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Background Multiple system atrophy (MSA) is recognized as an atypical Parkinsonian syndrome, distinguished by a more rapid progression than that observed in Parkinson’s disease. Unfortunately, the prognosis for MSA remains poor, with a notable absence of globally recognized effective treatments. Although preliminary studies suggest that transcranial magnetic stimulation (TMS) could potentially alleviate clinical symptoms in MSA patients, there is a significant gap in the literature regarding the optimal stimulation parameters. Furthermore, the field lacks consensus due to the paucity of robust, large-scale, multicenter trials. Methods This investigation is a multi-center, randomized, double-blind, sham-controlled trial. We aim to enroll 96 individuals diagnosed with MSA, categorized into Parkinsonian type (MSA-P) and cerebellar type (MSA-C) according to their predominant clinical features. Participants will be randomly allocated in a 1:1 ratio to either the TMS or sham stimulation group. Utilizing advanced navigation techniques, we will ensure precise targeting for the intervention, applying theta burst stimulation (TBS). To assess the efficacy of TBS on both motor and non-motor functions, a comprehensive evaluation will be conducted using internationally recognized clinical scales and gait analysis. To objectively assess changes in brain connectivity, functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) will be employed as sensitive indicators before and after the intervention. Discussion The primary aim of this study is to ascertain whether TBS can alleviate both motor and non-motor symptoms in patients with MSA. Additionally, a critical component of our research involves elucidating the underlying mechanisms through which TBS exerts its potential therapeutic effects. Ethics and dissemination All study protocols have been reviewed and approved by the First Affiliated Medical Ethics Committee of the Air Force Military Medical University (KY20232118-F-1). Trial registration Chinese Clinical Trial Registry ChiCTR2300072658. Registered on 20 June 2023.

Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of α-synuclein in GCI and a ‘prion hypothesis’ are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised.

Background Early stridor onset (≤ 3 years from disease onset) is a predictor of shorter survival in Multiple System Atrophy (MSA), but its role on disease progression is not yet established. In MSA, previous studies on trajectories of disease did not include stridor and REM sleep behavior disorder (RBD) as clinical variable. The aims of the study were: (1) to investigate disease progression in MSA patients with early stridor onset and with early stridor and/or RBD onset; (2) to assess cerebrospinal fluid (CSF) levels of neurofilament light chain protein (NfL) in MSA patients with early onset sleep disorders. Methods This is a retrospective and prospective cohort study including 208 (120 males) MSA patients. Occurrence of symptoms/signs, milestones of disease progression, and their latency from disease onset were collected. RBD and stridor were video-polysomnography (VPSG)-confirmed. CSF NfL levels were analyzed. Survival data and predictors of mortality were calculated. Results Out of 208 MSA patients (157 deceased), 91 were diagnosed with stridor and 160 with VPSG-confirmed RBD. Patients with early stridor onset ( n  = 41) and with early stridor and/or RBD onset ( n  = 132) showed an early autonomic involvement, developed a more progressive and severe disease and presented higher CSF NfL than those with late stridor and RBD onset. Early stridor and early RBD were independent risk factors on MSA survival. Conclusions The evidence of a more rapid and severe disease progression and of high CSF NfL levels in patients who early developed sleep disorders could define a different MSA phenotype with a widespread impairment of central-brainstem circuits.

Multiple system atrophy (MSA), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are the most common atypical parkinsonisms. These adult-onset and lethal neurodegenerative disorders of unknown etiology are clinically characterized by varying combinations of autonomic, levodopa-poorly responsive parkinsonsm, motor, non-motor, cerebellar syndromes, behavioral, cognitive and other neuropsychiatric disorders. Although their pathological hallmarks are different—MSA α-synucleinopathy, CBD and PSP 4-repeat (4R) tauopathies—their neuropsychiatric disturbances include anxiety, depression, agitations, attention-executive dysfunctions, less often compulsive and REM sleep behavior disorders (RBD), which may contribute to disease progression and reduced quality of life (QoL) of patients and caregivers. The present paper reviews the prevalence and type of neuropsychiatric profile in these atypical parkinsonian syndromes, their neuroimaging, and pathogenic backgrounds based on extensive literature research. MSA patients show anxiety, apathy (depression), initial RBD, attentional and executive dysfunction; PSP patients present with apathy, depression, disinhibition, and to a lesser extent, anxiety and agitation; CBD patients are featured by executive and visuospatial dysfunctions, irritability, alien limb phenomena, sleep and language disorders. Neuropsychiatric disorders in these syndromes are often similar, due to disruption of prefronto-subcortical (limbic) and striato-thalamo-cortical circuitries or default mode and attention network disorder. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Psychotic symptoms, hallucinations and delusions are rare. Neuropsychiatric changes in these disorders are often premature and anticipate motor dysfunctions; their assessment and further elucidation of their pathogenesis are warranted as a basis for early diagnosis and adequate treatment of these debilitating comorbidities.

Lower urinary tract (LUT) dysfunction presents early in multiple system atrophy (MSA), usually initially as urinary urgency, frequency and incontinence, and voiding difficulties/urinary retention becomes apparent over time. We have observed a subset of patients who instead presented initially with urinary retention requiring catheterisation. At presentation, these patients had only subtle neurological signs that would not fulfil the diagnostic criteria of MSA; however, the anal sphincter electromyography (EMG) was abnormal and they reported bowel and sexual dysfunction, suggesting localisation at the level of the sacral spinal cord. They subsequently developed classical neurological signs, meeting the diagnostic criteria for probable MSA. One patient was confirmed to have MSA at autopsy. We postulate that in a subset of patients with MSA, the disease begins in the sacral spinal cord and then spreads to other regions resulting in the classical signs of MSA. The transmissibility of alpha-synuclein has been demonstrated in animal models and the spread of pathology from sacral cord to other regions of the central nervous system is therefore plausible. Patients presenting with urinary retention and mild neurological features would be an ideal group for experimental trials evaluating neuroprotection in MSA

Background The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P). Methods This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3 years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model. Results Ninety patients developed symptomatic dysphagia within 3 years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3 years compared to those without (median: 4.2 years vs. 7.3 years; p  < 0.001). Symptomatic dysphagia within 3 years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients ( p  = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p  < 0.001 and p  = 0.046, respectively). Conclusion Symptomatic dysphagia within 3 years of onset predicts shorter survival in MSA-C and MSA-P patients.

Background Spinocerebellar ataxia 27B is the most common genetic late onset cerebellar ataxia (LOCA). However, it commonly overlaps with other genetic LOCA as with the cerebellar form of multiple system atrophy (MSA-C). Objectives To pinpoint which clinical signs and symptoms best discriminate between FGF14  + from FGF14  − patients at symptoms’ onset. Methods Twenty SCA27B (≥ 250 GAA repeat expansion) patients were retrospectively matched by gender and age at disease onset with 20 negative FGF14 (−) LOCA patients and with 20 MSA-C patients. Clinical features were ranked based on their contribution towards distinguishing between the groups (feature importance ranking). Results SCA27B patients had significantly higher rates of episodic symptoms, cerebellar oculomotor signs, dysdiadochokinesia, and alcohol intolerance than LOCA- FGF14  − ataxia patients. The lack of autonomic symptoms and MRI signs in SCA27B patients were the most discriminating features from MSA-C. An AUC of 0.87 was obtained if using the “top 3 clinical features model” (episodic symptoms, cerebellar oculomotor signs and dysdiadochokinesia) to distinguish SCAB27 from LCOA FGF14  − . Regarding MRI findings, no significant differences were found between SCA27B and FGF14  − patients, while a positive hot cross buns sign and the presence of brainstem atrophy were key distinguishing features between SCA27B from MSA-C patients ( p  < 0.005). Conclusion Our pilot case–control study contributes to the identification of early clinical symptoms to differentiate SCA27B to LOCA patients including FGF14 - and MSA-C ones. From a feature perspective, while clinical features are crucial, identifying surrogate biomarkers—such as ocular or gait parameters—could aid in the early diagnosis and follow-up of SCA27B patients.

While cognitive impairment, which was previously considered a red flag against the clinical diagnosis of multiple system atrophy (MSA), is a common symptom of this rare neurodegenerative disorder, behavioral disorders are reported in 30 to 70% of MSA patients. They include anxiety, apathy, impaired attention, compulsive and REM sleep behavior disorders (RBD), and these conditions, like depression, are early and pervasive features in MSA, which may contribute to disease progression. Despite changing concepts of behavioral changes in this synucleinopathy, the underlying pathophysiological and biochemical mechanisms are poorly understood. While specific neuropathological data are unavailable, neuroimaging studies related anxiety disorders to changes in the cortico-limbic system, apathy (and depression) to dysfunction of prefrontal–subcortical circuits, and compulsive behaviors to impairment of basal ganglia networks and involvement of orbito-frontal circuits. Anxiety has also been related to α-synuclein (αSyn) pathology in the amygdala, RBD to striatal monoaminergic deficit, and compulsive behavior in response to dopamine agonist therapy in MSA, while the basic mechanisms of the other behavioral disorders and their relations to other non-motor dysfunctions in MSA are unknown. In view of the scarcity of functional and biochemical findings in MSA with behavioral symptoms, further neuroimaging and biochemical studies are warranted in order to obtain better insight into their pathogenesis as a basis for the development of diagnostic biomarkers and future adequate treatment modalities of these debilitating comorbidities.

Background Orthostatic hypotension (OH) is a common symptom of multiple system atrophy (MSA), however, its role in cognitive impairment and the mechanism in these patients remains unclear. This study aims to assess the role of OH on cognitive impairment in MSA patients, as well as to explore the potential association of cerebral autoregulation (CA) and white matter hyperintensities (WMHs) on cognitive impairment. Methods This observational study was conducted in three general hospitals in China from January 2018 to October 2023, with patients at one center followed up for 6 months after enrollment. The primary outcomes included cognitive function assessed using the Mini-Mental State Examination (MMSE) and Montreal cognitive assessment (MoCA). Secondary outcomes included the results of the Head-up tilt test, scores for CA and the extent of WMHs. Results The 132 MSA patients included 72 men (54.54%) with a mean age of 61.16 (7.80) years. Among them, 80 patients (60.61%) had orthostatic hypotension, and 48 patients (36.36%) had cognitive impairment. OH plays an important role in cognitive impairment in MSA patients (OR = 0.328,95% CI 0.135–0.797, P  = 0.014). Cognitive impairment was associated with impaired CA (OR = 0.088,95% CI 0.012–0.657, P  = 0.018) and severe WMHs (OR = 0.030,95% CI 0.002–0.423, P  = 0.009), particularly in the presence of OH. Conclusion OH is associated with cognitive impairment in MSA patients, and cognitive decline is linked to impaired CA and increased WMHs. Future studies are needed to explore the mechanisms underlying cognitive impairment in MSA patients.