alpha-synuclein and Basal-Ganglia-Diseases

Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are forms of parkinsonism. PSP and CBD are 4R tauopathies and clinicopathologic overlaps exist between these two disorders. Neuropsychiatric symptoms including apathy, depression, anxiety are common features in patients with PSP and CBD. Disinhibition and impulsive behavior are also frequently observed in PSP patients, whereas hallucinations are seen only occasionally. Severe derangement in several neurotransmitter systems may account for behavioral symptoms observed in PSP and CBD, but substitutive therapy is not effective. Recent advances in genetics, epidemiology, biomarkers, pathophysiology, molecular mechanisms, and, in particular, the availability of treatments that may modify disease progression are opening new hopes in the care of these devastating disorders. MSA is a synucleinopathy with well characterized motor and autonomic dysfunction. MSA patients frequently show the presence of rapid eye movement (REM) behavior disorders, but the impact of neuropsychiatric disturbances and cognitive impairment in MSA needs further study. The availability of animal models and recent advances in the pathophysiology of α-synuclein accumulation are shedding light on the disease, opening new avenues for possible treatments.

Topics: alpha-Synuclein; Basal Ganglia Diseases; Humans; Multiple System Atrophy; Neurodegenerative Diseases; Parkinsonian Disorders; Supranuclear Palsy, Progressive

Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease. Neuropathologically, it is characterized by the degeneration of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene and that the filamentous lesions of Parkinson's disease are made of alpha-synuclein. The same is true of the Lewy body pathology that is associated with other neurodegenerative diseases, such as dementia with Lewy bodies. The filamentous inclusions of multiple system atrophy have also been found to be made of alpha-synuclein, thus providing an unexpected molecular link with Lewy body diseases. Recombinant alpha-synuclein assembles into filaments with similar morphologies to those found in the human diseases and with a cross-beta diffraction pattern characteristic of amyloid. The related proteins beta-synuclein and gamma-synuclein are poor at assembling into filaments. They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease.

Topics: alpha-Synuclein; Animals; Basal Ganglia Diseases; beta-Synuclein; gamma-Synuclein; Humans; Nerve Tissue Proteins; Parkinson Disease; Synucleins

Microglia are resident immunosurveillant cells in the central nervous system, and astrocytes are important for blood flow, plasticity, and neurotransmitter regulation. The aim of this study was to investigate whether astrocyte and microglial activation, estimated through markers in cerebrospinal fluid and serum, differed between synucleinopathies, tauopathies, and controls.. We analyzed the glial activation markers YKL-40 and soluble CD14 in serum and cerebrospinal fluid from 37 controls, 50 patients with Parkinson's disease (PD), and 79 P+ patients (those with progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy).. Cerebrospinal fluid levels of YKL-40 were decreased significantly in patients who had PD compared with controls (P < 0.05), patients who had multiple system atrophy (P < 0.01), and patients who had tauopathies (P < 0.0001). In addition, cerebrospinal fluid levels of YKL-40 were significantly lower in patients who had synucleinopathies than in those who had tauopathies (P < 0.0001).. The decreased cerebrospinal fluid levels of YKL-40 suggest that glial activation is reduced in the brains of patients who have Parkinson's disease and synucleinopathies compared with patients who have tauopathies and controls.

Topics: Adipokines; Aged; alpha-Synuclein; Analysis of Variance; Basal Ganglia Diseases; Chitinase-3-Like Protein 1; Female; Humans; Lectins; Lipopolysaccharide Receptors; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; Supranuclear Palsy, Progressive; Tauopathies

In Parkinson's disease (PD) and dementia with Lewy bodies (DLB) alpha-synuclein (alphaS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak's and McKeith's, currently in use for the assessment of alphaS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 alphaS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of alphaS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of alphaS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of alphaS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread alphaS pathology (Braak's PD stages 5-6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer's disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with alphaS pathology. However, finding that around half of the subjects with abundant alphaS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Basal Ganglia Diseases; Brain Stem; Cohort Studies; Dementia; Female; Humans; Male; Middle Aged; Prosencephalon; Retrospective Studies; Substantia Nigra

Extrapyramidal symptoms (EPS) in Alzheimer disease (AD) often increase with disease severity. Their neuropathological substrate is a matter of discussion. We investigated tau and alpha-synuclein (AS) pathologies in brainstem in AD patients with and without EPS. Among 160 elderly subjects with autopsy-proven AD (110 female, 50 male, aged 61-102, mean 84.1 +/- 8.3 SD years), 151 (94.4%) being demented, 35 (21.9%) had clinically reported EPS (rigidity, bradykinesia, gait impairment). Neuropathological examination included standardized classification of AD according to current criteria, and semiquantitative assessment of neuronal loss in substantia nigra (SN), locus coeruleus (LC), and of tau and AS lesions in brainstem, and, in addition, of cerebrovascular lesions. The prevalence of EPS was only slightly more frequent in higher Braak stages. Tau pathology in brainstem significantly increased with increasing Braak stages, while AS lesions did not. EPS correlated best with SN cell loss (P < 0.001) and much less with AS pathology in several brain areas (P < 0.05), except in medulla oblongata (P < 0.001). Although both pathologies in substantia nigra correlated with neuron loss (P < 0.001), nigral tau lesions, present in 88.5% of EPS positive cases (without AS lesions in 55.6%), did not correlate with EPS. Additional cerebrovascular changes apparently did not influence the development of EPS symptoms in fully developed AD. With other recent data, these results suggest that neuronal loss in SN, partly related to tau lesions, is a major pathological substrate of EPS in AD, but some cases with and without EPS may show no or only minimal nigral changes. However, often associated with nigral tau lesions and higher Braak stages, EPS in elderly patients may be a surrogate marker for severe neuritic AD pathology.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Basal Ganglia Diseases; Brain Stem; Female; Humans; Male; Middle Aged; Nerve Degeneration; Psychiatric Status Rating Scales; Retrospective Studies; Statistics, Nonparametric; tau Proteins

Intracytoplasmic aggregation of alpha-synuclein protein as Lewy bodies in the brainstem neurons is diagnostic for Parkinson's disease, whereas if this process also occurs in the cortical neurons, it is considered pathognomonic for dementia with Lewy bodies. However, the link between alpha-synuclein incorporation into inclusions, neuronal dysfunction, and clinical symptoms needs to be clarified. Another important issue of the pathogenetic puzzle is to understand where alpha-synuclein pathology begins and how it progresses in the brain. To study this, we collected all cases from autopsy material (N = 904) that had alpha-synuclein pathology in the dorsal motor nucleus of vagus, substantia nigra, and/or basal forebrain nuclei. In this way, our study has a unique design because the selection of material is entirely based on the presence of alpha-synuclein pathology regardless of clinical phenotype. Retrospective clinical assessment then showed that only 32 (30%) of 106 alpha-synuclein-positive cases were diagnosed with a neurodegenerative disorder. The distribution or load of alpha-synuclein pathology did not permit a dependable postmortem diagnosis of extrapyramidal symptoms or cognitive impairment. Some neurologically unimpaired cases had a reasonable burden of alpha-synuclein pathology in both brainstem and cortical areas, suggesting that alpha-synuclein-positive structures are not definite markers of neuronal dysfunction.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Basal Ganglia Diseases; Cognition Disorders; Dementia; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Immunohistochemistry; Inclusion Bodies; Male; Middle Aged; Nerve Tissue Proteins; Neuropsychological Tests; Retrospective Studies; Synucleins

Motor neuron disease (MND) may be complicated by frontotemporal dementia and/or an extrapyramidal movement disorder. Several studies have identified the pathological substrate for dementia in MND as being ubiquitin-immunoreactive inclusions and dystrophic neurites in the extramotor neocortex and hippocampus. Although degenerative changes have previously been noted in the basal ganglia and substantia nigra in MND, detailed pathological studies with clinical correlation are lacking. We examined postmortem material from eight patients with a history of MND and dementia, four of whom also had prominent extrapyramidal features. All cases showed the expected degenerative changes in the pyramidal motor system and ubiquitin-positive inclusions in the extramotor cortex. In addition, the cases with a history of extrapyramidal features had striking pathology in the basal ganglia and substantia nigra; neuronal loss and gliosis ranged from moderate to severe and immunohistochemistry demonstrated numerous neuronal inclusions and dystrophic neurites, which were reactive for ubiquitin, but not tau or alpha-synuclein. Similar pathology was either absent or much milder in cases without extrapyramidal features. This study illustrates the utility of ubiquitin immunohistochemistry in demonstrating the range of pathology in MND and provides a neuropathological correlate for the extrapyramidal features which may occur in MND with dementia.

Topics: alpha-Synuclein; Basal Ganglia Diseases; Corpus Striatum; Dementia; Glial Fibrillary Acidic Protein; Hippocampus; Humans; Immunohistochemistry; Inclusion Bodies; Motor Neuron Disease; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Neurons; Postmortem Changes; Substantia Nigra; Synucleins; tau Proteins; Ubiquitin