Progression Of Multiple System Atrophy Research Articles

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials.

Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts.

Role of complement activation and disruption of the blood–brain barrier in the pathogenesis of multiple system atrophy

Multiple system atrophy (MSA) is a progressive and sporadic neurodegenerative disorder characterized by the histological appearance of glial cytoplasmic inclusions primarily composed of α-synuclein. Recently, complement-mediated neuroinflammation has been proposed as a key factor in the pathogenesis of numerous neurodegenerative disorders. We conducted immunohistochemical/immunofluorescent assays targeting a number of complements to explore the role of complements in MSA pathogenesis using brain samples from deceased patients and controls. Complement deposition was notably increased in the cerebral vasculature and myelin sheath in the MSA brains. Furthermore, fibrinogen leakage resulting from the disruption of the blood–brain barrier (BBB) was observed, along with the presence of C1q-positive microglia clusters surrounding the MSA brain vessels. These immunohistochemical/immunofluorescent findings suggest that complement activation and BBB disruption play critical roles in MSA progression.

Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies.

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson’s disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies.We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson’s disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data.α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson’s disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson’s disease clinical scores (e.g. Unified Parkinson’s Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson’s disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson’s disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity.In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson’s disease and may provide a way to distinguish variations within Parkinson’s disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson’s disease. The assay distinguished multiple system atrophy patients from Parkinson’s disease patients and in contrast to Parkinson’s disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

REM Sleep Behaviour Disorder in Multiple System Atrophy: From Prodromal to Progression of Disease.

A higher frequency of motor and breathing sleep-related disorders in multiple system atrophy (MSA) populations is reported. REM sleep behaviour disorder (RBD) is one of the most robust markers of an underlying alpha-synucleinopathy. Although a large corpus of literature documented the higher prevalence of RBD in MSA, few studies have systematically investigated the prevalence of RBD as mode of disease onset and its role in disease progression. Moreover, there has been increasing interest in phenoconversion into synucleinopathies of cohorts of patients with isolated RBD (iRBD). Finally, some studies investigated RBD as predictive factor of conversion in isolated autonomic failure, a synucleinopathy presenting with autonomic failure as the sole clinical manifestation that could convert to a manifest central nervous system synucleinopathy. As the field of neurodegenerative disorders moves increasingly towards developing disease-modifying therapies, detecting individuals in the prodromal stage of these synucleinopathies becomes crucial. The aims of this review are to summarise (1) the prevalence of RBD during the course of MSA and as presenting feature of MSA (iRBD), (2) the RBD features in MSA, (3) MSA progression and prognosis in the subgroup of patients with RBD predating disease onset, and (4) the prevalence of MSA conversion in iRBD cohorts. Moreover, we summarise previous results on the role of RBD in the context of isolated autonomic failure as marker of phenoconversion to other synucleinopathies and, in particular, to MSA.

Reliability and validity of Japanese version of Unified Multiple System Atrophy Rating Scale

AbstractBackground/AimThe Unified Multiple System Atrophy Rating Scale (UMSARS) has been broadly used to assess the progression of multiple system atrophy (MSA). In this study, we translated UMSARS into Japanese and tested the reliability and validity of the translated version for the assessment of Japanese patients with MSA.MethodUMSARS was translated into Japanese. For the evaluation of the reliability of the translated version, 60 and 70 participants with MSA were assessed by two neurologists using the Japanese versions of UMSARS‐I and UMSARS‐II, respectively. For the validation, 70 participants with MSA were evaluated by one neurologist using the Japanese versions of UMSARS‐I and UMSARS‐II, and other scales. Cronbach's alpha coefficient, Cohen's kappa coefficient [κ (w)], and Spearman rank correlation were calculated.ResultsCronbach's alpha coefficients of the Japanese versions of UMSARS‐I and UMSARS‐II were 0.87 and 0.90, respectively. The κ (w) values of UMSARS‐I and UMSARS‐II items were 0.61‐0.81 and 0.51‐0.86, respectively. The total UMSARS‐I score correlated well with the scores of Barthel Index, Schwab and England Activities of Daily Living Scale, Functional Independence Measure, and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) part 2 (Spearman rank correlations, −0.75, −0.71, −0.82, and 0.81, respectively). The total UMSARS‐II score correlated well with the scores of International Cooperative Ataxia Rating Scale and MDS‐UPDRS part 3 (Spearman rank correlations, 0.85 and 0.86, respectively).ConclusionsThe Japanese version of UMSARS is reliable and valid for the assessment of the clinical severity of MSA in Japan.

Elevated Percentage of CD3+ T-Cells and CD4+/CD8+ Ratios in Multiple System Atrophy Patients.

α-synuclein is involved in the pathogenesis of multiple system atrophy (MSA) and can be regulated by peripheral immune activation (PIA). We aimed to clarify the correlations between PIA and the prevalence of MSA and to analyze the role of PIA in the progression of the disease. A total of 321 patients with probable MSA and 321 age- and gender-matched healthy controls were included in this study. Lymphocyte subsets, including CD3+, CD4+, and CD8+ cells, and the levels of immunoglobulins IgG, IgM, and IgA were evaluated. The proportions of CD3+ and CD4+ T-lymphocytes were significantly increased in MSA patients compared with those of normal controls. In addition, the ratio of CD4+ to CD8+ cells was significantly increased in male MSA patients and IgG concentrations were decreased in female MSA patients. Furthermore, the concentrations of IgM in female MSA patients were dynamically different at various disease stages and gradually decreased from the early stage until the end stage of the disease (p = 0.029). Other detected immunological indexes were not significantly different during the entire disease course. In this study, high proportions of CD3+ and CD4+ T-lymphocytes and decreased IgG levels were associated with an increased risk for MSA in a Chinese patient population. In addition, PIA may be involved in the progression of MSA.

Serum miR-30c-5p is a potential biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease that belongs to the α synucleinopathies. Clinically, there is an overlap between MSA and Parkinson's disease (PD), especially at the early disease stage. However, these two pathologies differ in terms of disease progression. Currently, no biomarker exists to differentiate MSA from PD. MicroRNAs are non-coding RNAs implicated in gene expression regulation. MiRNAs modulate cellular activity and they control a range of physiological and pathological functions. miRNAs are found in biofluids, such as blood, serum, plasma, saliva, and cerebrospinal fluid. Many groups, including ours, found that circulating miRNAs are differently expressed in blood, plasma, serum and cerebrospinal fluid of PD and MSA patients. In the present study, our primary aim was to determine if serum mir-30-5p and mir-148b-5p can be used as biomarkers for early diagnosis of PD and/or MSA. Our secondary goal was to determine if serum levels of those miRNAs can be correlated with the patients' clinical profile. Using quantitative PCR (qPCR), we evaluated expression levels of miR-30c-5p and miR148b-5p in serum samples from PD (n = 56), MSA (n = 49), and healthy control (n = 50) subjects. We have found that miR-30c-5p is significantly upregulated in MSA if compared with PD and healthy control subjects. Moreover, serum miR-30c-5p levels correlate with disease duration in both MSA and PD. No significant difference was found in miR-148b-5p among MSA, PD and healthy control subjects. Our results suggest a possible role of serum miR-30-5p as a biomarker for diagnosis and progression of MSA.

Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy.

SummaryMultiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets.

Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting α-syn modified for improved central nervous system penetration (CD5-D5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-α-syn transgenic mouse model of MSA. While the use of either CD5-D5 or lenalidomide alone had positive effects on neuroinflammation and/or α-syn accumulation in this mouse model of MSA, the combination of both approaches yielded better results than each single treatment. The combined treatment reduced astrogliosis, microgliosis, soluble and aggregated α-syn levels, and partially improved behavioral deficits in MBP-α-syn transgenic mice. These effects were associated with an activation of the Akt signaling pathway, which may mediate cytoprotective effects downstream tumor necrosis factor alpha (TNFα). These results suggest that a strategic combination of treatments may improve the therapeutic outcome in trials for MSA and related neurodegenerative disorders.

Oxidative Stress and Environmental Exposures are Associated with Multiple System Atrophy in Chinese Patients.

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). The aim of this study is to examine oxidant biomarkers including homocysteine (Hcys), bilirubin, uric acid, lipids, and potential environmental risk factors and to ascertain whether these data correlate with MSA in a Chinese population. In this study, serum levels of Hcys, bilirubin, uric acid, and lipids were studied in 55 MSA patients and 76 healthy controls (HCs). Education, anti-parkinsonian agent usage, smoking, drinking, farming, and living area of the subjects also were analyzed. The Unified MSA Rating Scale (UMSARS), Hoehn & Yahr stage, International Cooperative Ataxia Rating Scale, and Mini-Mental State Examination were used to assess the disease severity, the parkinsonism, ataxia, and the cognitive ability of MSA, respectively. The levels of Hcys were higher (p<0.001) and those of total bilirubin (p=0.007), indirect bilirubin (p=0.011), and total cholesterol (p=0.046) were lower in MSA patients than in healthy controls, whereas uric acid levels did not differ significantly between MSA and healthy controls. Moreover, Hcys levels in MSA patients had positive correlations with illness duration (r s =0.422, p=0.001) and UMSARS-I (r s =0.555, p<0.001), respectively. High-density lipoprotein cholesterol levels were negatively correlated with UMSARS-I (r s =-0.325, p=0.015). Farming was more frequent in MSA patients (1-20 years: odds ratio, 6.36; p20 years: odds ratio, 10.26; p=0.001), whereas current smoking was less frequent (odds ratio, 0.13, p=0.002). Elevated Hcys and decreased high-density lipoprotein cholesterol may be associated with the disease severity of MSA. Environmental exposures such as farming and smoking may contribute to the occurrence but not the progression of MSA.

Serum creatinine is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population

Objectives: Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Creatine, which is converted to creatinine, has an anti-oxidative effect. Our aim is to clarify the correlations between creatinine and the occurrence as well as the progression of MSA.Methods: A total of 115 patients with probable MSA and 115 age- and gender-matched healthy controls were included in the study. The serum creatinine level of all patients and controls were evaluated and compared.Results: The mean age of MSA patients was 58.18 ± 8.67 years and the mean disease duration was 2.85 ± 1.71 years. The creatinine level of MSA patients was significantly lower than that of healthy controls (P < 0.0001). The occurrence of MSA was decreased in the highest creatinine quartiles compared with the lowest creatinine quartiles. In a gender-specific analysis, patients with the highest quartiles and second quartiles of creatinine level had decreased occurrence than patients with the lowest quartile in females, but not in males. The serum level of creatinine was not found correlated with the mean rate of annualised changes, neither with other independent factors, such as age, body mass index (BMI), sex, Unified MSA Rating Scale (UMSARS) scores and disease duration at the initial visit in patients with MSA.Conclusion: High level of serum creatinine may be associated with a low occurrence of MSA in Chinese population, especially in female. However, serum creatinine does not deteriorate or ameliorate the progression of MSA.

Expanding the spectrum of neuronal pathology in multiple system atrophy.

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy.

Diagnosis and differential diagnosis of MSA: boundary issues.

Because the progression of multiple system atrophy (MSA) is usually rapid and there still is no effective cause-related therapy, early and accurate diagnosis is important for the proper management of patients as well as the development of neuroprotective agents. However, despite the progression in the field of MSA research in the past few years, the diagnosis of MSA in clinical practice still relies largely on clinical features and there are limitations in terms of sensitivity and specificity, especially in the early course of the disease. Furthermore, recent pathological, clinical, and neuroimaging studies have shown that (1) MSA can present with a wider range of clinical and pathological features than previously thought, including features considered atypical for MSA; thus, MSA can be misdiagnosed as other diseases, and conversely, disorders with other etiologies and pathologies can be clinically misdiagnosed as MSA; and (2) several investigations may help to improve the diagnosis of MSA in clinical practice. These aspects should be taken into consideration when revising the current diagnostic criteria. This is especially true given that disease-modifying treatments for MSA are under investigation.

Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy.

Multiple system atrophy (MSA) is a distinct member of a group of neurodegenerative diseases known as α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein in the brain. MSA is unique in that the principal site for α-synuclein deposition is in the oligodendrocytes rather than neurons. The cause of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Brain transcriptome perturbations during the onset and progression of MSA are mostly unknown. Using RNA sequencing, we performed a comparative transcriptome profiling analysis of the grey matter (GM) and white matter (WM) of the frontal cortex of MSA and control brains. The transcriptome sequencing revealed increased expression of the alpha and beta haemoglobin genes in MSA WM, decreased expression of the transthyretin (TTR) gene in MSA GM and numerous region-specific long intervening non-coding RNAs (lincRNAs). In contrast, we observed only moderate changes in the expression patterns of the α-synuclein (SNCA) gene, which confirmed previous observations by other research groups. Our study suggests that at the transcriptional level, MSA pathology may be related to increased iron levels in WM and perturbations of the non-coding fraction of the transcriptome.

Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

Serum lipid levels are associated with the prevalence but not with the disease progression of multiple system atrophy in a Chinese population

Objectives: Alpha-synuclein is involved in the pathogenesis of multiple system atrophy (MSA) and can be regulated by lipids. This study aims to validate the correlation between lipid levels and the prevalence of MSA as well as its progression.Methods: A total of 234 patients with probable MSA and 240 age- and gender-matched healthy controls were included in this study. Lipid contents, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), were evaluated. The unified MSA rating scale (UMSARS) was used to assess the severity of MSA.Results: Lipid levels in MSA patients were significantly lower than those in healthy controls. Patients with MSA-C were significantly younger, had higher body mass indices (BMIs), higher UMSARS scores, and lower HDL-C contents compared with MSA-P patients. Subjects with the lowest quartiles and the second quartiles of total cholesterol, LDL-C, and HDL-C had high prevalence of MSA compared with subjects with the highest quartiles. No correlation was found between the mean rate of annualized changes and serum levels of lipids as well as other independent factors, such as age, BMI, gender, subtypes (C-type or P-type), and disease duration at the initial visit, in 107 followed-up MSA patients.Discussion: Low levels of total cholesterol, LDL-C, HDL-C, and TG increased the prevalence of MSA in a Chinese population. Patients with MSA-C showed significantly lower levels of HDL-C than MSA-P patients. However, lipids did not deteriorate or improve the progression of MSA.

Uric acid is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Uric acid has an antioxidative effect. Our aim is to clarify the correlations between serum uric acid and MSA in Chinese population. A total of 234 patients with probable MSA and 240 age- and gender- matched healthy controls were included in the study. The serum uric acid levels of all the patients and controls were evaluated. The Unified MSA Rating Scale (UMSARS) was used to assess the severity and the mean rate of annualized changes of UMSARS to assess the progression of MSA. The mean age of MSA patients was 58.90 ± 9.00 years and the mean disease duration was 2.60 ± 1.75 years. The serum uric acid levels of MSA patients were significantly lower than that of controls in males (p = 0.0001). The occurrence of MSA was increased in the lowest uric acid quartiles compared with the highest uric acid quartiles (p = 0.005). In a gender-specific analysis, increased occurrence was found in the lowest quartiles and second quartiles compared with the highest quartiles in males (p = 0.001 and p = 0.0001 respectively), but not in females. No correlation was found between the mean rate of annualized changes and serum levels of uric acid, as well as other independent factors, such as age, BMI, gender, subtype (C-type or P-type) and disease duration at the initial visit in 107 followed-up patients. MSA patients have lower levels of serum uric acid than controls. High levels of serum uric acid may be associated with a lower prevalence of MSA in the Chinese population, especially in males. However, serum uric acid does not deteriorate or ameliorate the progression of MSA.

Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA Study Group (EMSA SG)

The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P<0.0001) and UMSARS I scores by 35.6% (P<0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Longitudinal change in REM sleep components in a patient with multiple system atrophy associated with REM sleep behavior disorder: paradoxical improvement of nocturnal behaviors in a progressive neurodegenerative disease

A 60-year-old patient with multiple system atrophy (MSA) who presented with rapid eye movement (REM) sleep behavior disorder was investigated longitudinally by all-night polysomnography. REM sleep components, i.e. rapid eye movements and chin muscle activity, were analyzed together with the frequency of behaviors/movements on the videorecording. Decreased frequency of elaborate motor activity during REM sleep with time in this patient was compatible with the observation by his wife, and this change seemed to correlate with predominant tonic chin electromyogram with relatively suppressed phasic chin muscle activity, but the reduction of the REM sleep behavior disorder (RBD) episodes could be interpreted as being due to the increased rigidity along with MSA progression. The chronological change in REM sleep components in RBD with neurological disorders is worth studying in large follow-up series to enlarge our knowledge about the mechanism of behavioral manifestation of RBD in humans.