Identifying New Subtypes of Multiple System Atrophy Using Cluster Analysis.

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.

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease.

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.

Multiple System Atrophy: Phenotypic spectrum approach coupled with brain 18-FDG PET.

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.

Cerebellar resting-state functional connectivity in Parkinson's disease and multiple system atrophy: Characterization of abnormalities and potential for differential diagnosis at the single-patient level.

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.

MRI supervised and unsupervised classification of Parkinson's disease and multiple system atrophy.

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.

Expanding concept of clinical conditions and symptoms in multiple system atrophy.

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.

Survival in synucleinopathies: A prospective cohort study.

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.

Minimal change multiple system atrophy: an aggressive variant?

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.

A disease-specific metabolic brain network associated with corticobasal degeneration.

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.

Tract based spatial statistics in multiple system atrophy: a comparison between clinical subtypes.

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.

Topographic distribution of cortical thinning in subtypes of multiple system atrophy.

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.

The natural history of multiple system atrophy: a prospective European cohort study.

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.

Assessment of the Scopa-Aut questionnaire in multiple system atrophy: relation to UMSARS scores and progression over time.

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.

Orthostatic hypotension is differentially associated with the cerebellar versus the parkinsonian variant of multiple system atrophy: a comparative study.

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.

[Functional assessment of nigro-striatal pathway with FP-CIT in patients with multiple system atrophy subtype C]. / Valoración funcional de la vía nigro-estriada mediante N-v-fluoropropil-2ßcarbometoxi-3ß-(4-Iodofenil) nortropano (FP-CIT) en pacientes con atrofia multisistémica subtipo cerebelosa.

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.

[Clinical features of multiple system atrophy].

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.

Diffusion-weighted imaging in multiple system atrophy: a comparison between clinical subtypes.

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.

Autonomic dysfunction in different subtypes of multiple system atrophy.

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.

Red flags for multiple system atrophy.

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.