Early-stage Multiple System Atrophy Research Articles

Differential diagnosis value of sympathetic skin response and cutaneous silent period on early-stage multiple system atrophy and Parkinson disease

PurposeEarly differentiation between Parkinson's disease (PD) and Multiple system atrophy (MSA), particularly the parkinsonian subtypes (MSA-P), is challenging due to similar clinical symptoms. We aimed to evaluate Sympathetic skin response (SSR) and Cutaneous silent period (CSP) parameters in patients with MSA-P and PD to identify possible biomarkers that could distinguish the two groups of patients in early stage. Methods22 individuals with early-stage MSA-P, 29 with early-stage PD, and 28 healthy controls were recruited from Guangdong Provincial People's Hospital. Demographic data was collected for all participants. Their SSR and CSP were evaluated using clinical electromyography equipment. Data were compared between different groups. The diagnostic accuracy of SSR and CSP parameters was calculated using the ROC curve. Logistic regression was used to produce an integration model to enhance diagnostic utility. ResultsFoot amplitude, CSP end latency and duration distinguished MSA-P from PD with the area under the curve (AUC) 0.770, 0.806, and 0.776, respectively. Foot and hand SSR amplitude distinguished PD from HC with the AUC 0.871 and 0.768, respectively. Foot SSR amplitude, hand SSR amplitude, and CSP end latency distinguished MSA-P from HC with the AUC 0.964, 0.872, and 0.812, respectively. The combination of SSR and CSP parameters differentiation between MSA-P and PD, PD and HC with the AUC 0.829 and 0.879, respectively. ConclusionsAnalysis of SSR and CSP parameters showed excellent diagnostic accuracy in discriminating patients with early-stage MSA-P from HC and good diagnostic accuracy in discriminating patients with MSA-P from PD with early stages.

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.

Prevalence and prognostic significance of malnutrition in early-stage multiple system atrophy

Prevalence and prognostic significance of malnutrition in early-stage multiple system atrophy

Multiple System Atrophy: Advances in Diagnosis and Therapy.

This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

Cystatin C predicts cognitive decline in multiple system atrophy: A 1-year prospective cohort study.

Accumulating evidence has suggested that cystatin C is associated with cognitive impairment in patients with neurodegenerative diseases. However, the association between cystatin C and cognitive decline in patients with multiple system atrophy (MSA) remains largely unknown. The objective was to determine whether cystatin C was independently associated with cognitive decline in patients with early-stage MSA. Patients with MSA underwent evaluation at baseline and the 1-year follow-up. Cognitive function was evaluated with Montreal cognitive assessment (MoCA). Changes in the MoCA score and the absolute MoCA score at the 1-year assessment were considered the main cognitive outcome. The cystatin C concentrations in patients with MSA and age, sex, and body mass index matched-healthy controls (HCs) were measured. A multiple linear regression model was used to test the association between cystatin C and cognitive decline. A total of 117 patients with MSA and 416 HCs were enrolled in the study. The cystatin C levels were significantly higher in patients with MSA than in HCs (p < 0.001). Cystatin C levels were negatively correlated with MoCA score at baseline and at 1-year follow-up. Multiple linear regression model adjusted for potential confounders showed that baseline cystatin C levels were significantly associated with the MoCA score (p = 0.004) or change in the MoCA score (p = 0.008) at 1-year follow-up. Our results suggested that cystatin C may serve as a potential biomarker of cognitive decline in patients with early-stage MSA.

Longitudinal evolution of motor and non-motor symptoms in early-stage multiple system atrophy: a 2-year prospective cohort study

BackgroundThe progression of motor and non-motor symptoms (NMS) and the sensitivity of each item of the Unified Multiple System Atrophy Rating Scale (UMSARS) to change remain unclear in Chinese patients with early-stage multiple system atrophy (MSA). We investigated the evolution of motor symptoms and NMS in early-stage MSA and the sensitivity of each item included in the UMSARS to change over a 2-year follow-up.MethodsMotor symptoms and NMS were recorded at baseline and at 1- and 2-year follow-ups based on the UMSARS and the NMS scale. Generalized estimating equation models were used. The sensitivity of an item included in the UMSARS to change was assessed by calculating a standardized effect using the mean annual change divided by the standard deviation of the change.ResultsWe enrolled 246 consecutive patients with MSA and 97 MSA completed the 2-year follow-up. The mean total UMSARS score increased by 11.90 and 22.54 points at the 1- and 2-year follow-ups, respectively. UMSARS-I items associated with motor functions were more sensitive to change and those associated with autonomic dysfunction showed less sensitivity to change. Items 4 (tremor at rest), 5 (action tremor), and 3 (ocular motor dysfunction) of the UMSARS-II were less sensitive to change. The prevalence and severity of NMS significantly increased over the 2-year follow-up.ConclusionsWe observed significant progression in motor symptoms and NMS in patients with early-stage MSA. Our results provide useful information to support the revision of the UMSARS.

Data-driven subtype classification of patients with early-stage multiple system atrophy

IntroductionPatients with multiple system atrophy (MSA) are conventionally identified as having MSA-P (prominent parkinsonism) or MSA-C (prominent cerebellar ataxia) based on their predominant motor manifestations. The objective of the present study was to conduct latent class analysis (LCA) of various motor and nonmotor symptoms in early MSA to characterize data-driven subgroups. MethodsSixty-one probable or possible MSA patients with disease durations of 3 years or less were included prospectively. LCAs were performed to identify similar clinical subgroups giving even weights to a wide range of MSA motor and nonmotor features. We ran latent models of up to 6 class solutions; the overall model fit was evaluated based on the parsimony of the derived classes, the fit indices, and clinical interpretability. ResultsThe LCA outcome supported categorization of at least three subgroups of patients with early MSA: the largest class 1, labeled “moderate parkinsonism + extensive dysautonomia”, included approximately half of our study patients and showed marked autonomic dysfunction with a burden of parkinsonism. The two other classes, class 2 “predominant parkinsonism + limited dysautonomia” and class 3 “predominant cerebellar symptoms + limited dysautonomia”, showed marked core motor features (parkinsonism or cerebellar symptoms) with generally mild dysautonomia. ConclusionsTo our knowledge, this is the first data-driven identification of disease subtypes covering various symptom constellations in early MSA (<3 years from motor symptom onset). The present LCA result did not replicate the conventional motor classification and supported the heterogeneity within MSA-P and MSA-C subtypes.

Fatigue in Patients With Multiple System Atrophy: A Prospective Cohort Study.

Nonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage. Patients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively. This study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up (p < 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894-0.987), OH (OR 2.806, 95% CI 1.253-6.286), and high HARS score (OR 1.014, 95% CI 1.035-1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066-10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043-1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C (p < 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA. Fatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA.

Pathological laughter and crying in multiple system atrophy with different subtypes: Frequency and related factors

Objective: The current study was aimed at examining the frequency of and potential factors related to pathological laughter and crying (PLC) in multiple system atrophy (MSA) as well as evaluating the impact of PLC on the survival of patients with early stage MSA. Methods: A total of 465 MSA patients were enrolled in the study. The binary logistic regression model was used to explore the potential factors related to PLC. Altogether, 142 patients in their early stage (disease duration ≤3 years), who were followed up for at least two years, were included in the propensity score matching (PSM) analysis. A Cox regression model was used to analyze the impact of PLC on the survival of patients with early stage MSA. Results: The frequency of PLC was 12.7%, 12.0%, and 13.2% in MSA, MSA-parkinsonian subtype (MSA-P), and MSA-cerebellar type (MSA-C), respectively. The binary logistic regression model indicated that younger age and higher total UMSARS scores were associated with PLC in MSA, MSA-P, and MSA-C patients. Additionally, for patients in the early stage, it was found that PLC was not a predictor for mortality in MSA, as indicated by the multivariate Cox regression model. Conclusion: PLC was not uncommon in patients with MSA, MSA-P, and MSA-C. Younger age and greater disease severity were associated with PLC in MSA, MSA-P, and MSA-C patients. PLC was not a predictor of mortality in patients with MSA.

Morphometric MRI profiles of multiple system atrophy variants and implications for differential diagnosis.

BackgroundManual width measurements of the middle cerebellar peduncle on MRI were shown to improve the accuracy of an imaging‐guided diagnosis of multiple system atrophy (MSA). Recently, automated volume segmentation algorithms were able to reliably differentiate patients with Parkinson's disease (PD) and the parkinsonian variant of MSA. The objective of the current study was to integrate probabilistic information of the middle cerebellar peduncle into an existing MRI atlas for automated subcortical segmentation and to evaluate the diagnostic properties of the novel atlas for the differential diagnosis of MSA (parkinsonian and cerebellar variant) versus PD.MethodsThree Tesla MRI scans of 48 healthy individuals were used to establish an automated whole‐brain segmentation procedure that includes the volumes of the putamen, cerebellar gray and white matter, and the middle cerebellar peduncles. Classification accuracy of segmented volumes were tested in early‐stage MSA patients (18 MSA‐parkinsonism, 13 MSA‐cerebellar) and 19 PD patients using a C4.5 classifier.ResultsPutaminal and infratentorial atrophy were present in 77.8% and 61.1% of MSA‐parkinsonian patients, respectively. Four of 18 MSA‐parkinsonian patients (22.2%) had infratentorial atrophy without evidence of putaminal atrophy. Infratentorial atrophy was present in all MSA‐cerebellar patients, with concomitant putaminal atrophy in 46.2% of these cases. The diagnostic algorithm using putaminal and infratentorial volumetric information correctly classified all PD patients and 96.8% of MSA patients.ConclusionsThe middle cerebellar peduncle was successfully integrated into a subcortical segmentation atlas, and its excellent diagnostic accuracy outperformed existing volumetric MRI processing strategies in differentiating MSA patients with variable atrophy patterns from PD patients. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Anle138b Partly Ameliorates Motor Deficits Despite Failure of Neuroprotection in a Model of Advanced Multiple System Atrophy.

The neurodegenerative disorder multiple system atrophy (MSA) is characterized by autonomic failure, cerebellar ataxia and parkinsonism in any combination associated with predominantly oligodendroglial α-synuclein (α-syn) aggregates (glial cytoplasmic inclusions = GCIs). To date, there is no effective disease modifying therapy. Previous experiments have shown that the aggregation inhibitor anle138b reduces neurodegeneration, as well as behavioral deficits in both transgenic and toxin mouse models of Parkinson's disease (PD). Here we analyzed whether anle138b improves motor skills and reduces neuronal loss, as well as oligodendroglial α-syn aggregation in the PLP-α-syn transgenic mouse challenged with the mitochondrial toxin 3-nitropropionic acid (3-NP) to model full-blown MSA. Following 1 month of treatment with anle138b, MSA mice showed signs of motor improvement affecting stride length, but not pole, grip strength, and beam test performance. Loss of dopaminergic nigral neurons and Purkinje cells was not attenuated and GCI density remained unchanged. These data suggest that the pathology in transgenic PLP-α-syn mice receiving 3-NP might be too advanced to detect significant effects of anle138b treatment on neuronal loss and intracytoplasmic α-syn inclusion bodies. However, the partial motor amelioration may indicate potential efficacy of anle138b treatment that may be mediated by its actions on α-syn oligomers or may reflect improvement of neuronal dysfunction in neural at risk populations. Further studies are required to address the efficacy of anle138b in transgenic α-syn models of early-stage MSA and in the absence of additional toxin application.

Differences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson’s disease

In Parkinson variant of multiple system atrophy (MSA-P), patterns of early speech impairment and their distinguishing features from Parkinson’s disease (PD) require further exploration. Here, we compared speech data among patients with early-stage MSA-P, PD, and healthy subjects using quantitative acoustic and perceptual analyses. Variables were analyzed for men and women in view of gender-specific features of speech. Acoustic analysis revealed that male patients with MSA-P exhibited more profound speech abnormalities than those with PD, regarding increased voice pitch, prolonged pause time, and reduced speech rate. This might be due to widespread pathology of MSA-P in nigrostriatal or extra-striatal structures related to speech production. Although several perceptual measures were mildly impaired in MSA-P and PD patients, none of these parameters showed a significant difference between patient groups. Detailed speech analysis using acoustic measures may help distinguish between MSA-P and PD early in the disease process.

Pregnancy in multiple system atrophy: a case report

IntroductionMultiple system atrophy is a late, adult-onset α-synucleinopathy with no data on the effect of pregnancy on the disease course. Early stage multiple system atrophy can be difficult to distinguish from Parkinson's disease.Case presentationWe describe the case of an Irish woman with parkinsonism starting at age 31, initially diagnosed as having dopa-responsive, idiopathic Parkinson's disease, who successfully delivered a full-term child at age 35. Her pregnancy was complicated by severe orthostatic hypotension and motor fluctuations. Two years post-partum, she underwent bilateral subthalamic nuclei deep brain stimulation for intractable motor fluctuations and disabling dyskinesia. After this treatment course she experienced deterioration of motor symptoms and death eight years after disease onset. Post-mortem neuropathological examination revealed striatonigral degeneration and α-synuclein-positive glial cytoplasmic inclusions in brain stem nuclei, basal ganglia and white matter tracts, consistent with a neuropathological diagnosis of multiple system atrophy.ConclusionsMultiple system atrophy can affect women of child-bearing age and pregnancy may be associated with marked disease progression.

The value of apparent diffusion coefficient values of cerebellar and the middle cerebellar peduncles in differential diagnosis of multiple system atrophy and Parkinson disease

Objective To evaluate the apparant diffusion coefficient (ADC) values of cerebellar and the middle cerebellar peduncles in the differential diagnosis of multiple system atrophy (MSA) and Parkinson disease (PD). Methods Conventional MRI and DWI were performed in 18 clinically proved MSA patients with 7 cases of early cases (early-stage MSA group), 19 PD patients (PD group) and 18 agematched normal controls (the control group). DWI was performed using a single shot-spin echo-echo planar imaging sequences, and ADC values were measured in the ROIs (0. 16 cm2) of the bilateral cerebellum, the middle cerebellar peduncles and cerebral white matter. Then one way ANOVA test was used for statistical analysis. Results Of the 18 MSA patients, 11 had MR abnormalities, 8 had hot-cross bun sign in the pens on T2-weighted images, 11 patients had pontine, cerebellar and medulla oblongata atrophy, 10 patients had atrophy of the middle cerebellar peduncles, 2 patients had hyperintense rim of the putamen and putaminal atrophy on T2-weighted images. The ADC values in the middle cerebellar peduncles were significantly increased in the MSA group[ (0. 98 ±0. 07) × 103 mm2/s] and early-stnge MSA group [ (0. 95 ±0. 05) ×103 mm2/s] as compared to PD group [ (0. 77 ±0. 04) × 103 mm2/s] and control group[ (0. 78 ±0. 04) ×103 mm2/s]. There was statistical significant difference among them (F = 91.049,55. 301, P ＜ 0.01 ).There was no overlap in the distribution of ADC values of the middle cerebellar peduncles among the MSA group [ (0.86-1.13 ) × 103 mm2/s ], early-stage MSA group [ (0. 86-1.02 ) × 103 mm2/s ] and PD group [ (0. 68-0. 84) × 103 mm2/s] and the control group [ (0. 69-0. 82) × 103 mm2/s]. The ADC values in the cerebellum were significantly increased in the MSA group[ (0. 95 ±0. 09) × 103 mm2/s] and early-stage MSA group [ (0. 92 ±0. 07) × 103 mm2/s] as compared to PD group [ (0. 78 ±0. 05) × 103 mm2/s] and control group[ (0. 79 ± 0. 05 ) × 103 mm2/s ]. Statistically significant difference was found among them (F =39. 274,18. 623 ,P ＜0. 01 ). There was overlap in the distribution of ADC values of the cerebellum [ MSAgroup(0. 80-1.10) × 103 mm2/s,early stage MSA group (0. 80-0. 99) × 103 mm2/s,PD group(0. 72-0. 90) × 103 mm2/s,control group (0. 71-0. 87) × 103 mm2/s]. There was no significant difference among the ADC values of MSA group, MSA group(early stages) and PD group and the control group in the cerebral white matter( P ＞ 0. 05 ). Conclusions ADC values in the cerebellum and the middle cerebellar peduncles have very important significance in differential diagnosis between MSA and PD. Key words: Multiple system atrophy; Parkinson disease; Diffusion magnetic resonance imaging

The Report on Fractures

<h3>Background and Objectives</h3> Nonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage. <h3>Methods</h3> Patients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively. <h3>Results</h3> This study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up (<i>p</i> &lt; 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894–0.987), OH (OR 2.806, 95% CI 1.253–6.286), and high HARS score (OR 1.014, 95% CI 1.035–1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066–10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043–1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C (<i>p</i> &lt; 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA. <h3>Discussion</h3> Fatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA.