alpha-synuclein and Cerebellar-Ataxia

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of α-synuclein in GCI and a 'prion hypothesis' are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised.

Topics: alpha-Synuclein; Brain; Cerebellar Ataxia; Cognitive Dysfunction; Humans; Inclusion Bodies; Magnetic Resonance Imaging; Multiple System Atrophy; Neurons; Oligodendroglia; Parkinsonian Disorders; Positron-Emission Tomography; Prion Diseases

Multiple system atrophy (MSA) is a late-onset, sporadic neurodegenerative disorder clinically characterized by autonomic failure and either poorly levodopa-responsive parkinsonism or cerebellar ataxia. It is neuropathologically defined by widespread and abundant central nervous system α-synuclein-positive glial cytoplasmic inclusions and striatonigral and/or olivopontocerebellar neurodegeneration. There are two clinical subtypes of MSA distinguished by the predominant motor features: the parkinsonian variant (MSA-P) and the cerebellar variant (MSA-C). Despite recent progress in understanding the pathobiology of MSA, investigations into the symptomatology and natural history of the cerebellar variant of the disease have been limited. MSA-C presents a unique challenge to both clinicians and researchers alike. A key question is how to distinguish early in the disease course between MSA-C and other causes of adult-onset cerebellar ataxia. This is a particularly difficult question, because the clinical framework for conceptualizing and studying sporadic adult-onset ataxias continues to undergo flux. To date, several investigations have attempted to identify clinical features, imaging, and other biomarkers that may be predictive of MSA-C. This review presents a clinically oriented overview of our current understanding of MSA-C with a focus on evidence for distinguishing MSA-C from other sporadic, adult-onset ataxias.

Topics: alpha-Synuclein; Animals; Cerebellar Ataxia; Cerebellum; Disease Models, Animal; Humans; Multiple System Atrophy; Parkinsonian Disorders

Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

Topics: Aged; alpha-Synuclein; Animals; Cerebellar Ataxia; Cerebellum; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Multiple System Atrophy

To test the hypothesis that myoclonus in patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) is associated with a heavier burden of α-synuclein deposition in the motor regions of the spinal cord, we compared the degree of α-synuclein deposition in spinal cords of 3 patients with MSA-C with myoclonus and 3 without myoclonus.. All human tissue was obtained by the Massachusetts General Hospital Department of Pathology with support from and according to neuropathology guidelines of the Massachusetts Alzheimer's Disease Research Center. Tissue was stained with Luxol fast blue and hematoxylin & eosin for morphologic evaluation, and with a mouse monoclonal antibody to α-synuclein and Vectastain DAB kit. Images of the spinal cord sections were digitized using a 10× objective lens. Grayscale versions of these images were transferred to ImageJ software for quantitative analysis of 8 different regions of interest (ROIs) in the spinal cord: dorsal column, anterior white column, left and right dorsal horns, left and right anterior horns, and left and right lateral corticospinal tracts. A mixed-effect, multiple linear regression model was constructed to determine if patients with and without myoclonus had significantly different distributions of α-synuclein deposition across the various ROIs.. Patients with myoclonus had more α-synuclein in the anterior horns (. In MSA-C, myoclonus appears to be associated with a higher burden of α-synuclein deposition within spinal cord motor regions. Future studies with more patients will be needed to confirm these findings.

Topics: alpha-Synuclein; Brain; Cerebellar Ataxia; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Myoclonus; Parkinson Disease; Spinal Cord

A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here.. Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology.. The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality.. These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

Topics: alpha-Synuclein; Autonomic Nervous System Diseases; Basal Ganglia; Brain; Cerebellar Ataxia; Cerebellum; Diagnosis, Differential; Inclusion Bodies; Multiple System Atrophy; Parkinsonian Disorders

Multiple system atrophy (MSA), a sporadic progressive synucleinopathy of advanced age, is separated into two clinic opathological subtypes: MSA-P (striatonigral degeneration [SND]) with predominant parkinsonian features and MSA-C (olivopontocerebellar atrophy [OPCA]) with predominant cerebellar ataxia. We propose a novel morphological grading system for both subtypes to compare lesion intensities and their possible clinical validity. Forty-two autopsy cases of MSA were separated into four grades (SND 0-III and OPCA 0-III) based on semiquantitative assessment of neuronal loss, astrogliosis, and presence of alpha-synuclein-positive glial cytoplasmic inclusions (GCI) in striatum, globus pallidus, substantia nigra, pontine basis, cerebellum, and inferior olives. Whereas a recent grading system restricted to SND reflected disease progression and dopa-responsiveness, there was considerable variation in the morphological combination between SND and OPCA, with only around half the cases with OPCA II (moderate) and III (severe) showing comparable grades of both types, whereas OPCA 0 and I (no or little degeneration) was combined with all grades of SND. Twenty-two cases showing OPCA 0 + SND II (n = 3), OPCA I + SND I-II (n = 11), and OPCA I + SND III (n = 8) were classified as pure or predominant SND, consistent with MSA-P. Twenty cases showing OPCA II + SND II/III (n = 7) and OPCA III + SND III (n = 13) were classified as predominant OPCA, consistent with MSA-C. In MSA-P, the mean age of onset was higher than it was in MSA-C (55.1 vs. 50.5 years), but the mean duration of illness was shorter in MSA-P (5.3 vs. 6.7 years). Presenting symptoms in MSA-P were mainly parkinsonism, whereas in MSA-C they were mainly gait disorders (14 vs. 1; P < 0.001). Among clinical key symptoms, parkinsonism was more frequent than were cerebellar signs in MSA-P; in MSA-C it was the reverse (P < 0.01), whereas other symptoms (autonomic/urinary failure) showed no differences. Parkinsonism was infrequent in MSA-C even when OPCA was associated with SND, suggesting a masking effect by cerebellar system involvement. High terminal Hoehn and Yahr stages were more frequent in MSA-P (P < 0.01), some with good-to-moderate initial levodopa (L-dopa) response. Although the proposed morphological grading of both MSA-P and -C correlates well with initial symptoms and clinical key features of both types, further prospective studies are required to validate the clinical utility of the proposed MSA gradi

Topics: alpha-Synuclein; Cerebellar Ataxia; Corpus Striatum; Diagnosis, Differential; Disease Progression; Humans; Middle Aged; Multiple System Atrophy; Nerve Degeneration; Olivopontocerebellar Atrophies; Severity of Illness Index

We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's disease (PD) in patients presenting over the age of 40 years. Familial PD cases were tested for alpha-synuclein or parkin mutations as appropriate. No mutations were found in any of the families investigated. We found no between-group differences in the age at onset of PD, the pattern or severity of parkinsonian features, the dose of antiparkinsonian medications or treatment related complications. Cases of familial and sporadic PD in our cohort of patients display similar clinical features. This may suggest similar etiologies for both familial and sporadic PD.

Topics: alpha-Synuclein; Antiparkinson Agents; Autonomic Nervous System Diseases; Cerebellar Ataxia; Chorea; Cohort Studies; Databases, Factual; Dementia; Disease Progression; Dystonia; Female; Humans; Ligases; Male; Middle Aged; Nerve Tissue Proteins; Paralysis; Parkinson Disease; Synucleins; Tremor; Ubiquitin-Protein Ligases