Subtypes Of Multiple System Atrophy Research Articles

Identifying New Subtypes of Multiple System Atrophy Using Cluster Analysis.

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. 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. 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. 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. 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.

Cellular iron deposition patterns predict clinical subtypes of multiple system atrophy

BackgroundMultiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology. MethodsIron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined. ResultsMSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes. ConclusionsOur comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels.

Impaired glymphatic clearance in multiple system atrophy: A diffusion spectrum imaging study

IntroductionImpaired α-synuclein clearance is pivotal in the pathogenesis of neurodegenerative diseases. We evaluated glymphatic clearance in multiple system atrophy (MSA) patients using advanced imaging. MethodsForty-four MSA patients (11 with MSA-parkinsonian type [MSA-P] and 33 with MSA-cerebellar type [MSA-C]) and 30 healthy controls were studied using diffusion spectrum magnetic resonance imaging (DSI-MRI). Diffusivities were measured along the x-, y-, and z-axes to calculate the Analysis Along the Perivascular Space (ALPS) index. Comparisons of the ALPS index were conducted between MSA patients and controls and among MSA subtypes. The ALPS index correlation with the Unified Multiple System Atrophy Rating Scale (UMSARS) scores was also analyzed. ResultsThe ALPS index differed significantly between patients with MSA and healthy controls, with lower values observed in the former (1.46 ± 0.17 versus1.63 ± 0.12, p < 0.001). Both MSA-P and MSA-C patients had lower ALPS-index (1.40 ± 0.13, p < 0.001; 1.47 ± 0.18, p = 0.003, respectively), but there was no significant difference between the two (p = 0.22). No correlation was found between the ALPS index and clinical scores for UMASRS I (r = −0.08, p = 0.61), UMASRS II (r = −0.04, p = 0.81), or UMASRS I + II (r = −0.05, p = 0.74). ConclusionMSA patients show reduced glymphatic clearance as measured by the ALPS index, underscoring the utility of this imaging method in neurodegenerative disease research.

Differentiation between Parkinson's Disease and the Parkinsonian Subtype of Multiple System Atrophy Using the Magnetic Resonance T1w/T2w Ratio in the Middle Cerebellar Peduncle.

Multiple system atrophy with predominant parkinsonism (MSA-P) can hardly be distinguished from Parkinson's disease (PD) clinically in the early stages. This study investigated whether a standardized T1-weighted/T2-weighted ratio (sT1w/T2w ratio) can effectively detect degenerative changes in the middle cerebellar peduncle (MCP) associated with MSA-P and PD and evaluated its potential to distinguish between these two diseases. We included 35 patients with MSA-P, 32 patients with PD, and 17 controls. T1w and T2w scans were acquired using a 1.5-T MR system. The MCP sT1w/T2w ratio was analyzed via SPM12 using a region-of-interest approach in a normalized space. The diagnostic performance of the MCP sT1w/T2w ratio was compared between the MSA-P, PD, and controls. Patients with MSA-P had significantly lower MCP sT1w/T2w ratios than patients with PD and controls. Furthermore, MCP sT1w/T2w ratios were lower in patients with PD than in the controls. The MCP sT1w/T2w ratio showed excellent or good accuracy for differentiating MSA-P or PD from the control (area under the curve (AUC) = 0.919 and 0.814, respectively) and substantial power for differentiating MSA-P from PD (AUC = 0.724). Therefore, the MCP sT1w/T2w ratio is sensitive in detecting degenerative changes in the MCP associated with MSA-P and PD and is useful in distinguishing MSA-P from PD.

Cerebellar, Not Nigrostriatal Degeneration Impairs Dexterity in Multiple System Atrophy.

Multiple system atrophy (MSA) clinically manifests with either predominant nigrostriatal or cerebellopontine degeneration. This corresponds to two different phenotypes, one with predominant Parkinson's symptoms (MSA-P [multiple system atrophy-parkinsonian subtype]) and one with predominant cerebellar deficits (MSA-C [multiple system atrophy-cerebellar subtype]). Both nigrostriatal and cerebellar degeneration can lead to impaired dexterity, which is a frequent cause of disability in MSA. The aim was to disentangle the contribution of nigrostriatal and cerebellar degeneration to impaired dexterity in both subtypes of MSA. We thus investigated nigrostriatal and cerebellopontine integrity using diffusion microstructure imaging in 47 patients with MSA-P and 17 patients with MSA-C compared to 31 healthy controls (HC). Dexterity was assessed using the 9-Hole Peg Board (9HPB) performance. Nigrostriatal degeneration, represented by the loss of cells and neurites, leading to a larger free-fluid compartment, was present in MSA-P and MSA-C when compared to HCs. Whereas no intergroup differences were observed between the MSAs in the substantia nigra, MSA-P showed more pronounced putaminal degeneration than MSA-C. In contrast, a cerebellopontine axonal degeneration was observed in MSA-P and MSA-C, with stronger effects in MSA-C. Interestingly, the degeneration of cerebellopontine fibers is associated with impaired dexterity in both subtypes, whereas no association was observed with nigrostriatal degeneration. Cerebellar dysfunction contributes to impaired dexterity not only in MSA-C but also in MSA-P and may be a promising biomarker for disease staging. In contrast, no significant association was observed with nigrostriatal dysfunction. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Urodynamic Study in Multiple System Atrophy: A Retrospective Observational Study.

This retrospective study aimed to evaluate the characteristics of neurogenic bladder in patients with multiple systemic atrophy and distinguish between cerebellar and parkinsonian-type urodynamic patterns. We reviewed 19 patients diagnosed with multiple systemic atrophy with low urinary tract symptoms who underwent an urodynamic study at Pusan National University Yangsan Hospital between March 2010 and February 2022. This study did not account for the differences observed between the multiple system atrophy subtypes in the voiding phase. Urodynamic study is an effective tool to understand the complicated bladder pattern in patients with multiple system atrophy.

Morphological differences between the two major subtypes of multiple system atrophy with cognitive impairment

ObjectiveTo compare the neuropathology between two types of multiple system atrophy - parkinsonism-predominant (MSA-P) and cerebellar ataxia-predominant (MSA-C) with cognitive impairment. Material & methods35 cases of MSA-P (mean age at death 60.5 ± 7.8 years) and 15 cases of MSA-C (mean age at death 61.3 ± 6.8 years), 35.% of which associated with mild to moderate cognitive impairment and one with severe dementia, were examined neuropathologically with semiquantitative evaluation of both α-synuclein and Alzheimer pathologies, including cerebral amyloid angiopathy (CAA) and other co-pathologies. ResultsWhile the mean age at death of both MSA subgroups was similar, the age at onset and duration of disease were slightly higher in the MSA-C group. In line with the classification, the αSyn pathology glial and neuronal inclusions in both the cortex and brainstem were significantly higher in the MSA-P group. With regard to the Alzheimer disease pathology, tau load in cases with mild to moderate cognitive impairment was slightly but not significantly higher in the MSA-P group, one with severe dementia showing fully developed Alzheimer co-pathology, while the amyloid-β (Aβ) load including the CAA was higher in the MSA-C group. The presence of Lewy co-pathology in this series (20%), being similar to that of other MSA cohorts, was more frequent in MSA cases with mild to severe cognitive impairment, but did not differ between the two subgroups and seems not essentially important for MCI in MSA. ConclusionsIn agreement with previous clinical studies that reported more severe cognitive dysfunction in patients with MSA-P, the present neuropathological study showed increased tau pathology in MSA-P and one with severe Alzheimer co-pathology, but only slightly increased amyloid pathology in the MSA-C group. Lewy co-pathology was more frequent in MSA-P cases with cognitive decline. In view of the limited data about the pathobiological basis of cognitive impairment in MSA, further studies to elucidate the differences between the two phenotypes are urgently needed.

Comparison of the second consensus statement with the movement disorder society criteria for multiple system atrophy: A single-center analysis

IntroductionThis study aimed at comparing the differences between the second consensus statement and Movement Disorder Society (MDS) criteria for Multiple System Atrophy (MSA) in a single Chinese cohort. MethodsWe retrospectively reviewed 73 patients with MSA over the past five years. They were categorized as patients with probable and possible MSA according to the second consensus statement in addition to clinically established and clinically probable MSA according to the MDS criteria. The core clinical, supportive clinical, and imaging features were analyzed and compared between the two MSA subtypes. ResultsA total of 40 patients with MSA-P and 33 patients with MSA-C were included in this study. Approximately 78.7% of the category of probable patients in the second consensus statement can be categorized as clinically established MSA in the MDS criteria and five patients with non-supporting features in the second consensus statement criteria can be diagnosed as clinically probable MSA in the MDS criteria. “Rapid progression” and “moderate to severe postural instability” within three years of motor onset dominated among the supportive features. Approximately 78.9% of patients possessed at least one imaging marker with predominant signal decrease of putamen on iron-sensitive sequences (38.0% of patients). Twenty-two patients could not be diagnosed as clinically established MSA mainly due to the lack of supportive or imaging features. ConclusionsA high degree of agreement was noticed between the two criteria sets. The supportive and imaging features played important role in the diagnosis of MSA and affected the diagnostic level in the current criteria.

Clinical polymorphism of multiple system atrophy: a clinical case series

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomous insufficiency and motor abnormalities, such as akinetic rigid syndrome and cerebellar ataxia. The diagnosis of this disorder is challenging, and quite frequently the patients are seen by other specialties or with other diagnoses. The paper presents three clinical observations of patients with various phenotypic MSA subtypes. In two of them, the diagnosis of MSA was clinically proven and in the third one, clinically probable. All patients were initially followed up with other diagnoses. The authors describe specifics of complaints and past history registration, neurological examination and typical signs of MSA at neuroimaging.

Somatic SNCA Copy Number Variants in Multiple System Atrophy are Related to Pathology and Inclusions.

Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains. The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions. We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP). We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions. The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Combined regional T1w/T2w ratio and voxel-based morphometry in multiple system atrophy: A follow-up study.

Several MRI techniques have become available to support the early diagnosis of multiple system atrophy (MSA), but few longitudinal studies on both MSA variants have been performed, and there are no established MRI markers of disease progression. We aimed to characterize longitudinal brain changes in 26 patients with MSA (14 MSA-P and 12 MSA-C) over a 1-year follow-up period in terms of local tissue density and T1w/T2w ratio in a-priori regions, namely, bilateral putamen, cerebellar gray matter (GM), white matter (WM), and substantia nigra (SN). A significant GM density decrease was found in cerebellum and left putamen in the entire group (10.7 and 33.1% variation, respectively) and both MSA subtypes (MSA-C: 15.4 and 33.0% variation; MSA-P: 7.7 and 33.2%) and in right putamen in the entire group (19.8% variation) and patients with MSA-C (20.9% variation). A WM density decrease was found in the entire group (9.3% variation) and both subtypes in cerebellum-brainstem (MSA-C: 18.0% variation; MSA-P: 5% variation). The T1w/T2w ratio increase was found in the cerebellar and left putamen GM (6.6 and 24.9% variation), while a significant T1w/T2w ratio decrease was detected in SN in the entire MSA group (31% variation). We found a more progressive atrophy of the cerebellum in MSA-C with a similar progression of putaminal atrophy in the two variants. T1w/T2w ratio can be further studied as a potential marker of disease progression, possibly reflecting decreased neuronal density or iron accumulation.

18 F-Florzolotau Tau Positron Emission Tomography Imaging in Patients with Multiple System Atrophy-Parkinsonian Subtype.

Anecdotal evidence suggests that patients diagnosed with the parkinsonian subtype of multiple system atrophy (MSA-P) may show uptake of the second-generation tau positron emission tomography (PET) tracer 18 F-Florzolotau (previously known as 18 F-APN-1607) in the putamen. This study systematically investigated the localization and magnitude of 18 F-Florzolotau uptake in a relatively large cohort of patients with MSA-P. 18 F-Florzolotau PET imaging was performed in 31 patients with MSA-P, 24 patients with Parkinson's disease (PD), and 20 age-matched healthy controls. 18 F-Florzolotau signal in the striatum was analyzed by visual inspection and classified as either positive or negative. Regional 18 F-Florzolotau binding was also expressed as standardized uptake value ratio (SUVR) to assess whether it was associated with core symptoms of MSA-P after adjustment for potential confounders. By visual inspection and semiquantitative SUVR comparisons, patients with MSA-P showed elevated 18 F-Florzolotau uptake in the putamen, globus pallidus, and dentate-a finding that was not observed in PD. This increased signal was significantly associated with the core symptoms of MSA-P. In addition, patients with MSA-P with cerebellar ataxia showed an elevated 18 F-Florzolotau uptake in the cerebellar dentate. 18 F-Florzolotau tau PET imaging findings may reflect the clinical severity of MSA-P and can potentially discriminate between this condition and PD. © 2022 International Parkinson and Movement Disorder Society.

COQ2 and SNCA polymorphisms interact with environmental factors to modulate the risk of multiple system atrophy and subtype disposition.

Multiple system atrophy (MSA) has no definitive genetic or environmental (G-E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G-E factors associated with MSA and its subtypes, MSA-P and MSA-C. A consecutive case-control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model. A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G-E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p&lt; 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671-0.847). Modulated risk of MSA-C, with MSA-P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p&lt; 0.05), with an AUC of 0.749 (95% CI=0.683-0.815). Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G-E interactions and MSA etiopathogenesis warrant further investigation.

Relationship Between Pneumonia and Dysphagia in Patients With Multiple System Atrophy.

IntroductionDysphagia is one of the most clinically significant disabilities in patients with multiple system atrophy (MSA), because it can cause aspiration pneumonia, which is potentially fatal. In this study, the Neuromuscular disease Swallowing Status Scale (NdSSS), which was developed to evaluate dysphagia in patients with neuromuscular diseases, was used to evaluate patients with MSA. In addition, correlation between a history of pneumonia and swallowing function was evaluated.MethodsStudy 1: Reliability, concurrent validity, and responsiveness of the NdSSS in patients with MSA. In 81 patients for whom evaluation items could be collected, the NdSSS was tested for its interrater and intrarater reliability using weighted kappa statistics. Concurrent validity was assessed by correlating the NdSSS with existing scales (Functional Oral Intake Scale (FOIS), Functional Intake LEVEL Scale (FILS), and the unified MSA rating scale (UMSARS)) using Spearman's rank correlation coefficients. Sixty-three patients were evaluated by videofluorographic (VF) swallowing examination. To evaluate concurrent validity, Spearman's rank correlation coefficients were calculated between the NdSSS and VF swallowing assessments. Additionally, scale responsiveness was determined using the standardized response mean (SRM) in 23 patients who could be followed up to assess their long-term course. Study 2: Cross-sectional survey of swallowing function and history of pneumonia. Data regarding history of pneumonia, UMSARS, NdSSS, age, sex, MSA subtype, and disease duration were retrospectively obtained from the medical records of 113 patients with MSA. Differences in these parameters and NdSSS stage between those with and without a history of pneumonia were examined using the Mann-Whitney test or chi-squared test. Furthermore, clinical factors related to a history of pneumonia were examined by binomial logistic regression analysis.ResultsThe NdSSS showed satisfactory reliability, concurrent validity, and responsiveness. A history of pneumonia was related to the severity of MSA, age, MSA subtype, and NdSSS stage. Binomial logistic regression analysis showed that NdSSS stage (odds ratio (OR), 0.490; 95% confidence interval (CI), 0.301–0.797, p = 0.001) and MSA subtype (OR, 4.031; 95% CI, 1.225–13.269, p = 0.021) were significantly associated with a history of pneumonia.ConclusionsIn patients with MSA, the NdSSS has sufficient reliability, concurrent validity, and responsiveness for assessing dysphagia. Patients with a history of pneumonia have more severe dysphagia. We found that the pneumonia risk was related to NdSSS stage and MSA-p (predominantly parkinsonism). Meticulous care to prevent aspiration is needed from early stages of the disease.

Improving the Accuracy of Diagnosis for Multiple-System Atrophy Using Deep Learning-Based Method.

Simple SummaryDiagnosis of neurodegenerative diseases requires examination of a variety of characteristics. A definitive diagnosis is obtained using a comprehensive evaluation of family history, neurological findings, brain imaging, genetic testing, and other medical information. Multiple-system atrophy (MSA) is a neurodegenerative disease associated with autonomic dysfunction, parkinsonism, and cerebellar ataxia, and early diagnosis is difficult because the disease changes over time. The aims of this study were to examine whether machine learning can improve diagnostic accuracy using MSA case data from a national survey, and to identify the features that are important for differentiation among MSA subtypes using machine learning.Multiple-system atrophy (MSA) is primarily an autonomic disorder with parkinsonism or cerebellar ataxia. Clinical diagnosis of MSA at an early stage is challenging because the symptoms change over the course of the disease. Recently, various artificial intelligence-based programs have been developed to improve the diagnostic accuracy of neurodegenerative diseases, but most are limited to the evaluation of diagnostic imaging. In this study, we examined the validity of diagnosis of MSA using a pointwise linear model (deep learning-based method). The goal of the study was to identify features associated with disease differentiation that were found to be important in deep learning. A total of 3377 registered MSA cases from FY2004 to FY2008 were used to train the model. The diagnostic probabilities of SND (striatonigral degeneration), SDS (Shy-Drager syndrome), and OPCA (olivopontocerebellar atrophy) were estimated to be 0.852 ± 0.107, 0.650 ± 0.235, and 0.858 ± 0.270, respectively. In the pointwise linear model used to identify and visualize features involved in individual subtypes, autonomic dysfunction was found to be a more prominent component of SDS compared to SND and OPCA. Similarly, respiratory failure was identified as a characteristic of SDS, dysphagia was identified as a characteristic of SND, and brain-stem atrophy was identified as a characteristic of OPCA.

Diagnostic efficacy of the magnetic resonance T1w/T2w ratio for the middle cerebellar peduncle in multiple system atrophy and spinocerebellar ataxia: A preliminary study.

The standardized T1-weighted/T2-weighted (sT1w/T2w) ratio for the middle cerebellar peduncle (MCP) has been reported to be sensitive for detecting degenerative changes in the cerebellar subtype of multiple system atrophy (MSA-C), even in the early stages. We aimed to investigate the diagnostic value of the MCP sT1w/T2w ratio for differentiating between MSA-C and spinocerebellar ataxia (SCA). We included 32 MSA-C, 8 SCA type 3 (SCA3), 16 SCA type 6 (SCA6) patients, and 17 controls, and the MCP sT1w/T2w ratio was analyzed using a region-of-interest approach. The diagnostic performance of the MCP sT1w/T2w ratio in discriminating among MSA-C, SCA3, and SCA6 was assessed and compared with diagnosis based on visual interpretation of MCP hyperintensities and the "hot cross bun" (HCB) sign. MCP sT1w/T2w ratio values were markedly lower in patients with MSA-C than in those with SCA3, those with SCA6, and controls (p < 0.001). The MCP sT1w/T2w ratio showed high diagnostic accuracy for distinguishing MSA-C from SCA3 (area under curve = 0.934), SCA6 (area under curve = 0.965), and controls (area under curve = 0.980). The diagnostic accuracy of the MCP sT1w/T2w ratio for differentiating MSA-C from SCA3 or SCA6 (90.0% for MSA-C vs. SCA3, and 91.7% for MSA-C vs. SCA6) was comparable to or superior than that of visual interpretation of MCP hyperintensities (80.0-87.5% in MSA-C vs. SCA3 and 87.6-97.9% in MSA-C vs. SCA6) or the HCB sign (72.5-80.0% in MSA-C vs. SCA3 and 77.1-93.8% in MSA-C vs. SCA6). The MCP sT1w/T2w ratio might be a sensitive imaging-based marker for detecting MSA-C-related changes and differentiating MSA-C from SCA3 or SCA6.

The Frontal and Cerebellar Metabolism Related to Cognitive Dysfunction in Multiple System Atrophy.

BackgroundCognitive dysfunctions have been reported in multiple system atrophy (MSA). However the underlying mechanisms remain to be elucidated. This study aimed to explore the possible cerebral metabolism associated with domain-specific cognitive performances in MSA.MethodsA total of 84 patients were diagnosed as probable or possible MSA, comprised of 27 patients as MSA with predominant parkinsonism (MSA-P) and 57 patients as MSA with predominant cerebellar ataxia (MSA-C). The comprehensive neuropsychological tests and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging were performed. Z-score was calculated to non-dimensionalize and unify indicators of different tests in the domains of executive function, attention, language, memory, and visuospatial function. Correlations between specific Z-score and cerebral 18F-FDG uptake were analyzed using statistical parametric mapping. The cognition-related metabolic differences between patients with MSA-P and MSA-C were analyzed using the post-hoc test.ResultsZ-scores of the domains including attention, executive function, and language correlated positively with the metabolism in the superior/inferior frontal gyrus and cerebellum, but negatively with that in the insula and fusiform gyrus (p < 0.001). No significant differences in neuropsychological performances and frontal metabolism were found between patients with MSA-P and MSA-C. Only lower metabolism in the cerebellum was observed in MSA-C.ConclusionMetabolic changes in the frontal lobe and cerebellum may participate in the cognitive impairments of patients with MSA. Nevertheless, cognitive and corresponding metabolic differences between the two subtypes of MSA still need more exploration.

Excessive Daytime Sleepiness Is Associated With Non-motor Symptoms of Multiple System Atrophy: A Cross-Sectional Study in China.

Objectives: Excessive daytime sleepiness (EDS) in multiple system atrophy (MSA) has received scant attention in the literature, thus the present cross-sectional study aimed to investigate the prevalence of EDS and its potential risk factors among Chinese patients with MSA.Methods: A total of 66 patients with MSA (60.6% males) were consecutively recruited. Eighteen patients (27.3%, 13 men) with Epworth Sleepiness Scale score >10 were defined as having EDS. Demographic, motor [Unified Multiple-System Atrophy (UMSARS)] and non-motor symptoms [Non-Motor Symptoms Scale (NMSS)], and sleep parameters [polysomnography (PSG)] were compared between patients with MSA with and without EDS. A logistic regression analysis was used to calculate the risk factors of EDS in patients with MSA.Results: There were no significant differences in age, sex, MSA onset age, disease duration, MSA sub-type, and motor symptom severity between MSA patients with and without EDS. However, compared with the MSA patients without EDS, their counterparts with EDS had higher scores of NMSS (65.3 ± 23.1 vs. 43.4 ± 25.3, P = .0002), Hamilton Anxiety (HAMA) [15.3 (10.3–20.0) vs. 9.5 (3.0–15.0), P = 0.006], Hamilton Depression (HAMD) [13.7 (12.5–17.8) vs. 9.0 (4.0–13.0), P = 0.015], and Fatigue Severity Scale (FSS) [29.8 (17.3–47.8) vs. 18.7 (10.3–21.8), P = 0.040]. Conversely, the patients with EDS had lower score of Mini-Mental State Examination (MMSE) [23.3 (20.3–27.0) vs. 25.7 (22.0–29.0), P = 0.023]. Similarly, there was a significantly lower percentage of N3 sleep (%) [0.3 (0–0) vs. 2.0 (0–0), P = 0.007] and a higher apnea-hypopnea index (AHI/h) [30.5 (14.5–47.8) vs. 19.3 (5.0–28.7), P = 0.034] in patients with EDS. After adjusting for age, sex, disease duration, MSA sub-type, and UMSARS score, the odds ratio (OR) (95% CI) of EDS was higher while increasing scores in FSS [1.06 (1.02–1.11)], HAMA [1.16 (1.04–1.28)], HAMD [1.13 (1.02–1.25)], NMSS [1.04 (1.01–1.07)], and AHI [1.03 (1.00–1.10)]. The OR of EDS was lower while the MMSE score was increasing [0.85 (0.72–1.00)].Conclusions: The presence and severity of EDS may be significantly associated with the non-motor dysfunction, including fatigue, anxiety, depression, cognitive dysfunction, and sleep-related breathing disorder, but not with the motor dysfunction in MSA.

Homer-3 Antibody Disease: A Potentially Treatable MSA-C Mimic.

Homer-3 Antibody Disease: A Potentially Treatable MSA-C Mimic.

Long-standing multiple system atrophy-Parkinsonism with limbic and FTLD-type α-synuclein pathology.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically marked by autonomic failure and variable degrees of parkinsonism and cerebellar ataxias. The average age of onset is in the sixth decade of life with a five-year survival, although fulminant and more benign courses have been described (1). The pathologic hallmark of MSA is abundant α-synuclein-positive protein aggregates within oligodendrocytes (glial cytoplasmic inclusions, GCI) and neurons (neuronal cytoplasmic inclusions, NCI, and neuronal nuclear inclusions, NNI). The density of GCIs has been correlated with disease duration and severity of neuronal loss (2). Here, we present an unusual case of MSA clinically characterized by rapid decline followed by a 20-year disease duration in a severely affected state. At autopsy, the brain showed severe gliosis and neuronal loss in a pattern characteristic of MSA. Additionally, there were atypical Pick body-like and ring-shaped α-synuclein inclusions, most prominent in limbic regions, consistent with a recently described subtype of MSA designated "atypical MSA" (3). Four different α-synuclein antibodies highlighted only scant α-synuclein-positive pathology; however, Gallyas and Campbell-Switzer silver stains identified additional GCIs most prominent in subcortical white matter. Interestingly, many of the α-synuclein-positive limbic inclusions were Gallyas-negative, while many of the Gallyas-positive inclusions were α-synuclein-negative (4). This observation of markedly disparate α-synuclein immunohistochemical versus Gallyas reactivity of MSA inclusions is unusual and could support the possibility that MSA inclusions have variable compositions, something which has been recently suggested (5).