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Background: Multiple system atrophy (MSA) is a disease with diverse symptoms and the commonly used classifications, MSA-P and MSA-C, do not cover all the different symptoms seen in MSA patients. Additionally, these classifications do not provide information about how the disease progresses over time or the expected outcome for patients., Objective: To explore clinical subtypes of MSA with a natural disease course through a data-driven approach to assist in the diagnosis and treatment of MSA., Methods: We followed 122 cases of MSA collected from 3 hospitals for 3 years. Demographic characteristics, age of onset, clinical signs, scale assessment scores, and auxiliary examination were collected. Age at onset; time from onset to assisted ambulation; and UMSARS I, II, and IV, COMPASS-31, ICARS, and UPDRS III scores were selected as clustering elements. K-means, partitioning around medoids, and self-organizing maps were used to analyze the clusters., Results: The results of all three clustering methods supported the classification of three MSA subtypes: The aggressive progression subtype (MSA-AP), characterized by mid-to-late onset, rapid progression and severe clinical symptoms; the typical subtype (MSA-T), characterized by mid-to-late onset, moderate progression and moderate severity of clinical symptoms; and the early-onset slow progression subtype (MSA-ESP), characterized by early-to-mid onset, slow progression and mild clinical symptoms., Conclusions: We divided MSA into three subtypes and summarized the characteristics of each subtype. According to the clustering results, MSA patients were divided into three completely different types according to the severity of symptoms, the speed of disease progression, and the age of onset.

Background: While multiple system atrophy (MSA) presents with high heterogeneous motor and nonmotor symptoms, the associations between clinical phenotypes and prognosis are unclear., Objective: We aimed to evaluate clinical phenotypes of MSA using data-driven approach and measure the impact of phenotypes on survival and bedbound status., Methods: 193 MSA patients were recruited from Xuanwu Hospital Capital Medical University, whose history, motor and non-motor symptoms were examined using cluster analysis. Ninety-five participants were followed-up via telephone after a mean of 31.87 months. We employed Kaplan- Meier analysis to examine survival and performed Cox and logistic regression analyses to identify factors associated with survival and bedbound status., Results: We identified four clinical profiles of MSA: cerebellar symptom-dominant, sleep and mood disorder-dominant, rigid akinetic-dominant, and malignant diffuse. The overall median survival was 7.75 years (95% CI 7.19-8.31). After adjusting for years from symptom onset to diagnosis, age and sex, patients in the malignant diffuse and rigid akinetic-dominant clusters had greater risk of death than sleep and mood disorder-dominant cluster. Furthermore, patients in the malignant diffuse and rigid akinetic-dominant clusters had higher risk of being bedbound than cerebellar symptom-dominant cluster., Conclusions: The malignant diffuse and sleep and mood disorder-dominant were identified besides the two classical subtypes, parkinsonism, and cerebellar symptom-variant. Patients with rigid-akinetic motor profiles have a worse prognosis than cerebellar symptom-dominant profiles in general. Diffuse symptoms, especially postural instability, and cognitive alterations at diagnosis, indicate rapid functional loss and disease progression. The different profiles and prognoses might indicate varied underlying pathological mechanisms.

Objective: To develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform., Methods: Plasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort., Results: Distinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations., Conclusions: Immune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: The 2008 diagnostic criteria classify Multiple System Atrophy (MSA) patients in a predominantly parkinsonian (MSA-P) or cerebellar (MSA-C) type. Phenotypic descriptions have since highlighted a clinical heterogeneity among patients (e.g., mixed-type, cognitive impairment, atypical longer survival). This study attempts to identify different phenotypes of patients with MSA and to describe corresponding brain 18-FDG Positron Emission Tomography (PET) patterns., Methods: Patients with a "probable" MSA diagnosis for whom a brain 18-FDG PET was performed were included. A retrospective analysis (from 2006 to 2017) was conducted using standardized data collection. We used Latent Class Analysis (LCA), an innovative statistical approach, to identify profiles of patients based on common clinical characteristics. Brain metabolism of different groups was studied at rest., Results: Eighty-five patients were included. Three different profiles were revealed (entropy = 0.835): 1. extrapyramidal, axial, laryngeal-pharyngeal involvement (LPI) and cerebellar symptoms (n = 46, 54.1%); 2. cerebellar and LPI symptoms (n = 30, 35.3%); 3. cerebellar and cognitive symptoms (n = 9, 10.6%). Brain metabolism analyses (k > 89; p < 0.001) showed hypometabolism of the basal ganglia, frontal/prefrontal, temporal cortices and left posterior cerebellum in profile 1. In profile 2 there was hypometabolism of the medulla, prefrontal, temporal, cingular cortices, putamen and bilateral cerebellar hemispheres. In profile 3 there was hypometabolism of bilateral posterior cerebellar hemispheres and vermis., Conclusion: Beyond the two most common phenotypes of MSA, a third and particularly atypical profile with cerebellar and cognitive symptoms but without LPI involvement is described. These profiles are supported by different brain metabolic abnormalities which could be useful for diagnostic purposes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Recent studies using resting-state functional connectivity and machine-learning to distinguish patients with neurodegenerative diseases from other groups of subjects show promising results. This approach has not been tested to discriminate between Parkinson's disease (PD) and multiple system atrophy (MSA) patients., Objectives: Our first aim is to characterize possible abnormalities in resting-state functional connectivity between the cerebellum and a set of intrinsic-connectivity brain networks and between the cerebellum and different regions of the striatum in PD and MSA. The second objective of this study is to assess the potential of cerebellar connectivity measures to distinguish between PD and MSA patients at the single-patient level., Methods: Fifty-nine healthy controls, 62 PD patients, and 30 MSA patients underwent resting-state functional MRI with a 3T scanner. Independent component analysis and dual regression were used to define seven resting-state networks of interest. To assess striatal connectivity, a seed-to-voxel approach was used after dividing the striatum into six regions bilaterally. Measures of cerebellar-brain network and cerebellar-striatal connectivity were then used as features in a support vector machine to discriminate between PD and MSA patients., Results: MSA patients displayed reduced cerebellar connectivity with different brain networks and with the striatum compared with PD patients and with controls. The classification procedure achieved an overall accuracy of 77.17% with 83.33% of the MSA subjects and 74.19% of the PD patients correctly classified., Conclusion: Our findings suggest that measures of cerebellar functional connectivity have the potential to distinguish between PD and MSA patients., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Multimodal MRI approach is based on a combination of MRI parameters sensitive to different tissue characteristics (eg, volume atrophy, iron deposition, and microstructural damage). The main objective of the present study was to use a multimodal MRI approach to identify brain differences that could discriminate between matched groups of patients with multiple system atrophy, Parkinson's disease, and healthy controls. We assessed the 2 different MSA variants, namely, MSA-P, with predominant parkinsonism, and MSA-C, with more prominent cerebellar symptoms., Methods: Twenty-six PD patients, 29 MSA patients (16 MSA-P, 13 MSA-C), and 26 controls underwent 3-T MRI comprising T2*-weighted, T1-weighted, and diffusion tensor imaging scans. Using whole-brain voxel-based MRI, we combined gray-matter density, T2* relaxation rates, and diffusion tensor imaging scalars to compare and discriminate PD, MSA-P, MSA-C, and healthy controls., Results: Our main results showed that this approach reveals multiparametric modifications within the cerebellum and putamen in both MSA-C and MSA-P patients, compared with PD patients. Furthermore, our findings revealed that specific single multimodal MRI markers were sufficient to discriminate MSA-P and MSA-C patients from PD patients. Moreover, the unsupervised analysis based on multimodal MRI data could regroup individuals according to their clinical diagnosis, in most cases., Conclusions: This study demonstrates that multimodal MRI is able to discriminate patients with PD from those with MSA with high accuracy. The combination of different MR biomarkers could be a great tool in early stage of disease to help diagnosis. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. MSA patients show various phenotypes during the course of their illness including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. MSA is classified into the parkinsonian (MSA-P) or cerebellar (MSA-C) variant depending on the clinical motor phenotype at presentation. MSA-P and MSA-C are predominant in Western countries and Japan, respectively. The mean age at onset is 55 to 60 years. Prognosis ranges from 6 to 10 years, but some cases survive for more than 15 years. Early and severe autonomic failure is a poor prognostic factor. MSA patients sometimes present with isolated autonomic failure or motor symptoms/signs, and the median duration from onset to the concomitant appearance of motor and autonomic symptoms was approximately 2 years in our previous study. As the presence of the combination of motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. We experienced MSA patients who died before presentation of the motor symptoms/signs diagnostic for MSA (i.e., premotor MSA). Detection of the nature of autonomic failure consistent with MSA and identification of the dysfunctional anatomical sites may increase the probability of a diagnosis of premotor MSA. Dementia is another problem in MSA. Although dementia had been thought to be rare in MSA, frontal lobe dysfunction is observed frequently during the early course of the illness. Magnetic resonance imaging can show progressive cerebral atrophy in longstanding cases. More recently, MSA patients presenting with frontotemporal dementia preceding the presence of motor and autonomic manifestations diagnostic of MSA have been reported. Novel diagnostic criteria based on an expanding concept of the clinical conditions and symptoms of MSA will be needed for the development of disease-modifying therapies and better management.

Objectives: Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) involve cytoplasmic deposition of α-synuclein and are considered to be synucleinopathies. Approximately 40% of patients with PD, most patients with MSA, and all patients with PAF have neurogenic orthostatic hypotension (OH). This study compared long-term survival in these synucleinopathies., Methods: In this prospective cohort study, survival data were obtained for 97.6% of 206 referred patients evaluated between 1994 and 2014 (47 PD + OH, 54 PD no OH, 15 cerebellar MSA [MSA-C], 57 parkinsonian MSA [MSA-P], 28 PAF). Individual diagnoses were confirmed by clinical criteria and results of pharmacologic, neurochemical, and neuroimaging tests of sympathetic noradrenergic innervation. The Cox proportional hazard model was used to calculate hazard ratios (HRs) from symptom onset and from time of evaluation to death., Results: Patients with MSA-C or MSA-P had shorter survival from symptom onset than did patients with PD + OH (age- and sex-adjusted HR = 6.1, 5.6; p < 0.0001 each), PAF (HR = 10.8, 9.9; p < 0.0001 each) or PD no OH (HR = 14.9, 13.6; p < 0.0001 each). Among parkinsonian patients who died, median times from motor onset to death were 7.5 years in MSA-P, 11.6 years in PD + OH, and 15.8 years in PD no OH. Probabilities of survival for 10 years from onset of relevant symptoms were 0.39 in MSA-C, 0.33 in MSA-P, 0.74 in PD + OH, 0.87 in PAF, and 0.93 in PD no OH., Conclusions: In synucleinopathies, survival depends on the particular disease, with the risk of death greater in MSA-P than in PD + OH and in PD + OH than in PD no OH., (© 2015 American Academy of Neurology.)

Background: Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus., Methods: Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases., Results: More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases., Conclusions: Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA. © 2015 International Parkinson and Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Using a novel method of tract-based spatial statistics (TBSS), this study aimed to investigate micro-structural white matter similarities and differences between the two MSA variants., Methods: Diffusion tensor image data were acquired from 10 MSA-P, 15 MSA-C patients and 15 controls. Using TBSS, we performed pairwise comparison by examining the fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD) and radial diffusivity (RD) maps of the white matter tract. Clusters showing diffusivity abnormalities were used as region of interests for correlation analysis., Results: Both in MSA-C and MSA-P, we detected significantly decreased FA values in bilateral corticospinal tract (CST) and right anterior thalamic radiation (ATR), increased RD values in bilateral CST, which correlated significantly with clinical severity. Direct comparison of two variants showed higher AD values of superior longitudinal fasciculus (SLF) in MSA-P than in MSA-C., Conclusions: These findings indicate that patients with MSA-C and MSA-P share similar diffusivity abnormalities in the bilateral CST and right ATR. Higher AD values of SLF in MSA-P than in MSA-C might be a reason for faster functional deterioration in MSA-P than in MSA-C., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Purpose: Despite the predominant degeneration of subcortical structures, recent studies have suggested the evidence of cortical involvement in multiple system atrophy (MSA). This study aimed to identify the different topographic pattern of cortical thinning in MSA according to clinical subtypes, and the association of cortical thinning with cerebellar atrophy and other disease related metrics., Materials and Methods: We used cortical thickness analysis in 53 non-demented probable MSA patients (29 with MSA-C, 24 with MSA-P) and 35 healthy subjects and modeled local cortical thickness as a linear association with cerebellar volume and disease related metrics including age, disease duration, cognition and disease severity., Results: We found five clusters (left ventromedial prefrontal, bilateral ventrolateral prefrontal cortex, right parahippocampal and lingual gyrus) exhibiting significant cortical thinning in MSA-C and two clusters (right primary sensory motor and left ventromedial prefrontal cortex) exhibiting a thinning tendency in MSA-P compared with the control group. In correlation analysis, we identified no cluster exhibiting a significant correlation with cerebellar atrophy in both of the MSA groups. However, cortical thickness in right parahippocampalgyrus and left ventrolateral prefrontal cortex showed significant negative correlation with International Cooperative Ataxia Rating Scale subscore of speech disorder in MSA-C group., Conclusions: We identified different topographic distributions of cortical thinning in MSA subtypes. Our study suggests that cortical thinning of MSA occurs independently of cerebellar atrophy as a primary disease process rather than secondary deafferentation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA., Methods: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test., Findings: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power., Interpretation: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression - that is the Unified MSA Rating Scale (UMSARS) - were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Orthostatic hypotension (OH) is a cardinal feature of autonomic failure in multiple system atrophy (MSA); however, there are few comparative data on OH in the motor subtypes of MSA. In the present retrospective study, postural blood pressure drop after 3 min of standing was determined in 16 patients with the cerebellar variant of MSA (MSA-C) and in 17 patients with the Parkinson variant (MSA-P). Twenty idiopathic Parkinson's disease (IPD) patients matched for age, sex, disease duration and dopaminergic therapy served as control group. OH frequency and severity were more pronounced in MSA-C followed by MSA-P and IPD. Differences in brainstem pathology are likely to account for the tight association of MSA-C and OH. A simple standing test should be obligatory in the work-up of patients with sporadic late-onset ataxias.

Background and Objective: To assess the functional state of nigro-striatal pathway using FP-CIT-I-123 in patients with clinical diagnosis of Multiple System Atrophy (MSA) subtype C., Patients and Methods: We included 10 patients with a clinical diagnosis of MSA-C and compared them with 10 patients diagnosed with essential tremor (controls) and 10 with Parkinson Disease (PD). The studies are evaluated by the striatum/occipital index (S/O). We calculated the diagnostic validity of the procedure by ROC curve analysis., Results: The average value of the S/O index showed a mean of 1.48 (0.23), 1.59 (0.17) and 1.22 (0.16) respectively for MSA-C, control group (p=0.25) and PD (p=0.00). ROC curve analysis: Az: 0.650; sensitivity: 0.50; specificity: 0.80. The comparison between the results of FP-CIT and clinical manifestations showed: 4 patients with parkinsonism (PK) and pathological study; 4 without PK and normal study; 1 with PK and normal study and 1 without PK and pathological study., Conclusions: FP-CIT study does not exclude completely the existence of an MSA-C. From a functional point of view, there does not always seem to be a consistency between the state of the nigro-striatal pathway and the existence of parkinsonism., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

This review deals with clinical features of multiple system atrophy (MSA), especially on natural history, sleep disordered breathing, and nocturnal sudden death, based on our recent analyses of definite MSA which we experienced in our institute. Fiberoptic laryngoscopic examination performed under propofol anesthesia revealed that upper airway obstruction is caused not only by vocal cord abductor paralysis but also by various mechanisms including floppy epiglottis and stenosis at the arytenoids during inspiration. We must be cautious not to exacerbate upper airway obstruction by continuous positive airway pressure (CPAP), which is now increasingly used to treat sleep disordered breathing of MSA. Our analyses also demonstrated that nocturnal sudden death was the most frequent cause of death in our MSA cohort, and CPAP could not be a prophylactic measure against sudden death. In order to prevent nocturnal sudden death, a new project is now under way using non-invasive positive airway pressure ventilation (NPPV) and/or artificial ventilation associated with tracheostomy.

Multiple system atrophy can be classified into two main types, a Parkinsonian (MSA-P) and a cerebellar (MSA-C) variant based on clinical presentation. We obtained diffusion-weighted magnetic resonance imaging (DWI) in 9 MSA-P and 12 MSA-C patients and 11 controls, and correlated DWI changes with disease duration and severity. We found that Trace (D) values in the entire and anterior putamen were significantly higher in MSA-P than in MSA-C patients and controls, whereas Trace (D) values in the cerebellum and middle cerebellar peduncle (MCP) were significantly higher in MSA-C than in MSA-P patients and controls. Increased disease duration was significantly correlated with increased Trace (D) values in pons of MSA-P patients, and in cerebellum and MCP of MSA-C patients. Both UMSARS and UPDRS motor scores positively correlated with entire and posterior putaminal Trace (D) values in MSA-P patients. The diffusivity changes parallel phenotypical and pathologic differences between MSA-P and MSA-C patients, suggesting that DWI is a feasible tool for in vivo evaluation of neurodegeneration in MSA. Based on our findings, Trace (D) measurements in the putamen and pons in MSA-P patients and in the cerebellum and MCP in MSA-C patients could serve as quantitative markers for microstructural damage in the course of disease.

Multiple system atrophy (MSA) can clinically be divided into the cerebellar (MSA-C) and the parkinsonian (MSA-P) variant. However, till now, it is unknown whether autonomic dysfunction in these two entities differs regarding severity and profile. We compared the pattern of autonomic dysfunction in 12 patients with MSA-C and 26 with MSA-P in comparison with 27 age- and sex-matched healthy controls using a standard battery of autonomic function tests and a structured anamnesis of the autonomic nervous system. MSA-P patients complained significantly more often about the symptoms of autonomic dysfunctions than MSA-C patients, especially regarding vasomotor, secretomotor, and gastrointestinal subsystems. However, regarding cardiovascular, sudomotor pupil, urogenital, and sleep subsystems, there were no significant quantitative or qualitative differences as analyzed by autonomic anamnesis and testing. Our results suggest that there are only minor differences in the pattern of autonomic dysfunction between the two clinical MSA phenotypes., ((c) 2007 Movement Disorder Society.)

The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/-7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P., ((c) 2008 Movement Disorder Society)

Sleep disturbances occur in 70% of the patients with multiple system atrophy (MSA). Disturbances of the hypothalamic hypocretin neurotransmission have been suggested as a possible cause. Since a systematic study of CSF hypocretin-1 levels in MSA has not yet been performed, we analysed CSF hypocretin-1 concentrations in 6 MSA-P and 6 MSA-C patients and 11 age-matched controls. We did not observe any differences from control values.

We investigated the clinical features and mode of disease progression in 142 patients with probable multiple system atrophy (MSA) according to the Consensus Criteria. The subjects included 84 men and 58 women with a mean age at onset of 58.2+/-7.1 years (range: 38-79 years). Cerebellar signs were detected in 87.3% of these patients at the time of initial examination, and were found in 95.1% of them at latest follow-up. MSA-C was diagnosed in 83.8% of the patients at their first examination. Parkinsonism was initially detected in 28.9% of the patients, increasing to 51.4% at the latest follow-up. Among all of the subjects, only 16.2% were classified as having MSA-P on initial examination. At the latest follow-up, parkinsonian features had become predominant over cerebellar features in 24.6% of the 65 patients with MSA-C who were followed for more than 3 years. Although parkinsonism usually masked the signs of cerebellar involvement in MSA-C patients, none of the patients with MSA-P at an early stage showed predominance of cerebellar features at the latest follow-up. Parkinsonism is the predominant feature of MSA among Western patients, even at an early stage, but this study showed that cerebellar deficits are the main feature in Japanese patients. This difference of disease manifestations between ethnic groups suggests that genetic factors may influence the clinical phenotype of MSA.

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene, shares clinical features with other movement disorders, particularly in the domains of gait ataxia, intention tremor and parkinsonism. However, the prevalence of FXTAS within other diagnostic categories is not well defined., Methods: A meta-analysis was conducted of all published (n = 14) genetic screens for expanded FMR1 alleles to assess the prevalence and CGG-repeat size bias of FMR1 premutation alleles in those populations., Results: In men with late-onset cerebellar ataxia, the prevalence of premutation alleles (1.5%; 16/1049) was 13 times greater than expected based on its prevalence in the general population (2%; 16/818 for age of onset >50 years; odds ratio 12.4; 95% confidence interval 1.6 to 93.5). Meta-analysis of CGG-repeat data for screened patients with premutation alleles shows a shift to larger repeat size than in the general population (p<0.001). 86% (19/22) of premutation alleles were larger than 70 repeats in the patients screened, whereas only approximately 22% of premutation alleles are larger than 70 repeats in the general population., Conclusions: Expanded FMR1 alleles contribute to cases of late-onset sporadic cerebellar ataxia, suggesting that FMR1 genetic testing should be carried out in such cases. The biased distribution of FMR1 allele sizes has substantial implications for genetic counselling of carriers with smaller alleles who are at a low risk of developing FXTAS, and suggests that the estimated prevalence of FXTAS among men >50 years of age in the general population may be two to threefold lower than the initial figure of 1 in 3000.

Background: Differentiating idiopathic late-onset cerebellar ataxia (ILOCA) from ataxia due to the cerebellar subtype of multiple-system atrophy (MSA-C) can be difficult in the early stages of the disease, Methods: The authors analyzed the levels of various CSF biomarkers in 27 patients with MSA-C and 18 patients with ILOCA and obtained cut-off points for each potential biomarker to differentiate MSA-C from ILOCA., Results: Increased levels of neurofilament light chain (NFL) and neurofilament heavy chain (NFHp35) and decreased levels of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleaceticacid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in MSA-C compared with ILOCA patients. Receiver operating characteristic analysis showed high sensitivity and specificity levels for NFL, NFHp35, and MHPG analysis. At a cut-off of 24.4 ng/L for the NFL analysis, a sensitivity of 79% and a specificity of 94% were obtained for differentiating MSA-C from ILOCA. At a cut-off point for NFHp35 of 129.5 ng/L, sensitivity was 87% and specificity 83%. Analysis of MHPG levels (cut-off 42.5 nM) resulted in a sensitivity of 86% with a specificity of 75%. A multivariate logistic regression model selected NFL, MHPG, and tau as independent predictive biomarkers that separated the MSA-C and ILOCA groups., Conclusions: Increased levels of neurofilament light chain and tau and decreased levels of 3-methoxy-4-hydroxyphenylethyleneglycol were associated with high accuracy levels in differentiating the cerebellar subtype of multiple-system atrophy from idiopathic late-onset cerebellar ataxia (LOCA). CSF analysis may thus serve as a useful tool in early diagnostic differentiation of LOCA.

Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

In 1964, Lewis reported a familial ataxia-dysautonomia syndrome reminiscent of Shy-Drager syndrome subsequently known as multiple system atrophy (MSA). Here we review this report and propose that the Lewis family may represent an unusual form of autosomal dominant cerebellar ataxia type I, which might be categorized either as SCA3 (Machado-Joseph disease) or a new SCA subtype. There remains no conclusive evidence to support the notion of hereditary MSA.

The epidemiology of multiple system atrophy (MSA) is scarcely known, and risk factors have not been definitely identified. We investigated the effect of family history for neurodegenerative diseases and environmental factors on MSA risk in a multicentric case-control study. A total of 73 MSA patients (42 men, 31 women; age, 64.3 +/- 8.1 years; disease duration, 4.8 +/- 3.9 years), 146 hospital controls (84 men, 62 women; age, 64.9 +/- 8.4 years), and 73 population controls (42 men, 31 women; age, 63.7 +/- 8.9 years) matched for sex, age (+/-3 years), and province of residence were enrolled consecutively at seven neurological centers from 1 January 1994 to 31 July 1998. The following variables were investigated: family history of neurodegenerative diseases, education, smoking habits, hobbies, and occupational history. Occupational history of farming was significantly more frequent among MSA cases than controls (OR adj = 2.52; 95% CI, 1.25 to 5.07, MSA vs. hospital controls; OR adj = 4.53; 95% CI, 1.68 to12.2, MSA cases vs. population controls). A dose-response analysis for years of farming corroborated this association. We recently found that smoking is significantly less frequent among MSA cases than controls (Vanacore et al. [2000] Neurology 54:114-119). Here, we report that the effects of farming and smoking on MSA risk do not interact. Our results suggest that occupational history of farming is a risk factor for MSA. Smoking and farming seem to influence MSA risk independently. Further epidemiological studies might provide clues on the etiopathogenesis of MSA., (Copyright 2004 Movement Disorder Society.)

Some abnormal findings in routine MRI have been proposed as helpful discriminators for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). However, what the most distinguishing MRI findings for MSA-p (parkinsonism dominant) or MSA-c (cerebellar dominant) are separately has not been systematically analyzed. To determine what the most helpful discriminators for MSA-p or MSA-c are and whether those findings are correlated with the presence of parkinsonism or cerebellar dysfunction, we compared 10 previously reported MRI findings in 36 patients with probable MSA-p, 27 patients with probable MSA-c and 30 patients with PD separately. In our results, hyperintense rim and putaminal atrophy among supratentorial parameters and the parameters of infratentorial atrophy were significantly prominent in MSA-p comparing to PD. Hyperintense rim showed the highest specificity in MSA-p patients (90.0%) with relatively suboptimal sensitivity (72.2%). In MSA-c, all infratentorial parameters had strong discriminating power comparing to PD. Signal increase in the middle cerebellar peduncle showed the highest specificity (100%) and had fair sensitivity (85.2%) in MSA-c. Compared between MSA-p and MSA-c, supratentorial parameters were not valid to differentiate MSA-c from MSA-p except for putaminal atrophy. On the contrary, infratentorial parameters were good for distinguishing MSA-c from MSA-p except dilatation of the fourth ventricle. Parkinsonism was not correlated with a hyperintense rim, but cerebellar symptoms were correlated with signal increase in the middle cerebellar peduncle. Our findings suggest the characteristic MRI can be helpful for differentiating MSA-p and MSA-c from PD, respectively, although they do not reflect the presence or lateralization of parkinsonism.

Unlabelled: Using (99m)Tc-TRODAT-1 ((99m)Tc-[2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl) amino]ethyl]amino]ethane-thiolato(3-)-N2,N2',S2,S2]oxo-[1R-(exo-exo)])) brain SPECT imaging, we measured striatal dopamine transporters (DATs) activity in multiple system atrophy (MSA) to investigate the possibility of differentiating it from Parkinson's disease (PD) and to correlate the findings with the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes of MSA., Methods: Forty-nine patients with probable MSA (30 MSA-P, 19 MSA-C), a disease control group of 36 age- and disease duration-matched patients with probable PD, and a healthy control group of 33 age-matched healthy volunteers participated in a SPECT study. The ratios of specific striatal binding-to-nonspecific occipital binding, including the striatum-to-occipital ratio (S/O), putamen-to-occipital ratio (P/O), caudate nucleus-to-occipital ratio (C/O), and putamen-to-caudate nucleus ratio (P/C), were calculated. The statistical analyses of uptakes among 4 groups used ANOVA followed by Games-Howell's multiple comparisons. The Spearman correlation coefficient between the motor scores of Unified Parkinson's Disease Rating Scale (UPDRS-III) and those binding ratios of the MSA-P and MSA-C groups and the PD group was also performed., Results: The striatal binding was more symmetrically reduced in the MSA-P (asymmetric index, 14.2) and MSA-C (asymmetric index, 8.1) groups, in contrast to the greater asymmetric reduction in the PD group (asymmetric index, 28.6). Overall striatal binding was significantly reduced in the MSA-P (-59.8%), MSA-C (-29.9%), and PD (-58.0%) groups with no overlap between these values and those of the control group. Like the PD group, bilateral P/O, C/O, and S/O ratio values were significantly reduced in the MSA-P and MSA-C groups. Nevertheless, the reduction of bilateral P/O and S/O ratios was more for the MSA-P group than for the MSA-C group. P/C ratios showed that the MSA-P and PD groups had similar patterns of nigral impairment, but the MSA-C group had a different pattern. No correlation between the UPDRS-III scores and (99m)Tc-TRODAT-1 bindings was found in both MSA-P and MSA-C groups; in contrast, a significant negative correlation was noted in the PD group., Conclusion: (99m)Tc-TRODAT-1 brain SPECT is capable of scientifically differentiating between the MSA-P and MSA-C subtypes, and MSA-P has more symmetric nigrostriatal damage than that in PD. (99m)Tc-TRODAT-1 brain SPECT imaging probably could provide important information to differentiate MSA from PD.

We analyzed parkinsonian features in multiple system atrophy (MSA) compared with age- and disease duration-matched Parkinson's disease (PD) patients, and assessed the applicability of the Unified Parkinson's Disease Rating Scale (UPDRS) -III motor scale as a means of rating their severity. Cross-sectional analysis of parkinsonism was done using UPDRS-III, International Cerebellar Atatia Rating Scale, and disability scales (Hoehn and Yahr [H&A], Schwab and England, Katz and Lawton) in 50 unselected MSA patients and in 50 matched PD patients. At symptom onset, falls occurred 10 times more frequently in MSA, whereas limb tremor was 10 times more common in PD. At first visit (10.2 months), hemiparkinsonism and pill-rolling rest tremor were less common in MSA. Hypomimia, atypical rest, postural or action tremor, as well as postural instability were more frequent in MSA. At study examination (62.4 months), parkinsonian signs in MSA patients were more frequently symmetrical and associated with axial rigidity, antecollis and postural instability. A levodopa response of >50% was seen in <10% of MSA patients. Modified H&Y stages (3.2 +/- 1.3 vs. 2.2 +/- 0.78) and UPDRS-III scores (48.14 +/- 19.5 vs. 31.74 +/- 12.9) were significantly (P = 0.0001) higher in MSA. The internal consistency of the UPDRS-III was fair in MSA patients (Cronbach's alpha >0.90), and correlated well with marked dependency on the Schwab and England and Katz and Lawton scales. Factor structure analysis of UPDRS-III in MSA showed five clinically distinct subscores accounting for 74% of the variance, differing from PD by the dependency of the face-speech and limb bradykinesia items and independence of the postural-action tremor from the rest tremor items. There was a significant correlation (R(2) = 0.70, P = 0.001) between ICARS ataxia and UPDRS-III scores in MSA patients. Results confirm a distinct profile of parkinsonism in MSA and greater severity and disability compared with PD. It also indicates that the UPDRS-III provides a useful severity measure of parkinsonism in MSA, albeit contaminated by additional cerebellar dysfunction., (Copyright 2002 Movement Disorder Society)

Several investigators have revealed features of multiple system atrophy (MSA) by magnetic resonance imaging (MRI). For use in clinical diagnosis, we determined the exact time when two main features of pontine and putaminal intensity changes appeared. Furthermore, in order to reveal the course from when the disorder first appeared and how it spread, we also investigated the course of MRI findings and differences between clinical subtypes. The cranial MRI of 42 patients with MSA were longitudinally studied including comments on the so called "cross sign" of pontine T2 high intensity, which was divided into 6 stages, and also on the linear T2 high intensity of the dorsolateral side of the putamen ("putaminal slit") which was divided into 4 stages. Patients were classified as 16 MSA-C, 7 autonomic dominant type (MSA-A), and 19 MSA-P. The age at onset ranged from 41 to 74 years (mean, 55 +/- 9). The duration of the disease in the MRI study ranged from 1 to 24 years. The pontine "cross sign" was completed (shows Cross, stage IV) earlier in MSA-C mainly before 5 years, later in MSA-P and even much later in MSA-A. Regarding the "putaminal slit", MSA-P shows earlier bilateral changes (stage II), mostly before 3 years, compared with MSA-C, which requires 4 years to reveal even a unilateral change (stage I), or MSA-A which requires even more time. MRI findings showed a tendency to relate to clinical findings, since MSA-C exhibits "cross sign" completion earlier than bilateral "putaminal slit"; however, MSA-P shows bilateral "putaminal slit" earlier than "cross sign", and MSA-A requires much more time to show both. Clinically, MSA-C, MSA-A, or MSA-P showed different MRI courses so that three subtypes could be defined also with MRI findings. Therefore these observations are useful not only for diagnosis of MSA itself, but also to distinguish clinical subtypes (MSA-C, MSA-A, or MSA-P) which have different rates of lesion progression.

We reviewed MRI findings in 29 patients with probable multiple system atrophy (MSA) to see whether there were common and or less common neuroradiological findings in the various clinical subtypes. We divided the patients into three clinical subtypes according to initial and predominant symptoms: 14 with olivopontocerebellar atrophy (OPCA), eight with the Shy-Drager syndrome (SDS) and seven with striatonigral degeneration (SND). The patients showed atrophy of the brain stem and cerebellum, high signal on T2-weighted images of the base of the pons and middle cerebellar peduncles, high and low signal on T2-weighted images of the putamen and atrophy of frontal and parietal lobes. The degree of atrophy of the middle cerebellar peduncle and cerebellum was greater in OPCA patients and a high-signal lateral rim to the putamen more frequent in SND. However, all findings were observed in all subtypes, and the degrees of atrophy of the putamen and pons and the frequency of high signal in the base of the pons were similar in the subtypes. We also found atrophy of the cerebral hemispheres, especially the frontal and parietal lobes, but its degree was not significantly different in the various subtypes. Our findings suggest that, although MSA can be divided clinically into three subtypes, most of the features on MRI are common and overlap in the subtypes, independently of the clinical presentation.

Multiple system atrophy is a sporadic, adult-onset neurodegenerative disease of unknown etiology. The condition may be unique among neurodegenerative diseases by the prominent, if not primary, role played by the oligodendroglial cell in the pathogenetic process. Recent developments in our understanding of multiple system atrophy have included the detection of glial cytoplasmic inclusions and alpha-synuclein accumulation in these inclusions. The latter finding links multiple system atrophy as an "alpha-synucleinopathy" to Parkinson's disease and dementia with Lewy bodies. This article reviews recent important findings of potential relevance to the pathogenesis of multiple system atrophy. We also speculate on areas in which further advances may be made to progress our understanding of this devastating condition.

Objectives: To study the involvement of pyramidal tracts and sensory pathways in multiple system atrophy (MSA)., Materials and Methods: Evoked potential studies were performed in 45 MSA patients suffering from either MSA of cerebellar type (MSA-C) or MSA of parkinsonian type (MSA-P)., Results: Motor evoked potentials were normal in all MSA patients, whereas visual and somatosensory evoked potential abnormalities were found in about 40% of the MSA patients with no significant difference between the cerebellar (MSA-C) and parkinsonian (MSA-P) subgroup. Abnormal latencies of wave III in brainstem auditory evoked potentials were significantly more frequent in MSA-C., Conclusions: Abnormalities of somatosensory, visual and auditory evoked potentials are frequent findings in MSA, whereas abnormal motor evoked potentials are not a characteristic feature of the disease.

Multiple system atrophy represents an enigmatic, clinico-pathologically defined neurodegenerative disease. According to findings of the last three decades, the historically derived, previously used terms olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager-syndrome should be avoided in clinical use because of both the clinical and morphological overlap between these syndromes. Complex neurodegenerative syndromes other than multiple system atrophy according to recently developed criteria, should rather be referred to as multiple system degenerations.

We report the results of a consensus conference on the diagnosis of multiple system atrophy (MSA). We describe the clinical features of the disease, which include four domains: autonomic failure/urinary dysfunction, parkinsonism and cerebellar ataxia, and corticospinal dysfunction. We set criteria to define the relative importance of these features. The diagnosis of possible MSA requires one criterion plus two features from separate other domains. The diagnosis of probable MSA requires the criterion for autonomic failure/urinary dysfunction plus poorly levodopa responsive parkinsonism or cerebellar ataxia. The diagnosis of definite MSA requires pathological confirmation.

We investigated neuropathologically the distribution of the cerebellar cortical lesions in three Japanese autopsy cases of multiple system atrophy (MSA) using hemisphere specimens. The lesions were classified as mild, moderate or severe. The distribution of cerebellar cortical lesions in all three cases were uniform: the cerebellar cortical lesions were more conspicuous in the vermis than in the hemisphere. These neuropathological findings differ from the established theory that cerebellar lesions of MSA are more pronounced in the hemisphere than in the vermis. The degree of cerebellar cortical lesions in our cases increased in relation to the duration of the disease. Our pathological data may contribute to the morphological differential diagnosis in various neurodegenerative disorders including late cortical cerebellar atrophy. Our neuropathological findings may also make a contribution to the neuroradiological progress in the differential diagnosis of spinocerebellar disease.

Multiple system atrophy (MSA) is a degenerative disease of the central nervous system with three components, usually variously expressed: nigrostriatal degeneration (NSD), olivopontocerebellar atrophy (OPCA) and Shy-Drager syndrome of autonomic system dysfunction (SDS). The clinical progression of MSA leads to death in a shorter time than in any of the components occurring separately. A common, and according to some authors, pathognomonic neuropathological finding in MSA cases is the presence of argyrophilic inclusions in the cytoplasm of glial cells, mainly oligodendrocytes, in the structures of the encephalon with most pronounced atrophic changes.