. These findings suggest that phosphorylation is not necessary to cause the conversion of soluble form to PK-resistant alpha-synuclein. Considering that native alpha-synuclein is a soluble protein localized to the presynaptic terminals, our findings suggest that PK-resistant alpha-synuclein may disturb the neurotransmission in alpha-synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Case-Control Studies; Cell Line, Transformed; Endopeptidase K; Humans; Lewy Bodies; Lewy Body Disease; Mice; Mice, Transgenic; Mutation; Postmortem Changes; Presynaptic Terminals; Synaptophysin; Transfection

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Brain; Humans; Lewy Body Disease

The clinical diagnosis of dementia with Lewy bodies (DLB) is made on the basis of consensus criteria; however, the sensitivity of the criteria is relatively low. There are no generally accepted biomarkers to distinguish DLB from other dementias. Here the utility of quantification of alpha-synuclein, beta-amyloid42 (Abeta42) and tau in the CSF of patients with DLB, Alzheimer's disease (AD) and other dementias was examined.. 86 patients were divided into three age and sex matched groups: DLB (n=34), AD (n=31) and other dementias (n=21). Two patients with alpha-synuclein gene (SNCA) duplication were also examined. Abeta and tau were quantified using an ELISA kit. A modified sandwich ELISA was developed which enables the sensitive quantification of CSF alpha-synuclein.. Total and phosphorylated tau levels as well as Abeta40/42 and tau/Abeta42 ratios were significantly higher in AD patients than in patients with DLB (p<0.01) and other dementias (p<0.01). CSF alpha-synuclein levels in DLB patients were significantly lower than those in patients with AD (p<0.05) and other dementias (p<0.01). CSF alpha-synuclein level correlated with the Abeta42 level in DLB patients (p=0.01, r=0.43). Two patients with SNCA duplication exhibited relatively low levels of CSF alpha-synuclein.. The study suggests that reduced levels of CSF alpha-synuclein in DLB may reflect the accumulation of alpha-synuclein with Lewy pathology in the brain and that quantification of CSF alpha-synuclein helps in the differentiation of DLB from AD and other dementias in combination with Abeta42 and tau analysis.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Peptide Fragments; Phenotype; tau Proteins

Transactivation response DNA-binding protein 43 (TDP-43) proteinopathies are classified based upon the extent of modified TDP-43 and include a growing number of neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration with ubiquitin-immunoreactive, tau-negative inclusions and frontotemporal lobar degeneration with motor neuron disease.. The purpose of the study was to examine whether proteolytic modifications of TDP-43 are a relevant finding in Parkinson's disease (PD) and dementia with Lewy bodies (DLB).. A novel site-directed caspase cleavage antibody, termed TDP caspase cleavage product antibody (TDPccp), was utilized based upon a known caspase 3 cleavage consensus site within TDP-43 at position 219.. Application of this antibody to postmortem brain sections from PD and DLB patients revealed the presence of caspase-cleaved TDP-43 in Lewy bodies and Hirano bodies in all cases examined. Colocalization of TDPccp with an antibody to alpha-synuclein (alpha-Syn), which served as a general marker for Lewy bodies, was evident within the substantia nigra in both alpha-synucleinopathies. Interestingly, the TDPccp antibody detected a greater number of Lewy bodies in PD and DLB compared to the alpha-Syn antibody. In addition, a semiquantitative analysis in both diseases confirmed this finding by indicating that the percentage of caspase-cleaved TDP-43 single-labeled Lewy bodies was approximately twice that of alpha-Syn labeling (in DLB 13.4 vs. 5.5%, while in PD 34.6 vs. 17.6%).. Collectively, these data have identified caspase-cleaved TDP-43 as a primary component of Lewy and Hirano bodies in PD and DLB, and suggest that the TDPccp antibody is an effective marker for the detection of Lewy bodies in these neurodegenerative diseases.

Topics: alpha-Synuclein; Antibodies, Monoclonal; Brain; Caspase 3; DNA-Binding Proteins; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Predictive Value of Tests; TDP-43 Proteinopathies; Trans-Activators

Important recent publications in the area of neuroscience and heart-brain medicine center largely around three topics: (1) mechanisms of cardiac sympathetic denervation in Parkinson disease, (2) cytoplasmic monoamine metabolites as autotoxins, and (3) the validity of power spectral analysis of heart rate variability to indicate cardiac sympathetic tone. Findings by Orimo et al support a centripetal, retrograde pathogenetic process involving alpha-synuclein deposition and degeneration of cardiac noradrenergic neurons in Parkinson disease. Several studies suggest that processes increasing cytoplasmic monoamines lead to neuronal loss from auto-oxidation or enzymatic oxidation. Lack of correlation between commonly used indices from power spectral analysis of heart rate variability and cardiac norepinephrine spillover casts doubt on the validity of power spectral analysis to indicate cardiac sympathetic tone.

Topics: alpha-Synuclein; Brain; Catecholamines; Free Radicals; Heart; Heart Rate; Humans; Lewy Body Disease; Myocardium; Nerve Degeneration; Neurons; Norepinephrine; Parkinson Disease; Sympathectomy; Sympathetic Nervous System

Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]).. We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome.. Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients.. These cases illustrate that the alpha-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Female; Follow-Up Studies; Humans; Lewy Body Disease; Longitudinal Studies; Male; Medical Records Systems, Computerized; Middle Aged; Multiple System Atrophy; Parkinson Disease; REM Sleep Behavior Disorder; Retrospective Studies; Time Factors; Young Adult

It has been reported that the development of TDP-43 pathology in cases of Lewy body disease (LBD) might be associated with the severity of tau pathology. However, the impact of α-synuclein pathology on TDP-43 accumulation in LBD remains unclear. To clarify whether α-synuclein pathology has an effect on TDP-43 accumulation, independent of tau pathology, we examined by immunohistochemistry 56 cases of LBD using a phosphorylation-dependent TDP-43 antibody. The frequency of TDP-43 pathology in all LBD cases was 18% (10/56). In 37 LBD cases with no or low tau burden (LBD-Ltau; Braak NFT stages 0-II), the frequency of TDP-43 pathology was 19% (7/37). The frequency of TDP-43 pathology in diffuse neocortical type LBD-Ltau cases was 36% (4/11), which was higher than those in limbic and brain stem-predominant types (11-14%). The amygdala and entorhinal cortex were the most frequently affected sites of TDP-43 pathology in LBD-Ltau cases. In LBD-Ltau cases, the proportion of diffuse neocortical type LBD was higher in the TDP-43-positive cases, than that in TDP-43-negative cases (57 vs. 23%). In all LBD cases, α-synuclein pathology in the temporal cortex was significantly more severe in TDP-43-positive cases, and significantly correlated with the severity of TDP-43 pathology in the amygdala. In a multivariate model, the presence of severe α-synuclein pathology was significantly associated with the development of TDP-43 pathology independent of age at death and tau pathology. In the amygdala, TDP-43 was often colocalized with α-synuclein or tau. Given these findings, we suggest that α-synuclein pathology is associated with TDP-43 accumulation in LBD cases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amygdala; Brain; Entorhinal Cortex; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Neocortex

To determine the association of the genes that encode alpha-, beta-, and gamma-synuclein (SNCA, SNCB, and SNCG, respectively) with diffuse Lewy body disease (DLBD).. Case-control study. Subjects A total of 172 patients with DLBD consistent with a clinical diagnosis of Parkinson disease dementia/dementia with Lewy bodies and 350 clinically and 97 pathologically normal controls.. Sequencing of SNCA, SNCB, and SNCG and genotyping of single-nucleotide polymorphisms performed on an Applied Biosystems capillary sequencer and a Sequenom MassArray pLEX platform, respectively. Associations were determined using chi(2) or Fisher exact tests.. Initial sequencing studies of the coding regions of each gene in 89 patients with DLBD did not detect any pathogenic substitutions. Nevertheless, genotyping of known polymorphic variability in sequence-conserved regions detected several single-nucleotide polymorphisms in the SNCA and SNCG genes that were significantly associated with disease (P = .05 to <.001). Significant association was also observed for 3 single-nucleotide polymorphisms located in SNCB when comparing DLBD cases and pathologically confirmed normal controls (P = .03-.01); however, this association was not significant for the clinical controls alone or the combined clinical and pathological controls (P > .05). After correction for multiple testing, only 1 single-nucleotide polymorphism in SNCG (rs3750823) remained significant in all of the analyses (P = .05-.009).. These findings suggest that variants in all 3 members of the synuclein gene family, particularly SNCA and SNCG, affect the risk of developing DLBD and warrant further investigation in larger, pathologically defined data sets as well as clinically diagnosed Parkinson disease/dementia with Lewy bodies case-control series.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; beta-Synuclein; Biological Evolution; Female; gamma-Synuclein; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Lewy Body Disease; Linkage Disequilibrium; Male; Phylogeny; Polymorphism, Single Nucleotide

The lower brain stem of 25 pathologically-confirmed Parkinson's disease (PD) cases was examined by alpha synuclein immunohistochemistry to characterize pathological accumulation of alpha synuclein (Lewy-type α-synucleinopathy, LTS) in the medulla oblongata, to examine differences between affected regions and test a proposed model of staging of pathology in PD. All cases had LTS in the medulla, including the dorsal motor nucleus of the vagus (dmX), when present. The distribution followed a consistent pattern and appeared to be concentrated in a tyrosine hydroxylase (TH) immunoreactive region, probably representing the dorsal IX/X nuclear complex and the intermediate reticular zone. LTS density was greatest in the dmX. A similar distribution pattern to PD was seen in 14 incidental Lewy body disease (ILBD) cases, five derived from the Queen Square Brain Bank tissue collection and nine identified in separate series of 60 neurologically-normal individuals, and in three cases with the G2019S mutation of LRRK2. Semiquantitative assessment showed that severity of pathology in the dmX was not correlated with the severity of cortical pathology. Semiquantitative assay of TH and ChAT peptide expression in the medulla showed that TH expression in PD and ILBD did not differ from controls. These findings broadly support the Braak hypothesis of caudo-rostral development but indicate that the extent of the disease in the cortex and the severity of pathology in the medulla were independent of one another.

Topics: Aged; alpha-Synuclein; Brain Stem; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurons; Odds Ratio; Parkinson Disease; Severity of Illness Index; Tyrosine 3-Monooxygenase

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, known to cause Gaucher disease (GD), are a risk factor for the development of Parkinson disease (PD) and related disorders. This association is based on the concurrence of parkinsonism and GD, the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world, and neuropathologic findings. The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia. Three individuals had GD and four were heterozygous for glucocerebrosidase mutations. All cases had no known family history of PD and the mean age of disease onset was 59 years (range 42-77). Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32-90% of Lewy bodies (mean 75%), some ubiquitinated and others non-ubiquitinated. In samples from seven subjects without mutations, <10% of Lewy bodies were glucocerebrosidase positive (mean 4%). This data demonstrates that glucocerebrosidase can be an important component of α-synuclein-positive pathological inclusions. Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregates.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Blotting, Southern; Brain; Female; Fluorescent Antibody Technique; Gaucher Disease; Glucosylceramidase; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Microscopy, Confocal; Middle Aged; Mutation; Neurites; Parkinson Disease; Ubiquitination

In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker α-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinson's disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of α-synuclein, amyloid-β 1-42 (Aβ1-42), total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF α-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Aβ1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower α-synuclein was related to lower MMSE-scores (β (SE) = 6(2) and p< 0.05) and fluency (β (SE) = 4(2), p< 0.05). Ultimately, CSF α-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (α-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF α-synuclein levels are related to worse cognitive performance.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Brief Psychiatric Rating Scale; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α-synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70-79, 80-89 and ≥ 90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80-89 and ≥ 90 year cases compared to 70-79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70-79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Cerebral Amyloid Angiopathy; Cerebral Cortex; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Neurites; Neurofibrillary Tangles; Neuropsychological Tests; Paraffin Embedding; Plaque, Amyloid; Presynaptic Terminals; Synaptophysin; Tissue Fixation

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0-I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Diagnosis, Differential; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Neurofibrillary Tangles; Parkinson Disease; tau Proteins

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-β does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-β may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognition Disorders; Diagnosis, Differential; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Severity of Illness Index; Statistics, Nonparametric; Thiazoles

The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites. Patients with both Alzheimer's disease (AD) and cortical Lewy pathology represent the Lewy body variant of AD (LBV) and constitute 25% of AD cases. C-terminally truncated forms of α-syn enhance the aggregation of α-syn in vitro. To investigate the presence of C-terminally truncated α-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated α-syn ending at residues 110 (α-syn110) and 119 (α-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that α-syn110 and α-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing α-syn140 also contained α-syn119; however, some aggregates contained α-syn119 without α-syn140, suggesting that α-syn119 may stimulate aggregate formation. Immunohistochemistry and image analysis of tissue microarrays of the cingulate cortex from patients with DLBD (n = 27), LBV (n = 27), and AD (n = 19) and age-matched controls (n = 15) revealed that AD is also characterized by frequent abnormal neurites containing α-syn119. Notably, these neurites did not contain α-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing α-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Case-Control Studies; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Middle Aged; Mutant Proteins; Neurites; Protein Isoforms; Protein Structure, Tertiary; Tissue Array Analysis

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are neurodegenerative disorders of the aging population characterized by the abnormal accumulation of alpha-synuclein (alpha-syn). Previous studies have suggested that excitotoxicity may contribute to neurodegeneration in these disorders, however the underlying mechanisms and their relationship to alpha-syn remain unclear. For this study we proposed that accumulation of alpha-syn might result in alterations in metabotropic glutamate receptors (mGluR), particularly mGluR5 which has been linked to deficits in murine models of PD. In this context, levels of mGluR5 were analyzed in the brains of PD and DLB human cases and alpha-syn transgenic (tg) mice and compared to age-matched, unimpaired controls, we report a 40% increase in the levels of mGluR5 and beta-arrestin immunoreactivity in the frontal cortex, hippocampus and putamen in DLB cases and in the putamen in PD cases. In the hippocampus, mGluR5 was more abundant in the CA3 region and co-localized with alpha-syn aggregates. Similarly, in the hippocampus and basal ganglia of alpha-syn tg mice, levels of mGluR5 were increased and mGluR5 and alpha-syn were co-localized and co-immunoprecipitated, suggesting that alpha-syn interferes with mGluR5 trafficking. The increased levels of mGluR5 were accompanied by a concomitant increase in the activation of downstream signaling components including ERK, Elk-1 and CREB. Consistent with the increased accumulation of alpha-syn and alterations in mGluR5 in cognitive- and motor-associated brain regions, these mice displayed impaired performance in the water maze and pole test, these behavioral alterations were reversed with the mGluR5 antagonist, MPEP. Taken together the results from study suggest that mGluR5 may directly interact with alpha-syn resulting in its over activation and that this over activation may contribute to excitotoxic cell death in select neuronal regions. These results highlight the therapeutic importance of mGluR5 antagonists in alpha-synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Autopsy; Brain; Excitatory Amino Acid Antagonists; Female; Humans; Immunoblotting; Immunohistochemistry; Lewy Body Disease; Male; Memory Disorders; Mice; Mice, Transgenic; Motor Activity; Neurodegenerative Diseases; Parkinson Disease; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Signal Transduction

Lewy bodies in Parkinson disease could be innocent bystanders or active agents responsible for neuronal death. Eighteen elderly patients with a Parkinson syndrome were studied prospectively and selected postmortem on the presence of Lewy bodies (14 cases with Parkinson disease, four with dementia with Lewy bodies). Information on disease duration was available in 17 cases. While akinesia and rigidity were linked with the neuronal loss, the percentages of Lewy body bearing neurons and of alpha-synuclein immunoreactive neurons in the substantia nigra were not correlated with the symptoms or the disease duration, and appeared stable, involving 3.6% of the neurons on average. Such stability indicated that, during the whole course of the disease, the destruction of the Lewy bodies was equal to their production. In the model that is proposed here, the Lewy bodies are eliminated when the neurons that bear them die. With the hypothesis that neuronal death is directly related to Lewy bodies, it is possible to estimate their life span, which was calculated to be 6.2 months (15.9 months for any type of alpha-synuclein inclusion).

Topics: Age of Onset; alpha-Synuclein; Cell Count; Cell Death; Disease Progression; Humans; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Neurons; Parkinson Disease; Parkinsonian Disorders; Prospective Studies; Substantia Nigra; Time Factors

Although the intralaminar thalamus is a target of alpha-synuclein pathology in Parkinson's disease, the degree of neuronal loss in Lewy body diseases has not been assessed. We have used unbiased stereological techniques to quantify neuronal loss in intralaminar thalamic nuclei concentrating alpha-synuclein pathology (the anterodorsal, cucullar, parataenial, paraventricular, central medial, central lateral and centre-median/parafascicular complex) in different clinical forms of Lewy body disease (Parkinson's disease with and without dementia, and dementia with Lewy bodies, N=21) compared with controls (N=5). Associations were performed in the Lewy body cases between intralaminar cell loss and the main diagnostic clinical (parkinsonism, dementia, fluctuation in consciousness, and visual hallucinations) and pathological (Braak stage of Parkinson's disease) features of these diseases, as well as between cell loss and the scaled severity of the alpha-synuclein deposition within the intralaminar thalamus. As expected, significant alpha-synuclein accumulation occurred in the intralaminar thalamus in the cases with Lewy body disease. Pathology concentrated anteriorly and in the central lateral and paraventricular nuclei was related to the Braak stage of Parkinson's disease, ageing, and the presence of dementia. Across all types of Lewy body cases there was substantial atrophy and neuronal loss in the central lateral, cucullar and parataenial nuclei, and neuronal loss without atrophy in the centre-median/parafascicular complex. Cases with visual hallucinations showed a greater degree of atrophy of the cucullar nucleus, possibly due to amygdala denervation. The significant degeneration demonstrated in the intralaminar thalamus is likely to contribute to the movement and cognitive dysfunction observed in Lewy body disorders.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Atrophy; Cell Count; Dementia; Female; Hallucinations; Humans; Intralaminar Thalamic Nuclei; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Thalamus

Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson's Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Brain Chemistry; Female; Humans; Immunohistochemistry; Lewy Body Disease; Logistic Models; Male; Middle Aged; Neuropsychological Tests; Olfactory Bulb; Parkinson Disease; Sensitivity and Specificity

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Brain Chemistry; Humans; Lewy Bodies; Lewy Body Disease; Olfactory Bulb; Parkinson Disease; Sensitivity and Specificity

The association of alpha-synuclein (alpha-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based alpha-syn biomarkers for these types of diseases. Recent studies show that alpha-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of alpha-syn in CSF down to 50pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF alpha-syn levels. AD patients had significantly lower alpha-syn levels than controls (median [inter-quartile range] 296 [234-372] and 395 [298-452], respectively, p<0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower alpha-syn than AD patients with MMSE scores of 20 or higher (p=0.02). There was also a tendency towards a negative correlation between alpha-syn levels and disease duration in the AD group (r=-0.247, p=0.06). Altogether, our results speak against CSF alpha-syn as a reliable biomarker for PD and DLB. The lower alpha-syn levels in AD, as well as the association of alpha-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Brain; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests; Parkinson Disease; Predictive Value of Tests; Synapses

Dementia with Lewy bodies (DLB) is characterized by widespread depositions of alpha-synuclein, which are described as Lewy bodies. Recently, it was shown that neuronal cells in culture constitutively release alpha-synuclein into the culture medium and that alpha-synuclein is normally present in human cerebrospinal fluid (CSF). The aim of the present study was to evaluate the diagnostic value of CSF alpha-synuclein levels in discriminating DLB from Alzheimer's disease (AD). Alpha-synuclein was measured in CSF from 16 patients with DLB and 21 patients with AD. Iodine-123 metaiodobenzylguanidine cardiac scintigraphy was also performed to assess Lewy body pathology. CSF alpha-synuclein levels did not differ significantly between DLB and AD patients. However, the duration of illness was associated with lower alpha-synuclein levels (p<0.05) in DLB, while no such association was found in AD. The present data show CSF alpha-synuclein levels are not sensitive diagnostic markers to discriminate DLB from AD. However, the lower alpha-synuclein levels in DLB patients with longer duration suggest a reduction in CSF alpha-synuclein in association with increased severity of alpha-synucleinopathy in the brain.

Topics: Age of Onset; Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Brain; Female; Genotype; Heart; Humans; Iodine Radioisotopes; Lewy Body Disease; Male; Middle Aged; Myocardial Perfusion Imaging; Predictive Value of Tests; Sympathetic Fibers, Postganglionic; tau Proteins

We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient disclosed unusual features characterized by diffuse Lewy body disease and generalized neurofibrillary tangle pathology but with no amyloid deposits in any region. Moreover, Lewy body pathology colocalized with neurofibrillary tangles in most affected neurons. Mutation screening that included all coding exons of presenilin 1 (PSEN1), presenilin 2 (PSEN2), alpha-synuclein (SNCA), beta-synuclein (SNCB), microtubule-associated protein tau (MAPT), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and exons 16 and 17 of the amyloid precursor protein (APP) genes did not identify any mutation. Genome-wide single nucleotide polymorphism was performed in 4 family members and ruled out any pathogenic duplication or deletion in the entire genome. In summary, we report a unique family with pathologically confirmed early-onset dementia with Lewy bodies with widespread tau and alpha-synuclein deposition. The absence of mutations in genes known to cause Lewy body disease suggests that a novel locus or loci are implicated in this neurodegenerative disease.

Topics: Adult; Aged, 80 and over; alpha-Synuclein; Brain; DNA Mutational Analysis; DNA-Binding Proteins; Family Health; Female; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neurofibrillary Tangles; Presenilins; tau Proteins; Tauopathies

A number of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy are characterized by the formation and intraneuronal accumulation of fibrillar aggregates of alpha-synuclein (alpha-syn) protein in affected brain regions. These and other findings suggest that the accumulation of alpha-syn in the brain plays an important role in the pathogenesis of these diseases. However, more recently it has been reported that early amyloid aggregates or 'soluble oligomers' are the pathogenic species that lead to neurodegeneration and neuronal cell death rather than the later 'mature fibrils'. In this study, we investigated the presence of alpha-syn oligomers in brain lysates prepared from frozen post-mortem brains of normal, Alzheimer's disease and DLB patients. The brain extracts were subjected to high speed centrifugation, to remove insoluble alpha-syn aggregates, followed by specific detection of soluble oligomers in the supernatants by employing FILA-1, an antibody that specifically binds to alpha-syn aggregates, but not to alpha-syn monomers, or to tau or beta-amyloid aggregates. Using this novel enzyme-linked immunosorbent assay (ELISA) method to quantify the amounts of alpha-syn oligomers in the brain extracts, our data clearly show an increase in the levels of soluble oligomers of alpha-syn in the DLB brains compared to those with Alzheimer's disease and the controls (P < 0.0001). Our findings provide strong evidence to support the contention that elevated soluble oligomers of alpha-syn are involved in the pathogenesis of DLB. Furthermore, these findings establish FILA-1 as a very sensitive tool for the detection of oligomeric forms of alpha-syn in human brain lysates.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Antibody Specificity; Brain; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Body Disease; Male; Middle Aged; Solubility; tau Proteins

Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the alpha-synuclein (alphaSYN) gene cause Parkinson's disease, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of alphaSYN protein fibrils. Moreover, alphaSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in neuropathological lesions. Using our (Thy1)-[A30P]alphaSYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)-[A30P]alphaSYN transgenic mice further developed age-dependent, specific neuritic/terminal alphaSYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)-[A30P]alphaSYN mice. Thus, alphaSYN becomes phosphorylated in distinct parts of the brain in this alpha-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem.

Topics: Aging; alpha-Synuclein; Amygdala; Animals; Brain; Cell Nucleus; Cells, Cultured; Cerebral Cortex; Conditioning, Psychological; Disease Models, Animal; Fear; Hippocampus; Hypothalamic Area, Lateral; Immunohistochemistry; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Parkinson Disease; Phosphorylation; Presynaptic Terminals; Serine

The alpha-synuclein aggregation in the brain is the hallmark of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies, and multiple system atrophy. Some epidemiological studies have revealed that estrogen therapy reduces the risk of Parkinson's disease in females. We examined the effects of estriol, estradiol, estrone, androstenedione, and testosterone on the formation and destabilization of alpha-synuclein fibrils at pH 7.5 and 37 degrees C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. These sex hormones, especially estriol, significantly exert anti-aggregation and fibril-destabilizing effects; and hence, could be valuable preventive and therapeutic agents for alpha-synucleinopathies.

Topics: alpha-Synuclein; Benzothiazoles; Estradiol; Estriol; Gonadal Steroid Hormones; Humans; In Vitro Techniques; Lewy Bodies; Lewy Body Disease; Microscopy, Electron; Molecular Structure; Neurofibrils; Neuroprotective Agents; Parkinson Disease; Spectrometry, Fluorescence; Testosterone; Thiazoles

When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging protocol described by Braak and colleagues in 2003, agreement was only 65%, and in some cases as low as 36%. When modifications of these strategies, i.e., McKeith's protocol by Leverenz and colleagues from 2009, Braak's staging by Müller and colleagues from 2005 were applied then the agreement increased to 78 and 82%, respectively. In both of these modifications, a reduced number of anatomical regions/blocks are assessed and still in a substantial number of cases, the inter-observer agreement differed significantly. Over 80% agreement in both typing and staging of alphaS pathology could be achieved when applying a new protocol, jointly designed by the BNE consortium. The BNE-protocol assessing alphaS-IR lesions in nine blocks offered advantages over the previous modified protocols because the agreement between the 22 observers was over 80% in most cases. Furthermore, in the BNE-protocol, the alphaS pathology is assessed as being present or absent and thus the quality of staining and the assessment of the severity of alphaS-IR pathology do not alter the inter-observer agreement, contrary to other assessment strategies. To reach these high agreement rates an entity of amygdala-predominant category was incorporated. In conclusion, here we report a protocol for assessing alphaS pathology that can achieve a high inter-observer agreement for both the assignment to brainstem, limbic, neocortical and amygdala-predominant categories of synucleinopathy and the Braak stages.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Severity of Illness Index

We studied alpha-synuclein pathology in the rhinencephalon of ten cases of Parkinson's disease (PD) and twelve neurologically normal controls, of which seven had incidental Lewy bodies in the substantia nigra at autopsy and five had no pathological evidence of neurological disease. In all PD and incidental Lewy bodies cases, alpha-synuclein pathology was found in all five subregions of the primary olfactory cortex that were sampled, and amongst them the pathology was significantly more severe in the temporal division of the piriform cortex than in the frontal division of the piriform cortex, olfactory tubercle or anterior portions of the entorhinal cortex. The orbitofrontal cortex, which is an area of projection from the primary olfactory cortex, was affected in some cases but overall the alpha-synuclein pathology was less severe in this area than in the primary olfactory cortex. Because different areas of the rhinencephalon are likely to play different roles in olfaction and our data indicate a differential involvement by alpha-synuclein deposition of structures implicated in smell, future prospective studies investigating the pathophysiological basis of hyposmia in PD should consider to examine the areas of primary olfactory cortex separately.

Topics: alpha-Synuclein; Analysis of Variance; Autopsy; Entorhinal Cortex; Frontal Lobe; Humans; Immunohistochemistry; Lewy Body Disease; Olfactory Pathways; Parkinson Disease; Substantia Nigra

Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alcohol-Induced Disorders, Nervous System; Alcoholism; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Biomarkers; Brain; Central Nervous System Depressants; Child; Cohort Studies; Dementia; Dementia, Vascular; Disease Progression; Ethanol; Female; Finland; Humans; Lewy Body Disease; Male; Middle Aged; tau Proteins; Young Adult

The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type alpha-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of ten brain regions from 417 subjects stained immunohistochemically for alpha-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson's disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer's disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson's Disease Rating Scale Part 3. Additionally, there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Brain; Cognition Disorders; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Movement Disorders; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Severity of Illness Index

The Dorsal Motor Nucleus of Vagus (DMV) is degenerated in many patients with early stage Lewy Body Diseases (LBD). Many patients with LBD also develop symptomatic autonomic dysfunction prior to motor and cognitive symptoms. The DMV, along with the Nucleus Ambiguous (NA) and Raphe Obscurus (RO) regulates a variety of autonomic reflexes, suggesting that there may be an association between the degree of neurodegenerative protein aggregation in the DMV and symptomatic autonomic dysfunction in patients with LBD. Using digital in vivo pathology, we quantified alphasynuclein, tau, ubiquitin and Heat Shock Protein 27 (HSP27) containing neurons in the DMV, NA, RO, in addition to the hypoglossal nucleus in 12 LBD patients. alphaSynuclein, ubiquitin and tau aggregates most greatly affected the DMV followed by the NA, RO, but never the hypoglossal nucleus. There was a positive correlation between DMV alphasynuclein and tau aggregation (p<0.05) and between DMV alphasynuclein and the patients' UPDRS scores (p<0.05) suggesting incremental DMV degeneration with disease progression. However, there was no correlation between DMV alphasynuclein, tau, ubiquitin or HSP27 density and the patient's autonomic dysfunction scores. The specific incremental nature of degeneration in the DMV, suggests that by characterizing region specific molecular mechanisms underpinning DMV as opposed to NA degeneration in LBD, the pathogenesis of the disorder may be better understood. Whether DMV degeneration is causative of symptomatic autonomic dysfunction in LBD remains to be determined.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autonomic Nervous System Diseases; Brain; Disease Progression; Female; Fluorescent Antibody Technique; HSP27 Heat-Shock Proteins; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Middle Aged; tau Proteins; Ubiquitin

Dementia and visual hallucinations are common complications of Parkinson's disease (PD), yet their patho-anatomical bases are poorly defined. We studied alpha-synuclein (alphaSyn), tau and amyloid-beta (Abeta) pathology in the claustrum of 20 PD cases without dementia, 12 PD cases with dementia (PDD) and 7 cases with dementia with Lewy bodies (DLB). alphaSyn positivity was observed in 75% of PD cases without dementia and in 100% of PDD and DLB cases. Abeta was observed in the claustrum in 25% of PD, 58% of PDD and 100% of DLB cases. Tau was negligible in all cases restricting further analysis. Compared to PD cases without dementia, PDD cases demonstrated a significantly greater alphaSyn burden in the claustrum (p=0.0003). In addition, DLB cases showed a significantly increased alphaSyn deposition when compared to PDD (p=0.02) and PD without dementia (p=0.0002). A similar hierarchy, PD

Topics: alpha-Synuclein; Amyloid beta-Peptides; Basal Ganglia; Hallucinations; Humans; Immunohistochemistry; Lewy Body Disease; Parkinson Disease; tau Proteins

Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common known cause of Parkinson disease, but how this protein results in the pathobiology of Parkinson disease is unknown. Moreover, there is variability in pathology among cases, and alpha-synuclein (alpha-syn) neuronal inclusions are often present, but whether LRRK2 is present in these pathological inclusions is controversial. This study characterizes novel LRRK2 antibodies, some of which preferentially recognize an aggregated form of LRRK2, as observed in cell culture models. Large perinuclear aggregates containing LRRK2 were promoted by proteasome inhibition and prevented by microtubule polymerization inhibition. Furthermore, they were vimentin- and gamma-tubulin- but not lamp1-immunoreactive, suggesting that these structures fit the definition of aggresomes. Inhibition of heat shock protein 90 led to the degradation of only the soluble/cytosolic pool of LRRK2, suggesting that the aggresomes formed independent of the stability provided by the heat shock protein 90. Although these novel anti-LRRK2 antibodies identified aggregates in model cell systems, they did not immunostain pathological inclusions in human brains. Furthermore, coexpression of LRRK2 and alpha-syn did not recruit alpha-syn into aggresomes in cultured cells, even in the presence of proteasome inhibition. Thus, although LRRK2 is a model system for aggresome formation, LRRK2 is not present in alpha-syn pathological inclusions.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Antibodies; Brain; Cell Line; Chlorocebus aethiops; COS Cells; Female; HSP90 Heat-Shock Proteins; Humans; Inclusion Bodies; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; Protein Serine-Threonine Kinases

Amyloid-beta (Abeta) plaques are a pathological hallmark of Alzheimer's disease and a current target for positron emission tomography (PET) imaging agents. Whilst [(11)C]-PiB is currently the most widely used PET ligand in clinic, a novel family of benzoxazole compounds have shown promise as Abeta imaging agents; particularly BF227. We characterised the in vitro binding of [(18)F]-BF227 toward alpha-synuclein to address its selectivity for Abeta pathology, to establish whether [(18)F]-BF227 binds to alpha-synuclein/Lewy bodies, in addition to Abeta plaques. In vitro [(18)F]-BF227 saturation studies were conducted with 200 nM alpha-synuclein or Abeta(1-42) fibrils or 100 microg of Alzheimer's disease, pure dementia with Lewy bodies or control brain homogenates. Non-specific binding was established with PiB (1 microM). In vitro binding studies indicated that [(18)F]-BF227 binds with high affinity to two binding sites on Abeta(1-42) fibrils (K(D1) = 1.31 and K(D2) = 80 nM, respectively) and to one class of binding sites on alpha-synuclein fibrils (K(D) = 9.63 nM). [(18)F]-BF227 bound to Abeta-containing Alzheimer's disease brain (K(D) = 25 +/- 0.5 nM), but failed to bind to Abeta-free dementia with Lewy bodies or age-matched control homogenates. Moreover, BF227 labelled both Abeta plaques and Lewy bodies in immunohistochemical/fluorescence analysis of human Alzheimer's disease and Parkinson's disease brain sections, respectively. This study suggests that [(18)F]-BF227 is not Abeta-selective. Evaluation of BF227 as a potential biomarker for Parkinson's disease is warranted.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Benzoxazoles; Brain; Fluorine Radioisotopes; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Peptide Fragments; Protein Binding; Substrate Specificity; Thiazoles

Experimental studies indicate that dopaminergic neurons in the ventral periaqueductal gray matter (PAG) are involved in maintenance of wakefulness. Excessive daytime sleepiness (EDS) is a common manifestation of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) but involvement of these neurons has not yet been explored.. We sought to determine whether there is loss of dopaminergic neurons in the ventral PAG in MSA and DLB. We studied the midbrain obtained at autopsy from 12 patients (9 male, 3 female, age 61 +/- 3) with neuropathologically confirmed MSA, 12 patients (11 male, 1 female, age 79 +/- 4) with diagnosis of DLB and limbic or neocortical Lewy body disease, and 12 controls (7 male, 5 female, ages 67 +/- 4). Fifty-micron sections were immunostained for tyrosine hydroxylase (TH) or alpha-synuclein and costained with thionin. Cell counts were performed every 400 mum throughout the ventral PAG using stereologic techniques.. Compared to the total estimated cell numbers in controls (21,488 +/- 8,324 cells), there was marked loss of TH neurons in the ventral PAG in both MSA (11,727 +/- 5,984; p < 0.01) and DLB (5,163 +/- 1,926; p < 0.001) cases. Cell loss was more marked in DLB than in MSA. There were characteristic alpha-synuclein inclusions in the ventral PAG in both MSA and DLB.. There is loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons in both multiple system atrophy and dementia with Lewy bodies, which may contribute to excessive daytime sleepiness in these conditions.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cell Count; Cell Death; Dopamine; Female; Humans; Inclusion Bodies; Lewy Body Disease; Male; Mesencephalon; Middle Aged; Multiple System Atrophy; Neurons; Periaqueductal Gray; Thionins; Tyrosine 3-Monooxygenase

The consortium on dementia with Lewy bodies has established consensus guidelines for the neuropathologic diagnosis of dementia with Lewy bodies (DLB) including the likelihood that the neuropathologic findings associate with the clinical syndrome. Nevertheless, clinico-pathological correlations remain controversial. We applied the consensus guidelines for determining Lewy-related pathology (LRP) and evaluated the clinical presentation in the prospective, population-based Vantaa 85+ study consisting of individuals at least 85 years of age. LRP was seen in 36% of 304 subjects and categorized as follows: 3% brainstem-predominant, 14% limbic, 15% diffuse neocortical type (4% could not be categorized). The likelihood that the neuropathology predicts the DLB clinical syndrome was low in 6%, intermediate in 13%, and high in 13% of all 304 subjects. In the latter two groups, 77% were demented, 35% had at least one extrapyramidal symptom, and 15% had visual hallucinations. Surprisingly, DLB clinical features associated better with high neurofibrillary stage than with diffuse neocortical LRP. Moreover, the neurofibrillary stage, substantia nigra neuron loss, and grade of Lewy neurites in hippocampal CA2-3 region, each showed a significant association with the extent of LRP. In conclusion, the neuropathologic DLB in this very elderly population was common, but the clinical symptoms tended to associate better with severe neurofibrillary pathology than with extensive LRP.

Topics: Aged, 80 and over; alpha-Synuclein; Brain; Brain Stem; Catchment Area, Health; Female; Finland; Humans; Lewy Body Disease; Limbic System; Male; Neurofibrillary Tangles; Population Surveillance

Topics: Adult; alpha-Synuclein; Humans; Incidence; Lewy Body Disease; Male; Myocardium; Stellate Ganglion

Accumulation of the synaptic protein alpha-synuclein (alpha-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD), a heterogeneous group of disorders with dementia and parkinsonism, where Alzheimer's disease and PD interact. Accumulation of alpha-syn in these patients might be associated with alterations in the autophagy pathway. Therefore, we postulate that delivery of beclin 1, a regulator of the autophagy pathway, might constitute a strategy toward developing a therapy for LBD/PD. Overexpression of alpha-syn from lentivirus transduction in a neuronal cell line resulted in lysosomal accumulation and alterations in autophagy. Coexpression of beclin 1 activated autophagy, reduced accumulation of alpha-syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and alpha-syn accumulation were partially blocked by 3-MA and completely blocked by bafilomycin A1. In contrast, rapamycin enhanced the effects of beclin 1. To evaluate the potential effects of activating autophagy in vivo, a lentivirus expressing beclin 1 was delivered to the brain of a alpha-syn transgenic mouse. Neuropathological analysis demonstrated that beclin 1 injections ameliorated the synaptic and dendritic pathology in the tg mice and reduced the accumulation of alpha-syn in the limbic system without any significant deleterious effects. This was accompanied by enhanced lysosomal activation and reduced alterations in the autophagy pathway. Thus, beclin 1 plays an important role in the intracellular degradation of alpha-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.

Topics: alpha-Synuclein; Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Brain; Cell Line, Tumor; Disease Models, Animal; Gene Transfer Techniques; Humans; Lewy Body Disease; Mice; Mice, Transgenic; Nerve Degeneration; Neurons; Parkinson Disease; Rats; Signal Transduction

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of genetically inherited Parkinson's disease (PD) and its more severe variant diffuse Lewy body disease (DLB). Pathological mutations in Lrrk2 are autosomal dominant, suggesting a gain of function. Mutations in alpha-synuclein also produce autosomal dominant disease. Here we report an interaction between Lrrk2 and alpha-synuclein in a series of diffuse Lewy body (DLB) cases and in an oxidative stress cell based assay. All five cases of DLB, but none of five controls, showed co-immunoprecipitation of Lrrk2 and alpha-synuclein in soluble brain extracts. Colocalization was also found in pathological deposits in DLB postmortem brains by double immunostaining. In HEK cells transfected simultaneously with plasmids expressing Lrrk2 and alpha-synuclein, co-immunoprecipitation of Lrrk2 and alpha-synuclein was detected when they were exposed to oxidative stress by H(2)O(2). Taken together, these results suggest the possibility that in PD and related synucleinopathies, oxidative stress upregulates alpha-syn and Lrrk2 expression, paving the way for pathological interactions. New therapeutic approaches to PD and the synucleinopathies may result from limiting the interaction between Lrrk2 and alpha-synuclein.

Topics: alpha-Synuclein; Brain; Cell Line; Humans; Immunoprecipitation; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Oxidative Stress; Protein Serine-Threonine Kinases; RNA, Messenger

Lewy bodies (LBs) appear in the brains of nondemented individuals and also occur in a range of neurodegenerative disorders, such as dementia with Lewy bodies (DLB) and Parkinson's disease. A number of people with a definite diagnosis of Alzheimer's disease (AD) also exhibit these intraneuronal inclusions in allo- and/or neocortical areas. The latter, referred to as Lewy body variant of AD (LBV), bears a clinical resemblance to AD in terms of age at onset, duration of illness, cognitive impairment, and illness severity. Since the presence of LBs is accompanied by neuronal cytoskeleton changes, it is possible that the latter may influence neuronal connectivity via alterations to the synaptic network. To address this, we examined the expression of synaptic proteins (synaptophysin, syntaxin, SNAP-25, and alpha-synuclein) and two cytoskeletal proteins (tau and MAP2) in the brain tissue of subjects enrolled in a population-based autopsy study (n = 47). They were divided into groups with no memory problems (control group, n = 15), LBV (n = 5), AD devoid of LBs (n = 17), cerebrovascular dementia (n = 3), and mixed dementia (n = 7). The LBV and AD groups had a similar degree of cognitive impairment and neuropathological staging in terms of Braak staging and CERAD score. In comparison with the control group and the dementia groups without LBs, the LBV group had significantly lower levels of syntaxin and SNAP-25 (23%) in the neocortex, and depletion of MAP2 (64%), SNAP-25 (34%), and alpha-synuclein (44%) proteins in the medial temporal lobes. These findings suggest that the t-SNARE complex deficit present in LBV may be associated with the presence of LB-related pathology and may explain the more profound cholinergic loss seen in these patients.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Microtubule-Associated Proteins; Neocortex; Phosphorylation; SNARE Proteins; Synaptosomes; tau Proteins; Temporal Lobe

Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF.. A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG.. We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay.. The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Biomarkers; Brain; Dementia, Vascular; Diagnosis, Differential; Female; gamma-Synuclein; Humans; Immunoglobulin G; Immunohistochemistry; Lewy Body Disease; Male; Predictive Value of Tests; Sensitivity and Specificity

There is limited information on the validity of the pathologic criteria of the Third Consortium on Dementia with Lewy bodies (CDLB), and none are based on prospectively diagnosed cases. In this study, the core clinical features of dementia with Lewy bodies (DLB) and the suggestive clinical feature of rapid eye movement sleep behavior disorder were assessed using a battery of standardized clinical instruments in 76 patients with the clinical diagnosis of either DLB or Alzheimer disease. At autopsy, 29 patients had high-likelihood, 17 had intermediate-likelihood, and 6 had low-likelihood DLB pathology. The frequency of core clinical features and the accuracy of the clinical diagnosis of probable DLB were significantly greater in high-likelihood than in low-likelihood cases. This is consistent with the concept that the DLB clinical syndrome is directly related to Lewy body pathology and inversely related to Alzheimer pathology. Thus, the Third Consortium on DLB neuropathologic criteria scheme performed reasonably well and are useful for estimating the likelihood of the premortem DLB syndrome based on postmortem findings. In view of differences in the frequency of clinically probable DLB in cases with Braak neurofibrillary tangle stages V (90%) and VI (20%) and diffuse cortical Lewy bodies, a possible modification of the scheme is to consider cases with neurofibrillary tangle stage VI to be low-likelihood DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurofibrillary Tangles; Pathology; Plaque, Amyloid; Predictive Value of Tests; Prospective Studies; REM Sleep Behavior Disorder; Reproducibility of Results

The use of alpha-synuclein immunohistochemistry has altered our concepts of the cellular pathology, anatomical distribution and prevalence of Lewy body disorders. However, the diversity of methodology between laboratories has led to some inconsistencies in the literature. Adoption of uniformly sensitive methods may resolve some of these differences. Eight different immunohistochemical methods for demonstrating alpha-synuclein pathology, developed in eight separate expert laboratories, were evaluated for their sensitivity for neuronal elements affected by human Lewy body disorders. Identical test sets of formalin-fixed, paraffin-embedded sections from subjects diagnosed neuropathologically with or without Lewy body disorders were stained with the eight methods and graded by three observers for specific and nonspecific staining. The methods did not differ significantly in terms of Lewy body counts, but varied considerably in their ability to reveal neuropil elements such as fibers and dots. One method was clearly superior for revealing these neuropil elements and the critical factor contributing to its high sensitivity was considered to be its use of proteinase K as an epitope retrieval method. Some methods, however, achieved relatively high sensitivities with optimized formic acid protocols combined with a hydrolytic step. One method was developed that allows high sensitivity with commercially available reagents.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Formaldehyde; Humans; Immunohistochemistry; Lewy Body Disease; Paraffin Embedding; Pathology, Clinical; Reproducibility of Results; Sensitivity and Specificity; Staining and Labeling; Tissue Fixation

Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) and Parkinson's disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid beta protein (Abeta) oligomers has been identified as one of the central toxic events in AD, accumulation of alpha-synuclein (alpha-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Abeta promotes alpha-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear.. In order to understand the molecular mechanisms involved in potential Abeta/alpha-syn interactions, immunoblot, molecular modeling, and in vitro studies with alpha-syn and Abeta were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Abeta and alpha-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Abeta binds alpha-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Abeta and the N-terminus and C-terminus of alpha-syn. Interacting alpha-syn and Abeta dimers that dock on the membrane incorporated additional alpha-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Abeta interacted with alpha-syn, forming hybrid pore-like oligomers. Moreover, cells expressing alpha-syn and treated with Abeta displayed increased current amplitudes and calcium influx consistent with the formation of cation channels.. These results support the contention that Abeta directly interacts with alpha-syn and stabilized the formation of hybrid nanopores that alter neuronal activity and might contribute to the mechanisms of neurodegeneration in AD and PD. The broader implications of such hybrid interactions might be important to the pathogenesis of other disorders of protein misfolding.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Calcium; Computer Simulation; Electrophysiology; Humans; Lewy Body Disease; Mice; Mice, Transgenic; Parkinson Disease; Protein Denaturation; Protein Folding; Protein Structure, Tertiary

The increasing life expectancy will cause an increasing share for neurodegenerative and dementing illnesses in the total cost for health care. New developments such as the discovery of TDP-43 as disease protein have opened new viewpoints on frontotemporal dementias, as well as its relation to amyotrophic lateral sclerosis. As pathologists and neuropathologists we are committed to contributing to the progress of clinical diagnosis, which often proves difficult, by standardized post-mortem diagnosis. The diagnostic responsibility will increase with the development of new specific therapeutics and knowledge of contraindications such as the use of neuroleptics in patients suffering from Lewy body dementia. The Reference Center for Neurodegenerative Diseases of the German Society of Neuropathology and Neuroanatomy and the German Brain Bank (Brain-Net) at the Institute for Neuropathology, Ludwig-Maximilians-University Munich, are available for diagnosis in difficult or complex cases.

Topics: alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Diagnosis, Differential; DNA-Binding Proteins; Humans; Lewy Body Disease; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Pick Disease of the Brain; tau Proteins

HtrA2/Omi is a mitochondrial serine protease that is released into the cytosol and promotes apoptotic processes by binding to several members of the inhibitors of apoptosis protein family. HtrA2/Omi knockout mice show a parkinsonian phenotype, and mutations in the gene encoding HtrA2/Omi have been identified as susceptibility factors for Parkinson disease (PD). These results suggest that HtrA2/Omi may be involved in the pathogenesis of PD. We performed immunohistochemical studies of HtrA2/Omi on brains from patients with alpha-synuclein-related disorders, including PD, dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA); patients with other neurodegenerative diseases; and controls. HtrA2/Omi is expressed in normal brain tissue, and there was some anti-HtrA2/Omi immunostaining of neurons in normal brains as well as those with other neurodegenerative diseases. In PD and DLB brains, both classic (i.e. brainstem-type) and cortical Lewy bodies were intensely immunostained; pale bodies were also strongly immunopositive for HtrA2/Omi. In MSA brains, numerous glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were also intensely immunoreactive for HtrA2/Omi. These results suggest that widespread accumulation of HtrA2/Omi may occur in pathologic alpha-synuclein-containing inclusions in brains with PD, DLB, or MSA and that HtrA2/Omi may be associated with the pathogenesis of alpha-synucleinopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Autopsy; Blotting, Western; Brain; Brain Chemistry; Female; Fluorescent Antibody Technique, Indirect; High-Temperature Requirement A Serine Peptidase 2; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Mice; Mice, Knockout; Middle Aged; Mitochondrial Proteins; Multiple System Atrophy; Nervous System Diseases; Neuroglia; Neurons; Parkinson Disease; Serine Endopeptidases

Previous studies in Lewy body diseases (LBDs), including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), have shown oxidative stress damage more extended than the expected for the distribution of Lewy pathology. Since malondialdehyde (MDA) can form adducts with lysine residues of proteins, MDA-Lys immunoprecipitation and alpha-synuclein immunoblotting has been carried out in frontal cortex and substantia nigra homogenates from five patients with PD, five DLB, three iPD and seven aged-matched controls to decipher the extent of lipoxidized alpha-synuclein in LBDs. MDA-Lys-lipoxidation of alpha-synuclein in the substantia nigra and frontal cortex has been found in all DLB and PD cases examined, but also in the frontal cortex in 3/3 and in the substantia nigra in 2/3 cases with iPD. In addition, one control case had MDA-Lys-modified alpha-synuclein in the frontal cortex, and another in the substantia nigra. This work provides evidence of extended lipoxidative modification of alpha-synuclein in LBDs. Moreover, it demonstrates that alpha-synuclein lipoxidation is an early event in LBDs which precedes alpha-synuclein solubility modification and aggregation, and formation of Lewy bodies and neurites.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Immunoprecipitation; Lewy Body Disease; Lysine; Male; Middle Aged; Neocortex; Oxidation-Reduction; Parkinson Disease

Alternative splicing is an important mechanism to generate a large number of mRNAs, thus increasing proteome diversity and tissue specificity. Three transcript variants of alpha-synuclein, a neuronal protein mainly involved in synapses, have been described so far. Whereas alpha-synuclein 140 is the whole and main transcript, alpha-synuclein 112 and 126 are short proteins that result from in-frame deletions of exons 3 and 5, respectively. Because the aforesaid alpha-synuclein isoforms show differential expression changes in Lewy body diseases (LBDs), in the present work, we searched for a fourth alpha-synuclein isoform and studied its expression levels in LBD brains. By using isoform-specific primers, isoform co-amplification and direct sequencing, we identified alpha-synuclein 98, which lacks exons 3 and 5. mRNA expression analyses in non-neuronal tissue revealed that alpha-synuclein 98 is a brain-specific splice variant with varying expression levels in different areas of fetal and adult brain. Additionally, we studied alpha-synuclein 98 expression levels by real-time semi-quantitative RT-PCR in the frontal cortices of LBD patients and compared them with those of Alzheimer disease (AD) patients and control subjects. Overexpression of alpha-synuclein 98 in LBD and AD brains would indicate its specific involvement in the pathogenesis of these neurodegenerative disorders.

Topics: Adult; alpha-Synuclein; Alternative Splicing; Alzheimer Disease; Amino Acid Sequence; Base Sequence; Brain; Case-Control Studies; DNA Primers; Exons; Fetus; Frontal Lobe; Gene Expression; Humans; Lewy Body Disease; Molecular Sequence Data; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Homology, Amino Acid

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Hydrogen-Ion Concentration; Lewy Body Disease; Mice; Mice, Transgenic; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Peptide Fragments

Degeneration of the cardiac sympathetic nerve occurs in both Parkinson's disease (PD) and dementia with Lewy bodies and begins early in the disease progression of PD, accounting for reduced cardiac uptake of meta-iodobenzylguanidine even in the early stages of Lewy body disease (LBD). We previously demonstrated that degeneration of the distal axons of the cardiac sympathetic nerve precedes loss of their mother neurons in the paravertebral sympathetic ganglia, suggesting distal dominant degeneration of the cardiac sympathetic nerve in PD. Because alpha-synuclein is one of the key molecules in the pathogenesis of this disease, we further investigated how alpha-synuclein aggregates are involved in this distal-dominant degeneration. Both cardiac tissues and paravertebral sympathetic ganglia were obtained for comparison from 20 patients with incidental Lewy body disease (ILBD), 10 with PD, 20 with multiple system atrophy (MSA) and 10 control subjects. Immunohistochemical analysis was performed using antibodies against tyrosine hydroxylase (TH) as a marker for sympathetic nerves, phosphorylated neurofilament as a marker for axons and phosphorylated alpha-synuclein for pathological deposits. We found that (i) alpha-synuclein aggregates in the epicardial nerve fascicles, namely the distal axons of the cardiac sympathetic nerve, were much more abundant in ILBD with preserved TH-ir axons than in this disease with decreased TH-ir axons and PD; (ii) alpha-synuclein aggregates in the epicardial nerve fascicles were closely related to the disappearance of TH-ir axons; (iii) in ILBD with preserved TH-ir axons, alpha-synuclein aggregates were consistently more abundant in the epicardial nerve fascicles than in the paravertebral sympathetic ganglia; (iv) this distal-dominant accumulation of alpha-synuclein aggregates was reversed in ILBD with decreased TH-ir axons and PD, which both showed fewer of these axons but more abundant alpha-synuclein aggregates in the paravertebral sympathetic ganglia and (v) MSA was completely different from ILBD and PD based on the preservation of TH-ir axons and the scarcity of alpha-synuclein aggregates in either the cardiac tissues or the paravertebral sympathetic ganglia. These findings indicate that accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that heralds centripetal degeneration of the car

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Axons; Female; Ganglia, Sympathetic; Heart; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Nerve Degeneration; Parkinson Disease; Pericardium; Sympathetic Nervous System; Tyrosine 3-Monooxygenase

Alpha-synuclein accumulated in the brain of dementia with Lewy bodies (DLB) is phosphorylated at serine129 (palpha-synuclein). We investigated the accumulation of palpha-synuclein in the brains of patients with DLB and Alzheimer's disease (AD). We employed 18 DLB patients with neocortical Lewy body type pathology (nLBTP) with or without AD. We also employed the same number of AD cases without significant nLBTP. We refer to the former group as the nLBTP group and to the latter as the AD type pathology (ADTP) group. In the nLBTP group, palpha-synuclein positive neurite pathology such as threads and dots occurs in all layers of the temporal neocortex. It was comparable in degree with tau pathology in AD. Fifteen cases in the nLBTP group were associated with Abeta deposition that meets the CERAD plaque score "C" and one case with a score "B". In these plaque-associated cases, the severity of palpha-synuclein pathology was related to the degree of Abeta deposition. In the cases with relatively moderate Abeta deposition, tau pathology was disproportionately mild in the nLBTP group, while the total of tau and palpha-synuclein pathology was proportionate to Abeta deposition in both the nLBTP and ADTP groups. Our results support the ideas that there is an overlap in the pathology between AD and DLB and that Abeta promotes accumulation of both alpha-synuclein and tau. The procession from Abeta to neurite pathology in the cerebral cortex of AD and DLB may be unifiable.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Analysis of Variance; Cerebral Cortex; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Microscopy, Immunoelectron; Middle Aged; Phosphorylation; Plaque, Amyloid; Serine; Statistics, Nonparametric; tau Proteins

Abnormal aggregation of human alpha-synuclein in Lewy bodies and Lewy neurites is a pathological hallmark of Parkinson disease and dementia with Lewy bodies. Studies have shown that oxidation and nitration of alpha-synuclein lead to the formation of stable dimers and oligomers through dityrosine cross-linking. Previously we have reported that tyrosine-to-cysteine mutations, particularly at the tyrosine 39 residue (Y39C), significantly enhanced alpha-synuclein fibril formation and neurotoxicity. In the current study, we have generated transgenic mice expressing the Y39C mutant human alpha-synuclein gene controlled by the mouse Thy1 promoter. Mutant human alpha-synuclein was widely expressed in transgenic mouse brain, resulting in 150% overexpression relative to endogenous mouse alpha-synuclein. At age 9-12 months, transgenic mice began to display motor dysfunction in rotarod testing. Older animals aged 15-18 months showed progressive accumulation of human alpha-synuclein oligomers, associated with worse motor function and cognitive impairment in the Morris water maze. By age 21-24 months, alpha-synuclein aggregates were further increased, accompanied by severe behavioral deficits. At this age, transgenic mice developed neuropathology, such as Lewy body-like alpha-synuclein and ubiquitin-positive inclusions, phosphorylation at Ser(129) of human alpha-synuclein, and increased apoptotic cell death. In summary, Y39C human alpha-synuclein transgenic mice show age-dependent, progressive neuronal degeneration with motor and cognitive deficits similar to diffuse Lewy body disease. The time course of alpha-synuclein oligomer accumulation coincided with behavioral and pathological changes, indicating that these oligomers may initiate protein aggregation, disrupt cellular function, and eventually lead to neuronal death.

Topics: Aging; alpha-Synuclein; Amino Acid Substitution; Animals; Brain; Dimerization; Disease Models, Animal; Humans; Lewy Bodies; Lewy Body Disease; Maze Learning; Mice; Mice, Transgenic; Neurites; Oxidation-Reduction; Parkinson Disease; Promoter Regions, Genetic; Thy-1 Antigens

Pathogenic aggregates of alpha-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing alpha-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, alpha-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of alpha-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by alpha-synuclein and suppressed the accumulation of Abeta. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Brain; Cell Death; Humans; Lewy Body Disease; Mice; Mice, Knockout; Mice, Transgenic; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Peptides; Proteasome Endopeptidase Complex; Signal Transduction; Ubiquitin

Alpha-synuclein, parkin, and synphilin-1 are proteins mainly involved in the pathogenesis of Lewy body (LB) diseases. mRNAs of all three undergo alternative splicing, so that the existence of various isoforms has been described. Since increasing evidence supports the importance of differential isoform-expression changes in disease development, we have established isoform-expression profiles in frontal cortices of LB disease brains in comparison with those of Alzheimer disease (AD) and control frontal cortices. The differential expression of four alpha-synuclein, seven parkin, and four synphilin-1 isoforms was ascertained by the use of isoform-specific primers and relative expression analysis with SybrGreen and beta-actin as an internal standard. The establishment of isoform-expression profiles revealed that these are disease specific. Moreover, isoform-expression deregulation of mainly one gene in each disease could be observed. All four alpha-synuclein isoforms were affected in the case of the pure form of dementia with LB, most parkin transcript variants in common LB disease, and all synphilin-1 isoforms in Parkinson disease. Only minor involvement was detected in AD. Finally, the existence of a proprietary isoform-expression profile in common LB disease indicates that this disease develops as a result of its own molecular mechanisms, and so, at the molecular level, it does not exactly share changes found in pure dementia with LB and AD. In conclusion, isoform-expression profiles in LB diseases represent additional evidence for the direct involvement of isoform-expression deregulation in the development of neurodegenerative disorders.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Base Sequence; Carrier Proteins; Case-Control Studies; DNA Primers; Female; Frontal Lobe; Gene Expression; Gene Expression Profiling; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Nerve Tissue Proteins; Parkinson Disease; Polymerase Chain Reaction; Protein Isoforms; RNA, Messenger; Ubiquitin-Protein Ligases

Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy are caused by alpha-synuclein aggregates. At present, there is no good biochemical method defining alpha-synuclein aggregates formed in vivo versus oligomers as a means to investigate alpha-synuclein aggregation and its mechanisms of neurodegeneration. A simple method, therefore, for the selective and sensitive detection of alpha-synuclein aggregates suited for screening purposes would be useful. Since in contrast to prions a proper detection of alpha-synuclein aggregates by Western blot analysis is difficult, we developed a protein aggregate filtration (PAF) assay. It takes advantage of the inherent insolubility of aggregated alpha-synuclein using microfiltration to separate it from soluble isoforms. For the first time, this assay even makes quantitative comparisons possible. We describe how the PAF assay can be applied to human brain tissue and animal and cell culture models, as well as used as a screening method for the subcellular location of alpha-synuclein aggregates. Since it detects the pathological isoform instead of surrogate markers, the PAF assay may have also potential in diagnosis of PD and DLB.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; Protein Denaturation; Subcellular Fractions; Ultrafiltration

It is proposed that alpha-synucleinopathy (AS) initially affects the medulla oblongata and progresses to more rostral brain areas in a hierarchical sequence ("Braak hypothesis"). Predominant involvement of the amygdala is also described. This study examines the applicability of these patterns, and their relationship to Alzheimer disease (AD) pathology, in brains of a population-based donor cohort.. Brains donated in two of six Cognitive Function and Ageing Study cohorts (Cambridgeshire and Nottingham) were examined. More than 80% were older than 80 years at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein was carried out in 208 brains to establish Braak stage and the pattern and severity of AS.. Seventy-six brains showed Lewy bodies. Half (51%) conformed to the Braak hypothesis while 17% had pathology in a higher region which was absent in a lower region. A further 29% showed amygdala-predominant pathology. Six brains showed predominant neocortical pathology with minimal pathology in amygdala or substantia nigra. The stage of AD pathology was not associated with particular patterns of AS.. alpha-Synucleinopathy (AS) is common in older people, and frequently associated with Alzheimer disease-type pathology. Although half of brains corresponded to the Braak hypothesis, and 29% to amygdala-predominant AS, there were a high proportion of cases which did not fit a staging system. An unexpectedly high proportion with a cortical form of Lewy body disease was identified.

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Amygdala; Biomarkers; Brain; Brain Stem; Cohort Studies; Diagnosis, Differential; Disease Progression; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Longitudinal Studies; Male; Neurons; Parkinson Disease; Predictive Value of Tests; Prospective Studies; Registries; tau Proteins; Tissue Donors; United Kingdom

Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the alpha-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer's, in comparison to control and this reduction correlated with both the severity and duration of dementia. Application of proteasome inhibitors to rodent cortical primary neurones in vitro and by direct injection onto rodent cholinergic forebrain neurons in vivo gave rise to dose dependent neuronal death and in rodent cortex -- marked cholinergic deficits accompanied by the accumulation of inclusions that stained positive for alpha-synuclein and ubiquitin. These findings suggest that proteasomal abnormalities are present within cortical Lewy body disease and the experimental inhibition of proteasomal function mirrors the neuropathological changes seen within the disorder.

Topics: Acetylcholine; Acetylcysteine; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Basal Nucleus of Meynert; Cell Death; Cells, Cultured; Cerebral Cortex; Cholinergic Fibers; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Nerve Degeneration; Nerve Tissue Proteins; Neural Pathways; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Rats; Rats, Sprague-Dawley; Ubiquitin

We report an 84-year-old woman who was clinically diagnosed with late-life major depression (LLMD) and having a diffuse type of dementia with Lewy bodies (DLB) neuropathologically. Clinically, this case showed depressive mood, anxiety, and irritation, but did not show cognitive dysfunction, visual hallucination, fluctuation of alertness and parkinsonism, which define the criteria for diagnosing DLB. Neuropathological examination demonstrated abundant Lewy-related pathology including Lewy bodies and neurites in the hippocampal region and the cerebral cortex, and moderate levels in brain stem nuclei including the substantia nigra, locus ceruleus and dorsal raphe nucleus. These findings suggest the possibility that Lewy-related pathology is associated with the depressive symptoms. Furthermore, it must be noted that some patients diagnosed with LLMD clinically may develop pathology of DLB without the typical or usual clinical symptoms.

Topics: Aged, 80 and over; alpha-Synuclein; Anxiety; Basal Ganglia; Brain; Brain Stem; Cerebral Cortex; Depressive Disorder, Major; Female; Hippocampus; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Neurofibrillary Tangles; Plaque, Amyloid

Multiplication of the alpha-synuclein gene (SNCA) (OMIM 163890) has been identified as a causative mutation in hereditary Parkinson disease or dementia with Lewy bodies.. To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA.. Four-generation family study.. Academic research. Patients We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.. We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.. Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated alpha-synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients.. Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated alpha-synuclein in the brains of patients.

Topics: Age of Onset; Aged; Alleles; alpha-Synuclein; Brain; Cognition Disorders; Consanguinity; DNA Mutational Analysis; Exons; Female; Gene Dosage; Gene Duplication; Genetic Carrier Screening; Homozygote; Humans; Lewy Bodies; Lewy Body Disease; Male; Microsatellite Repeats; Middle Aged; Neuropsychological Tests; Parkinsonian Disorders; Phosphorylation

Topics: Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Autopsy; Brain; Corpus Striatum; Dementia; Disease Progression; Humans; Lewy Body Disease; Parkinson Disease; Plaque, Amyloid; Predictive Value of Tests; tau Proteins

Deposition of alpha-synuclein (alphaS) aggregates inside brain cells is a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Recently, extracellular alphaS was detected in cerebrospinal fluid (CSF) and plasma of humans. We investigated whether CSF influences alphaS aggregation in vitro using fluorescence spectroscopy with thioflavin S and electron microscopy. We found that CSF obtained from Alzheimer's disease (AD) and DLB patients enhanced the alphaS fibril formation compared with tauopathy and non-central nervous system disease. Thus, CSF of AD and DLB characterized by aggregation of Abeta or alphaS might promote falphaS formation.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Benzothiazoles; Female; Humans; Immunoglobulin G; Lewy Body Disease; Male; Microscopy, Electron; Middle Aged; Psychiatric Status Rating Scales; Spectrometry, Fluorescence; tau Proteins; Thiazoles

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia reflecting changes in the brain, but which specific neuronal networks are involved in human RBD pathogenesis has not yet been determined. To date, only one case of idiopathic RBD has undergone autopsy, in which "incidental Lewy body disease" was found. Due to the severe neuronal loss and gliosis in the substantia nigra (SN) and locus ceruleus (LC) in this case, degeneration of brainstem monoaminergic neurons was postulated as the underlying substrate for RBD. Additional cases of idiopathic RBD with neuropathologic examination may help clarify which key brainstem structures are involved.. Case report with neuropathologic analysis.. A man with polysomnographically proven RBD (onset age 57 years), but no other neurologic signs or symptoms, underwent neuropathologic examination upon his death at age 72. Histopathologic analysis showed Lewy body disease, but no significant neuronal loss or gliosis was present in the SN or LC.. This case represents another example of Lewy body disease associated with RBD. The minimal degenerative changes in the SN and LC call into question the role of these nuclei in RBD, at least in our case. We suggest additional cases of idiopathic RBD undergo neuropathologic analyses to better delineate the neurologic substrate of this intriguing parasomnia.

Topics: Aged; alpha-Synuclein; Brain Stem; Dyspnea; Electromyography; Gliosis; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Degeneration; Neurofibrillary Tangles; Polysomnography; Severity of Illness Index; Sleep, REM

Alpha-synuclein (alphaS) is the major component of the filamentous inclusions that constitute defining characteristics of Lewy body diseases (LBD) and multiple system atrophy (MSA). Clinically, antioxidant vitamins, such as vitamin E and the vitamin-like substance coenzyme Q10, have been used in the treatment of LBD with some efficacy. Using fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy, here we examined the effects of ten antioxidant vitamins and vitamin-like substances, vitamin A (retinol, retinal and retinoic acid), beta-carotene, vitamins B2, B6, C, E, coenzyme Q10 and alpha-lipoic acid, on the formation of alphaS fibrils (falphaS) and on preformed falphaS. Among them, vitamin A, beta-carotene and coenzyme Q10 dose-dependently inhibited the formation of falphaS. Moreover, they also dose-dependently destabilized preformed falphaS. With such potent anti-fibrillogenic as well as fibril-destabilizing activities, these compounds could be useful in the treatment and prevention of LBD and MSA.

Topics: alpha-Synuclein; Antioxidants; Benzothiazoles; beta Carotene; Coenzymes; Humans; Lewy Body Disease; Microscopy, Atomic Force; Microscopy, Electron; Microscopy, Fluorescence; Neurofibrils; Neuroprotective Agents; Parkinson Disease; Thiazoles; Ubiquinone; Vitamin A; Vitamins

The pathogenesis of idiopathic Parkinson's disease (PD) remains elusive, although evidence has suggested that neuroinflammation characterized by activation of resident microglia in the brain may contribute significantly to neurodegeneration in PD. It has been demonstrated that aggregated alpha-synuclein potently activates microglia and causes neurotoxicity. However, the mechanisms by which aggregated alpha-synuclein activates microglia are not understood fully.. We investigated the role of prostaglandin E2 receptor subtype 2 (EP2) in alpha-synuclein aggregation-induced microglial activation using ex vivo, in vivo and in vitro experimental systems.. Results demonstrated that ablation of EP2(EP2-/-) significantly enhanced microglia-mediated ex vivo clearance of alpha-synuclein aggregates (from mesocortex of Lewy body disease patients) while significantly attenuating neurotoxicity and extent of alpha-synuclein aggregation in mice treated with a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Furthermore, we report that reduced neurotoxicity by EP2-/- microglia could be attributed to suppressed translocation of a critical cytoplasmic subunit (p47-phox) of NADPH oxidase (PHOX) to the membranous compartment after exposure to aggregated alpha-synuclein.. Thus, it appears that microglial EP2 plays a critical role in alpha-synuclein-mediated neurotoxicity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; Humans; Lewy Body Disease; Mice; Mice, Inbred BALB C; Mice, Knockout; Microglia; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype

Topics: alpha-Synuclein; Brain Diseases; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Neurodegenerative Diseases; Neuroglia; Parkinson Disease; Protein Kinases

Topics: alpha-Synuclein; Cognition Disorders; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Lewy Body Disease; Microscopy, Confocal; Microscopy, Electron; Middle Aged; Multiple System Atrophy

We investigated Lewy pathologies in the claustrum and the related cerebral cortices and subcortical nuclei of dementia with Lewy bodies (DLB) brains using alpha-synuclein-immunohistochemistry to clarify the relationship between Lewy pathology in the claustrum and visual misidentification of DLB patients. The claustrum is known to have strong reciprocal connections with the visual areas. Consequently, the claustrum demonstrated many Lewy bodies (LB) and LB-related neurites. The insular and inferior temporal cortices, amygdala, BA 18, 19, transentohrinal and cingulate cortices showed stronger or similar Lewy pathology as compared with the claustrum, while BA 17, precentral, postcentral and transverse temporal cortices showed weaker Lewy pathology. Comparing the correlation coefficient of Lewy pathology between the clausturm and other regions, BA 18 and 19 as well as the insular and transentorhinal cortices demonstrated a higher correlation coefficient. These findings suggest that Lewy pathology in the claustrum is more closely associated with that in visual areas than in auditory, somatosensory or motor areas, and that dysfunction of the visuo-claustral pathway participates in visual misidentification in addition to the visuo-amygdaloid pathway. The paralimbic cortices including the insular and transentorhinal cortices may connect visual areas with limbic areas by relay of the visuo-claustral or visuo-amygdaloid pathway.

Topics: Aged; alpha-Synuclein; Amygdala; Basal Ganglia; Entorhinal Cortex; Female; Gyrus Cinguli; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Temporal Lobe; Visual Cortex; Visual Pathways

Lewy bodies, the pathological hallmark of dementia with Lewy bodies (DLB), are large juxtanuclear inclusions of aggregated alpha-synuclein. However, the small number of cortical Lewy bodies relative to the total neuron count does not correlate with the extent of cognitive impairment. In contrast to dopaminergic neurons in Parkinson's disease, nerve cell loss is usually less prevalent in the cortex of DLB, suggesting a different mechanism of neurodegeneration. Because antibodies used for immunodetection per se do not generally differentiate the aggregated from the physiological and monomeric isoform of alpha-synuclein, we developed the paraffin-embedded tissue (PET) blot and the protein aggregate filtration (PAF) assay for the sensitive and selective detection of alpha-synuclein aggregates in tissue slides and brain homogenates, respectively. In contrast to common immunohistochemistry, the PET blot detected an enormous number of small alpha-synuclein aggregates, which, in contrast to the few Lewy bodies, may explain the cognitive impairment in DLB. Using the PAF assay, we demonstrate that the absolute majority of alpha-synuclein aggregates are located at presynaptic terminals, suggesting a severe pathological impact on synaptic function. Indeed, parallel to the massive presynaptic accumulation of alpha-synuclein aggregates, we observed significant synaptic pathology with almost complete loss of dendritic spines at the postsynaptic area. Our results provide strong evidence for a novel concept of neurodegeneration for DLB in which synaptic dysfunction is caused by presynaptic accumulation of alpha-synuclein aggregates. This concept may also be valid for Parkinson's disease.

Topics: alpha-Synuclein; Centrifugation, Density Gradient; Dendrites; Filtration; Frontal Lobe; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Paraffin Embedding; Presynaptic Terminals; Synaptic Transmission; Synaptosomes

Lewy bodies (LB) usually extend from the brainstem to the cerebrum in patients with Parkinson's disease. However, whether the patterns of progression of LB and neuronal loss in Parkinson's disease are identical to those in other Lewy body diseases (LBD) remains unclear. In addition, pathological data on the autonomic nervous system involvement in LBD are limited. We present here the clinicopathological characteristics of two autopsy cases with both Alzheimer's disease and dementia with Lewy bodies (DLB), possibly diagnosed as having Lewy body variant of Alzheimer's disease (LBV/AD). Our patients presented clinically with dementia without parkinsonism. Histopathologically, phosphorylated alpha-synuclein-positive LB and Lewy neurites were abundant in the limbic system, especially in the amygdala, and to a lesser degree, in the neocortex, including the primary motor cortex. The amygdala was also most severely affected by neuronal loss, and the other limbic areas and neocortex were affected to a lesser degree. Despite the existence of a small number of LB and many Lewy neurites, neurons in the brainstem nuclei were relatively well preserved. The Braak stages of concurrent neurofibrillary changes and senile plaques were stage V and C, respectively, in both cases. Tyrosine hydroxylase-positive nerve fibers were relatively well spared in one case examined compared with Parkinson's disease cases. Furthermore, many Lewy neurites immunopositive for phosphorylated a-synuclein were found in the nerve fascicles of the epicardium in one case examined and in Parkinson's disease cases to a lesser degree. These findings suggest that: (i) in at least some LBV/AD cases, the amygdala develops neuronal loss and Lewy-related pathology prior to the brainstem nuclei; and (ii) the depletion of nerves in the heart tissue of LBV/AD is not necessarily complete despite the development of Lewy-related pathology.

Topics: Age of Onset; alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Autopsy; Brain Stem; Cerebral Cortex; Dementia; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurofibrillary Tangles; Plaque, Amyloid; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Presenilin-1

The aggregation of alpha-synuclein (alphaS) has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and Parkinson's disease (PD). We used fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy to examine the effects of nicotine, pyridine, and N-methylpyrrolidine on the formation of alphaS fibrils (f alphaS) from wild-type alphaS (alphaS (WT)) and A53T mutant alphaS (A53T) and on preformed f alpha Ss. Nicotine dose-dependently inhibited the f alphaS formation from both alphaS (WT) and A53T. Moreover, nicotine dose-dependently destabilized preformed f alpha Ss. These effects of nicotine were similar to those of N-methylpyrrolidine. The anti-fibrillogenic activity of nicotine may be exerted not only by the inhibition of f alphaS formation but also by the destabilization of preformed f alphaS. Additionally, this effect may be attributed to N-methylpyrrolidine moieties of nicotine.

Topics: alpha-Synuclein; Benzothiazoles; Humans; Kinetics; Lewy Body Disease; Microfibrils; Microscopy, Atomic Force; Microscopy, Electron; Mutation; Nicotine; Nicotinic Agonists; Pyridines; Pyrrolidines; Reverse Transcriptase Polymerase Chain Reaction; Spectrometry, Fluorescence; Thiazoles

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized pathologically by the presence of neuronal inclusions termed Lewy bodies (LBs). A common feature found in LBs are aggregates of alpha-synuclein (alpha-Syn), and although it is now recognized that alpha-Syn is the major building block for these toxic filaments, the mechanism of how this occurs remains unknown. In the present study, we demonstrate that proteolytic processing of alpha-Syn by the protease calpain I leads to the formation of aggregated high-molecular weight species and adoption of a beta-sheet structure. To determine whether calpain-cleavage of alpha-Syn occurs in PD and DLB, we designed site-directed calpain-cleavage antibodies to alpha-Syn and tested their utility in several animal model systems. Detection of calpain-cleaved alpha-Syn was evident in mouse models of cerebral ischemia and PD and in a Drosophila model of PD. In the human PD and DLB brain, calpain-cleaved alpha-Syn antibodies immunolabeled LBs and neurites in the substantia nigra. Moreover, calpain-cleaved alpha-Syn fragments identified within LBs colocalized with activated calpain in neurons of the PD and DLB brains. These findings suggest that calpain I may participate in the disease-linked aggregation of alpha-Syn in various alpha-synucleinopathies.

Topics: Aged; alpha-Synuclein; Animals; Area Under Curve; Blotting, Western; Brain; Calpain; Cell Line, Tumor; Drosophila; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Immunoprecipitation; Lewy Body Disease; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neurons; Parkinson Disease; Protein Structure, Secondary

Lewy body disease is defined as Lewy body-related neuronal degeneration involving the nigrostriatal system, limbic-neocortical system, and peripheral autonomic nervous system (PANS). We investigated whether the adrenal gland, which is evolutionarily related to sympathetic ganglia and is routinely examined in general autopsy, could be used to assess pathology of the PANS in Lewy body disease. Brains, spinal cords, and adrenal glands from 783 consecutive autopsy cases from a general geriatric hospital were examined immunohistochemically with antiphosphorylated alpha-synuclein antibodies and routine staining. Parkinson disease (PD) with dementia and dementia with Lewy bodies (DLB) were defined using 1996 Consensus Guidelines for DLB and the secondary Lewy body-related alpha-synucleinopathy or amygdala variants using previously established criteria. Lewy body-related alpha-synucleinopathy was found in 207 (26.4%) of 783 cases, with 1 case solely in the adrenal gland. In all 18 PD cases with or without dementia and in 33 of 38 DLB cases, the adrenal gland was involved, but it was spared in all cases of amygdala variants. Our results indicate that the adrenal gland can provide useful information for evaluation of the PANS in Lewy body disease.

Topics: Adrenal Glands; Aged; Aged, 80 and over; alpha-Synuclein; Autonomic Nervous System; Autopsy; Chi-Square Distribution; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Tyrosine 3-Monooxygenase

To determine the prevalence of alpha-synuclein (AS) aggregates in abdominopelvic autonomic plexuses in the general population and to evaluate the relationship between this finding and the subsequent development of neurologic dysfunction.. First, surgical specimens from 100 patients (ages 44 to 84) undergoing a wide resection of an abdominopelvic organ were examined by anti-AS immunostaining. Second, 16 patients (6 AS+ and 10 randomly selected AS-) participated in yearly double-blinded neurologic assessments.. AS aggregates were found in autonomic plexuses in 9% of the whole sample (95% CI 3.4 to 14.6%) but were more common in vesicoprostatic (26%) than in digestive tract (4%) specimens. At 16 months after the biopsy, no prevalent cases of Parkinson disease, dementia, or autonomic failure were diagnosed among participants. One AS+ patient had previously been diagnosed with REM sleep behavior disorder. Seven of 10 control subjects but none of the 6 AS+ patients had a diagnosis of hypertension (p = 0.01). During phase IV of Valsalva maneuver, AS+ group exhibited a longer blood pressure recovery time (p = 0.03), with one patient showing absence of blood pressure overshoot. Cardiac [(123)I]metaiodobenzylguanidine uptake was reduced in the AS+ group (p = 0.03). Striatal [(123)I]ioflupane uptake was abnormally low in only one AS+ patient. At 30 months after the biopsy, lower cardiac and striatal uptake values tended to correlate with higher Unified Parkinson's Disease Rating Scale III scores (p = 0.07).. The common presence of alpha-synuclein aggregates in peripheral autonomic neurons may represent an early presymptomatic phase in the development of Lewy body disorders.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Autonomic Nervous System Diseases; Biomarkers; Cardiovascular System; Cohort Studies; Comorbidity; Corpus Striatum; Cross-Sectional Studies; Disease Progression; Female; Ganglia, Autonomic; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Macromolecular Substances; Male; Middle Aged; Neurologic Examination; Neurons; Parkinson Disease; Predictive Value of Tests; Prevalence

Lewy-type pathology is a characteristic of a number of neurodegenerative disorders, including Parkinson's disease and dementia with Lewy bodies. Thus far, the definitive diagnosis of these dementias can only be confirmed at post-mortem. However, it is known that the loss of smell (anosmia) is an early symptom in patients who develop dementia, and the use of the smell test has been proposed as an early diagnostic procedure. The aim of this study was to understand further the extent of Lewy pathology in the olfactory system of patients with neurodegenerative disorders. Post-mortem tissue from 250 subjects was obtained from the OPTIMA brain bank. Five areas of the olfactory pathway were examined by immunolabelling for alpha-synuclein - a major component of Lewy pathology: the olfactory tract/bulb (n = 79), the anterior olfactory nucleus in the lateral olfactory gyrus (n = 193), the region of olfactory projection to the orbito-frontal cortex (n = 225), the hippocampus (n = 236) and the amygdala (n = 201). Results show that Lewy pathology affects different parts of the olfactory pathways differentially, suggesting a specific pattern of development of pathology. Clinical Parkinson's disease is most likely to be identified if the orbito-frontal cortex is affected, while the diagnosis is less likely if the pathology is restricted to the olfactory bulb or tract. These results suggest that pathology in the olfactory bulb and tract occurs prior to clinical signs of Parkinson's disease. Furthermore, the results presented here provide further evidence supporting the possible value of a smell test to aid the clinical diagnosis of neurodegenerative diseases.

Topics: Aged; alpha-Synuclein; Amygdala; Dementia; Hippocampus; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Neurodegenerative Diseases; Odds Ratio; Olfaction Disorders; Olfactory Bulb; Olfactory Pathways; Parkinson Disease

Depression is a feature of both Lewy body disorders and multiple system atrophy (MSA). Since serotonergic neurons of the rostral raphe have been implicated in depression, we sought to determine whether there is a differential involvement of these neurons in cases with clinically diagnosed dementia with Lewy bodies (DLB) or MSA. We studied the brainstem obtained at autopsy from fourteen patients with diagnosis of DLB and pathological limbic or neocortical stage Lewy body disease, 13 patients with clinical and neuropathological diagnosis of MSA, and 12 controls with no history of neurologic disease. The clinical features of these patients were analyzed retrospectively by reviewing their medical records. Serial sections were immunostained for tryptophan hydroxylase (TrOH) and alpha-synuclein and cell counts were performed in the dorsal raphe (DR), median raphe (MR) and medullary raphe nuclei. There was loss of serotonergic cells in both the DR and MR in DLB compared to control cases: For the DR, the number of cells/section were 53 +/- 6 in DLB versus 159 +/- 13 (P < 0.001) respectively, and for the MR 70 +/- 11 in DLB versus 173 +/- 23 (P < 0.001) respectively. In contrast, these cells were relatively preserved in MSA. The caudal raphe groups were affected both in MSA and in DLB. There is a differential involvement of raphe neurons in DLB and MSA. Although loss of rostral raphe neurons may contribute to depression in DLB, this appears to be less likely in MSA. Factors other than the neurochemical phenotype determine neuronal vulnerability in MSA.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cell Count; Depression; Female; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Raphe Nuclei; Tryptophan Hydroxylase

We used an autopsy series to determine whether the newest dementia with Lewy bodies (DLB) consensus pathologic classification correlates with premortem diagnosis of DLB. Neocortical sections from a total of 95 cases with Lewy bodies were stained with alpha-synuclein antibodies. We assigned cases according to the DLB consensus' categories and found a significant association with the premortem clinical diagnosis of DLB. Clinical diagnosis of DLB, however, depended on the presence of low Alzheimer disease pathology (by Braak staging) rather than on Lewy body distribution.

Topics: alpha-Synuclein; Alzheimer Disease; Brain; Brain Stem; Diagnosis, Differential; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Limbic System; Neocortex; Neurons; Phenotype; Predictive Value of Tests

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Topics: Aged; alpha-Synuclein; Comorbidity; DNA-Binding Proteins; Female; Hippocampus; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; tau Proteins; Ubiquitin

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized by the formation and intraneuronal accumulation of fibrillar aggregates of alpha-synuclein (alpha-syn) protein in affected brain regions. alpha-Syn has biochemical properties and a structural motif characteristic of fatty acid binding proteins. Using the fatty acid binding resin Lipidex-1000, we investigated the capture of alpha-, beta-, and gamma-syn proteins as lipid-associated proteins from normal and DLB brain lysates, and from normal human cerebrospinal fluid (CSF). These were eluted from Lipidex-1000 and analyzed by SDS-NuPAGE followed by Western blotting. Using this methodology, we have been able to extract full-length and truncated forms of alpha-syn from brain lysates. We also extracted low levels of beta-syn from DLB brains, but failed to extract any gamma-syn. We were able to capture only full-length monomeric alpha-syn from normal human CSF. Our data confirm the fatty acid binding properties of alpha-syn, and to a lesser extent beta-syn, but suggest that gamma-syn does not share this same characteristic.

Topics: alpha-Synuclein; beta-Synuclein; Binding, Competitive; Brain; Brain Chemistry; Cerebrospinal Fluid; Dextrans; Electrophoresis, Polyacrylamide Gel; gamma-Synuclein; Humans; Lewy Body Disease; Membrane Lipids; Synucleins

Topics: Aged; alpha-Synuclein; Atrophy; Brain; Cognition Disorders; Depressive Disorder; Diagnosis, Differential; Disease Progression; Electroencephalography; Fatal Outcome; Gait Disorders, Neurologic; Genetic Markers; Genetic Predisposition to Disease; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Memory Disorders; Psychotic Disorders; REM Sleep Behavior Disorder; Sleep Apnea Syndromes; Urination Disorders

Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of alpha-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Abeta plaques are also present in most DLB cases. The contribution of Abeta to the development of DLB is unclear. [11C]-Pittsburgh compound B ([11C]-PIB) is a thioflavin-T derivative that has allowed in vivo Abeta burden to be quantified using positron emission tomography (PET). [11C]-PIB PET studies have shown similar high cortical [11C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to alpha-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human alpha-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [3H]-PIB binds to alpha-synuclein fibrils but with lower affinity than that demonstrated/reported for Abeta(1-42) fibrils. Furthermore, [3H]-PIB was observed to bind to Abeta plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Abeta plaque-free ("pure DLB"). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Abeta plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [11C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [11C]-PIB PET studies is largely attributable to PIB binding to Abeta plaques and not Lewy bodies.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Aniline Compounds; Binding Sites; Cerebral Cortex; Humans; In Vitro Techniques; Lewy Bodies; Lewy Body Disease; Positron-Emission Tomography; Thiazoles

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; DNA-Binding Proteins; Female; Humans; Lewy Body Disease; Male; Middle Aged; Postmortem Changes; tau Proteins; Ubiquitin

Impaired transduction of transforming growth factor-beta signaling has recently been implicated in Alzheimer disease. Transforming growth factor-beta signals are transduced by Smads, which are phosphorylated and translocated to the nucleus, where they initiate gene transcription. In Alzheimer disease, neurofibrillary tangles sequester phosphorylated Smad 2/3 (pSmad2/3) and reduce its nuclear translocation. We have now investigated the relationship between pSmad2/3 and phospho-tau in 3 other tauopathies, Pick disease, progressive supranuclear palsy, and corticobasal degeneration, and in 2 alpha-synucleinopathies, dementia with Lewy bodies and multiple system atrophy. In Pick disease, progressive supranuclear palsy, and corticobasal degeneration, pSmad2/3 was demonstrated in neuronal and glial nuclei but also colocalized with cytoplasmic tau inclusions. No pSmad2/3 was detected in glial cytoplasmic inclusions in multiple system atrophy or in Lewy bodies in dementia with Lewy bodies. Our data indicate that phospho-tau but not alpha-synuclein cytoplasmic inclusions bind pSmad2/3. The preservation of neuronal nuclear pSmad2/3 in Pick disease, progressive supranuclear palsy, and corticobasal degeneration suggests that cytoplasmic sequestration of pSmad2/3 is likely to have less impact on transforming growth factor-beta signal transduction in these diseases than in Alzheimer disease.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Blotting, Western; Brain; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Multiple System Atrophy; Neurodegenerative Diseases; Phosphorylation; Pick Disease of the Brain; Protein Transport; Smad Proteins; Supranuclear Palsy, Progressive; tau Proteins

Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We raised a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immunolabled LBs, and found that alpha-synuclein is one of the major components of LBs. Thus, the deposition of alpha-synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells, was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in and multiplication of alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific posttranslational modifications that characterize and underlie the aggregation of alpha-synuclein in synucleinopathy brains by mass spectrometry and using a specific antibody, and found that serine 129 of alpha-synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. Furthermore we generated transgenic C. elegans overexpressing alpha-synuclein in neurons, and found that overexpression of familial PD-linked mutant form of alpha-synuclein impairs functions of dopamine neurons. These findings collectively underscore the importance of deposition of alpha-synuclein as well as its phosphorylation in the pathogenesis of alpha-synucleinopathies.

Topics: alpha-Synuclein; Biomarkers; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Protein Processing, Post-Translational

Mutations in the PSEN1 gene encoding presenilin 1 (PS1) are linked to a vast majority of pedigrees with early-onset, autosomal dominant forms of familial Alzheimer's disease (FAD). Lewy body (LB) pathology is frequently found in the brains of FAD patients harboring PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (deltaT440) in a familial case diagnosed as having the neocortical type of dementia with LBs (DLB) and variant AD. In this report, we investigated the possible involvement of PS1 deltaT440 mutation in aberrant alpha-synuclein accumulation. We established cell lines that stably express either wild-type (WT) PS1 or the FAD-linked PS1 H163R, E280A, deltaE9, and PS1 deltaT440 mutants and now demonstrate that the expression of the PS1 deltaT440 mutant led to a marked elevation in the ratio of beta-amyloid (Abeta) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated alpha-synuclein increase in neuronal and non-neuronal cells expressing the PS1 deltaT440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated alpha-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 deltaT440 mutation. These observations raise the intriguing suggestion that the mechanism(s) by which the PS1 deltaT440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of Abeta(42/40) peptides, respectively, in the brain.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glioma; Humans; Lewy Body Disease; Mice; Middle Aged; Mutation; Neuroblastoma; Phosphorylation; Presenilin-1; Rats; Receptors, Notch; Threonine; Transfection

Dementia is relatively common in Parkinson's Disease (PD). When dementia occurs in the setting of PD, it is referred to as Parkinson's disease dementia (PDD), which is distinguished from the clinical syndrome in which dementia precedes extrapyramidal features, dementia with Lewy bodies (DLB). In this report, the neuropathology of PDD and DLB is reviewed and preliminary findings are reported on striatal pathology in 28 brains, including 7 PD, 7 PDD and 14 DLB. Sections of putamen immunostained for a-synuclein and investigated with image analysis show that striatal pathology is common and that both cortical and striatal a-synuclein pathology is greater in PDD and DLB than PD. Most cases of PDD and DLB have Alzheimer-type pathology, particularly amyloid plaques, which may act in an additive or synergistic manner with a-synuclein pathology. There are few pathologic differences between PDD and DLB, despite differences in their clinical course.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Corpus Striatum; Dementia; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Parkinson Disease

Topics: Adult; alpha-Synuclein; Brain; Carbon Radioisotopes; Chromosome Aberrations; Cocaine; DNA Mutational Analysis; Female; Gene Expression; Genes, Dominant; Genetic Carrier Screening; Humans; Lewy Body Disease; Middle Aged; Neurologic Examination; Parkinson Disease; Phenotype; Positron-Emission Tomography; Raclopride; Receptors, Dopamine; Receptors, Presynaptic

Vesicular monoamine transporter 2 (VMAT2) is responsible for packing dopamine into vesicles, and reduces the effects of neurotoxins by sequestering them into vesicles. In this report, we tested the hypothesis that VMAT2 is associated with Lewy body (LB) formation by immunohistochemical staining of midbrain and cortical sections of autopsied brains of patients with Parkinson's disease (PD) and diffuse Lewy body disease (DLBD) for VMAT2 using a polyclonal antibody against VMAT2. LBs in the substantia nigra (SN) of PD and DLBD were immunoreactive for VMAT2, especially in the peripheral zone. Previous electron microscopic studies also revealed the presence of numerous dense core vesicles around the LBs, suggesting that these vesicles are related to LB formation. Indeed, the presence of a few vesicle-linked proteins such as synaptophysin and chromogranin A in LBs has been reported. Together with the low expression of VMAT2 in the SN of PD, the involvement of VMAT2 in LBs of the SN suggests the association of this protein in the neurodegeneration of nigral neurons in PD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Case-Control Studies; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Plaque, Amyloid; Substantia Nigra; Vesicular Monoamine Transport Proteins

Alpha-synuclein is a major constituent of Lewy bodies, the fibrillar aggregates that form within neurons in Parkinson's disease and dementia with Lewy bodies (DLB). Recent biochemical data show that alpha-synuclein accumulates in Parkinson's disease in a detergent insoluble form. We now examine the relationship between detergent insoluble alpha-synuclein and the presence of Lewy bodies, clinical measures of dementia and biochemical parameters in a series of individuals with DLB. We found that Triton X-100 insoluble alpha-synuclein enriched nearly twofold in the temporal cortex of patients with DLB compared to age-matched controls. By contrast the total amount of alpha-synuclein protein was unchanged. Surprisingly, the degree of Triton X-100 insoluble alpha-synuclein did not correlate with either the duration of illness or the number of Lewy bodies counted using stereological methods from an adjacent block of tissue. However, the Triton X-100 soluble fraction of alpha-synuclein did correlate strongly with the expression of several heat shock proteins (HSPs) in DLB but not control cases, suggesting a coordinated HSP response in DLB neocortex.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Detergents; Enzyme-Linked Immunosorbent Assay; Female; Glial Fibrillary Acidic Protein; Heat-Shock Proteins; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Neocortex; Octoxynol; Solubility; Synaptophysin; Temporal Lobe

The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Various antioxidants not only inhibit the formation of beta-amyloid fibrils (fAbeta), but also destabilize preformed fAb in vitro. Using fluorescence spectroscopy with thioflavin S and electron microscopy, here we examined the effects of the antioxidants nordihydroguaiaretic acid, curcumin, rosmarinic acid, ferulic acid, wine-related polyphenols [tannic acid, myricetin, kaempferol (+)-catechin and (-)-epicatechin], docosahexaenoic acid, eicosapentaenoic acid, rifampicin and tetracycline on the formation of alphaS fibrils (falphaS) and on preformed falphaS. All molecules, except for docosahexaenoic acid and eicosapentaenoic acid, dose-dependently inhibited the formation of falphaS. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity of the molecules examined was in the order of: tannic acid=nordihydroguaiaretic acid=curcumin=rosmarinic acid=myricetin>kaempferol=ferulic acid>(+)-catechin=(-)-epicatechin>rifampicin=tetracycline. These compounds with anti-fibrillogenic as well as antioxidant activities could be key molecules for the development of preventives and therapeutics for LBD and MSA as well as Alzheimer's disease.

Topics: Aged; alpha-Synuclein; Antioxidants; Cerebrospinal Fluid; Dose-Response Relationship, Drug; Female; Humans; Lewy Body Disease; Male; Microscopy, Electron, Transmission; Molecular Structure; Neurofibrillary Tangles; Plant Extracts; Spectrometry, Fluorescence

Oxidative stress, inflammation and alpha-synuclein overexpression confer risk for development of alpha-synucleinopathies-neurodegenerative diseases that include Parkinson disease and Lewy body dementia. Dopaminergic neurons undergo degeneration in these diseases and are particularly susceptible to oxidative stress because dopamine metabolism itself creates reactive oxygen species. Intraneuronal deposition of alpha-synuclein as amyloid fibrils or Lewy bodies is the hallmark of these diseases. Herein, we demonstrate that concentrations of oxidative cholesterol metabolites derived from reactive oxygen species are elevated in the cortices of individuals with Lewy body dementia relative to those of age-matched controls, and we show that these metabolites accelerate alpha-synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses alpha-synuclein. By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable alpha-synuclein aggregation, leading to a pathologic cycle.

Topics: alpha-Synuclein; Brain; Cell Line; Cholesterol; Dopamine; Humans; Lewy Body Disease; Microscopy, Electron; Neurons; Oxidative Stress; Time Factors

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy; REM Sleep Behavior Disorder

alpha-Synucleinopathies are a group of neurological disorders characterized by the presence of intracellular inclusion bodies containing alpha-synuclein. We previously demonstrated that synphilin-1 interacts with alpha-synuclein, implying a role in Parkinson's disease. We now report the identification and characterization of synphilin-1A, an isoform of synphilin-1, which has enhanced aggregatory properties and causes neurotoxicity. The two transcripts encoding synphilin-1A and synphilin-1 originate from the SNCAIP gene but differ in both their exon organization and initial reading frames used for translation. Synphilin-1A binds to alpha-synuclein and induces the formation of intracellular aggregates in human embryonic kidney 293 cells, primary neuronal cultures, and human dopaminergic cells. Overexpression of synphilin-1A in neurons results in striking cellular toxicity that is attenuated by the formation of synphilin-1A inclusions, which recruit alpha-synuclein. Synphilin-1A is present in Lewy bodies of patients with Parkinson's disease and Diffuse Lewy Body disease, and is observed in detergent-insoluble fractions of brain protein samples obtained from Diffuse Lewy Body disease patients. These findings suggest that synphilin-1A may contribute to neuronal degeneration in alpha-synucleinopathies and also provide important insights into the role of inclusion bodies in neurodegenerative disorders.

Topics: alpha-Synuclein; Base Sequence; Carrier Proteins; Cell Death; Cell Line; Cloning, Molecular; Codon; Exons; Humans; Kidney; Lewy Body Disease; Molecular Sequence Data; Nerve Tissue Proteins; Neurons; Parkinson Disease; Protein Isoforms

Dysfunction of the 140 aa protein alpha-synuclein plays a central role in Lewy body disorders, including Parkinson's disease, as well as in multiple system atrophy. Here, we show that the expression of truncated human alpha-synuclein(1-120), driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of alpha-synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.

Topics: alpha-Synuclein; Animals; Dopamine; Humans; Lewy Bodies; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Neurons; Olfactory Bulb; Parkinson Disease; Promoter Regions, Genetic; Rats; Substantia Nigra; Tyrosine 3-Monooxygenase

We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmann's area 17), secondary visual pathway (pulvinar, Brodmann's areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amygdala; Autopsy; Brain; Cell Count; Disease Progression; Female; Hallucinations; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurons; Substantia Nigra; Visual Pathways

The primary feature of dementia with Lewy bodies (DLB) is the aggregation of alpha-synuclein into characteristic lesions: Lewy bodies (LBs) and Lewy neurites. However, in most of DLB cases, LBs are associated with neurofibrillary tangles and amyloid plaques (both Alzheimer disease [AD]-related lesions). We wanted to determine if this overlap of lesions is statistical, as a result of the late onset of both diseases, or results from a specific physiopathological synergy between synucleinopathy and either tauopathy or amyloid pathology. All patients with DLB from our prospective and multidisciplinary study were analyzed. These cases were compared with cases with pure AD and patients with Parkinson disease and controls. All cases were analyzed thoroughly at the neuropathologic and biochemical levels with a biochemical staging of aggregated alpha-synuclein, tau, and Abeta species. All sporadic cases of DLB were associated with abundant deposits of Abeta x-42 that were similar in quality and quantity to those of AD. Amyloid precursor protein (APP) dysfunction is a risk factor for AD as demonstrated by pathogenic mutations and Abeta accumulation. The constant and abundant Abeta x-42 deposition in sporadic DLB suggests that synucleinopathy is also promoted by APP dysfunction. Therefore, we conclude that APP is a therapeutic target for both AD and DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Cerebral Cortex; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Lewy Body Disease; Male; Mass Spectrometry; Middle Aged; Parkinson Disease; tau Proteins

Lewy bodies (LBs) are alpha-synuclein-immunoreactive neuronal inclusions with a predilection for specific cortical and subcortical regions, including the amygdala. In this study, the presence of LBs was assessed in 347 cases of Alzheimer disease (AD). In 87 cases, LB pathology was diagnostic of brainstem (n=3), transitional (n=32), or diffuse (n=52) Lewy body disease (LBD). The remaining 260 cases of AD were screened for amygdala LBs (AD/ALB) and 62 (24%) cases were found. If AD/LBD cases are included, LBs were detected in 149 (43%) cases of AD. The presence alpha-synuclein pathology was assessed in multiple brain regions of the 62 cases of AD/ALB and 57 randomly selected cases of AD, and only sparse alpha-synuclein pathology was detected in both. The burden of alpha-synuclein pathology in brainstem nuclei, amygdala, and neocortex was significant lower in AD/ALB than in AD/LBD. In comparison to AD/LBD, AD/ALB did not differ in age at death, disease duration, male-to-female ratio, brain weight, Braak neurofibrillary tangle stage, average senile plaque density, or apolipoprotein E epsilon4 allele frequency. The results suggest that AD/ALB is pathologically different from AD/LBD, suggesting that it is a neuropathologically distinct and isolated alpha-synucleinopathy.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amygdala; Demography; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neurons; Retrospective Studies; Statistics as Topic

A comprehensive, unbiased inventory of synuclein forms present in Lewy bodies from patients with dementia with Lewy bodies was carried out using two-dimensional immunoblot analysis, novel sandwich enzyme-linked immunosorbent assays with modification-specific synuclein antibodies, and mass spectroscopy. The predominant modification of alpha-synuclein in Lewy bodies is a single phosphorylation at Ser-129. In addition, there is a set of characteristic modifications that are present to a lesser extent, including ubiquitination at Lys residues 12, 21, and 23 and specific truncations at Asp-115, Asp-119, Asn-122, Tyr-133, and Asp-135. No other modifications are detectable by tandem mass spectrometry mapping, except for a ubiquitous N-terminal acetylation. Small amounts of Ser-129 phosphorylated and Asp-119-truncated alpha-synuclein are present in the soluble fraction of both normal and disease brains, suggesting that these Lewy body-associated forms are produced during normal metabolism of alpha-synuclein. In contrast, ubiquitination is only detected in Lewy bodies and is primarily present on phosphorylated synuclein; it therefore likely occurs after phosphorylated synuclein has deposited into Lewy bodies. This invariant pattern of specific phosphorylation, truncation, and ubiquitination is also present in the detergent-insoluble fraction of brain from patients with familial Parkinson's disease (synuclein A53T mutation) as well as multiple system atrophy, suggesting a common pathogenic pathway for both genetic and sporadic Lewy body diseases. These observations are most consistent with a model in which preferential accumulation of normally produced Ser-129 phosphorylated alpha-synuclein is the key event responsible for the formation of Lewy bodies in various Lewy body diseases.

Topics: alpha-Synuclein; Amino Acid Sequence; Female; Humans; Lewy Body Disease; Middle Aged; Molecular Sequence Data; Phosphorylation; Serine

Amyloidogenic proteins (Abeta peptide) in Alzheimer's disease (AD) and alpha-synuclein (alpha-Syn) in Parkinson's disease (PD) are typically soluble monomeric precursors, which undergo remarkable conformational changes and culminate in the form of aggregates in diseased condition. Overlap of clinical and neuropathological features of both AD and PD are observed in dementia with Lewy body (DLB) disease, the second most common form of dementia after AD. The identification of a 35-amino acid fragment of alpha-Syn in the amyloid plaques in DLB brain have raised the possibility that Abeta and alpha-Syn interact with each other. In this report, the molecular interaction of alpha-Syn with Abeta40 and/or Abeta42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound alpha-Syn with Abeta peptide and vice versa. These Abeta-alpha-Syn interactions are demonstrated by reduced amide peak intensity or change in chemical shift of amide proton of the interacting proteins. Based on NMR results, the plausible molecular mechanism of overlapping pathocascade of AD and PD in DLB due to interactions between alpha-Syn and Abeta is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between Abeta and alpha-Syn which may lead to onset of DLB.

Topics: alpha-Synuclein; Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Brain; Humans; Lewy Body Disease; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Peptide Fragments

Alpha-synuclein, a main component of Lewy bodies in synucleinopathies and senile plaques in Alzheimer disease, is centrally involved in neurodegeneration. Three different isoforms (alpha-synuclein 112, 126, and 140) resulting from alternative splicing have been described so far. The present study explores alpha-synuclein 126 mRNA expression levels in the prefrontal cortex of six patients with dementia with Lewy bodies, eight patients with Lewy body variant of Alzheimer disease, eight patients with Alzheimer disease, and 10 controls. Relative alpha-synuclein 126 expression levels were determined by real-time polymerase chain reaction with competimer technology. Alpha-synuclein 126 mRNA expression was markedly decreased in the three dementias in comparison with controls, suggesting an important role of this alpha-synuclein isoform in the normal brain.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Female; Gene Expression Regulation; Humans; Lewy Body Disease; Male; Middle Aged; Postmortem Changes; Prefrontal Cortex; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Alignment

We report the case of an elderly man of Greek background who presented with progressive cognitive decline and motor parkinsonism on a background of a strong family history of Parkinson's disease. Associated symptoms included visual hallucinations, excessive daytime drowsiness, recurrent falls, orthostatic hypotension and urinary incontinence. His major clinical symptoms and signs fulfilled consensus criteria for a clinical diagnosis of dementia with Lewy bodies. An alpha-synuclein gene mutation analysis for the G209A substitution was positive. We conclude that the alpha-synuclein (G209A) gene mutation genotype should be considered in the differential diagnosis of dementia with Lewy bodies, particularly in patients with European ancestry and a family history of Parkinson's disease.

Topics: Accidental Falls; Aged; alpha-Synuclein; Cognition Disorders; Diagnosis, Differential; Disease Progression; DNA Mutational Analysis; Fatal Outcome; Genetic Markers; Genetic Predisposition to Disease; Genotype; Greece; Hallucinations; Humans; Hypotension, Orthostatic; Lewy Body Disease; Male; Mutation; Parkinsonian Disorders; Respiratory Tract Infections; Urinary Incontinence

Protein misfolding and inclusion formation are common events in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) or Huntington's disease (HD). Alpha-synuclein (aSyn) is the main protein component of inclusions called Lewy bodies (LB) which are pathognomic of PD, Dementia with Lewy bodies (DLB), and other diseases collectively known as LB diseases. Heat shock proteins (HSPs) are one class of the cellular quality control system that mediate protein folding, remodeling, and even disaggregation. Here, we investigated the role of the small heat shock proteins Hsp27 and alphaB-crystallin, in LB diseases. We demonstrate, via quantitative PCR, that Hsp27 messenger RNA levels are approximately 2-3-fold higher in DLB cases compared to control. We also show a corresponding increase in Hsp27 protein levels. Furthermore, we found that Hsp27 reduces aSyn-induced toxicity by approximately 80% in a culture model while alphaB-crystallin reduces toxicity by approximately 20%. In addition, intracellular inclusions were immunopositive for endogenous Hsp27, and overexpression of this protein reduced aSyn aggregation in a cell culture model.

Topics: alpha-Crystallin B Chain; alpha-Synuclein; Animals; Cell Aggregation; Cell Line; Cell Survival; Heat-Shock Proteins; Heat-Shock Proteins, Small; HSP27 Heat-Shock Proteins; Humans; Lewy Body Disease; Molecular Chaperones; Neoplasm Proteins; Neurons; Neurotoxins; Rats

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; beta-Adrenergic Receptor Kinases; Brain; Female; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinase 5; Humans; Lewy Bodies; Lewy Body Disease; Male; Neurodegenerative Diseases; Neurofibrillary Tangles; Neuroglia; Neurons; Phosphorylation; Pick Disease of the Brain; Protein Serine-Threonine Kinases; Supranuclear Palsy, Progressive; tau Proteins

The objective of this comparative neuropathologic study was to determine the extent to which dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) are distinct entities or part of a continuum with respect to the duration of parkinsonism.. We evaluated the relationship between cortical alpha-synuclein pathology, plaques (Consortium to Establish a Registry for Alzheimer's Disease [CERAD]), tangles (Braak staging), and cholinergic deficits (choline acetyltransferase in temporal cortex) in 57 prospectively assessed patients (29 DLB, 28 PDD), confirmed at autopsy. The PDD group was divided according to the median duration of parkinsonism prior to dementia.. There was an association between longer duration of parkinsonism prior to dementia and less severe cortical alpha-synuclein pathology (chi(2) 10.4, df 2, p = 0.006) and lower CERAD plaque scores (chi(2) 26.6, df 9, p = 0.002), but not Braak staging. These findings were confirmed in a further correlation analysis, which also identified an unexpected correlation between more pronounced cortical cholinergic deficits and longer duration of parkinsonism prior to dementia (R = -0.37, p = 0.04).. While there is a clear relationship between the duration of Parkinson disease prior to the onset of dementia and key neuropathologic and neurochemical characteristics, there is a gradation of these differences across the dementia with Lewy bodies/Parkinson disease dementia spectrum and the findings do not support an arbitrary cut-off between the two disorders.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Choline O-Acetyltransferase; Female; Humans; Lewy Body Disease; Male; Neurofibrillary Tangles; Parkinson Disease; Plaque, Amyloid; Prospective Studies; Temporal Lobe; Time Factors

A triplication of the alpha-synuclein gene was found to cause autosomal dominant Lewy body disease in two distinct families.. We searched for alterations of alpha-synuclein gene dosage and analysed the entire coding region for point mutations in 54 dementia with Lewy body disease (DLB) and in 103 young onset Parkinson's disease (PD) patients from Central Europe.. We could not detect any quantitative alterations in the gene dosage of alpha-synuclein. Mutational screening of the entire coding region of alpha-synuclein revealed only one silent mutation V3V (adenine9guanine) in one case.. Thus, this phenomenon appears not to be a major cause in the pathogenesis of sporadic DLB and young onset PD in this European population.

Topics: Adult; Age of Onset; Aged; alpha-Synuclein; Cohort Studies; DNA Mutational Analysis; Europe; Female; Gene Dosage; Gene Duplication; Genetic Predisposition to Disease; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Point Mutation

We investigated the occurrence and distribution of tuft-shaped astrocytes (TuSAs) in 60 brains from patients with Lewy body disease (LBD), which were clinically diagnosed as Parkinson's disease (PD) or dementia with Lewy bodies (DLB), and 85 brains from control subjects. TuSAs have been documented as a neuropathological hallmark of progressive supranuclear palsy (PSP). We found phosphorylated tau (p-tau)-positive and alpha-synuclein-negative TuSAs in 10 of 60 patients with LBD and 3 of 85 control cases. TuSAs were mainly located within the precentral and premotor gyri of the frontal lobe cortex. There were only few TuSAs, but the distribution pattern and morphological and immunohistological features were similar to that in PSP. Furthermore, other p-tau positive structures, including aggregates in neurons, coiled-like glial cells and threads showed a similar distribution to those in PSP; mainly in the hippocampus, striatum, subthalamic nucleus, precentral and premotor gyri, brainstem nucleus, and dentate nucleus. In these cases, however, neuronal loss and gliosis were not seen in the regions involved in PSP, such as the subthalamic nucleus, pallidum, inferior olivary, cerebellar dentate nuclei, and periaqueductal gray matter. Clinical features were indistinguishable between the LBD with and without TuSAs. The appearance of TuSAs was not related to the frequency of Lewy bodies, neurofibrillary tangles, and senile plaques, but was significantly more pronounced with advancing age in both LBD and controls. These findings suggest that in a subgroup of elderly individual cases, especially associated with LB pathology, the glial and neuronal p-tau accumulation is increased and has a distributional pattern similar to PSP.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Astrocytes; Brain; Cell Size; Female; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Synucleins; tau Proteins

To explore the association between APOE*4 and pathologically confirmed cases of the Lewy body (LB) variant of Alzheimer disease (AD).. With use of alpha-synuclein (AS) immunohistochemistry, LBs were detected in 74 of 131 (56.5%) of the AD + LB cases; the remaining 57 cases (43.5%) did not have LBs.. There were no differences in gender or age between Caucasian subjects with AD + LB or AD alone or control subjects. The APOE*4 allele frequency was highest in the AD + LB group (47.3%; 95% CI = 37.8 to 57.0%), intermediate in the AD-alone group (35.1%; 95% CI = 25.3 to 46.3%), and lowest in the control group (14.2%; 95% CI = 10.5 to 18.9%). With use of logistic regression analysis, the odds of having AD + LB vs AD alone were 2.1-fold (95% CI = 1.0 to 4.5, p = 0.055) greater in persons with an APOE*4 allele than in those without an APOE*4 allele.. The APOE*4 allele is associated with the presence of concomitant Lewy bodies in Alzheimer disease.

Topics: Age of Onset; Aged; Aged, 80 and over; Alleles; alpha-Synuclein; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Brain; Comorbidity; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Lewy Bodies; Lewy Body Disease; Male; Nerve Tissue Proteins; Pennsylvania; Synucleins; White People

We report early-onset parkinsonism and dementia of 18 years' duration in a 52-year-old man whose grandfather and father had suffered from a similar neurological disease. In this patient, we found neuronal loss in various brain regions including the substantia nigra and cerebral cortex, Lewy bodies, cotton wool plaques, corticospinal tract degeneration, cerebral amyloid angiopathy, and a novel three-base pair deletion in exon 12 of the presenilin-1 (PSEN1) gene. We considered that the mutant PSEN1 might play an important role in the pathogenetic process of both aggregation of alpha-synuclein into Lewy bodies and deposition of beta-amyloid into cotton wool plaques.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; DNA Mutational Analysis; Exons; Humans; Immunohistochemistry; Lewy Body Disease; Male; Membrane Proteins; Middle Aged; Mutation; Nerve Tissue Proteins; Neurologic Examination; Plaque, Amyloid; Presenilin-1; Synucleins

We report here a case of diffuse Lewy body disease with the A53T mutation in the alpha-synuclein gene. The proband presented at the age of 41 years with parkinsonism that was poorly responsive to levodopa. She subsequently developed cognitive impairment and moderate dementia, and died at the age of 50. Her father, paternal grandfather and uncle were all reported to have suffered from Parkinson's disease. Staining of tissue sections from the proband's brain with hematoxylin-eosin and alpha-synuclein antibodies showed small numbers of Lewy bodies in a few brain regions. This contrasted with large numbers of Lewy neurites and neuroaxonal spheroids in many brain regions. By electron microscopy, Lewy neurites consisted of abnormal filaments and dense granular material. Isolated filaments resembled those previously described in idiopathic Parkinson's disease and dementia with Lewy bodies. They were decorated by antibodies specific for the N and C termini of alpha-synuclein, indicating the presence of the full-length protein. Nucleus accumbens and the lower layers in limbic areas of the cerebral cortex showed prominent vacuolation, with frequent clustering of microvacuoles around Lewy neurites. Nerve cell loss was most extensive in dorsal motor nucleus of the vagus nerve, substantia nigra and nucleus basalis of Meynert. Neurofibrillary tangles and senile plaques were not observed. However, in several brain regions, a few widely scattered tau-positive nerve cell bodies and neurites were present. By electron microscopy, Alzheimer-type paired helical and straight filaments were seen.

Topics: Adult; alpha-Synuclein; Brain; Cytoplasm; DNA Mutational Analysis; Female; Genetic Markers; Genetic Predisposition to Disease; Humans; Inclusion Bodies; Inheritance Patterns; Lewy Bodies; Lewy Body Disease; Male; Microscopy, Electron, Transmission; Mutation; Neurites; Retrospective Studies; Vacuoles

To examine the neuropsychological profile of dementia patients from a community-based autopsy sample of dementia, comparing Alzheimer disease (AD), Lewy body pathology (LBP) alone, and LBP with coexistent AD (AD/LBP).. The authors reviewed 135 subjects from a community-based study of dementia for whom autopsy and brain tissue was available. Diagnostic groups were determined according to standard neuropathologic methods and criteria, and the presence of LBs was determined using alpha-synuclein immunostaining. Neuropathologically defined diagnostic groups of AD, AD/LBP, and LBP were examined for differences on neuropsychological test performance at the time of initial study enrollment.. There were 48 patients with AD alone, 65 with LB and AD pathology (AD/LBP), and 22 with LBP alone (LBP alone). There were no significant differences between groups demographically or on performance of enrollment Mini-Mental State Examination (MMSE) or Dementia Rating Scale (DRS). AD patients performed worse than the LBP patients on memory measures (Fuld Object Memory Evaluation Delayed Recall, Wechsler Memory Scale Logical Memory Immediate and Delayed Recall; p < 0.05) and a naming task (Consortium to Establish a Registry for Alzheimer's Disease Naming; p < 0.05). LBP patients were more impaired than AD patients on executive function (Trail Making Test Part B; p < 0.05) and attention tasks (Wechsler Adult Intelligence Scale-Revised Digit Span; p < 0.05). Decline in MMSE and DRS scores over time were greatest in the patients with AD/LBP.. In a community-based sample of older, medically complicated patients with dementia, there are neuropsychological differences between dementia subtypes at the time of diagnosis. In particular, patients with Alzheimer disease (AD) alone and AD/Lewy body pathology (LBP) had more severe memory impairment than patients with LBP. LBP alone was associated with more severe executive dysfunction. Patients with AD/LBP had the most rapid rate of cognitive decline.

Topics: Age of Onset; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amygdala; Autopsy; Biomarkers; Brain; Cognition Disorders; Cohort Studies; Comorbidity; Diagnosis, Differential; Disease Progression; Educational Status; Female; Humans; Lewy Body Disease; Male; Neuropsychological Tests; Prognosis

We examined 7 patients from a family harboring a novel mutation in the alpha-synuclein gene (E46K) that segregated with a phenotype of parkinsonism and dementia with Lewy bodies. An abnormal restless sleep was the presenting symptom in 2 of them. Polysomnographic (PSG) studies were performed in 4 of the 7 patients and in 2 asymptomatic carriers of the mutation. A severe loss of both rapid eye movement (REM) and non-REM sleep was observed in 2 patients complaining of insomnia and in a third parkinsonian member of the family who did not complain of trouble with sleeping. Another parkinsonian family member had a mild disorganization of the sleep architecture. The 2 asymptomatic carriers also had minor changes in the PSG findings. Episodes of bizarre behavior at night were reported historically in the 2 symptomatic patients, but we did not observed the behaviors during the PSG studies. REM sleep behavior disorder could not be recorded in any case. Our findings expand the spectrum of sleep disorders reported in synucleinopathies whether sporadic or familial.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Diagnosis, Differential; DNA Mutational Analysis; Electroencephalography; Electromyography; Electrooculography; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinsonian Disorders; Pedigree; Point Mutation; Polysomnography; REM Sleep Behavior Disorder; Restless Legs Syndrome; Sleep Initiation and Maintenance Disorders

alpha-Synuclein belongs to a small group of natively unfolded proteins that can transiently bind to lipid membranes and acquire a partial alpha-helical conformation. Its relevance to Parkinson's disease (PD) is based on mutations found in familial cases of the disease and its presence in filaments of Lewy bodies (LB) and Lewy neurites (LN) in sporadic cases where it is packed in a beta-sheet configuration. This structural plasticity of alpha-synuclein has raised the possibility that neurodegeneration may be a consequence of abnormal protein folding. The extent to which abnormal folding and aggregation of neuronal proteins is directly toxic to the cell, an inert biochemical marker of an underlying harmful metabolic defect, or a protective reaction remains to be seen. We review the function of alpha-synuclein and recent studies that have shed light on the mechanisms by which it aggregates.

Topics: alpha-Synuclein; Animals; Chromosomes, Human, Pair 6; Cytoskeleton; Drosophila; Humans; In Vitro Techniques; Lewy Body Disease; Mice; Parkinson Disease; Phenotype; Phosphorylation; Point Mutation

Oxidative stress has been well documented in the substantia nigra in Parkinson disease (PD), but little is known about oxidative damage, particularly lipoxidation, advanced glycation (AGE), and AGE receptors (RAGE) in other structures, including the cerebral cortex, in early stages of diseases with Lewy bodies. The present study was undertaken to analyze these parameters in the frontal cortex (area 8), amygdala, and substantia nigra in selected cases with no neurologic symptoms and with neuropathologically verified incidental Lewy body disease-related changes, comparing them with healthy age-matched individuals. Results of the present study have shown mass spectrometric and immunologic evidences of increased lipoxidative damage by the markers malondialdehyde-lysine (MDAL) and 4-hydroxynonenal-lysine (HNE), increased expression of AGE in the substantia nigra, amygdala, and frontal cortex, and increased and heterogeneous RAGE cellular expression in the substantia nigra and frontal cortex in cases with early stages of parkinsonian neuropathology. In addition, increased content of the highly peroxidizable docosahexaenoic acid in the amygdala and frontal cortex. These changes were not associated to alpha-synuclein aggregation in cortex, contrasting with aggregates found in SDS-soluble fractions of frontal cortex in dementia with Lewy bodies (DLB) cases. The pattern of lipidic abnormalities differed in DLB and incidental Lewy body disease. Furthermore, although AGE and RAGE expression were raised in DLB, no increase in the total amount of HNE and MDAL adducts was found in the cerebral cortex in DLB. Preliminary analyses have identified 2 proteins with lipoxidative damage, alpha-synuclein and manganese superoxide dismutase (SOD2), in incidentally Lewy body disease cortex. This study demonstrates abnormal fatty acid profiles, increased and selective lipoxidative damage, and increased AGE and RAGE expression in the frontal cortex in cases with early stages of parkinsonian neuropathology without treatment. These findings further support antioxidant therapy in the treatment of PD to reduce cortical damage associated with oxidative stress.

Topics: Aged; Aged, 80 and over; Aldehydes; alpha-Synuclein; Blotting, Western; Docosahexaenoic Acids; Electrophoresis, Gel, Two-Dimensional; Fatty Acids; Female; Glycation End Products, Advanced; Humans; Immunohistochemistry; Lewy Body Disease; Male; Malondialdehyde; Mass Spectrometry; Neocortex; Nerve Tissue Proteins; Oxidative Stress; Parkinson Disease; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Synucleins

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty-five autopsied DLB cases were examined using alpha-synuclein-immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem-predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex-predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/ pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico-pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.

Topics: Aged; alpha-Synuclein; Brain; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Nerve Tissue Proteins; Synucleins

The protein alpha-synuclein (ASYN) is thought to be involved in the development of dementia with Lewy bodies (DLB). Overexpression of ASYN has been linked to cellular toxicity and human disease, and in experimental models, chaperones such as heat shock proteins (HSPs) are protective against ASYN toxicity. We have assessed the abundance of mRNA for ASYN and chaperones and the abundance and solubility of the encoded proteins in temporal cortex from sporadic human DLB. We found a reduction of ASYN mRNA in DLB (44.9% of control). The abundance of the Triton-soluble fraction (bioavailable protein) was not altered, but there was an increase of the Triton-insoluble component (likely representing aggregates). We evaluated 3 chaperones: HSP70, HSP90, and HDJ1. HSP70 mRNA was increased in DLB, whereas the mRNAs for HSP90 and HDJ1 were unchanged. HSP70 accumulated in the Triton-soluble fraction, whereas HSP90 and HDJ1 proteins accumulated in the Triton-insoluble fraction. These observations suggest that sporadic DLB is not associated with overexpression of ASYN. Rather, the persistence of normal soluble ASYN protein levels, despite the reduction of its mRNA, suggests a primary defect in clearance of the protein. However, this reduced clearance cannot be attributed to a failure of chaperone expression, because their mRNA is unchanged or increased in the DLB brain.

Topics: alpha-Synuclein; Case-Control Studies; Detergents; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lewy Body Disease; Molecular Chaperones; Octoxynol; Polymerase Chain Reaction; RNA, Messenger; Solubility; Temporal Lobe

Cases of early-onset Alzheimer disease (AD) with an autosomal dominant inheritance pattern (familial AD [FAD]) are rare but have greatly advanced our understanding of the molecular pathogenesis of AD. We describe herein a kindred with very early-onset FAD (age, <40 years) with unusual pathological features and a novel mutation in the presenilin 1 (PSEN1) gene (S170F) and review the existing literature on very early-onset FAD.. To analyze the neuropathological and genetic features of a family with onset of AD in the third decade of life.. The proband underwent full clinical assessment and postmortem examination at the Washington University Alzheimer's Disease Research Center, St Louis, Mo. Limited pathological samples and autopsy records of 2 affected family members were available. The proband underwent screening for mutations in genes linked with FAD.. Dementia developed in 3 family members in this kindred at a mean age of 27 years; the proband had myoclonus, seizures, and rigidity, similar to findings in previously described kindreds with PSEN1 mutations. All 3 family members were confirmed to have AD by neuropathological examination. The proband also had widespread Lewy body pathology in the brainstem, limbic areas, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members. The proband had a single mutation (S170F) in exon 6 of the PSEN1 gene, which segregates with disease.. A novel PSEN1 mutation causes very-early-onset FAD with associated Lewy bodies. To our knowledge, this kindred has the earliest reported onset of pathologically confirmed FAD and dementia with Lewy bodies.

Topics: Adult; Age of Onset; alpha-Synuclein; Alzheimer Disease; Amino Acid Substitution; Brain; Chromosome Disorders; Disease Progression; Exons; Family Health; Fatal Outcome; Female; Genetic Predisposition to Disease; Humans; Lewy Bodies; Lewy Body Disease; Male; Membrane Proteins; Mutation; Neurofibrillary Tangles; Pedigree; Plaque, Amyloid; Presenilin-1

The intracytoplasmic aggregation of alpha-synuclein (alphaS) protein is a common denominator for a group of neurodegenerative disorders currently known as synucleinopathies. It is generally assumed that the incorporation of alphaS protein into compact inclusions compromises the function and viability of its host cell via mechanical disruption. Herein, we report a widespread and abundant alphaS pathology in an elderly subject, whose medical history gave no indication of any neurodegenerative disease. We compared neuronal and glial components in this neurologically unimpaired subject with a patient with a clinical syndrome of dementia with Lewy bodies (DLB) by using a range of antigenic determinants and an in situ end-labeling technique. We detected no differences in vascular pathologies, in gliosis, or in apoptosis that would have explained the incompatible clinical end-points. With respect to the Alzheimer's disease-related changes, the only differences noted were the beta-amyloid aggregates in the putamen found in the DLB patient alone. Our findings suggest that there must be some currently unidentified factors rather than alphaS-positive inclusions that are responsible for the neuronal dysfunction. The alphaS-positive inclusions may well represent detoxified reserves that cells can tolerate for years, and thus prevention of their development could actually accelerate the diseases process.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Apoptosis; Brain; Humans; Immunohistochemistry; Lewy Body Disease; Neuroglia; Neurons

Lewy bodies (LBs), which are the hallmark pathologic features of Parkinson's disease and of dementia with LBs, have several morphologic and molecular similarities to aggresomes. Whether such cytoplasmic inclusions contribute to neuronal death or protect cells from the toxic effects of misfolded proteins remains controversial. In this report, the role of aggresomes in cell viability was addressed in the context of over-expressing alpha-synuclein and its interacting partner synphilin-1 using engineered 293T cells. Inhibition of proteasome activity elicited the formation of juxtanuclear aggregates with characteristics of aggresomes including immunoreactivity for vimentin, gamma-tubulin, ubiquitin, proteasome subunit, and hsp70. As expected from the properties of aggresomes, the microtubule disrupting agents, vinblastin and nocodazole, markedly prevented the formation of these inclusions. Similar to LBs, the phosphorylated form of alpha-synuclein co-localized in these synphilin-1-containing aggresomes. Although the caspase inhibitor z-VAD-fmk significantly reduced the number of apoptotic cells, it had no impact on the percentage of aggresome-positive cells. Finally, quantitative analysis revealed aggresomes in 60% of nonapoptotic cells but only in 10% of apoptotic cells. Additionally, alpha-synuclein-induced apoptosis was not coupled with increased prevalence of aggresome-bearing cells. Taken together, these observations indicate a disconnection between aggresome formation and apoptosis, and support a protective role for these inclusions from the toxicity associated with the combined over-expression of alpha-synuclein and synphilin-1.

Topics: alpha-Synuclein; Amino Acid Chloromethyl Ketones; Apoptosis; Carrier Proteins; Cell Line; Cell Survival; Cysteine Proteinase Inhibitors; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Macromolecular Substances; Microtubules; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Nocodazole; Parkinson Disease; Recombinant Proteins; Synucleins; Transfection; Vinblastine

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated alpha-synuclein (anti-PSer129). Phosphorylated alpha-synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated alpha-synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Cell Count; Cellular Structures; Ganglia, Sympathetic; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Middle Aged; Multiple System Atrophy; Nerve Tissue Proteins; Neurons; Parkinson Disease; Postmortem Changes; Staining and Labeling; Synucleins

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.

Topics: Aged; alpha-Synuclein; Amino Acid Sequence; Base Sequence; Brain; DNA Mutational Analysis; DNA Primers; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Molecular Sequence Data; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Parkinson Disease; Pedigree; Polymerase Chain Reaction; Sequence Homology; Synucleins; Tomography, Emission-Computed, Single-Photon

Aggregation and cytotoxicity of misfolded alpha-synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated alpha-synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of alpha-synuclein in an alpha-synuclein transgenic mouse model and in an in vitro model of alpha-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding alpha-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble alpha-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble alpha-synuclein species and protected cells from alpha-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated alpha-synuclein species in vivo and in vitro and protect it from alpha-synuclein-dependent toxicity.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Cell Line, Tumor; HSP70 Heat-Shock Proteins; Humans; Lewy Body Disease; Mice; Mice, Transgenic; Molecular Weight; Nerve Tissue Proteins; Octoxynol; Protein Folding; Synucleins

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.

Topics: Adolescent; Age of Onset; alpha-Synuclein; beta-Synuclein; Brain; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Nerve Tissue Proteins; Polymerase Chain Reaction; Synucleins

The present study examines alpha-synuclein interactions with rab3a and rabphilin by antibody arrays, immunoprecipitation and pull-down methods in the entorhinal cortex of control cases and in diffuse Lewy body disease (LBD) cases. Alpha-synuclein immunoprecipitation revealed alpha-synuclein binding to rabphilin in control but not in LB cases. Immunoprecipitation with rab3a disclosed rab3a binding to rabphilin in control but not in LB cases. Moreover, rab3a interacted with high molecular weight (66 kDa) alpha-synuclein only in LB cases, in agreement with parallel studies using antibody arrays. Results were compared with pull-down assays using His(6)/Flag-tagged rab3, rab5 and rab8, and anti-Flag immunoblotting. Weak bands of 17 kDa, corresponding to alpha-synuclein, were obtained in LB and, less intensely, in control cases. In addition, alpha-synuclein-immunoreactive bands of high molecular weight (36 kDa) were seen only in LB cases after pull-down assays with rab3a, rab5 or rab8. These findings corroborate previous observations showing rab3a-rabphilin interactions in control brains, and add substantial information regarding decreased binding of rab3a to rabphilin and increased binding of rab3a to alpha-synuclein aggregates in LB cases. Since, alpha-synuclein, rab3a and rabphilin participate in the docking and fusion of synaptic vesicles, it can be suggested that exocytosis of neurotransmitters may be impaired in LB diseases.

Topics: Adaptor Proteins, Signal Transducing; Aged; alpha-Synuclein; Female; Humans; Lewy Body Disease; Male; Nerve Tissue Proteins; rab GTP-Binding Proteins; rab3 GTP-Binding Proteins; rab3A GTP-Binding Protein; Rabphilin-3A; Synucleins; Vesicular Transport Proteins

The authors recently have shown that triplication of the alpha-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Cohort Studies; DNA Mutational Analysis; England; Family Health; Female; Finland; Gene Dosage; Gene Duplication; Gene Expression Regulation; Genetic Predisposition to Disease; Hispanic or Latino; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Synucleins; United States; White People

To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD).. The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity.. Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation.. Mutations in the beta-synuclein gene may predispose to DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amino Acid Sequence; Amino Acid Substitution; Animals; beta-Synuclein; Brain Chemistry; Cattle; Codon; Cystic Fibrosis; Disease Progression; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Japan; Lewy Body Disease; Male; Mice; Middle Aged; Molecular Sequence Data; Mutation, Missense; Nerve Tissue Proteins; Parkinson Disease; Pedigree; Point Mutation; Rats; Sequence Alignment; Sequence Homology, Amino Acid; Species Specificity; Synucleins; Thrombophilia; Washington

To elucidate the role of alpha-synuclein in the pathogenesis of Parkinson's disease, both human alpha-synuclein transgenic mice and targeted overexpression of human alpha-synuclein in rat substantia nigra using viral vector-based methods have been studied, however, little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in brains with Parkinson's disease are recapitulated in these models. Here, we used the recombinant adeno-associated viral (rAAV) vector system for human alpha-synuclein gene transfer to rat substantia nigra and observed approximately 50% loss of dopaminergic neurons at 13 weeks after infection, which was comparably slower than the progression of neurodegeneration reported in other studies. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of Parkinson's disease, such as phosphorylation of alpha-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing alpha-synuclein via rAAV. Our results indicate that overexpression of alpha-synuclein via rAAV apparently recapitulates several important features of brains with Parkinson's disease and dementia with Lewy bodies, and thus alpha-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of Parkinson's disease and dementia with Lewy bodies.

Topics: alpha-Synuclein; Animals; Caspase 9; Caspases; Cell Line; Disease Models, Animal; Dopamine; Enzyme Activation; Gene Expression; Gene Targeting; Genes, Reporter; Genetic Vectors; Humans; Immunohistochemistry; Lewy Body Disease; Macromolecular Substances; Male; Nerve Tissue Proteins; Neurons; Parkinson Disease; Phosphorylation; Rats; Rats, Sprague-Dawley; Substantia Nigra; Synucleins

To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging and various neurodegenerative disorders, its incidence and topographic pattern were examined in 260 brains of elderly patients, including 116 autopsy-proven cases of Alzheimer disease (AD), 71 cases of clinically and autopsy-proven Parkinson disease (PD), 38 of dementia with Lewy bodies (DLB), 8 patients with progressive supranuclear palsy (PSP), one with senile tremor, and 26 age-matched controls without neuropsychiatric disorders. Using immunohistochemistry, alpha-synuclein (AS) positive lesions were assessed semiquantitatively. For technical reasons, the olfactory system was not systematically studied. All PD-brains showed AS-positive lesions in medullary, pontine and mesencephalic nuclei, with involvement of the nucleus basalis (90.1%), limbic cortex (58.9%), cingulate cortex (46%), amygdala, CA 2/3 hippocampal region (36.2%), neocortex (28.8%), and striatum (11%). 88% of clinical PD cases corresponded to LB pathology stages 4-6, 12% to stage 3 according to Braak et al. (2003). 84% of DLB brains were PD stage 5 or 6 and 17% stage 4, without significant differences between DLB with and without neuritic AD pathology, suggesting morphologic similarities betwee these disorders. 6/8 PSP and senile tremor cases, 49.1% of AD and 69% of aged controls were negative. AS-positive lesions in AD showed decreasing incidence from midbrain (24-28%), limbic cortex and amygdala (17-18%), nucleus basalis and medullary nuclei (13-17%), cingulate cortex (12%), CA 2/3 region (8%) to neocortex (2%), without gender differences or relationship to the severity of AD pathology (mean Braak stage 5.1). AD cases with AS positive lesions, particularly those with AS pathology in the amygdala, were older at death than negative ones (86.6 vs 83.3 yrs), but this difference was not statistically significant. 15 AD cases (seven of them with mild PD symptoms) and 3 aged controls without parkinsonian signs but LB pathology stages 3 (n=5) and 4 (n=13) were considered "incidental LB disease". 16 AD brains without parkinsonian symptoms had AS positive lesions in various areas without medullary involvement, suggesting deviation from the proposed stereotypic expansion pattern. Located AS-pathology in the midbrain and limbic cortex was seen in 31% of asymptomatic aged controls. These data 1. largely confirm Braak's staging of LB-pathology in PD; 2. suggest morphologic and pathogenic relations between PD (brainst

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Cohort Studies; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Movement Disorders; Nerve Tissue Proteins; Parkinson Disease; Reference Values; Retrospective Studies; Supranuclear Palsy, Progressive; Synucleins

Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for alpha-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block alpha-synuclein accumulation. beta-Synuclein, the nonamyloidogenic homologue of alpha-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding beta-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) beta-synuclein (lenti-beta-synuclein) was tested in a transgenic (tg) mouse model of halpha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-beta-synuclein reduced the formation of halpha-synuclein inclusions and the accumulation of halpha-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of beta-synuclein neuroprotection involve binding of this molecule to halpha-synuclein and Akt, resulting in the decreased aggregation and accumulation of halpha-synuclein in the synaptic membrane. Together, these data further support a role for beta-synuclein in regulating the conformational state of alpha-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.

Topics: alpha-Synuclein; Animals; beta-Synuclein; Binding, Competitive; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Lentivirus; Lewy Body Disease; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Synapses; Synucleins; Transduction, Genetic

Missense mutations (A30P and A53T) in alpha-synuclein and the overproduction of the wild-type protein cause familial forms of Parkinson's disease and dementia with Lewy bodies. Alpha-synuclein is the major component of the filamentous Lewy bodies and Lewy neurites that define these diseases at a neuropathological level. Recently, a third missense mutation (E46K) in alpha-synuclein was described in an inherited form of dementia with Lewy bodies. Here, we have investigated the functional effects of this novel mutation on phospholipid binding and filament assembly of alpha-synuclein. When compared to the wild-type protein, the E46K mutation caused a significantly increased ability of alpha-synuclein to bind to negatively charged liposomes, unlike the previously described mutations. The E46K mutation increased the rate of filament assembly to the same extent as the A53T mutation. Filaments formed from E46K alpha-synuclein often had a twisted morphology with a cross-over spacing of 43 nm. The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in alpha-synuclein.

Topics: alpha-Synuclein; Amino Acid Substitution; Animals; Binding Sites; Humans; Kinetics; L Cells; Lewy Body Disease; Liposomes; Mice; Mutagenesis, Site-Directed; Mutation, Missense; Nerve Tissue Proteins; Parkinson Disease; Phospholipids; Synucleins

alpha-Synuclein aggregation and toxicity play a major role in Parkinson's disease and dementia with Lewy bodies. Hsp70 is a multipurpose stress response chaperone protein that mediates both refolding and degradation of misfolded proteins. We have shown that Hsp70 is able to block both alpha-synuclein toxicity and aggregation. Here we introduce a mutation into the ATPase domain of Hsp70 (K71S) and demonstrate that this abolishes Hsp70 refolding activity. Nonetheless, Hsp70K71S continues to mediate alpha-synuclein degradation and blocks aggregate formation. In contrast to wild type Hsp70, the ATPase domain mutant mediates alpha-synuclein degradation through a non-proteasome inhibitor sensitive pathway. Although Hsp70K71S can diminish levels of alpha-synuclein to an even greater extent than Hsp70, HSP70K71S does not protect against alpha-synuclein toxicity. The Hsp70K71S mutant appears to dissociate the formation of aggregates, which it blocks, and toxicity, which it does not block. These data suggest that the ability of Hsp70 to prevent toxicity is distinct from degradation of alpha-synuclein and is dependent on its ATPase domain.

Topics: alpha-Synuclein; Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; Cell Line, Tumor; Drosophila melanogaster; HSP70 Heat-Shock Proteins; Humans; Lewy Body Disease; Molecular Sequence Data; Nerve Tissue Proteins; Parkinson Disease; Protein Folding; Protein Structure, Tertiary; Sequence Alignment; Synucleins

Dementia with Lewy bodies (DLB) is characterized by the widespread presence of Lewy bodies (LBs) in the brain. alpha-Synuclein, the main component of LBs, is expressed as two main isoforms (112 and 140), but little is known about their differential expression in the brain. We compared alpha-synuclein 112 and alpha-synuclein 140 expression levels in the prefrontal cortices of six DLB patients, eight Alzheimer disease (AD) patients, and six control subjects. Relative alpha-synuclein 112 and alpha-synuclein 140 expression levels were determined by real-time polymerase chain reaction with competimer technology using a LightCycler System. Whereas total alpha-synuclein levels were just marginally elevated in DLB in comparison with the other groups, alpha-synuclein 112 was seen to be markedly increased in DLB compared with AD cases and controls. In contrast, alpha-synuclein 140 levels were significantly diminished in both neurodegenerative disorders in comparison with controls. These results show differential overexpression of alpha-synuclein 112 in DLB, a finding that could be of importance in DLB pathogenesis.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain Chemistry; DNA Primers; Female; Humans; Isomerism; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Prefrontal Cortex; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synucleins

Abnormal accumulation of alpha-synuclein filaments in Lewy bodies is a neuropathological hallmark of Parkinson's disease and sequestration of cellular protein into these protein aggregates may contribute to the degenerative process. We identified the transcriptional co-factor high mobility group protein 1 (HMGB-1) as a ligand for alpha-synuclein filaments by a filament spin-down technique, mass spectrometric peptide mapping and immunoblotting. HMGB-1 binds preferentially to aggregated alpha-synuclein and is present in alpha-synuclein filament-containing Lewy bodies isolated from brain tissue affected with dementia with Lewy bodies or Parkinson's disease. Our results demonstrate that alpha-synuclein filaments hold the potential for disturbing the cellular gene expression as they can sequester a component involved in cellular transcription regulation.

Topics: alpha-Synuclein; Animals; Brain; HMGB1 Protein; Humans; Immunoblotting; Immunohistochemistry; Iodine Isotopes; Lewy Bodies; Lewy Body Disease; Ligands; Microscopy, Immunoelectron; Nerve Tissue Proteins; Neurites; Neurons; Parkinson Disease; Peptide Mapping; Protein Binding; Rats; Recombinant Proteins; Synucleins

Diffuse Lewy body disease (DLBD) is a degenerative disease of the nervous system, involving the brain stem, diencephalic nuclei and cerebral cortex, associated with abnormal a-synuclein aggregation and widespread formation of Lewy bodies and Lewy neurites. DLBD presents as pure forms (DLBDp) or in association with Alzheimer disease (AD) in the common forms (DLBDc). Several neurotransmitter abnormalities have been reported including those of the nigrostriatal and mesocorticolimbic dopaminergic system, and central noradrenergic, serotoninergic and cholinergic pathways. The present work examines metabotropic glutamate receptor (mGluR) expression and signaling in the frontal cortex of DLBDp and DLBDc cases in comparison with age-matched controls. Abnormal L-[3H]glutamate specific binding to group I and II mGluRs, and abnormal mGluR1 levels have been found in DLBD. This is associated with reduced expression levels of phospholipase C beta1 (PLCbeta1), the effector of group I mGluRs following protein G activation upon glutamate binding. Additional modification in the solubility of PLCbeta1 and reduced PLCbeta1 activity in pure and common DLBD further demonstrates for the first time abnormal mGluR signaling in the cerebral cortex in DLBD. In order to look for a possible link between abnormal mGluR signaling and a-synuclein accumulation in DLBD, immunoprecipitation studies have shown alpha-synuclein/PLCbeta1 binding in controls and decreased alpha-synuclein/PLCbeta1 binding in DLBD. This is accompanied by a shift in the distribution of a-synuclein, but not of PLCbeta1, in DLBD when compared with controls. Together, these results support the concept that abnormal a-synuclein in DLBD produces functional effects on cortical glutamatergic synapses, which are associated with reduced alpha-synuclein/PLCbeta1 interactions, and, therefore, that mGluRs are putative pharmacological targets in DLBD. Finally, these results emphasize the emergence of a functional neuropathology that has to be explored for a better understanding of the effects of abnormal protein interactions in degenerative diseases of the nervous system.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cell Fractionation; Cell Membrane; Cerebral Cortex; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Female; Glutamic Acid; Guanosine Triphosphate; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Lewy Body Disease; Male; Membrane Proteins; Microscopy, Confocal; Middle Aged; Nerve Tissue Proteins; Postmortem Changes; Proline; Propionates; Protein Binding; Quisqualic Acid; Radioligand Assay; Receptors, Glutamate; Signal Transduction; Synaptosomal-Associated Protein 25; Synucleins; Tritium; Type C Phospholipases

Lewy bodies (LBs) containing alpha-synuclein (alphaSYN) fibrils are the hallmark lesions of Parkinson disease, dementia with LBs, and related neurodegenerative diseases. Here we have investigated the susceptibility to proteolysis of alphaSYN from brain samples of patients with different subtypes of LB diseases. While soluble alphaSYN was completely degradable in all samples, the affected brain regions additionally contained insoluble, proteinase K (PK)-resistant alphaSYN. In brainstem-predominant subtype LB disease cases, PK-resistant alphaSYN was found in the medulla and substantia nigra, but not in cerebral cortex. In limbic subtype LB disease cases, PK resistance of alphaSYN spread to the cingulate and parahippocampal cortex, and further to the frontal cortex in neocortical subtype LB disease cases. Variable amounts of neuritic PK-resistant alphaSYN were found in the striatum of all cases. Thus, PK resistance of alphaSYN may be useful for the development of biomarkers of LB diseases.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Blotting, Western; Brain; Brain Stem; Drug Resistance; Endopeptidase K; Female; Humans; Immunoblotting; Lewy Body Disease; Limbic System; Male; Middle Aged; Neocortex; Nerve Tissue Proteins; Paraffin Embedding; Synucleins; Tissue Distribution

Lewy body disease (LBD) refers to a heterogeneous group of disorders presenting with parkinsonism and Lewy body (LB) formation. Although the relationship between dementing syndromes with LBs, Parkinson's disease, and Alzheimer's disease is unclear, the former constitute a common form of degenerative dementia and may account for up to 20% of cases in the elderly. We recently demonstrated triplication of the alpha-synuclein gene as the cause of disease in the Spellman-Muenter kindred. Neuropathological examination of affected members of the kindred demonstrated extensive LB pathology consistent with diffuse LBD. We examined a large collection of pathologically confirmed LBD cases and found no evidence for multiplication of the alpha-synuclein gene, suggesting that this mechanism is not a common cause of LBD.

Topics: Aged; alpha-Synuclein; Brain; Brain Chemistry; Gene Dosage; Genomic Instability; Humans; Lewy Bodies; Lewy Body Disease; Nerve Tissue Proteins; Neurons; Synucleins

Diffuse Lewy body disease (DLBD) is characterized by the presence of Lewy bodies (LB) in the neurons and neurites of cortical, subcortical, and brain stem structures. Recently, alpha-synuclein (alphaS) has been found to be a central constituent of LB. In DLBD, abnormal accumulation of alphaS has been reported in both neurons and glia, but studies on glial lesions in DLBD have been limited. We examined in detail the constituents and distribution of glial lesions in eight patients with DLBD and report the pathogenesis of the glial lesions. alphaS-positive neuronal cytoplasmic inclusions (NI), neuropil threads (NT), and coiled bodies (CB) showed similar immunostaining profiles. Without pretreatment, NI, NT, and CB were detected by all antibodies against alphaS. The immunostaining profile of star-like astrocytes (SLA) was quite different from those of NI, NT, and CB. A few SLA were stained by an antibody against the non-Abeta component portion of alphaS without pretreatment, but formic acid pretreatment dramatically enhanced SLA immunoreactivity. SLA and CB were found in all eight brains with DLBD. SLA were scarce in the brain stem, but there were hundreds of SLA per visual field at x100 magnification in the temporal cortex of most cases, while CB were found diffusely in both the cerebral cortex and brain stem, similar to NI. This suggests that the pathogenesis of SLA is different from those of NI and CB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Astrocytes; Brain; Coiled Bodies; Female; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Microscopy, Confocal; Microscopy, Electron, Scanning; Middle Aged; Nerve Tissue Proteins; Neuroglia; Neurons; Neuropil Threads; Synucleins

Accumulation of misfolded proteins as insoluble aggregates occurs in several neurodegenerative diseases. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), alpha-synuclein (alpha S) accumulates in insoluble inclusions. To identify soluble alpha S oligomers that precede insoluble aggregates, we probed the cytosols of mesencephalic neuronal (MES) cells, normal and alpha S-transgenic mouse brains, and normal, PD, and DLB human brains. All contained highly soluble oligomers of alpha S whose detection was enhanced by delipidation. Exposure of living MES neurons to polyunsaturated fatty acids (PUFAs) increased alpha S oligomer levels, whereas saturated FAs decreased them. PUFAs directly promoted oligomerization of recombinant alphaS. Transgenic mice accumulated soluble oligomers with age. PD and DLB brains had elevated amounts of the soluble, lipid-dependent oligomers. We conclude that alpha S interacts with PUFAs in vivo to promote the formation of highly soluble oligomers that precede the insoluble alpha S aggregates associated with neurodegeneration.

Topics: Age Factors; alpha-Synuclein; Amino Acid Substitution; Animals; Brain; Brain Chemistry; Cell Line; Cytosol; Fatty Acids; Fatty Acids, Unsaturated; Humans; Lewy Body Disease; Macromolecular Substances; Mesencephalon; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Parkinson Disease; Protein Binding; Recombinant Proteins; Solubility; Synucleins

We carried out immunohistochemical examinations of the brains (cerebella) of patients who had suffered from Parkinson's disease (PD), diffuse Lewy body disease (DLBD) or multiple system atrophy (MSA), using antibodies specific for alpha-synuclein. Alpha-synuclein-positive doughnut-shaped structures were found occasionally in the cerebellar molecular layer in some of these patients. Double-labeling immunofluorescence and immunoelectron microscopy studies revealed that these alpha-synuclein-positive doughnut-shaped structures were located in the glial fibrillary acidic protein-positive radial processes of Bergmann glia, corresponding to the outer area of Lewy body-like inclusions, and consisted of granulo-filamentous structures. These findings indicate that, although not frequently, Bergmann glia of the cerebellum are also the targets of alpha-synuclein pathology in alpha-synucleinopathies such as PD, DLBD and MSA.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Cerebellum; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Microglia; Microscopy, Immunoelectron; Middle Aged; Multiple System Atrophy; Nerve Tissue Proteins; Neurodegenerative Diseases; Parkinson Disease; Synucleins

Our institution is currently engaged in ongoing genetic studies of familial Alzheimer's disease (AD), which include clinical ascertainment and brain autopsy of both affected and non-affected family members. Here we describe the analysis of 22 AD families, each with at least one family member with a postmortem diagnosis of dementia with Lewy bodies (DLB). For this study, 47 brains were examined according to NINCDS-Reagan Institute criteria for the diagnosis of AD. Lewy body pathology was evaluated with alpha-synuclein immunohistochemistry. Four families, with either one or two autopsies showing Lewy body pathology, demonstrated linkage to 12p. Five families had two or more autopsies with Lewy body pathology, but their linkage status was unknown. The remaining 13 families had one autopsy demonstrating Lewy bodies. These findings suggest that at least one pathological form of DLB may be familial. In some families, the pathological phenotype is identical in all examined affected family members; but in others, there may be several pathologies that coexist. Careful neuropathological examination of affected family members may prove critical for future genetic analysis of AD and DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Autopsy; Chromosomes, Human, Pair 12; Female; Genetic Linkage; Genetic Variation; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Synucleins

The major protein constituent of Lewy bodies (LBs), the pathological hallmark of Parkinson disease and dementia with Lewy bodies, is considered to be alpha-synuclein, but other proteins, in particular the microtubule-associated protein tau, have been implicated in the pathogenesis of LBs. Tau is the major structural component of neurofibrillary tangles (NFTs). Both direct immunochemical studies of partially purified LBs and indirect immunohistochemical studies have suggested that LBs may contain tau, but most of these studies were based upon a single tau antibody, and immunologic cross-reactivity was not completely excluded. To gain insight into the relation between tau and alpha-synuclein in LBs, double immunostaining was performed in Lewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel of monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, CP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. Tau-immunoreactive LBs were present in the medulla in 80% of the cases, irrespective of Braak stage. All tau antibodies recognized at least some LBs, arguing against nonspecific antibody cross-reactivity. In most lesions the tau immunostaining was present at the periphery of the LB. The phospho-tau antibody, TG3, detected more LBs than any of the other tau antibodies. The proportion of LBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such as those in the locus ceruleus and basal nucleus of Meynert, and least in neurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the medulla. The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Basal Nucleus of Meynert; Brain; Epitopes; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Locus Coeruleus; Male; Medulla Oblongata; Middle Aged; Nerve Tissue Proteins; Neurofibrillary Tangles; Neurons; Parkinson Disease; Synucleins; tau Proteins

We investigated 10 dementia with Lewy bodies (DLB) brains showing various degrees of Lewy pathology using alpha-synuclein-immunohistochemistry, and morphologically divided cortical Lewy bodies (LB) into six developmental stages. Further, we demonstrated the ultrastructure of each stage of cortical LB using alpha-synuclein-immunoelectron microscopy. In the initial stage, alpha-synuclein accumulated in part of the neuronal cytoplasm without filamentous components, then formed LB and LB-related neurites composed of granulo-filamentous components. Finally, LB degraded to extracellular LB composed of loose filamentous components with involved astroglial processes. In addition, we immunohistochemically investigated the accumulation of axonal transported substances in cortical LB, and showed that APP, chromogranin-A, synphilin-1 and synaptophysin accumulated in cortical LB from stages 1, 2, 3 and 4, respectively. These findings suggest that chronic axonal transport blockage is implicated in the development of cortical LB in DLB brains.

Topics: alpha-Synuclein; Amyloid beta-Protein Precursor; Axonal Transport; Carrier Proteins; Cerebral Cortex; Chromogranin A; Chromogranins; Disease Progression; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Nerve Tissue Proteins; Neurofilament Proteins; Neurons; Peptide Fragments; Synaptophysin; Synucleins; Tubulin; Ubiquitins

alpha-Synuclein is known to be a major constituent of the Lewy bodies (LBs) in Parkinson's disease (PD) and the neuronal and glial cytoplasmic inclusions (NCIs, GCIs) in multiple system atrophy. alpha-Synuclein-positive inclusions such as LBs, NCIs and GCIs sometimes show colocalization with tau-positive neurofilaments. Studies using alpha-synuclein immunohistochemistry have often found LBs in the amygdala of patients with familial or sporadic Alzheimer's disease (AD), as well as in patients with Down's syndrome and AD. However, no studies have reported alpha-synuclein-positive structures in cases of diffuse neurofibrillary tangles with calcification (DNTC), which is characterized by numerous neurofibrillary tangles (NFTs) throughout the cerebral cortex but few, if any, senile plaques. We investigated the distribution of alpha-synuclein-positive structures in two cases of DNTC: a 65-year-old woman (brain weight, 850 g) and a 75-year-old woman (brain weight, 800 g). In both cases, severe cerebral atrophy predominant in the temporal lobe was noted. Microscopically, alpha-synuclein-positive intracytoplasmic inclusions and neurites were found in the superior temporal lobe (within the temporal pole), amygdala, parahippocampus, entorhinal cortex and insula, the regions most affected by the NFTs. alpha-Synuclein-positive intracytoplasmic inclusions were rare or absent in other regions of the cerebral cortex and brainstem. This distribution pattern differs from that of PD or dementia with LBs. Our findings suggest that the accumulation pattern of alpha-synuclein is a pathological feature of DNTC, and that DNTC is associated with accumulation of both tau and alpha-synuclein.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Brain; Calcinosis; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Microscopy, Immunoelectron; Middle Aged; Nerve Tissue Proteins; Neurofibrillary Tangles; Neuroglia; Neurons; Parkinson Disease; Phosphorylation; Synucleins; tau Proteins

alpha-Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are neurodegenerative disorders in which abnormal inclusions containing alpha-synuclein accumulate in selectively vulnerable neurons and glia. In this report, immunohistochemistry demonstrates ubiquitin in subsets of alpha-synuclein inclusions in dementia with Lewy bodies and multiple system atrophy. Biochemistry demonstrates that alpha-synuclein in the sodium dodecyl sulfate-soluble fractions of diseased brains is ubiquitinated, with mono- and di-ubiquitinated species predominating over polyubiquitinated forms. Similar immunohistochemical and biochemical characteristics were observed in an A53T mutant human alpha-synuclein transgenic mouse model of neurodegenerative alpha-synucleinopathies. Furthermore, in vitro ubiquitination of alpha-synuclein fibrils recapitulated the pattern of alpha-synuclein ubiquitination observed in human disease and the A53T alpha-synuclein mouse model. These results suggest that ubiquitination of alpha-synuclein is not required for inclusion formation and follows the fibrillization of alpha-synuclein.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Cell Fractionation; Disease Models, Animal; Female; Gyrus Cinguli; Humans; Inclusion Bodies; Lewy Body Disease; Male; Mice; Mice, Transgenic; Middle Aged; Multiple System Atrophy; Nerve Tissue Proteins; Spinal Cord; Synucleins; Ubiquitin

In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.

Topics: Aged; alpha-Synuclein; Amyotrophic Lateral Sclerosis; Antibodies; Cell Line; DNA-Binding Proteins; Female; Humans; Inclusion Bodies; Lewy Body Disease; Male; Middle Aged; Molecular Weight; Multiple System Atrophy; Nerve Tissue Proteins; Neuroglia; Neurons; Parkinson Disease; Protein Binding; Superoxide Dismutase; Superoxide Dismutase-1; Synucleins; Ubiquitin; Ubiquitin-Protein Ligases

In dementia with Lewy bodies (DLB), the Lewy bodies (LBs) are an essential substrate. Although LB pathology has gained increasing attention as one of the major causes of dementia, little is known about the exact prevalence of LB pathology in the general population. In addition, the pathology of Alzheimer-type dementia (ATD) is frequently associated with DLB. To investigate the prevalence of LB pathology in a community-based population and to evaluate the relationship between LB and ATD pathology, we performed an analysis of 102 consecutive autopsy cases. The survey extended over 2.5 years and autopsy rate was 70.5%. LB pathology was detected using alpha-synuclein immunohistochemistry and was assessed based on consensus guidelines for DLB. ATD pathology was evaluated by both CERAD and NIA-RI criteria. Twenty-nine subjects were clinically demented. LB pathology was present in 23 (22.5%) of 102 cases, and in 12 (41.4%) of the demented subjects. The LB score was not significantly different between DLB cases and non-demented subjects with LB pathology (nd-LB), while the Braak stages were significantly different between the two groups. Prevalence of LB pathology constantly increased with age. DLB cases accompanying severe ATD pathology showed more rapid increase of LB scores than did DLB cases without severe ATD pathology. Moreover, DLB cases with severe ATD pathology had poorer prognoses than those without severe ATD pathology. Our results suggested that aging and severe ATD pathology have a strong effect on the evolution of LB pathology.

Topics: Age of Onset; Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Brain Stem; Case-Control Studies; Female; Gyrus Cinguli; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Mental Status Schedule; Neocortex; Nerve Tissue Proteins; Prevalence; Risk Factors; Statistics as Topic; Substantia Nigra; Survival Rate; Synucleins

Two mutations in alpha-synuclein, the main constituent of Lewy bodies, have been identified in familial Parkinson's disease. We have stereotactically injected lentiviral vectors encoding wild-type and A30P mutant human alpha-synuclein in different brain regions (striatum, substantia nigra, amygdala) of mice. Overexpression of alpha-synuclein induced time-dependent neuropathological changes reminiscent of Lewy pathology: abnormal accumulation of alpha-synuclein in cell bodies and neurites, alpha-synuclein-positive neuritic varicosities and cytoplasmic inclusions that stained with ubiquitin antibodies and became larger and more frequent with time. After one year, alpha-synuclein- and ubiquitin-positive neurons displayed a degenerative morphology and a significant loss of alpha-synuclein-positive cells was observed. Similar findings were observed with both the wild-type and the A30P mutant form of alpha-synuclein and this in different brain regions. This indicates that overexpression of alpha-synuclein is sufficient to induce Lewy-like pathology and neurodegeneration and that this effect is not restricted to dopaminergic cells. Our data also demonstrate the use of lentiviral vectors to create animal models for neurodegenerative diseases.

Topics: alpha-Synuclein; Amygdala; Animals; Blotting, Western; Cell Count; Corpus Striatum; Disease Models, Animal; Female; Humans; Immunohistochemistry; Inclusion Bodies, Viral; Lentivirus Infections; Lewy Body Disease; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Mutation; Nerve Tissue Proteins; Neurites; Neuroblastoma; Neurodegenerative Diseases; Neurons; Substantia Nigra; Synucleins; Time Factors; Transduction, Genetic; Tumor Cells, Cultured; Tyrosine 3-Monooxygenase; Ubiquitin

Alpha-synuclein has an important role in the pathogenesis of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), comprising a new disease concept, that of alpha-synucleinopathies. Cerebellar degeneration with Purkinje cell depletion is present in the majority of MSA cases. By contrast, cerebellar pathology has not been demonstrated unequivocally in either PD or DLB. Recent immunohistochemical studies using anti-alpha-synuclein antibodies have shown that LB-type degeneration in PD and DLB is more widespread than previously recognized. To determine whether cerebellar Purkinje cells might be involved in alpha-synuclein pathology, we carried out immunohistochemical examinations of the cerebella of patients with PD (n = 10), DLB (n = 7), MSA (n = 10), Alzheimer disease and other tauopathies (n = 9), and age-matched control subjects (n = 10), using antibodies specific for alpha-synuclein. Although no abnormal accumulation of alpha-synuclein was noted in the Purkinje cell somata, numerous alpha-synuclein-positive, round inclusions were found in the cerebellar white matter in all the patients with PD and DLB. Immunohistochemical and ultrastructural examinations revealed that the majority of these inclusions was located in the Purkinje cell axons and consisted of granulo-filamentous structures. No such inclusions were observed in MSA, tauopathies, or controls. These findings indicate that Purkinje cells are also the victims of a-synuclein pathology in PD and DLB, but not in MSA.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Calbindins; Cell Count; Cerebellum; Cerebral Cortex; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Microscopy, Immunoelectron; Middle Aged; Multiple System Atrophy; Nerve Tissue Proteins; Neurites; Parkinson Disease; Purkinje Cells; S100 Calcium Binding Protein G; Synucleins

Olfactory dysfunction increases with disease severity in Alzheimer's disease (AD), is early and independent of disease severity in Parkinson's disease (PD), but is absent in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Previous histopathologic studies of olfactory bulbs in AD have shown neurofibrillary tangles (NFTs) and senile plaques while Lewy bodies (LBs) have been described in PD. Little is known about olfactory bulb pathology in PSP and CBD. Tau and alpha-synuclein pathology was assessed with immunohistochemistry in olfactory bulbs of AD (N=15), Lewy body disease (LBD; N=10), LBD with concurrent AD (AD/LBD; N=19), PSP (N=27), CBD (N=3) and cases with no significant neurodegenerative pathology (NSP; N=15). The Braak NFT stage, counts of senile plaques and NFT in cortical and hippocampal sections, and counts of LBs in amygdala and cortical sections were recorded for each case. Apolipoprotein E (APOE) genotypes were determined on DNA prepared from frozen brain tissue. All AD and AD/LBD cases and nine of 10 LBD cases had tau pathology in the anterior olfactory nucleus (AON), but it was uncommon in PSP (9/27), CBD (0/3) and NSP (5/15). Multiple linear regression analysis demonstrated that tau pathology in the AON correlated with Braak stage (P<0.001), cortical LB counts (P<0.001), as well as APOE epsilon4. Tau pathology is common in the olfactory bulb of AD and LBD but is minimal or absent in PSP and CBD. It correlates with APOE epsilon4, severity of tau pathology in the brain and surprisingly with cortical and amygdala LBs, suggesting a possible synergistic effect between tau and synuclein in the AON in cases with both pathologic processes.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Female; Gene Frequency; Humans; Immunohistochemistry; Lewy Body Disease; Linear Models; Male; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurofibrillary Tangles; Olfactory Bulb; Supranuclear Palsy, Progressive; Synucleins; tau Proteins

Accumulation of alpha-synuclein has been associated with neurodegenerative disorders, such as Lewy body disease and multiple system atrophy. We previously showed that expression of wild-type human alpha-synuclein in transgenic mice results in motor and dopaminergic deficits associated with inclusion formation. To determine whether different levels of human alpha-synuclein expression from distinct promoters might result in neuropathology mimicking other synucleopathies, we compared patterns of human alpha-synuclein accumulation in the brains of transgenic mice expressing this molecule from the murine Thy-1 and platelet-derived growth factor (PDGF) promoters. In murine Thy-1-human alpha-synuclein transgenic mice, this protein accumulated in synapses and neurons throughout the brain, including the thalamus, basal ganglia, substantia nigra, and brainstem. Expression of human alpha-synuclein from the PDGF promoter resulted in accumulation in synapses of the neocortex, limbic system, and olfactory regions as well as formation of inclusion bodies in neurons in deeper layers of the neocortex. Furthermore, one of the intermediate expressor lines (line M) displayed human alpha-synuclein expression in glial cells mimicking some features of multiple system atrophy. These results show a more widespread accumulation of human alpha-synuclein in transgenic mouse brains. Taken together, these studies support the contention that human alpha-synuclein expression in transgenic mice might mimic some neuropathological alterations observed in Lewy body disease and other synucleopathies, such as multiple system atrophy.

Topics: alpha-Synuclein; Animals; Gene Expression; Humans; Lewy Body Disease; Limbic System; Mice; Mice, Transgenic; Multiple System Atrophy; Neocortex; Nerve Tissue Proteins; Neuroglia; Neurons; Platelet-Derived Growth Factor; Promoter Regions, Genetic; Substantia Nigra; Synucleins; Thy-1 Antigens

Clusterin/apolipoprotein J protein expression in cases with "alpha-synucleinopathies", such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), was investigated using an immunohistochemical method for the labeling of multiple antigens. About 50% of the cortical Lewy bodies in the cases with DLB were immunoreactive for clusterin, whereas brain-stem Lewy bodies in PD and DLB were rarely associated with clusterin. Clusterin was also immunopositive in around 10% of the glial cytoplasmic inclusions (GCIs) in the cases with MSA. Colocalization of clusterin with alpha-synuclein in such bodies or inclusions was clearly correlated with the immunostaining pattern of alpha-synuclein. Subcellular localization of clusterin was almost completely overlapped with the homogeneous immunoreaction of alpha-synuclein in the cortical Lewy bodies; however, clusterin immunoreactivity was not detected in the halo or ring-like structures of the brain-stem Lewy bodies. Furthermore, some Lewy bodies with intense immunoreactivity for clusterin showed only a weak signal for alpha-synuclein. These results suggest that clusterin may modify the formation of alpha-synuclein-positive inclusion bodies such as Lewy bodies and GCIs, through a previously proposed chaperone property of clusterin.

Topics: alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Brain; Clusterin; Glycoproteins; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Molecular Chaperones; Multiple System Atrophy; Nerve Tissue Proteins; Neurofibrillary Tangles; Neuroglia; Parkinson Disease; Peptide Fragments; Pick Disease of the Brain; Supranuclear Palsy, Progressive; Synucleins

Intracytoplasmic inclusions composed of alpha-synuclein (alpha-syn) are characteristic of neurodegenerative Lewy body disorders. Using novel monoclonal antibodies raised against altered alpha-syn, we uncovered an unprecedented and extensive burden of alpha-syn pathology in the striatum of Lewy body disorders. The highest density of striatal pathology was observed in patients with a combination of Alzheimer's disease and dementia with Lewy bodies or pure dementia with Lewy bodies, and these alpha-syn aggregates may contribute to the parkinsonism seen in these disorders.

Topics: alpha-Synuclein; Antibodies, Monoclonal; Corpus Striatum; Humans; Lewy Body Disease; Molecular Weight; Nerve Tissue Proteins; Nitrates; Peptide Fragments; Synucleins

Nonselenium glutathione peroxidase (NSGP) is a new member of the antioxidant family. Using antibodies to recombinant NSGP we have examined the distribution of this enzyme in normal, Parkinson's disease (PD), and dementia with Lewy body disease (DLB) brains. We have also co-localized this enzyme with alpha-synuclein as a marker for Lewy bodies. In normal brains there was a very low level of NSGP staining in astrocytes. In PD and DLB there were increases in the number and staining intensity of NSGP-positive astrocytes in both gray and white matter. Cell counting of NSGP cells in PD and DLB frontal and cingulated cortices indicated there was 10 to 15 times more positive cells in gray matter and three times more positive cells in white matter than in control cortices. Some neurons were positive for both alpha-synuclein and NSGP in PD and DLB, and double staining indicated that NSGP neurons contained either diffuse cytoplasmic alpha-synuclein deposits or Lewy bodies. In concentric Lewy bodies, alpha-synuclein staining was peripheral whereas NSGP staining was confined to the central core. Immunoprecipitation indicated there was direct interaction between alpha-synuclein and NSGP. These results suggest oxidative stress conditions exist in PD and DLB and that certain cells have responded by up-regulating this novel antioxidant enzyme.

Topics: alpha-Synuclein; Antibodies; Brain; Glutathione Peroxidase; Humans; Lewy Body Disease; Nerve Tissue Proteins; Parkinson Disease; Recombinant Proteins; Synucleins; Up-Regulation

TorsinA, a protein with homology to yeast heat shock protein104, has previously been demonstrated to colocalize with alpha-synuclein in Lewy bodies, the pathological hallmark of Parkinson's disease. Heat shock proteins are a family of chaperones that are both constitutively expressed and induced by stressors, and that serve essential functions for protein refolding and/or degradation. Here, we demonstrate that, like torsinA, specific molecular chaperone heat shock proteins colocalize with alpha-synuclein in Lewy bodies. In addition, using a cellular model of alpha-synuclein aggregation, we demonstrate that torsinA and specific heat shock protein molecular chaperones colocalize with alpha-synuclein immunopositive inclusions. Further, overexpression of torsinA and specific heat shock proteins suppress alpha-synuclein aggregation in this cellular model, whereas mutant torsinA has no effect. These data suggest that torsinA has chaperone-like activity and that the disease-associated GAG deletion mutant has a loss-of-function phenotype. Moreover, these data support a role for chaperone proteins, including torsinA and heat shock proteins, in cellular responses to neurodegenerative inclusions.

Topics: alpha-Synuclein; Alzheimer Disease; Carrier Proteins; Cell Line; Gene Expression; Heat-Shock Proteins; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Macromolecular Substances; Molecular Chaperones; Nerve Tissue Proteins; Protein Binding; Protein Folding; Substantia Nigra; Synucleins; Transfection

Aggregation of alpha-synuclein has been implicated in the formation of proteinaceous inclusions in the brain (Lewy bodies, Lewy neurites) that are characteristic of neurodegenerative diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLBs). The etiology of PD is unknown, but recent work has shown that except in rare cases, there appears to be no direct genetic basis. However, several studies have implicated environmental factors, especially pesticides and metals. Here we show that certain pesticides and metals induce a conformational change in alpha-synuclein and directly accelerate the rate of formation of alpha-synuclein fibrils in vitro. In addition, the simultaneous presence of metal and pesticide led to synergistic effects on the rate of fibrillation. We propose a model in which environmentalfactors in conjunction with genetic susceptibility may form the underlying molecular basis for idiopathic PD.

Topics: alpha-Synuclein; Aluminum Chloride; Aluminum Compounds; Chlorides; Circular Dichroism; Drug Synergism; Humans; Lewy Body Disease; Metals; Nerve Tissue Proteins; Parkinson Disease; Parkinson Disease, Secondary; Pesticides; Protein Conformation; Spectrometry, Fluorescence; Synucleins

The pathological modifications of alpha-synuclein (alphaS) in Parkinson disease and related diseases are poorly understood. We have detected misfolded alphaS in situ based on the proteinase K resistance (PK resistance) of alphaS fibrils, and using specific antibodies against S129-phosphorylated alphaS as well as oxidized alphaS. Unexpectedly massive neuritic pathology was found in affected human brain regions, in addition to classical alphaS pathology. PK resistance and abnormal phosphorylation of alphaS developed with increasing age in (Thy1)-h[A30P] alphaS transgenic mice, concomitant with formation of argyrophilic, thioflavin S-positive, and electron-dense inclusions that were occasionally ubiquitinated. alphaS pathology in the transgenic mice was predominantly in the brainstem and spinal cord. Astrogliosis was found in these heavily affected tissues. Homozygous mice showed the same pathology approximately one year earlier. The transgenic mice showed a progressive deterioration of locomotor function. Thus, misfolding and hyperphosphorylation of alphaS may cause dysfunction of affected brain regions.

Topics: alpha-Synuclein; Animals; Brain; Drug Resistance; Endopeptidase K; Female; Gene Dosage; Humans; In Vitro Techniques; Lewy Body Disease; Locomotion; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphorylation; Protein Folding; Synucleins

A reduction in nicotinic receptor (nAChR) binding has previously been observed in putamen in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The present study demonstrates no concommitant reduction in the expression of alpha2-alpha7, beta2 and beta3 nAChR subunit proteins. Alphasynuclein, which can interfere with membrane protein function and is a key constituent of PD and DLB pathology, was increased (insoluble fraction) in both disorders, although nAChR binding loss did not correlate with alpha-synuclein expression within patient groups. The results point to a possible abnormality of striatal nicotinic receptor assembly in PD and DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Lewy Body Disease; Male; Nerve Tissue Proteins; Nicotinic Agonists; Parkinson Disease; Putamen; Pyridines; Radioligand Assay; Receptors, Nicotinic; Synucleins; Tritium

Using tau immunohistochemistry and alpha-synuclein immunohistochemistry, we quantitatively investigated the most frequent sites and the formation process of neurofibrillary tangles (NFT) and Lewy bodies (LB) in the hippocampus from 20 patients with dementia with Lewy bodies (DLB). NFT were most frequently found in the CA2 and the subiculum-pre-CA1, while LB were most frequently found in the CA3-4 and the subiculum-pre-CA1. In the intrahippocampal routes of the perforant pathway, tau immunoelectron microscopy demonstrated distal axons containing aggregated tau-positive microtubules, while alpha-synuclein immunoelectron microscopy revealed terminal axons containing aggregated alpha-synuclein-positive tubular or filamentous components. These findings suggest that NFT and LB are first formed in the CA2 and the CA3-4 related to degeneration of the nonperforating route of the perforant pathway, respectively, and subsequently in the subiculum-pre-CA1 chiefly related to degeneration of the perforating route. Coexistence of NFT and LB in the same neurons was found most frequently in the subiculum-pre-CA1. In addition, coexistence of tau and alpha-synuclein was found in terminal axons of the perforant pathway, and tau accumulated not in paired helical filaments but in the periphery of alpha-synuclein-positive components immunoelectron-microscopically, suggesting that alpha-synuclein stimulates the accumulation of phosphorylated tau in terminal axons.

Topics: Aged; alpha-Synuclein; Hippocampus; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Microscopy, Immunoelectron; Nerve Tissue Proteins; Neurofibrillary Tangles; Perforant Pathway; Synucleins; tau Proteins

Familial diffuse Lewy body disease (DLBD) is rare and not yet associated with a defect in the synuclein gene. In the differential diagnosis of the parkinsonian syndromes, defects in vertical gaze tend to be identified with progressive supranuclear palsy. False-positive diagnosis of progressive supranuclear palsy can occur, and defects in vertical gaze have been reported in DLBD, although so far a pure vertical gaze palsy associated with pathological abnormalities in the substrate for vertical gaze has not been described.. To report the clinical and pathological findings in 2 siblings with DLBD, and to relate the distribution of the pathological abnormalities in the brainstem to centers for vertical gaze.. For several years, 2 Irish siblings experienced a progressive parkinsonism-dementia complex associated in one with a defect in vertical gaze and in both with visual hallucinations.. In both patients, results of pathological examination revealed (1) Lewy bodies positive for ubiquitin and alpha-synuclein together with cell loss and gliosis in the substantia nigra, locus ceruleus, and neocortex; and (2) similar findings in the rostral interstitial nucleus of the medial longitudinal fasciculus, the posterior commissure, and the interstitial nucleus of Cajal (substrates for vertical gaze).. Familial DLBD (not shown to be genetically as distinct from environmentally transmitted) has been shown to exist in an Irish family. Caution should be enjoined in the interpretation of defects in vertical gaze in the differential diagnosis of the parkinsonian syndromes.

Topics: Aged; alpha-Synuclein; Brain; Diagnosis, Differential; Eye Movements; Female; Humans; Lewy Body Disease; Male; Nerve Tissue Proteins; Parkinsonian Disorders; Synucleins; Tissue Distribution; Ubiquitin

Several components of Lewy bodies have been identified, but the precise mechanism responsible for the formation of Lewy bodies remains undetermined. The 14-3-3 protein family is involved in numerous signal transduction pathways and interacts with alpha-synuclein, which is a major constituent of Lewy bodies. To elucidate the role of 14-3-3 proteins in neuro-degenerative disorders associated with Lewy bodies, we performed immunohistochemical studies on 14-3-3 in brains from 5 elderly control subjects and from 10 patients with Parkinson disease (PD) or diffuse Lewy body disease (DLBD). In the normal controls, 14-3-3-like immunoreactivity was mainly observed in the neuronal somata and processes in various cortical and subcortical regions. In the PD and DLBD cases, a similar immunostaining pattern was found and immunoreactivity was generally spared in the surviving neurons from the severely affected regions. In addition, both classical and cortical Lewy bodies were intensely immunolabeled and some dystrophic neurites were also immunoreactive for 14-3-3. Our results suggest that 14-3-3 proteins may be associated with Lewy body formation and may play an important role in the pathogenesis of PD and DLBD.

Topics: 14-3-3 Proteins; Aged; Aged, 80 and over; alpha-Synuclein; Blotting, Western; Brain; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Reference Values; Synucleins; Tissue Distribution; Tyrosine 3-Monooxygenase

Using alpha-synuclein-immunohistochemistry, 27 brains of dementia with Lewy bodies (DLB) were investigated to identify the progression of Lewy pathology including Lewy bodies (LB) and LB-related neurites in the cerebrum. The numbers of alpha-synuclein-positive LB and LB-related neurites were semiquantitatively evaluated in the amygdala, hippocampus, entorhinal cortex, transentorhinal cortex, insular cortex, middle temporal cortex and superior frontal cortex. The results indicated that Lewy pathology within the neuron progresses first in the axonal terminal, subsequently in the cell body and finally in the dendrite, that Lewy pathology in the cerebral cortex progresses first in layers V-VI, subsequently in layer III and finally in layer II, and that Lewy pathology in the cerebrum progresses first in the amygdala, subsequently in the limbic cortex and finally in the neocortex. In addition, Lewy pathology was graded from stage I to stage IV based on the progression of Lewy pathology. The 27 brains examined were classified into 3 brains showing stage I, 11 showing stage II, 7 showing stage III and 6 showing stage IV. Comparing these stages with the pathological subtypes of DLB brains, brains of the subtype showing severe Alzheimer pathology corresponded to brains showing an advanced stage, suggesting that Alzheimer pathology exacerbates Lewy pathology.

Topics: Aged; alpha-Synuclein; Antibody Specificity; Brain; Disease Progression; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Microscopy, Electron; Nerve Tissue Proteins; Neurites; Neurons; Synucleins

The synucleinopathies are a group of neurodegenerative disorders characterized by the presence of alpha-synuclein inclusions in neurons (Lewy body diseases, LBD) or glial cells (multiple system atrophies, MSA). Recently, nitration of alpha-synuclein has been reported as the possible modification that induces its aggregation and deposition in these disorders. In this study we investigated the distribution and relationships of alpha-synuclein inclusions and 3-nitrotyrosine (3-NT), a marker of protein nitration through oxidative mechanisms, in brains diagnosed with LBD or MSA and control brains using double immunohistochemical techniques. In LBD cases, 3-NT colocalized with alpha-synuclein immunoreactivity in classic and cortical Lewy bodies and in dystrophic neurites in substantia nigra. However, most pale bodies and diffuse deposits in substantia nigra and Lewy neurites in hippocampus lack 3-NT immunoreactivity. A majority of cases showed diffuse cytoplasmic 3-NT staining in pyramidal cells of the CA2-3 regions of the hippocampus that was independent of alpha-synuclein deposits. All MSA cases showed 3-NT immunoreactivity in glial inclusions. 3-NT neuronal staining was restricted to pontine nuclei with three cases showing nuclear and one case cytoplasmic staining. There was no colocalization of 3-NT nuclear immunoreactivity with alpha-synuclein-immunopositive nuclear inclusions in pontine neurons. These data show that protein nitration in LBD and MSA cases has a widespread distribution and is not only associated with the alpha-synuclein deposits. The presence of alpha-synuclein-positive deposits lacking 3-NT immunoreactivity suggests that nitration is not a prerequisite for alpha-synuclein deposition.

Topics: Aged; alpha-Synuclein; Brain; Cell Nucleus; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Neurites; Neuroglia; Neurons; Nitrates; Oxidative Stress; Striatonigral Degeneration; Synucleins; Tyrosine

Intracellular inclusions containing alpha-synuclein (alpha SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alpha SN, this study compared the levels, solubility and molecular weight species of alpha SN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alpha SN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alpha SN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble alpha SN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alpha SN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alpha SN between grey and white matter in disease may result from different processing of alpha SN in neurons compared with oligodendrocytes. Highly insoluble alpha SN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alpha SN are involved in the pathogenesis of other alpha SN-related diseases.

Topics: Aged; alpha-Synuclein; Blotting, Western; Brain Chemistry; Cerebellum; Electrophoresis, Polyacrylamide Gel; Frontal Lobe; Humans; Lewy Body Disease; Middle Aged; Molecular Weight; Multiple System Atrophy; Myelin Sheath; Nerve Tissue Proteins; Neurons; Oligodendroglia; Parkinson Disease; Pons; Reference Values; Sodium Dodecyl Sulfate; Solubility; Synucleins

Glial involvement in the degeneration process of Lewy body (LB)-bearing neurons and the degradation process of LBs in the cerebral cortex and amygdala in brains of dementia with Lewy bodies was investigated immunohistochemically. HLA-DR-positive microglia frequently extended their processes to degenerated neurons with alpha-synuclein-positive LBs, while some GFAP-positive astroglial processes attached to weakly alpha-synuclein-positive extracellular LBs. Some intracellular LBs were immunoreactive to anti-C4d antibody, and these LB-bearing neurons were involved by activated microglia. About half of the intracellular LBs were immunoreactive to anti-chromogranin-A (CGA) antibody, and most of CGA-positive LB-bearing neurons were surrounded by microglia. Although we could find no evident participation of TNF-alpha, a candidate cytokine that is up-regulated by microglia following CGA stimulation, in the degeneration process of LB-bearing neurons, some intracellular LBs were immunoreactive to the antibody to NF-kappaB, a transcriptional factor activated by cytokines. These findings suggest that microglia participate in the degeneration process of LB-bearing neurons via varying immunogenic elements including complement proteins, CGA and probably some cytokines, and that astroglia participate in the degradation process of LBs.

Topics: alpha-Synuclein; Brain; Brain Chemistry; Chromogranin A; Chromogranins; Humans; Immunohistochemistry; Lewy Body Disease; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Neurons; NF-kappa B; Synucleins; Tumor Necrosis Factor-alpha

alpha-Synuclein has been identified as a component of Lewy bodies in Parkinson's disease and diffuse Lewy body disease, and glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). To explore the role of alpha-synuclein in the pathogenesis, we searched for molecules interacting with alpha-synuclein and discovered that GCIs are stained by anti-Elk-1 antibody. To seek the role of Elk-1 in synucleinopathies, we cotransfected alpha-synuclein and Elk-1 to cultured cells, and found small granular structure complexes where the two molecules colocalized. Moreover, alpha-synuclein and Elk-1 were co-immunoprecipitated from the cell lysates. For formation of the complex, the presence of both ETS and B-box domains of Elk-1 was required. Although there was no evidence of direct binding between alpha-synuclein and Elk-1, we discovered that alpha-synuclein and Elk-1 both bind to ERK-2, a MAP kinase. The effect of alpha-synuclein on the MAP kinase pathway was assessed using the Pathdetect system, which showed prominent attenuation of Elk-1 phosphorylation with alpha-synuclein, and especially A53T mutant. Our results suggest that alpha-synuclein reacts with the MAP kinase pathway, which might cause dysfunction of neurons and oligodendrocytes and lead to neurodegeneration in Parkinson's disease and MSA.

Topics: alpha-Synuclein; Amino Acid Motifs; Animals; Binding Sites; Cell Line; Cytoplasmic Granules; DNA-Binding Proteins; ets-Domain Protein Elk-1; Humans; Lewy Body Disease; Macromolecular Substances; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1; Multiple System Atrophy; Mutagenesis, Site-Directed; Nerve Tissue Proteins; Neuroglia; Neurons; Parkinson Disease; Phosphorylation; Precipitin Tests; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins; Synucleins; Transcription Factors; Transfection

We neuropathologically and immunohistochemically investigated characteristics of the central amygdaloid nucleus lesion and its relationship with the substantia nigra lesion in dementia with Lewy bodies (DLB) brains. Nine DLB, four Parkinson's disease (PD) and four Alzheimer-type dementia (ATD) cases were examined. The degree of neuronal loss in the substantia nigra was (+)-(+++) in DLB cases, (+++) in PD cases and (+) in ATD cases. All DLB cases showed spongy change and ubiquitin-positive spheroids in the central nucleus. The degree of spongy change was (+)-(+++) in DLB cases, (+) in PD cases and (-)-(+) in ATD cases, which was correlated with the degree of neuronal loss in the substantia nigra in DLB cases. The number of ubiquitin-positive spheroids was parallel to the degree of spongy change. The central nucleus receives dense dopaminergic fibers from the substantia nigra. Many ubiquitin-positive spheroids were also positive to alpha-synuclein and tyrosine-hydroxylase, suggesting that they derive from the degeneration of terminal or distal axons of Lewy body-bearing dopaminergic neurons in the substantia nigra. The disturbance of the dopaminergic connections from the substantia nigra to the central nucleus may be responsible for psychotic symptoms in DLB patients.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amygdala; Female; Humans; Immunohistochemistry; Lewy Body Disease; Locus Coeruleus; Male; Middle Aged; Nerve Degeneration; Nerve Tissue Proteins; Neural Pathways; Neurons; Substantia Nigra; Synucleins; Tyrosine 3-Monooxygenase; Ubiquitins

TorsinA, a novel protein in which a mutation causes dominant, early onset torsion dystonia, may serve as a chaperone for misfolded proteins that require refolding or degradation. It has been hypothesized that misfolded alpha-synuclein, a protein in which two mutations cause autosomal dominantly inherited Parkinson's disease, serves as a nidus for the development of a Lewy body. We hypothesized that torsinA plays a role in the cellular processing of alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies and Lewy neurites in the substantia nigra and cortex. Using sensitive fluorescent resonance energy transfer (FRET) techniques, we find evidence of a close association between torsinA and alpha-synuclein in Lewy bodies.

Topics: alpha-Synuclein; Carrier Proteins; Energy Transfer; Hippocampus; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Microscopy, Confocal; Molecular Chaperones; Nerve Tissue Proteins; Reference Values; Spectrometry, Fluorescence; Substantia Nigra; Synucleins

Alpha-synuclein is mutated in some hereditary cases of Parkinson's disease and the protein precipitates in Lewy bodies, the pathological hallmark of both Parkinson's disease and Lewy body disease. Transgenic mice overexpressing human wild-type alpha-synuclein develop alpha-synuclein-immunoreactive inclusions in brain regions typically affected with Lewy body disease. We used in situ hybridization to characterize alpha-synuclein expression and examine mRNA levels in patients affected with Lewy body disease and controls. Substantia nigra was avoided because of the extensive neuronal loss and cingulate gyrus was chosen as it is one of the diagnostic regions in Lewy body disease where Lewy bodies most frequently are demonstrated. beta-tubulin was used to control for neuronal degeneration. The alpha-synuclein probe showed intense labeling of pyramidal cells in lamina III and V in both patients and controls. We found no difference in alpha-synuclein mRNA levels and beta-tubulin mRNA was not significantly altered (P=0.06) in patient brains. There was no difference in the ratio of alpha-synuclein and beta-tubulin mRNA levels between patients and controls. Further, we found no relationship between alpha-synuclein mRNA levels and Lewy bodies. Great variability in alpha-synuclein mRNA levels among patients indicates that Lewy body disease may be a heterogeneous disorder with regard to alpha-synuclein involvement.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Frontal Lobe; Gyrus Cinguli; Humans; Image Processing, Computer-Assisted; In Situ Hybridization; Lewy Bodies; Lewy Body Disease; Male; Nerve Tissue Proteins; Neurofibrillary Tangles; Plaque, Amyloid; Pyramidal Cells; RNA, Messenger; Synucleins; Tubulin

Proteasomal dysfunction has been recently implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and diffuse Lewy body disease. We have developed an in vitro model of proteasomal dysfunction by applying pharmacological inhibitors of the proteasome, lactacystin or ZIE[O-tBu]-A-leucinal (PSI), to dopaminergic PC12 cells. Proteasomal inhibition caused a dose-dependent increase in death of both naive and neuronally differentiated PC12 cells, which could be prevented by caspase inhibition or CPT-cAMP. A percentage of the surviving cells contained discrete cytoplasmic ubiquitinated inclusions, some of which also contained synuclein-1, the rat homologue of human alpha-synuclein. However the total level of synuclein-1 was not altered by proteasomal inhibition. The ubiquitinated inclusions were present only within surviving cells, and their number was increased if cell death was prevented. We have thus replicated, in this model system, the two cardinal pathological features of Lewy body diseases, neuronal death and the formation of cytoplasmic ubiquitinated inclusions. Our findings suggest that inclusion body formation and cell death may be dissociated from one another.

Topics: Acetylcysteine; alpha-Synuclein; Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Cell Differentiation; Cyclic AMP; Cysteine Endopeptidases; Immunoblotting; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Multienzyme Complexes; Nerve Tissue Proteins; Neuroprotective Agents; Oligopeptides; Parkinson Disease; PC12 Cells; Protease Inhibitors; Proteasome Endopeptidase Complex; Rats; Synucleins; Ubiquitins

The main objective of this study was to determine if levels of alpha-, beta- and/or gamma-synuclein mRNAs are differentially affected in brains of Lewy body disease (LBD) and Alzheimer's disease (AD) patients, compared to controls. In control cases, highest levels of expression were observed in the neocortex and the lowest in basal ganglia and substantia nigra. beta-Synuclein was the most abundant message (75-80%), followed by gamma-synuclein (10-15%) and alpha-synuclein (8-10%). Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of alpha-synuclein were increased in cases of diffuse LBD (DLBD), levels of beta-synuclein were decreased in AD and DLBD, and levels of gamma-synuclein were increased in AD cases. This study suggests that a critical balance among products of the synuclein gene is important to maintain normal brain function and that alterations in this balance might be associated with neurodegenerative disorders.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; beta-Synuclein; Brain; gamma-Synuclein; Gene Expression; Humans; Lewy Body Disease; Linear Models; Neocortex; Nerve Tissue Proteins; RNA, Messenger; Statistics as Topic; Substantia Nigra; Synucleins

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.

Topics: Aged; Aged, 80 and over; Algorithms; alpha-Synuclein; Diagnosis, Differential; Humans; Lewy Body Disease; Middle Aged; Nerve Tissue Proteins; Neurons; Parahippocampal Gyrus; Parkinson Disease; Severity of Illness Index; Synucleins; Ubiquitin

Argyrophilic glial inclusions, which are immunohistochemically positive for alpha-synuclein but negative for tau protein, were examined in the brain of Parkinson's disease (PD) patients. Autopsied brains of 10 individuals who died from PD, of two incidental Lewy body disease cases and of five age-matched individuals whose deaths were caused by non-neurological diseases were studied, histopathologically, by Gallyas-Braak staining and, immunohistochemically, with anti-alpha-synuclein antibody, anti-ubiquitin, and anti-tyrosine hydroxylase. All postmortem PD brains showed a significant number of argyrophilic glial inclusions, but no glial inclusions were found in control brains. The inclusions were found not only in the regions showing neuronal loss and gliosis, such as the substantia nigra, locus ceruleus and dorsal vagal nucleus, but also in regions without neuronal loss and gliosis, such as the cerebral cortex, cerebral white matter, striatum, globus pallidus, thalamus, cerebellum and spinal cord. The distribution and density of glial inclusions in PD brains varied from case to case but, in the cerebral cortex, the number of glial inclusions were fairly well correlated with the number of Lewy bodies. The distribution pattern of glial inclusions also showed a striking resemblance to that of catecholaminergic neurones and fibres. The abnormal accumulation of alpha-synuclein in glial cells was more widespread than neurone loss, and appears to be an important pathological feature of PD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Central Nervous System; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Microscopy, Immunoelectron; Middle Aged; Nerve Tissue Proteins; Neurites; Neuroglia; Neurons; Parkinson Disease; Silver Staining; Synucleins; Tyrosine 3-Monooxygenase; Ubiquitin

Alpha-synuclein is a major component of Lewy bodies (LBs) in Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in multiple system atrophy. However, epitope mapping for alpha-synuclein is distinctive in different neurodegenerative diseases. The reasons for this are poorly understood but may reflect fundamental differences in disease mechanisms.. To investigate the alpha-synuclein epitope mapping properties of LBs in familial Alzheimer disease.. We compared LBs in familial Alzheimer disease with those in synucleinopathies by probing 6 brains of persons with familial Alzheimer disease using a panel of antibodies to epitopes spanning the alpha-synuclein protein. Results were compared with data from brains of persons with Parkinson disease, dementia with LBs, and multiple system atrophy.. The brains of persons with familial Alzheimer disease showed consistent staining of LBs with all antibodies, similar to Parkinson disease and dementia with LBs but different from alpha-synuclein aggregates that occurred in multiple system atrophy.. These data suggest that the epitope profiles of alpha-synuclein in LBs are similar, regardless of whether the biological trigger is related to synuclein or a different genetic pathway. These findings support the hypothesis that the mechanism of alpha-synuclein aggregation is the same within cell types but distinctive between cell types.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Antibodies, Monoclonal; Epitope Mapping; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Parkinson Disease; Synucleins

alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.

Topics: alpha-Synuclein; Amino Acids; Animals; Binding Sites; Blotting, Western; Brain; Detergents; Disease Models, Animal; Humans; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Solubility; Subcellular Fractions; Synaptosomes; Synucleins

The expression of mitogen-activated protein kinases, extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinases, c-Jun N-terminal kinases (SAPK/JNK), and p38 kinases is examined in Parkinson disease (PD), in Dementia with Lewy bodies (DLB), covering common and pure forms, and in age-matched controls. The study is geared to gaining understanding about the involvement of these kinases in the pathogenesis of Lewy bodies (LBs) and associated tau deposits in Alzheimer changes in the common form of DLB. Active, phosphorylation dependent MAPK (MAPK-P) is found as granular cytoplasmic inclusions in a subset of cortical neurons bearing abnormal tau deposits in common forms of DLB. Phosphorylated p-38 (p-38-P) decorates neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in common forms of DLB. Phosphorylated SAPK/JNK (SAPK/JNK-P) expression occurs in cortical neurons with neurofibrillary tangles in the common form of DLB. Lewy bodies (LBs) in the brain stem of PD and DLB are stained with anti-ERK-2 antibodies, but they are not recognized by MAPK-P, SAPK/JNK-P and p-38-P. Yet MAPK-P, p-38-P and SAPK/JNK-P immunoreactivity is found in cytoplasmic granules in the vicinity of LBs or in association with irregular-shaped or diffuse alpha-synuclein deposits in a small percentage of neurons, not containing phosphorylated tau, of the brain stem in PD and DLB. MAPK-P, p-38-P and SAPK-P are not expressed in cortical LBs or in cortical neurons with alpha-synuclein-only inclusions in DLB. MAPK-P, p-38-P and SAPK/JNK-P are not expressed in alpha-synuclein-positive neurites (Lewy neurites) in PD and DLB as revealed by double-labeling immunohistochemistry. These results show that MAPKs are differentially regulated in neurons with alpha-synuclein-related inclusions and in neurons with abnormal tau deposits in DLB. Moreover, different kinase expression in brain stem and cortical LBs suggest a pathogenesis of brain stem and cortical LBs in LB diseases. Finally, no relationship has been observed between MAPK-P, p-38-P and SAPK/JNK-P expression and increased nuclear DNA vulnerability, as revealed with the method of in situ end-labeling of nuclear DNA fragmentation, and active, cleaved caspase-3 expression in neurons and glial cells in the substantia nigra in PD and DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Caspase 3; Caspases; DNA Fragmentation; Female; Humans; Immunohistochemistry; Lewy Body Disease; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; Neurites; Neurofibrillary Tangles; Neurons; p38 Mitogen-Activated Protein Kinases; Parkinson Disease; Synucleins; tau Proteins

To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

Topics: alpha-Synuclein; Animals; Brain; Dopamine; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Microscopy, Electron; Motor Activity; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Substantia Nigra; Synucleins; Tyrosine 3-Monooxygenase; Ubiquitins

alpha-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of alpha-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double alpha-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4-5% more intracytoplasmic structures, especially diffuse alpha-synuclein deposits that were ubiquitin negative. In addition to LB, alpha-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha-synuclein staining was seen in substantia nigra: from diffuse "cloud-like" inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Fluorescent Antibody Technique; Humans; Lewy Bodies; Lewy Body Disease; Limbic System; Male; Middle Aged; Neocortex; Nerve Tissue Proteins; Neurites; Neurons; Substantia Nigra; Synucleins; Ubiquitins

We investigated the degeneration process of Lewy bodies (LB) in the brains of dementia with Lewy bodies, using alpha-synuclein-immunohistochemistry. Intracellular LB, LB-related neurites and some extracellular LB were positively immunostained with anti-alpha-synuclein antibodies. Concentric LB-bearing neurons had no microglial involvement, while degenerated neurons with ill-defined LB displayed intense microglial involvement. The late stage of extracellular LB were immunoelectron-microscopically composed of loose aggregates of filamentous components with lost alpha-synuclein-immunoreactivity and penetrated astroglial processes. These findings suggest that microglias are involved during the stages from degenerated LB-bearing neurons to extracellular LB, while astroglias are involved during the stage of extracellular LB. Some intracellular LB were positive for anti-C3d and -C4d antibodies, suggesting that the classical complement pathway is activated in degenerated LB-bearing neurons, inducing microglial activation and neuronal death.

Topics: Aged; alpha-Synuclein; Astrocytes; Brain; Cell Death; Disease Progression; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Microglia; Microscopy, Electron; Nerve Degeneration; Nerve Tissue Proteins; Neurites; Neurons; Synucleins

The alpha-synuclein (alpha SN) protein is thought to play a central role in the pathogenesis of neurodegenerative diseases where it aggregates to form intracellular inclusions. We have used Western blotting to examine the expression levels and solubility of alpha SN in brain homogenates from dementia with Lewy bodies (DLB), Parkinson's disease (PD), Alzheimer's disease (AD), and normal controls using samples from the parahippocampus/transentorhinal cortex. Compared to controls, DLB brains accumulate significantly greater amounts of sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble alpha SN but levels of TBS-soluble alpha SN did not change. Levels of synaptophysin, a marker of synaptic integrity, were significantly lower in DLB cases than in normal aged controls regardless of whether concurrent changes of AD were present. This limbic synaptic dysfunction may contribute to cognitive impairment in DLB. Whether aggregated alpha SN is a cause or effect of the disease process in DLB and PD remains to be determined, but the presence of aggregated alpha SN is consistent with a pathogenesis similar to that associated with aggregates of Abeta amyloid in AD.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Blotting, Western; Brain; Entorhinal Cortex; Humans; Lewy Body Disease; Middle Aged; Nerve Tissue Proteins; Parahippocampal Gyrus; Parkinson Disease; Reference Values; Solubility; Synaptophysin; Synucleins

The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight alpha-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dementia with psychosis.

Topics: alpha-Synuclein; Brain; Chromosomes, Human, Pair 4; Genetic Linkage; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Synucleins

Alpha-synuclein has assumed particular neuropathological interest in the light both of its identification as a non-beta-amyloid plaque constituent in Alzheimer disease (AD), and the recent association between dominant inheritance of Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the synuclein protein. We report a systematic study of alpha-synuclein, tau, and ubiquitin immunoreactivity in representative neurodegenerative disorders of late life. The alpha-synuclein association with Lewy bodies is variable, peripheral, and is not stable with respect to proteases or acid treatment, whereas there is no association with Pick bodies. Stable patterns of immunoreactivity included neurites and a novel inclusion body. Although there is an overlap between the presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is seen only in the presence of concomitant neuropathological features of AD. The novel alpha-synuclein inclusion body identified in pyramidal cells of the medial temporal lobe in particular was found in AD and in the Lewy body variant of AD, and was associated neither with ubiquitin nor tau protein. The inclusion is therefore neither a Lewy body nor a PHF-core body, but may be confused with the Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of alpha-synuclein leading to its deposition in the form of proteolytically stable deposits is a particular feature of the intermediate stages of AD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Brain; Entorhinal Cortex; Female; Hippocampus; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Microscopy, Confocal; Microscopy, Fluorescence; Middle Aged; Nerve Tissue Proteins; Synucleins

The defining neuropathological deposits of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are strongly immunoreactive for alpha-synuclein. We have shown previously that isolated filaments from dementia with Lewy bodies and multiple system atrophy brains are labelled in a characteristic fashion by a number of alpha-synuclein antibodies. Here we have extracted filaments from substantia nigra of patients with idiopathic Parkinson's disease. Antibodies directed against the carboxy-terminal region of alpha-synuclein labelled isolated filaments along their entire lengths. By contrast, an antibody directed against the amino-terminal region of alpha-synuclein only labelled one filament end. These characteristics were identical to those of filaments extracted from brains of patients with dementia with Lewy bodies and multiple system atrophy.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Antibodies; Cytoskeleton; Humans; Lewy Body Disease; Microscopy, Electron; Multiple System Atrophy; Nerve Tissue Proteins; Parkinson Disease; Substantia Nigra; Synucleins

Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha-synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.

Topics: alpha-Synuclein; Alzheimer Disease; Antibodies, Monoclonal; Blotting, Western; Brain; Brain Chemistry; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Microscopy, Immunoelectron; Multiple System Atrophy; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Oxidative Stress; Parkinson Disease; Synucleins; Tyrosine

Inflammatory mechanisms have been demonstrated in Alzheimer's disease (AD) but their presence in other neurodegenerative disorders is not well documented. Complement factors and activated microglia have been reported in the substantia nigra of Parkinson's disease (PD). In the present study we investigated the cingulate gyrus of 25 autopsied patients with clinically and neuropathologically well-documented PD, with or without dementia, for the presence of (activated) microglial cells and their relation with Lewy body (LB)-bearing neurons. In addition, we studied the presence of complement factors in LBs. Of the 25 patient, 15 were clinically demented, fulfilling criteria for dementia with LBs (DLB); 7 also fulfilled CERAD morphological criteria for probable or definite Alzheimer type of dementia. Microglia clustering was seen around congophilic plaques with or without tau pathology. Microglial cells were not associated with LB-bearing neurons or noncongophilic plaques. The cortex of DLB patients without AD plaques did not show more microglial cells than the cortex of non-demented controls. The number of microglia was the lowest in young control patients who died immediately after trauma. Complement factor C3d was occasionally seen in diffusely ubiquinated neurons but late complement factors were not detected in these neurons. Double staining for complement and alpha-synuclein was negative, suggesting the absence of complement in LBs. In contrast, AD plaques in the same sections showed complement factors C3c, C3d, C1q and C5-9. In conclusion, we have found no evidence that inflammatory mechanism are involved in LB formation in cerebral cortex.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Complement System Proteins; Encephalitis; Gyrus Cinguli; Humans; Lewy Bodies; Lewy Body Disease; Microglia; Middle Aged; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Parkinson Disease; Ricin; Synucleins; tau Proteins; Ubiquitins

alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Brain Chemistry; Female; Humans; In Vitro Techniques; Lewy Bodies; Lewy Body Disease; Lipids; Male; Microscopy, Immunoelectron; Middle Aged; Nerve Tissue Proteins; Neurons; Parkinson Disease; Synucleins; Ubiquitins

Using antibodies generated against the latent membrane protein 1 of Epstein-Barr virus, intense immunoreactivity of Lewy bodies (in PD and dementia with Lewy bodies) and glial cytoplasmic inclusions (in multiple system atrophy) was demonstrated. ELISA and Western blotting techniques confirmed that this immunolabeling was due to cross-reactivity of the antiviral antibody with alpha-synuclein, a neuronal protein implicated in the pathogenesis of PD. This example of cross-reactivity between Epstein-Barr virus and alpha-synuclein may bear implications for further elucidating infectious or autoimmune mechanisms in PD.

Topics: alpha-Synuclein; Antibodies, Monoclonal; Brain; Enzyme-Linked Immunosorbent Assay; Herpesvirus 4, Human; Humans; Immunoblotting; Immunohistochemistry; Lewy Body Disease; Nerve Tissue Proteins; Parkinson Disease; Synucleins

Dementia with Lewy bodies (DLB) is characterized pathologically by widespread Lewy body (LB) neuronal inclusions in the brain, but the contribution of LBs to the clinical syndrome of dementia and parkinsonism is unclear. In a clinical-pathological study of 25 cases with DLB, we examined the regional neuroanatomical distribution of Lewy-related pathology using alpha-synuclein immunostaining to evaluate the relationship between LBs, neuronal loss, Alzheimer-type changes, and the clinical phenotype. Compared to traditional ubiquitin immunostaining, alpha-synuclein immunohistochemistry was more specific and slightly more sensitive, staining about 5% more intracytoplasmic structures. There was a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, limbic, and neocortical structures, which was independent of concomitant Alzheimer-type changes. There were no significant differences in regional LB densities among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls or parkinsonism. Duration of disease correlated weakly with LB density. There was no neuronal loss in superior temporal sulcus or entorhinal cortex in pure DLB cases compared to nondemented controls. Thus, DLB is characterized by a specific neuroanatomical vulnerability to LB pathology, distinct from AD pathology, with a complicated relationship to clinical symptoms.

Topics: Aged; alpha-Synuclein; Brain; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Nerve Tissue Proteins; Neurons; Synucleins

alpha-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which alpha-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in alpha-synuclein aggregation. When recombinant alpha-synuclein was coincubated with cytochrome c/hydrogen peroxide, alpha-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such as N-acetyl-L-cysteine. Hemin/hydrogen peroxide similarly induced aggregation of alpha-synuclein, and both cytochrome c/hydrogen peroxide- and hemin/hydrogen peroxide-induced aggregation of alpha-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that iron-catalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting alpha-synuclein aggregation. Furthermore, double labeling studies for cytochrome c/alpha-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease. Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stress-induced aggregation of alpha-synuclein in Parkinson's disease and related disorders.

Topics: Acetylcysteine; alpha-Synuclein; Antioxidants; Brain; Cytochrome c Group; Deferoxamine; Humans; Hydrogen Peroxide; Immunohistochemistry; Lewy Body Disease; Nerve Tissue Proteins; Oxidative Stress; Recombinant Proteins; Synucleins

The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid (NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB). The microtubule-associated protein tau is an integral component of filaments of neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons is rare. Double-immunofluorescence study and peroxidase-immunohistochemical study in serial sections, performed to examine the co-localization of tau- and NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different epitopes of tau including phosphorylation-dependent and independent ones were present in a minority of LBs, but more often than previously considered. A tau (tau2)-epitope was localized to filaments in the outer layers of brainstem-type LBs by immunoelectron microscopy. Therefore, we conclude that tau is incorporated into filaments in certain LBs. Extensive investigation has enabled us to classify this co-localization into four types: type 1, LBs with ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP- and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and tau-immunoreactive dystrophic neurites. This study raises a new question whether aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the collapse of intraneuronal organization of microtubules due to NACP-filament aggregation in neuronal perikarya and axons.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Epitopes; Female; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Phosphoproteins; Phosphorylation; Synucleins; tau Proteins

Pathogenic alpha-synuclein (alphaS) gene mutations occur in rare familial Parkinson's disease (PD) kindreds, and wild-type alphaS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease, but beta-synuclein (betaS) and gamma-synuclein (gammaS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to alphaS and betaS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to gammaS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the alphaS- and betaS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative "synucleinopathies" by implicating betaS and gammaS, in addition to alphaS, in the onset/progression of PD and DLB.

Topics: alpha-Synuclein; Axons; beta-Synuclein; gamma-Synuclein; Hippocampus; Humans; Lewy Body Disease; Microscopy, Electron; Nerve Tissue Proteins; Parkinson Disease; Synucleins

Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). DLB is the second most common neurodegenerative dementia after Alzheimer's disease, which is characterized clinically by fluctuating cognitive impairments, visual hallucinations and parkinsonism, and pathologically by the appearance of cortical LBs. To characterize the components of LBs, we have developed a purification procedure for LBs from cortices of patients with DLB using sucrose density separation followed by fluorescence-activated particle sorting. We then raised monoclonal antibodies (mAbs) to purified LBs, and obtained a mAb (LB509) that intensely immunolabeled LBs and specifically reacted with a approximately 18kDa brain protein, which was identified as alpha-synuclein. LB509 as well as other antibodies to alpha-synuclein, but not to beta-synuclein, immunostained brainstem and cortical LBs in sporadic PD and DLB brains. Recently, a point mutation in alpha-synuclein gene was identified in some autosomal-deminantly inherited familial PD pedigrees. Moreover, glial cytoplasmic inclusions in the brains of patients with multiple system atrophy (MSA) were shown to be alpha-synuclein positive. Taken together, our data strongly implicate alpha-synuclein in the formation of LBs and the selective neuronal degeneration in PD, DLB and MSA.

Topics: alpha-Synuclein; beta-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Nerve Tissue Proteins; Parkinson Disease; Phosphoproteins; Synucleins