alpha-synuclein and Atrophy

Cognitive impairment may appear at the earliest stages in Parkinson's disease (PD). To assess the prevalence of mild cognitive impairment (MCI) and its different subtypes, as transitional stage, is complicated by the lack of consensus diagnostic criteria.. To review MCI in PD (MCI-PD), diagnostic criteria and predictive factors of conversion to dementia.. Systematic review of articles published in Medline (PubMed) using the combination of keywords 'mild cognitive impairment' and 'Parkinson's disease'.. MCI-PD diagnostic criteria published by the Movement Disorders Society are an interesting tool for the diagnosis, in spite they are not validated. Its implementation has the following limitations: 1) the heterogeneity of cognitive deficits described in PD; 2) a variable evolution of cognitive symptoms in PD which difficult the identification of dementia predictors; 3) selection of the more appropriate neuropsychological tests and cut-off points; 4) patient characteristics, disease stage and type of antiparkinsonian treatment.. Neuropsychological subtypes, neuroimaging, biomarkers or limitation in some instrumental activities seem to be very sensitive for detecting patients with MCI-PD and increased risk of conversion to dementia.. Subtipos de deterioro cognitivo leve en la enfermedad de Parkinson y factores predictores de conversion a demencia.. Introduccion. El deterioro cognitivo puede aparecer en las etapas mas iniciales de la enfermedad de Parkinson (EP). Determinar la prevalencia del deterioro cognitivo leve (DCL) como etapa de transicion o sus diferentes perfiles resulta complicado por la ausencia de criterios diagnosticos consensuados. Objetivo. Revisar el concepto de DCL en la EP, sus criterios diagnosticos y los factores predictores de conversion a demencia. Pacientes y metodos. Revision sistematica de los articulos publicados en Medline (PubMed) utilizando la combinacion de las palabras clave 'deterioro cognitivo leve' y 'enfermedad de Parkinson'. Resultados. Los criterios diagnosticos del DCL en la EP publicados por la Sociedad de Trastornos del Movimiento, a pesar de no estar validados, constituyen una importante herramienta para el diagnostico de estos pacientes. Su aplicacion se ve influida por las siguientes limitaciones: la heterogeneidad de los deficits cognitivos descritos en la EP, su evolucion variable, que dificulta el hallazgo de factores predictores de conversion a demencia, la seleccion de las pruebas neuropsicologicas mas apropiadas y la determinacion de los puntos de corte mas idoneos, y las caracteristicas del paciente, etapa de la enfermedad y tipo de tratamiento antiparkinsoniano. Conclusiones. Marcadores neuropsicologicos, de neuroimagen, biomarcadores o la limitacion en algunas actividades instrumentales son muy prometedores para la deteccion de pacientes con DCL en la EP y riesgo elevado de conversion a demencia.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Atrophy; Attention; Biomarkers; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Disease Progression; Executive Function; Humans; Language Disorders; Longitudinal Studies; Memory Disorders; Neuroimaging; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Prevalence; Quality of Life; Research Design; Risk Factors; Severity of Illness Index; Symptom Assessment

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor symptoms. The neuropathological characteristics of idiopathic PD are the degeneration of dopaminergic neurons in the striatum, and the propagation of aggregates of misfolded α-synuclein in the brain following a specific pattern (Braak et al., 2006). The relationship of this pattern with motor and cognitive symptoms is still equivocal. Therefore, we investigated longitudinally the spatio-temporal patterns of atrophy propagation in PD, their inter-individual variability and associations with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 controls were acquired at up to 15 time-points per subject, and over observation periods of up to 8.8 years (mean: 3.7 years). MR images were analyzed by Deformation-based Morphometry to measure region volumes and their longitudinal changes. Differences of these regional volume data between patients and controls and their associations with clinical symptoms were calculated. At baseline, group differences in the regional volumes were found mainly in areas of the sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, and in the substantia nigra, among others. The longitudinal analysis yielded more widespread and more pronounced group differences, with significantly accelerated volume decreases in PD patients in the occipital and temporal lobes, the inferior parietal lobule, as well as in the insula, putamen and nucleus basalis Meynert. The white matter was less affected than the gray matter. Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of the basal ganglia. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-synuclein pathology in PD stages 3-5 as proposed by Braak and colleagues. Thus, longitudinal DBM appears to depict already in-vivo the progression of neuropathological changes.

Topics: alpha-Synuclein; Atrophy; Brain; Gray Matter; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Nervous System Diseases; Parkinson Disease

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodro

Topics: Aged; alpha-Synuclein; Atrophy; Brain; Cerebral Cortical Thinning; Female; Gene Expression; Humans; Male; Neurodegenerative Diseases; Prions; REM Sleep Behavior Disorder; Synucleinopathies

α-Synuclein pathology is associated with neuronal degeneration in Parkinson's disease (PD) and considered to sequentially spread across the brain (Braak stages). According to a new hypothesis of distinct α-synuclein spreading directions based on the initial site of pathology, the "brain-first" spreading subtype would be associated with a more asymmetric cerebral and nigrostriatal pathology than the "body-first" subtype.. Here, we tested if proposed markers of brain-first PD (ie, higher dopamine transporter [DaT] asymmetry; absence of rapid eye movement sleep behavior disorder [RBD]) are associated with a greater or more asymmetric reduction in gray matter volume (GMV) in comparison to body-first PD.. Data of 255 de novo PD patients and 110 healthy controls (HCs) were retrieved from the Parkinson's Progression Markers Initiative. Structural magnetic resonance images were preprocessed, and GMVs and their hemispherical asymmetry were obtained for each of the neuropathologically defined Braak stages. Group and correlation comparisons were performed to assess differences in GMV and GMV asymmetry between PD subtypes.. PD patients demonstrated significantly smaller bilateral GMVs compared to HCs, in a pattern denoting stage-dependent disease-related brain atrophy. However, the degree of putaminal DaT asymmetry was not associated with reduced GMV or higher GMV asymmetry. Furthermore, RBD-negative and RBD-positive patients did not demonstrate a significant difference in GMV or GMV asymmetry.. Our findings suggest that putative brain-first and body-first patients do not present diverging brain atrophy patterns. Although certainly not disproving the brain-first/body-first spreading hypothesis, this study fails to provide evidence in support of it. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Atrophy; Brain; Dopamine Plasma Membrane Transport Proteins; Gray Matter; Humans; Parkinson Disease; REM Sleep Behavior Disorder

Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously.. The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership.. Data were drawn from autopsied longitudinally followed participants of two cohorts (total N = 1,346), community-based cohort at the University of Kentucky Alzheimer's Disease Research Center (n = 365) and National Alzheimer's Coordinating Center (n = 981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups.. GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline.. Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously.

Topics: Age Factors; Aged; Aging; alpha-Synuclein; Alzheimer Disease; Atrophy; Autopsy; Brain; Cognition; Cognitive Dysfunction; Disease Progression; Female; Humans; Longitudinal Studies; Male; Neurodegenerative Diseases; Neurofibrillary Tangles; Neuropsychological Tests; Organ Size

It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD).. We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aβ, and α-synuclein measured in post-mortem tissue from 92 individuals with intermediate to high AD neuropathology. Receiver-operating characteristic (ROC) curves were analyzed for each subregion in order to discriminate TDP-43-negative and TDP-43-positive patients.. TDP-43 was strongly associated with anterior MTL regions, whereas tau was relatively more associated with the posterior hippocampus. Among the MTL regions, the anterior hippocampus showed the highest area under the ROC curve (AUC).. We found specific contributions of different pathologies on MTL substructure in this population with AD neuropathology. The anterior hippocampus may be a relevant region to detect concomitant TDP-43 pathology in the MTL of patients with AD.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Atrophy; DNA-Binding Proteins; Humans; Magnetic Resonance Imaging; tau Proteins; Temporal Lobe

Topics: alpha-Synuclein; Atrophy; Humans; Multiple System Atrophy; Myoclonus; Spinal Cord

It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinson disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and, eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding and prion-like propagation of endogenous α-synuclein via axonal projections. However, the mechanisms that translate local "synucleinopathy" to large-scale network dysfunction and atrophy remain unknown. Here, we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity, and gene expression and to predict sequential volume loss due to neurodegeneration. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence α-synuclein concentration and local regional vulnerability. Functional coactivation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.

Topics: alpha-Synuclein; Atrophy; Brain; Connectome; Databases, Factual; Diffusion Magnetic Resonance Imaging; Humans; Models, Theoretical; Nerve Net; Neurodegenerative Diseases; Parkinson Disease; Transcriptome

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

Although a significant genetic contribution to the risk of developing sporadic Parkinson's disease has been well described, the relationship between local genetic factors, pathogenesis, and subsequent spread of pathology throughout the brain has been largely unexplained in humans. To address this question, we use network diffusion modelling to infer probable pathology seed regions and patterns of disease spread from MRI atrophy maps derived from 232 de novo subjects in the Parkinson's Progression Markers Initiative study. Allen Brain Atlas regional transcriptional profiles of 67 Parkinson's disease risk factor genes were mapped to the inferred seed regions to determine the local influence of genetic risk factors. We used hierarchical clustering and L1 regularized regression analysis to show that transcriptional profiles of immune-related and lysosomal risk factor genes predict seed region location and the pattern of disease propagation from the most likely seed region, substantia nigra. By leveraging recent advances in transcriptomics, we show that regional microglial abundance quantified by high fidelity gene expression also predicts seed region location. These findings suggest that early disease sites are genetically susceptible to dysfunctional lysosomal α-synuclein processing and microglia-mediated neuroinflammation, which may initiate the disease process and contribute to spread of pathology along neural connectivity pathways.

Topics: alpha-Synuclein; Atrophy; Brain; Disease Progression; Female; Gene Expression; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Male; Microglia; Middle Aged; Neuroimmunomodulation; Parkinson Disease; Risk Factors; Substantia Nigra

Multiple genes have been implicated in Parkinson disease pathogenesis, but the relationship between regional expression of these genes and regional dysfunction across the brain is unknown. We address this question by joint analysis of high resolution magnetic resonance imaging data from the Parkinson's Progression Markers Initiative and regional genetic microarray expression data from the Allen Brain Atlas. Regional brain atrophy and genetic expression was co-registered to a common 86 region brain atlas and robust multivariable regression analysis was performed to identify genetic predictors of regional brain atrophy. Top candidate genes from GWAS analysis, as well as genes implicated in trans-synaptic alpha-synuclein transfer and autosomal recessive PD were included in our analysis. We identify three genes with expression patterns that are highly significant predictors of regional brain atrophy. The two most significant predictors are LAG3 and RAB5A, genes implicated in trans-synaptic synuclein transfer. Other well-validated PD-related genes do not have expression patterns that predict regional atrophy, suggesting that they may serve other roles such as disease initiation factors.

Topics: alpha-Synuclein; Antigens, CD; Atrophy; Brain; Brain Mapping; Correlation of Data; Disease Progression; Female; Gene Expression Regulation; Genetic Testing; Humans; Image Processing, Computer-Assisted; Lymphocyte Activation Gene 3 Protein; Magnetic Resonance Imaging; Male; Parkinson Disease; rab5 GTP-Binding Proteins

Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy.. We investigated that dementia with RBD might show distinctive cortical atrophic patterns.. A total of 31 patients with idiopathic Parkinson's disease (IPD), 23 with clinically probable Alzheimer's disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects.. Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes.. The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α-synucleinopathy.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Atrophy; Brain; Case-Control Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Polysomnography; REM Sleep Behavior Disorder; Statistics, Nonparametric; Surveys and Questionnaires

Several clinical studies point to a high prevalence of psychotic symptoms in frontotemporal dementia associated with C9ORF72 mutations, but clinicopathological studies addressing the association between C9ORF72 mutations and delusions are lacking.. Seventeen patients with pathologically proven frontotemporal lobar degeneration (FTLD) associated with C9ORF72 mutations were identified from Neurodegenerative Disease Brain Bank. Of the 17 cases with C9ORF72 mutation, 4 exhibited well-defined delusions. The clinical history, neurological examination, neuropsychological testing, neuroimaging analysis, and postmortem assessment of the patients with delusions were evaluated and compared with the other cases.. The content of the delusions was mixed including persecution, infidelity, and grandiosity. All cases showed parkinsonism; voxel-based morphometry analysis showed greater precuneus atrophy in patients with delusions than those without delusions. All 4 had unclassifiable FTLD with TAR DNA-binding protein inclusions, with characteristics of both type A and type B. Three cases had additional τ pathology and another had α-synuclein pathology.. C9ORF72 carriers with well-defined delusions likely associated with additional pathologies and parietal atrophy in neuroimaging. Patients presenting with middle-aged onset of delusions should be screened for C9ORF72 mutations, especially if family history and parkinsonism are present.

Topics: Adult; Aged; alpha-Synuclein; Atrophy; Autopsy; Delusions; DNA-Binding Proteins; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Heterozygote; Humans; Male; Middle Aged; Mutation; Neuroimaging; Neurologic Examination; Neuropsychological Tests; Open Reading Frames; Parietal Lobe; Parkinsonian Disorders; tau Proteins

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a progressive degeneration of the striatonigral, olivo-ponto-cerebellar, and autonomic systems. Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein represent the hallmark of MSA and are recapitulated in mice expressing alpha-synuclein in oligodendrocytes. To assess if oligodendroglial expression of human wild-type alpha-synuclein in mice (proteolipid promoter, PLP-SYN) could be associated with age-related deficits, PLP-SYN and wild-type mice were assessed for motor function, brain morphometry, striatal levels of dopamine and metabolites, dopaminergic loss, and distribution of GCIs. PLP-SYN displayed age-related impairments on a beam-traversing task. MRI revealed a significantly smaller brain volume in PLP-SYN mice at 12 months, which further decreased at 18 months together with increased volume of ventricles and cortical atrophy. The distribution of GCIs was reminiscent of MSA with a high burden in the basal ganglia. Mild dopaminergic cell loss was associated with decreased dopamine turnover at 18 months. These data indicate that PLP-SYN mice may recapitulate some of the progressive features of MSA and deliver endpoints for the evaluation of therapeutic strategies.

Topics: Age Factors; alpha-Synuclein; Animals; Atrophy; Brain; Cell Death; Cerebral Ventricles; Corpus Striatum; Dopamine; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Movement Disorders; Multiple System Atrophy; Neuroglia; Organ Size

Cerebrospinal fluid (CSF) α-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF α-synuclein in Alzheimer's disease (AD). No study has explored effects of CSF α-synuclein on brain atrophy. Here we tested if baseline CSF α-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD.. Baseline CSF α-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF α-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF α-synuclein and diagnosis (testing NL versus MCI, and NL versus AD).. The effects of CSF α-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF α-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF α-synuclein, P=0.063). CSF α-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006).. With the possible exception of caudate and brainstem, the overall weak effects of CSF α-synuclein on atrophy rates in NL, MCI and AD argues against CSF α-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF α-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF α-synuclein levels, respectively.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Atrophy; Brain; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Organ Size

Huntington's disease (HD) is the most common of nine inherited neurological disorders caused by expanded polyglutamine (polyQ) sequences which confer propensity to self-aggregate and toxicity to their corresponding mutant proteins. It has been postulated that polyQ expression compromises the folding capacity of the cell which might affect other misfolding-prone proteins. α-Synuclein (α-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies. Point mutations in α-syn that favor self-aggregation or α-syn gene duplications lead to familial PD, thus indicating that increased α-syn aggregation or levels are sufficient to induce neurodegeneration. Since polyQ inclusions in HD and other polyQ disorders are immunopositive for α-syn, we speculated that α-syn might be recruited as an additional mediator of polyQ toxicity. Here, we confirm in HD postmortem brains and in the R6/1 mouse model of HD the accumulation of α-syn in polyQ inclusions. By isolating the characteristic filaments formed by aggregation-prone proteins, we found that N-terminal mutant huntingtin (N-mutHtt) and α-syn form independent filamentous microaggregates in R6/1 mouse brain as well as in the inducible HD94 mouse model and that N-mutHtt expression increases the load of α-syn filaments. Accordingly, α-syn knockout results in a diminished number of N-mutHtt inclusions in transfected neurons and also in vivo in the brain of HD mice. Finally, α-syn knockout attenuates body weight loss and early motor phenotype of HD mice. This study therefore demonstrates that α-syn is a modifier of polyQ toxicity in vivo and raises the possibility that potential PD-related therapies aimed to counteract α-syn toxicity might help to slow HD.

Topics: alpha-Synuclein; Animals; Apoptosis; Atrophy; Disease Models, Animal; Female; Humans; Huntingtin Protein; Huntington Disease; Inclusion Bodies; Longevity; Male; Mice; Mice, Knockout; Motor Activity; Mutation; Neostriatum; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Phenotype; Weight Loss

A Japanese male developed deafness, pyramidal signs and ataxia at age 50. A cerebrospinal fluid examination showed elevated levels of iron, transferrin and ferritin. Brain MRI showed atrophy of the cerebellum and pons as well as potential iron deposits on the surface of the brain. At autopsy, the brain weighed 1090 g and showed severe atrophy and necrosis of the cerebellum. No vascular malformation was observed. Extensive deposits of hemosiderin that were well stained with Berlin blue and ferritin immunohistochemistry were present at the surface and in the superficial layers of the cerebrum, brainstem, cerebellum and spinal cord. In these regions, numerous AT8 (p-τ)-immunopositive deposits were present in neurons and glia. In addition, phosphorylated α-synuclein-immunopositive Lewy bodies and neurites were observed in the brainstem nuclei. In the present report, the authors derive the novel insight that superficial siderosis is a distinctive entity associated with tauopathy and synucleinopathy.

Topics: Aged; alpha-Synuclein; Atrophy; Autopsy; Central Nervous System; Cerebrum; Fatal Outcome; Ferritins; Hemosiderin; Hemosiderosis; Humans; Iron; Magnetic Resonance Imaging; Male; Middle Aged; Synucleins; Transferrin

Here we report studies of the burden of neurodegenerative neuropathologies in a cohort of Medical Examiner (ME) subjects from the County of Santa Clara (California) to determine if this unique population of decedents manifested evidence of neurodegeneration that might underlie causes of death seen in an ME practice. We found that 13% of the brains from ME cases showed significant tau pathology, including 55% of those 65 years old and older and 63% of those 70 years old and older. The histochemical and immunohistochemical findings were consistent with Alzheimer's disease (AD) in 7 subjects and frontotemporal lobar degeneration (FTLD) tauopathy type in six cases. There were no cases of Parkinson's disease, dementia with Lewy Bodies or other neurodegenerative conditions. Our study suggests that decedents >65 years of age in an ME practice are afflicted by common causes of dementia such as AD and FTLD which could contribute wholly or in part to their causes of death.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Atrophy; Benzothiazoles; Brain; Brain Edema; Cohort Studies; Coroners and Medical Examiners; Female; Forensic Pathology; Frontotemporal Lobar Degeneration; Humans; Hygiene; Ill-Housed Persons; Immunohistochemistry; Male; Malnutrition; Middle Aged; Neurofibrillary Tangles; Neuropil Threads; Plaque, Amyloid; Staining and Labeling; Tauopathies; Thiazoles; Young Adult

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

To determine whether variable thalamic degeneration in Parkinson's disease (PD) contributes to less drug responsive clinical features. Formalin-fixed thalami from longitudinally followed patients with PD and early dystonia (N = 6), early falls (N = 5) or no dystonia or falls (N = 6) and age-matched controls without neuropathology (N = 10) were serially sectioned, stained, and analyzed. Neurons in the centromedian parafascicular (CM-Pf) nucleus were quantified using the optical disector method and analysis of variance with post hoc testing used to determine variability in neurodegeneration between groups. Patients with PD were confirmed to have significant neurodegeneration in the CM-Pf complex, with no difference in the degree of neurodegeneration between patients with PD with early falls compared with patients with no history of falls or dystonia. In contrast, patients with PD with early dystonia had significantly less neurodegeneration of the CM but not the Pf than patients without this feature. Preservation of the CM in patients with PD with early dystonia would result in a relative increase in CM activity through the direct basal ganglia pathway and increased primary motor cortex activity. Overall this data provides evidence for pathway-specific neurodegeneration as an underlying feature of the clinical variability observed in patients with PD.

Topics: Aged; alpha-Synuclein; Antiparkinson Agents; Atrophy; Cell Count; Disease Progression; Dystonia; Female; Humans; Imaging, Three-Dimensional; Intralaminar Thalamic Nuclei; Lewy Bodies; Male; Middle Aged; Nerve Degeneration; Parkinson Disease

Topics: alpha-Synuclein; Atrophy; Brain; Fatal Outcome; Follow-Up Studies; Humans; Lewy Bodies; Magnetic Resonance Imaging; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Pneumonia, Aspiration; Spinal Cord; Urinary Bladder, Neurogenic

Topics: Aged; alpha-Synuclein; Atrophy; Brain; Comorbidity; Dementia; Disease Progression; DNA Mutational Analysis; Fatal Outcome; Gene Duplication; Genetic Markers; Genetic Predisposition to Disease; Humans; Magnetic Resonance Imaging; Male; Mutation; Parkinson Disease; Tomography, Emission-Computed, Single-Photon

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

The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 )< 0.03; P > 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolatera

Topics: Aged; alpha-Synuclein; Amygdala; Atrophy; Cell Count; Cell Death; Female; Hallucinations; Humans; Immunohistochemistry; Lewy Bodies; Male; Nerve Tissue Proteins; Neurites; Neurons; Olfaction Disorders; Parkinson Disease; Synucleins