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Background and Purpose: Centers for training in autonomic nervous system (ANS) disorders are not widely available and the recent coronavirus 2019 pandemic temporarily reduced training opportunities in autonomic medicine across European countries. Here we evaluated the current state of education, clinical skills and postgraduate educational preferences on ANS disorders of European neurology residents and consultants., Methods: A 23-item questionnaire was developed and distributed online amongst European neurology residents and consultants via mailing lists of the European Academy of Neurology. The questions assessed demographics, current training opportunities and learning preferences in ANS disorders. Six multiple-choice questions were used to self-evaluate knowledge of ANS disorders., Results: In all, 285 individuals answered the survey (60% female, mostly 25-34 years of age). All respondents considered clinical autonomic skills necessary for good clinical neurological practice, and 92% would like to increase their ANS knowledge. Female respondents and those who trained in Southern/Eastern/Greater Europe more frequently judged ANS skills important for clinical practice than male respondents (p = 0.012) and respondents from Northern/Western Europe (p = 0.011). Female and younger respondents felt less confident in managing ANS disorders (p = 0.001 and p < 0.001, respectively). Respondents below 45 years of age (p < 0.001) and those with lower confidence in managing ANS disorders (p = 0.004) were more likely to recommend that ANS education is embedded in the residency curriculum., Conclusions: Most European neurology residents and consultants reported a need for more autonomic education, with additional gender, age and regional differences. These findings underscore the importance of increasing the educational content on autonomic medicine in European medical and postgraduate curricula., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA., (© 2022. The Author(s).)

Background: Pain is a frequent yet poorly characterized symptom of multiple system atrophy (MSA). Understanding the factors influencing pain and its burden is crucial for improving the symptomatic treatment and quality of life of MSA individuals., Objective: This study aimed at assessing the prevalence, characteristics, and current treatment strategies for pain in MSA., Methods: A community-based, online survey was conducted from February to May 2023. Invitations were extended to MSA individuals and informal MSA caregivers through patient advocacies and social media., Results: We included 190 persons with MSA and 114 caregivers. Eighty-seven percent of MSA individuals reported pain, which was more prevalent among women (odds ratio [OR]: 6.38 [95% confidence interval, CI: 1.27-32.08], P = 0.025) and low-income groups (OR: 5.02 [95% CI: 1.32-19.08], P = 0.018). Neck and shoulders (58%), back (45%), and legs (45%) were mostly affected. In the neck and shoulders, pain was associated with MSA core features, like orthostatic intolerance (OR: 4.80 [95% CI: 1.92-12.02], P = 0.001) and antecollis (OR: 3.24 [95% CI: 1.54-6.82], P = 0.002). Seventy-six percent of individuals experiencing pain received treatment, mostly nonsteroidal anti-inflammatory drugs (47%), acetaminophen (39%), and opioids (28%). Only 53% of respondents reported at least partial satisfaction with their current pain management. Pain mostly impacted work, household activities, and hobbies of MSA individuals, and caregivers' social activities., Conclusions: Pain is more prevalent than previously reported in MSA and particularly affects women and low-income groups. Despite its frequency, pain management remains suboptimal, highlighting an urgent therapeutic need, likely entailing an optimized management of MSA core motor and non-motor features. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies., Competing Interests: Declaration of interests V.K. is a cofounder of and senior advisor to DaCapo Brainscience and Yumanity Therapeutics, companies focused on CNS diseases. C.Y.C. and X.J. contributed to this work as employees of Yumanity Therapeutics. T.I. and Y.K. contributed to this work as employees of Nikon Corporation. I.L., A.N., J. Sandoe, and V.K. are inventors on a patent application filed by Brigham and Women’s Hospital related to the induced inclusion iPSC models., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

Introduction: Gait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot study demonstrated a significant improvement of gait in patients with MSA of parkinsonian type (MSA-P) after physiotherapy and matching home-based exercise, as reflected by sensor-based gait parameters. In this study, we aim to investigate whether a gait-focused physiotherapy (GPT) and matching home-based exercise lead to a greater improvement of gait performance compared with a standard physiotherapy/home-based exercise programme (standard physiotherapy, SPT)., Methods and Analysis: This protocol was deployed to evaluate the effects of a GPT versus an active control undergoing SPT and matching home-based exercise with regard to laboratory gait parameters, physical activity measures and clinical scales in patients with Parkinson's disease (PD), MSA-P and PSP. The primary outcomes of the trial are sensor-based laboratory gait parameters, while the secondary outcome measures comprise real-world derived parameters, clinical rating scales and patient questionnaires. We aim to enrol 48 patients per disease group into this double-blind, randomised-controlled trial. The study starts with a 1 week wearable sensor-based monitoring of physical activity. After randomisation, patients undergo a 2 week daily inpatient physiotherapy, followed by 5 week matching unsupervised home-based training. A 1 week physical activity monitoring is repeated during the last week of intervention., Ethics and Dissemination: This study, registered as 'Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility&#95;APP)' at clinicaltrials.gov (NCT04608604), received ethics approval by local committees of the involved centres. The patient's recruitment takes place at the Movement Disorders Units of Innsbruck (Austria), Erlangen (Germany), Lausanne (Switzerland), Luxembourg (Luxembourg) and Bolzano (Italy). The data resulting from this project will be submitted to peer-reviewed journals, presented at international congresses and made publicly available at the end of the trial., Trial Registration Number: NCT04608604., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Individuals with multiple system atrophy (MSA) often complain about pain, nonetheless this remains a poorly investigated non-motor feature of MSA., Objectives: Here, we aimed at assessing the prevalence, characteristics, and risk factors for pain in individuals with MSA., Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, we systematically screened the PubMED, Cochrane, and Web of Science databases for papers published in English until September 30, 2022, combining the following keywords: "pain," "multiple system atrophy," "MSA," "olivopontocerebellar atrophy," "OPCA," "striatonigral degeneration," "SND," "Shy Drager," and "atypical parkinsonism.", Results: The search identified 700 records. Sixteen studies provided information on pain prevalence in cohorts of MSA individuals and were included in a qualitative assessment based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Thirteen studies (11 cross-sectional, two longitudinal) scored ≥14 points on QUADAS assessment and were included in a quantitative analysis, pooling data from 1236 MSA individuals. The resulting pooled prevalence of pain in MSA was 67% (95% confidence intervals [CI] = 57%-75%), and significantly higher in individuals with MSA of parkinsonian rather than cerebellar type (76% [95% CI = 63%-87%] vs. 45% [95% CI = 33%-57%], P  = 0.001). Pain assessment tools and collected information were highly heterogeneous across studies. Two studies reported pain treatment strategies and found that only every second person with MSA complaining about pain had received targeted treatment., Conclusions: We found that pain is a frequent, but still under-recognized and undertreated feature of MSA. Further research is needed to improve pain detection and treatment in MSA., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival., Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms., Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study., Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years., Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Cardiovascular autonomic dysfunction may reportedly occur after a coronavirus-disease-2019 (COVID-19) infection, but the available evidence is scattered. Here we sought to understand the acute and mid-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on cardiovascular autonomic function., Methods: We performed a systematic PubMed, Embase, Web of Science, medRxiv, and bioRxiv search for cases of cardiovascular autonomic dysfunction during an acute SARS-CoV-2 infection or post-COVID-19 condition. The clinical-demographic characteristics of individuals in the acute versus post-COVID-19 phase were compared., Results: We screened 6470 titles and abstracts. Fifty-four full-length articles were included in the data synthesis. One-hundred and thirty-four cases were identified: 81 during the acute SARS-CoV-2 infection (24 thereof diagnosed by history) and 53 in the post-COVID-19 phase. Post-COVID-19 cases were younger than those with cardiovascular autonomic disturbances in the acute SARS-CoV-2 phase (42 vs. 51 years old, p = 0.002) and were more frequently women (68% vs. 49%, p = 0.034). Reflex syncope was the most common cardiovascular autonomic disorder in the acute phase (p = 0.008) and postural orthostatic tachycardia syndrome (POTS) the most frequent diagnosis in individuals with post-COVID-19 orthostatic complaints (p < 0.001). Full recovery was more frequent in individuals with acute versus post-COVID-19 onset of cardiovascular autonomic disturbances (43% vs. 15%, p = 0.002)., Conclusions: There is evidence from the scientific literature about different types of cardiovascular autonomic dysfunction developing during and after COVID-19. More data about the prevalence of autonomic disorders associated with a SARS-CoV-2 infection are needed to quantify its impact on human health., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Study Objectives: Sleep disorders, daytime sleepiness, and autonomic dysfunction are commonly reported among patients with multiple system atrophy and Parkinson disease (PD). We aimed to assess sleep and autonomic function in these patients to evaluate the relationships between sleep disorders, excessive daytime sleepiness, and autonomic function., Methods: Twenty patients with multiple system atrophy (n = 7) and PD (n = 13) underwent clinical assessment including questionnaires for autonomic function and sleep. Cardiovascular autonomic function tests and 2-night video-polysomnography were followed by administration of the Multiple Sleep Latency Test. Rapid eye movement sleep without atonia was quantified in the chin, flexor digitorum superficialis, tibial anterior, and sternocleidomastoid muscles., Results: Rapid eye movement sleep behavior disorder was associated with orthostatic hypotension ( P  = .017) and constipation ( P  = .019) in PD. Patients with orthostatic hypotension had higher rapid eye movement sleep without atonia indices than those without orthostatic hypotension ( P  < .001). The Sleep Innsbruck Barcelona rapid eye movement sleep without atonia index ("any" chin and/or flexor digitorum superficialis) correlated with systolic/diastolic blood pressure fall upon tilt-table examination in patients with multiple system atrophy ( P  < .05) and with gastrointestinal ( P  = .010), urinary ( P  = .022), and total Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction scores ( P  = .006) in all patients. Patients with a pathological deep breathing ratio showed higher Sleep Innsbruck Barcelona indices ( P  = .031). Objective daytime sleepiness was exclusively present in PD ( P  = .034) and correlated with levodopa-equivalent dosage ( P  = .031)., Conclusions: The relationship of autonomic dysfunction with rapid eye movement sleep without atonia in PD and multiple system atrophy is accounted for by shared brainstem neuropathology and likely identifies patients in a more advanced stage of disease. Excessive daytime sleepiness is found exclusively in PD and may be secondary to levodopa treatment and not related to α-synuclein disease., Citation: Eckhardt C, Fanciulli A, Högl B, et al. Analysis of sleep, daytime sleepiness, and autonomic function and multiple system atrophy and Parkinson disease: a prospective study. J Clin Sleep Med. 2023;19(1):63-71., (© 2023 American Academy of Sleep Medicine.)