Multiple System Atrophy Patients Research Articles

Ligand Profiling as a Diagnostic Tool to Differentiate Patient-Derived α-Synuclein Polymorphs.

Amyloid fibrils are characteristic of many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. While different diseases may have fibrils formed of the same protein, the supramolecular morphology of these fibrils is disease-specific. Here, a method is reported to distinguish eight morphologically distinct amyloid fibrils based on differences in ligand binding properties. Eight fibrillar polymorphs of α-synuclein (αSyn) were investigated: five generated de novo using recombinant αSyn and three generated using protein misfolding cyclic amplification (PMCA) of recombinant αSyn seeded with brain homogenates from deceased patients diagnosed with Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Fluorescence binding assays were carried out for each fibril using a toolkit of six different ligands. The fibril samples were separated into five categories based on a binary classification of whether they bound specific ligands or not. Quantitative binding measurements then allowed every fibrillar polymorph to be uniquely identified, and the PMCA fibrils derived from PD, MSA, and DLB patients could be unambiguously distinguished. This approach constitutes a novel and operationally simple method to differentiate amyloid fibril morphologies and to identify disease states using PMCA fibrils obtained by seeding with patient samples.

Detection of α-Synuclein in Oral Mucosa by Seed Amplification Assay in Synucleinopathies and Isolated REM Sleep Behavior Disorder.

Evidence of abnormal α-synuclein (α-Syn) deposition in the brain is required for definitive diagnosis of synucleinopathies, which remains challenging. The seed amplification assay (SAA) is an innovative technique that can detect the seeding activity of misfolded α-Syn, enabling the amplification and detection of minute quantities of pathogenic α-Syn aggregates. This study aimed to evaluate oral mucosa α-Syn SAA as possible diagnostic and prodromal biomarkers for synucleinopathies. A total of 107 Parkinson's disease (PD) patients, 99 multiple system atrophy (MSA) patients, 33 patients with isolated rapid eye movement sleep behavior disorder (iRBD) and 103 healthy controls (HC) were included. The SAA was applied to detect the seeding activity of α-Syn from oral mucosa. A combination of morphological, biochemical, and biophysical methods was also used to analyze the fibrils generated from the oral mucosa α-Syn SAA. Structured illumination microscopy images revealed the increased α-Syn species in oral mucosa of PD, MSA, and iRBD patients than in HCs. Oral mucosa α-Syn SAA distinguished patients with PD from HC with 67.3% sensitivity and 90.3% specificity. Oral mucosa was α-Syn SAA positive in 53.5% MSA patients and 63.6% iRBD patients. Furthermore, the α-Syn fibrils generated from MSA demonstrated greater resistance to proteinase K digestion and exhibited stronger cytotoxicity compared to those from PD patients. Oral mucosa α-Syn seeding activity may serve as novel non-invasive diagnostic and prodromal biomarkers for synucleinopathies. The α-Syn aggregates amplified from the oral mucosa of PD and MSA exhibited distinct biochemical and biophysical properties. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognition in Multiple System Atrophy patients: The impact of sex and motor phenotype

Cognition in Multiple System Atrophy patients: The impact of sex and motor phenotype

Severity of sleep apnea as a prognostic factor for mortality in patients with multiple system atrophy

BackgroundWe determined whether the severity of sleep apnea increases the risk of mortality in patients with multiple system atrophy (MSA) with and without stridor.MethodsThis retrospective study included patients who underwent polysomnography within one year after diagnosis of probable MSA. Stridor, sleep apnea, and arousal from sleep were determined using full-night polysomnography. Disease severity was measured using the Unified MSA Rating Scale (UMSARS). Survival data were collected and analyzed using Cox regression analysis. ResultsSixty-four patients with MSA were included. During a median follow-up of 34.5 months, 49 (76.6 %) patients died. Stridor was present in 56.3 % of patients. Patients with stridor had more severe sleep apnea and shorter sleep time than those without, but the hazard ratio (HR) for death did not differ between patients with and without stridor. Among patients without stridor, apnea-hypopnea index ≥30/h (HR, 6.850; 95 % confidence interval [CI], 1.983–23.664; p = 0.002) and a score of UMSARS I + II (HR, 1.080; 95 % CI, 1.040–1.121; p < 0.001) were independently associated with death. In contrast, among patients with stridor, frequent arousals from sleep (HR, 0.254; 95 % CI, 0.089–0.729; p = 0.011) were a significant factor associated with longer survival, while MSA-cerebellar type tended to be associated with poor survival (HR, 2.195; 95 % CI, 0.941–5.120; p = 0.069). ConclusionThe severity of sleep apnea might be a significant predictor of shorter survival in MSA patients without stridor, whereas frequent arousals from sleep might be a significant predictor for longer survival in MSA patients with stridor.

Comparison of autonomic dysfunction in patients with Parkinson's Disease, progressive supranuclear palsy, and multiple system atrophy.

To assess and compare autonomic nervous system (ANS) dysfunction, especially cardiovascular dysautonomia, in Parkinson's Disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls. Assessment of ANS can be useful in differential diagnosis. Dysautonomia affects quality of life and can lead to potentially life-threatening complications. There is very little literature data regarding dysautonomia in PSP in relation to other parkinsonian syndromes. This study expands the knowledge about ANS dysfunction in parkinsonisms, especially PSP. Patients with PD, MSA and PSP were prospectively recruited to our study. Demographic data and information about clinical and neuropsychological assessment, medication and comorbidities was collected. SCOPA-AUT questionnaire, 5-minute tilt test, and 5-minute heart rate variability (HRV) analysis in time and frequency domains were used to assess ANS. Analysis was also performed in patients with PSP-RS and PSP-P phenotypes, and in a subgroup with eliminated confounding factors, including age and disease duration. 76 PD, 25 PSP, and 12 MSA patients, and 20 controls, were included. Symptoms of dysautonomia revealed by a SCOPA-AUT questionnaire were present in all groups of patients. Urinary dysfunction was more pronounced in atypical parkinsonisms, and cardiovascular symptoms in α-synucleinopathies. HRV was disrupted in all groups of patients. However, when PSP-P and PSP-RS phenotypes were considered, HRV was diminished in PSP-RS, but there were no differences in HRV parameters between PSP-P and controls. Neurogenic orthostatic hypotension was present in 25% of PD and 58% of MSA patients, but it was absent in PSP patients and the control group. 13 PD and nine PSP patients and 16 controls were included in subanalysis. This revealed that PSP, but not PD, patients had significantly more symptoms of dysautonomia and lower HRV indices compared to controls, and that orthostatic hypotension was even more common in PD than in controls. Our study suggests that dysautonomia is common in PD, MSA and PSP, even though it has different profiles in the different diseases. NOH is present in PD and MSA, but not in PSP.

Early Screening for the Parkinson Variant of Multiple System Atrophy: A 6-Item Score.

A 4-item score based on ≥2 features out of orthostatic hypotension, overactive bladder, urinary retention and postural instability was previously shown to early distinguish the Parkinson-variant of multiple system atrophy (MSA-P)from Parkinson's disease (PD) with 78% sensitivity and 86% specificity. To replicate and improve the 4-item MSA-P score. We retrospectively studied 161 patients with early parkinsonism [ie, ≤2 years disease duration or no postural instability, aged 64 (57; 68) years, 44% females] and a diagnosis of clinically established MSA-P (n = 38) or PD (n = 123) after ≥24 months follow-up. The 4-item MSA-P score had a 92% sensitivity and 78% specificity for a final MSA-P diagnosis. By including dopaminergic responsiveness and postural deformities into a 6-item score (range: 0-6), reaching ≥3 points at early disease identified MSA-P patients with 89% sensitivity and 98% specificity. The 6-item MSA-P score is a cost-effective tool to pinpoint individuals with early-stage MSA-P.

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.

Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study

ObjectiveFreezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. MethodLow-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. ResultsRegarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. ConclusionThis study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

The potential of phosphorylated α-synuclein as a biomarker for the diagnosis and monitoring of multiple system atrophy.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by the presence of glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-Syn). Accurate diagnosis and monitoring of MSA present significant challenges, which can lead to potential misdiagnosis and inappropriate treatment. Biomarkers play a crucial role in improving the accuracy of MSA diagnosis, and phosphorylated α-synuclein (p-syn) has emerged as a promising biomarker for aiding in diagnosis and disease monitoring. A literature search was conducted on PubMed, Scopus, and Google Scholar using specific keywords and MeSH terms without imposing a time limit. Inclusion criteria comprised various study designs including experimental studies, case-control studies, and cohort studies published only in English, while conference abstracts and unpublished sources were excluded. Increased levels of p-syn have been observed in various samples from MSA patients, such as red blood cells, cerebrospinal fluid, oral mucosal cells, skin, and colon biopsies, highlighting their diagnostic potential. The α-Syn RT-QuIC assay has shown sensitivity in diagnosing MSA and tracking its progression. Meta-analyses and multicenter investigations have confirmed the diagnostic value of p-syn in cerebrospinal fluid, demonstrating high specificity and sensitivity in distinguishing MSA from other neurodegenerative diseases. Moreover, combining p-syn with other biomarkers has further improved the diagnostic accuracy of MSA. The p-syn stands out as a promising biomarker for MSA. It is found in oligodendrocytes and shows a correlation with disease severity and progression. However, further research and validation studies are necessary to establish p-syn as a reliable biomarker for MSA. If proven, p-syn could significantly contribute to early diagnosis, disease monitoring, and assessing treatment response.

427 Defining the Impact of the Fecal Microbiome and Secretome on Multiple System Atrophy and α-Synuclein Aggregation

OBJECTIVES/GOALS: Aim 1: We will determine whether temporal changes in the fecal microbiome signature correlate with a clinical multiple system atrophy (MSA) phenotype. Aim 2: We will evaluate whether secretomes cultured from fecal samples from MSA patients enhance intracellular and extracellular α-synuclein (αSyn) aggregation using in vitro functional assays. METHODS/STUDY POPULATION: Aim 1: Gut microbiome profiling will be performed by 16S rRNA gene sequencing, tandem mass spectrometry for expression proteomics, and targeted metabolomics in fecal samples from 30 MSA cases matched to 30 healthy controls, a Parkinson’s disease comparison group, and household controls. Aim 2: Microbial species will be isolated using dilution-to-extinction on MSA fecal samples and then will be cultured to obtain secretomes. To assess the effect of MSA fecal secretomes on αSyn aggregation, culture media from microbial isolates will be used in fluorescence resonance energy transfer (FRET) assays and luciferase reporter assays, both modified to measure αSyn aggregation. Positive tests will undergo expanded metagenomic characterization of the microbes and secretome to identify potential causative agent(s). RESULTS/ANTICIPATED RESULTS: Based on cross-sectional metagenomic studies on MSA, MSA cases are expected to have genus reductions in Blautia and Dorea (acetate production); Paraprevotella (succinic and acetic acid production); and Ruminococcus, Coprococcus, and Faecalibacterium (butyrate production). Increases in genus Bacteroides (clinical pathogen) and Akkermansia (mucin degradation) and pro-inflammatory families Clostridiaceae and Rikenellaceae are also expected. MSA is predicted to be associated with reduced levels of short chain fatty acids and increased lipopolysaccharide. These microbial proteins and metabolites are anticipated to modulate intracellular and extracellular αSyn aggregation in vitro. Microbe isolation and secretome culturing methods are expected to identify additional drivers of αSyn aggregation. DISCUSSION/SIGNIFICANCE: This study’s novel use of longitudinal sampling, household controls, and secretome culturing aim to develop a more comprehensive understanding of the complex interactions between the gut microbiome and MSA. The success of this work offers the potential for new insights into the impact of the gut microbiome and secretome on MSA and αSyn aggregation.

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.

Impaired vestibular function associated with orthostatic hypotension in patients with multiple system atrophy.

Orthostatic hypotension (OH) is one of the most common symptoms in patients with multiple system atrophy (MSA). Vestibular system plays an important role in blood pressure regulation during orthostatic challenges through vestibular-sympathetic reflex. The current study aimed to investigate the relationship between vestibular function and OH in patients with MSA. Participants with MSA, including 20 with OH (mean age, 57.55 ± 8.44years; 7 females) and 15 without OH (mean age, 59.00 ± 8.12years; 2 females) and 18 healthy controls (mean age, 59.03 ± 6.44years; 8 females) were enrolled. Cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) tests were conducted to evaluate vestibular function. Patients with MSA presented with significantly higher rate of absent cVEMPs (57.1% vs 11.1%, p = 0.001) and oVEMPs (25.7% vs 0, p = 0.021) than controls. MSA patients with OH showed more absent cVEMPs (75.0% vs 11.1%, Bonferroni corrected p < 0.001) and oVEMPs (40.0% vs 0, Bonferroni corrected p = 0.003) than controls. Patients with OH also showed higher rate of absent cVEMPs than those without OH (33.3%, Bonferroni corrected p = 0.014). Our results demonstrated that impairment of vestibular function was associated with MSA, particularly in those with OH. Absent VEMPs may be a potential marker for MSA severity. Our findings suggest that impaired vestibular function is involved in OH development and may serve as an intervention target.

Reduced maximal range of ocular movements and its response to acute levodopa challenge in Parkinson's disease.

Although restriction of vertical ocular range of motion is known to be the hallmark of progressive supranuclear palsy (PSP), the maximal amplitude of ocular movement has not been quantitatively assessed despite of accumulating evidences of oculomotor dysfunction in Parkinson's disease (PD). Here, we evaluated the maximal oculomotor range and its response to levodopa in PD, and compare findings to atypical parkinsonism. We recruited 159 healthy controls (HC) as well as 154 PD, 30 PSP, and 16 multiple system atrophy (MSA) patients. Oculomotor range was assessed using a kinetic perimeter-adapted device for the vertical and horizontal axes (four positions). Parameters were reassessed after levodopa challenge and compared among PD, PSP, and MSA patients. Maximum oculomotor range in PD patients was reduced as compared to HC. Levodopa improved oculomotor range in all directions; corrective effects of upward range positively correlated with improvements in Unified Parkinson's Disease Rating Scale III and bradykinesia sub-scores among PD patients. Although oculomotor range was markedly restricted among PSP and MSA patients, the beneficial effects of levodopa was less pronounced. Reduced oculomotor range of motion was more significant among PSP as compared to PD or MSA patients; MSA patients did not significantly differ from PD patients. The range of upward gaze was optimally sensitive for differentiating among PD, PSP, and MSA patients. Maximum oculomotor range was reduced among PD patients significantly improved by levodopa treatment. Variations in, as well as the positively effects of levodopa on, the range of upward gaze assist diagnostic differentiation among PD, PSP, and MSA patients.

Corneal confocal microscopy may help to distinguish Multiple System Atrophy from Parkinson’s disease

Multiple system atrophy (MSA) and Parkinson’s disease (PD) have clinical overlapping symptoms, which makes differential diagnosis difficult. Our research aimed to distinguish MSA from PD using corneal confocal microscopy (CCM), a noninvasive and objective test. The study included 63 PD patients, 30 MSA patients, and 31 healthy controls (HC). When recruiting PD and MSA, questionnaires were conducted on motor and non-motor functions, such as autonomic and cognitive functions. Participants underwent CCM to quantify the corneal nerve fibers. Corneal nerve fiber density (CNFD) and corneal nerve fiber length (CNFL) values in MSA are lower than PD (MSA vs. PD: CNFD, 20.68 ± 6.70 vs. 24.64 ± 6.43 no./mm2, p < 0.05; CNFL, 12.01 ± 3.25 vs. 14.17 ± 3.52 no./mm2, p < 0.05). In MSA + PD (combined), there is a negative correlation between CNFD and the Orthostatic Grading Scale (OGS) (r = −0.284, p = 0.007). Similarly, CNFD in the only MSA group was negatively correlated with the Unified Multiple System Atrophy Rating Scale I and II (r = −0.391, p = 0.044; r = −0.382, p = 0.049). CNFD and CNFL were inversely associated with MSA (CNFD: β = −0.071; OR, 0.932; 95% CI, 0.872 ~ 0.996; p = 0.038; CNFL: β = −0.135; OR, 0.874; 95% CI, 0.768–0.994; p = 0.040). Furthermore, we found the area under the receiver operating characteristic curve (ROC) of CNFL was the largest, 72.01%. The CCM could be an objective and sensitive biomarker to distinguish MSA from PD. It visually reflects a more severe degeneration in MSA compared to PD.

Exploring machine learning approaches for transcriptome-based diagnosis and subgrouping of multiple system atrophy✰

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease, where the cause of the disease is not well understood yet. This disease affects the nervous system and then gradually damages the nerve cells in the brain. The consequences of the disease are very serious such as affecting the body balance, body movements and involuntary nervous system, which are closely connected to many crucial body functions including breathing, digestion and bladder control. Even though this disease starts between the age of 50 and 60, it can begin any time after 30 years. This disease can be presented as two main subtypes, one is predominating parkinsonian called as MSA-parkinsonian (MSA-P) and the other one is predominating cerebellar ataxia called as MSA-cerebellar (MSA-C). For such a complicated disease, on-time diagnosis and subgrouping is very crucial. However, there are no specific tests or diagnosis methods so far for the on time identification. Hence, this study checks the possibility of using transcriptome data of MSA patients in the diagnosis and subgrouping of MSA. Mutual information is used in the feature selection and the selected features are used with three different machine learning algorithms to select the model with the highest accuracy. Results show that random forest classifier performs comparably better in both of the classifications with the accuracy value of 0.8 ± 0.20 for subgrouping and 0.86 ± 0.16 for diagnosis.

Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-Synuclein Aggregation.

The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease. Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients. STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process. These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Low Dose Amantadine and Escitalopram in Progressive Supranuclear Palsy and Multiple System Atrophy

Background: Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are less responsive to usual antiparkinsonian drugs. Purpose: To assess the treatment outcome of the combination of low-dose amantadine and escitalopram in the study population. Methods: A retrospective study of PSP and MSA patients from June 2021 to December 2022 treated with the dose of amantadine 100 mg and escitalopram 5 mg per day with a follow-up of 2 months at a tertiary care centre in India. The primary outcome measure was a change in the PSP and MSA severity rating scale scores, while cognition, neuropsychiatric symptoms and functionality scale scores were secondary outcomes on follow-up visits. Repeated measures ANOVA and Friedman rank test were used to analyse the data. Results: A total of 21 patients (8 PSP and 13 MSA), including 19 males, with a mean age of 72.84 years, were included. The mean total PSP rating scale score had a significant decline from baseline to week 2 and 8 ( p &lt; .001), along with the scores for limb symptoms ( p &lt; .001), ocular ( p = .001), history ( p = .003), gait ( p = .007), mentation ( p = .014) and bulbar ( p = .018) symptoms. Similarly, the mean score of the MSA rating scale significantly decreased on follow-up visits ( p &lt; .001). The cognition, functional disability and behavioural symptoms scores also had significant improvement with p &lt; .01. Conclusion: The PSP and MSA patients had clinically significant improvement with the combination treatment in both motor and non-motor domains. Further prospective trials for longer durations are needed to establish the effect size and stability of response.

Reliability of the unified multiple system atrophy rating scale using the telephone

ObjectiveThe unified multiple system atrophy rating scale (UMSARS) was used to evaluate various symptoms of multiple system atrophy (MSA). And UMSARS part 1 was originally developed for use in interviews, but the need for telemedicine is increasing in COVID-19 pandemic. The purpose of this study is to evaluate the reliability of the UMSARS part 1 telephone survey. MethodsThirty-two MSA patients took the UMSARS part 1 face-to-face, followed by two more telephone evaluations. Intraclass correlation coefficients (ICC) and Cronbach’s alpha (α) coefficients were calculated, and the inter-rater reliability was determined. At the same time, we asked about the problems in COVID-19 pandemic. ResultsThe study participants included 15 men and 17 women with mean age of 67.1 years (SD, 8.3). For the total UMSARS part 1 score, the inter-rater ICC and Cronbach’s α coefficient were 0.89 to 0.92, and 0.84 to 0.87, respectively. More than half of the items had a relatively high ICC. Cronbach’s α coefficients were more than 0.7 for all items. Changes that occurred in COVID-19 pandemic included reduced outings and lack of rehabilitation in about half of the cases. ConclusionThe UMSARS part 1 has high inter-rater reliability and internal consistency. Evaluation of subjective symptoms showed that some variability could occur. In addition, there was concern about the influence of lack of rehabilitation due to COVID-19 pandemic.

IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.

A Systematic Review of the Spectrum and Prevalence of Non-motor Symptoms in Multiple System Atrophy.

Patients with Multiple System Atrophy (MSA) frequently report non-motor symptoms, and several research groups have highlighted this. We systematically searched for and reviewed papers assessing prevalence of non-motor symptoms (NMS) in MSA patients as reported in the scientific literature. We performed a systematic review of studies of subjects with MSA (involving > 10 patients) who were assessed for NMS, published in the English literature in PUBMED and EMBASE databases from 1947-2022. 23 research papers, with data from 2648 clinically diagnosed and 171 pathologically verified cases of MSA were included, along with 238 controls. Mean age for MSA cases was 61.3 (9.2) years, mean disease duration 3.6 (2.7) years. 57.9% were male. Our analysis showed that the prevalence of cognitive issues in MSA variedwidely (between 15-100%); dementia per se was uncommon, but assessment in advanced stagesof MSA is impacted by unintelligible speech (which may be noted in a quarter of cases). The prevalence of depressive symptoms in MSA was between 44-88%. Sleep disturbances were reported by 17-89%, with REM-sleep behaviour disorder (RBD) rates as high as 75%. Pain was reported by 40-47% of patients: rheumatic or musculoskeletal sources of pain being commonest. Fatigue was reported by 29-60%of patients. Symptoms of autonomic failure in MSA were seen in 34-96.5% patients at baseline. In routine clinical practice, NMS in MSA are under-recognised by clinicians. These impact hugely on patient quality of life and contribute to theiroverall morbidity. A methodical ascertainment of these complaints will address an unmet need, and lead to a more holisticapproach of care forindividuals with MSA.