Effects of physiotherapy and home-based training in parkinsonian syndromes: protocol for a randomised controlled trial (MobilityAPP).

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_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.

Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Sex-related differences in the clinical presentation of multiple system atrophy.

PURPOSE: To investigate sex-related differences in the clinical presentation of multiple system atrophy (MSA) through a literature review and an analysis of a retrospective cohort. METHODS: The PubMed database was searched for articles including sex-related information in MSA. In a retrospective Innsbruck cohort, we investigated the baseline to last available follow-up clinical-demographic differences between men and women with MSA in a univariate fashion, followed by multivariable binary regression analysis. RESULTS: The literature search yielded 46 publications with sex-related information in MSA. Most studies found comparable survival rates between the sexes, while some recent reports suggested a potential survival benefit for women, possibly due to initial motor onset and overall less severe autonomic failure compared to men. The retrospective Innsbruck MSA cohort comprised 56 female and 60 male individuals with a comparable median follow-up of 27 months. At baseline, female sex was independently associated with depression (odds ratio [OR] 4.7; p = 0.007) and male sex with severe orthostatic hypotension (OR 5.5; p = 0.016). In addition, at last follow-up, female sex was associated with the intake of central nervous system-active drugs (OR 4.1; p = 0.029), whereas male sex was associated with the presence of supine hypertension (OR 3.0; p = 0.020) and the intake of antihypertensive medications (OR 8.7; p = 0.001). Male sex was also associated with initiation of antihypertensive medications over the observation period (OR 12.4; p = 0.004). CONCLUSION: The available literature and findings of the present study indicate sex-related differences in the clinical presentation of MSA and its evolution over time, highlighting the importance of considering sex in symptom exploration, therapeutic decision-making, and future clinical trial design.

Emotion Recognition in Multiple System Atrophy: An Exploratory Eye-Tracking Study.

OBJECTIVE: Emotional processing is a core feature of social interactions and has been well studied in patients with idiopathic Parkinson's disease (PD), albeit with contradictory. RESULTS: . However, these studies excluded patients with atypical parkinsonism, such as multiple system atrophy (MSA). The objective of this exploratory study was to provide better insights into emotion processing in patients with MSA using eye tracking data. METHODS: We included 21 MSA patients, 15 PD patients and 19 matched controls in this study. Participants performed a dynamic and a static emotion recognition task, and gaze fixations were analyzed in different areas of interest. Participants underwent neuropsychological testing and assessment of depression and alexithymia. RESULTS: MSA patients were less accurate in recognizing anger than controls (p = 0.02) and had overall fewer fixations than controls (p = 0.001). In the static task, MSA patients had fewer fixations (p < 0.001) and a longer time to first fixation (p = 0.026) on the eye region. Furthermore, MSA patients had a longer fixation duration overall than PD patients (p = 0.004) and longer fixations on the nose than controls (p = 0.005). Alexithymia scores were higher in MSA patients compared to controls (p = 0.038). CONCLUSION: This study demonstrated impaired recognition of anger in MSA patients compared to HCs. Fewer and later fixations on the eyes along with a center bias suggest avoidance of eye contact, which may be a characteristic gaze behavior in MSA patients.

Symptomatic Care in Multiple System Atrophy: State of the Art.

Without any disease-modifying treatment strategy for multiple system atrophy (MSA), the therapeutic management of MSA patients focuses on a multidisciplinary strategy of symptom control. In the present review, we will focus on state of the art treatment in MSA and additionally give a short overview about ongoing randomized controlled trials in this field.

A Review on the Clinical Diagnosis of Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative disorder with major diagnostic challenges. Aiming for a better diagnostic accuracy particularly at early disease stages, novel Movement Disorder Society criteria for the diagnosis of MSA (MDS MSA criteria) have been recently developed. They introduce a neuropathologically established MSA category and three levels of clinical diagnostic certainty including clinically established MSA, clinically probable MSA, and the research category of possible prodromal MSA. The diagnosis of clinically established and clinically probable MSA is based on the presence of cardiovascular or urological autonomic failure, parkinsonism (poorly L-Dopa-responsive for the diagnosis of clinically established MSA), and cerebellar syndrome. These core clinical features need to be associated with supportive motor and non-motor features (MSA red flags) and absence of any exclusion criteria. Characteristic brain MRI markers are required for a diagnosis of clinically established MSA. A research category of possible prodromal MSA is devised to capture patients manifesting with autonomic failure or REM sleep behavior disorder and only mild motor signs at the earliest disease stage. There is a number of promising laboratory markers for MSA that may help increase the overall clinical diagnostic accuracy. In this review, we will discuss the core and supportive clinical features for a diagnosis of MSA in light of the new MDS MSA criteria, which laboratory tools may assist in the clinical diagnosis and which major differential diagnostic challenges should be borne in mind.

A multiplex pedigree with pathologically confirmed multiple system atrophy and Parkinson's disease with dementia.

Multiple system atrophy is considered a sporadic disease, but neuropathologically confirmed cases with a family history of parkinsonism have been occasionally described. Here we report a North-Bavarian (colloquially, Lion's tail region) six-generation pedigree, including neuropathologically confirmed multiple system atrophy and Parkinson's disease with dementia. Between 2012 and 2020, we examined all living and consenting family members of age and calculated the risk of prodromal Parkinson's disease in those without overt parkinsonism. The index case and one paternal cousin with Parkinson's disease with dementia died at follow-up and underwent neuropathological examination. Genetic analysis was performed in both and another family member with Parkinson's disease. The index case was a female patient with cerebellar variant multiple system atrophy and a positive maternal and paternal family history for Parkinson's disease and dementia in multiple generations. The families of the index case and her spouse were genealogically related, and one of the spouse's siblings met the criteria for possible prodromal Parkinson's disease. Neuropathological examination confirmed multiple system atrophy in the index case and advanced Lewy body disease, as well as tau pathology in her cousin. A comprehensive analysis of genes known to cause hereditary forms of parkinsonism or multiple system atrophy lookalikes was unremarkable in the index case and the other two affected family members. Here, we report an extensive European pedigree with multiple system atrophy and Parkinson`s disease suggesting a complex underlying α-synucleinopathy as confirmed on neuropathological examination. The exclusion of known genetic causes of parkinsonism or multiple system atrophy lookalikes suggests that variants in additional, still unknown genes, linked to α-synucleinopathy lesions underlie such neurodegenerative clustering.

Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022?

Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare disease.

Female sexual dysfunction in multiple system atrophy: a prospective cohort study.

PURPOSE: The diagnosis of probable multiple system atrophy relies on the presence of severe cardiovascular or urogenital autonomic failure. Erectile dysfunction is required to fulfil the latter criterion in men, whereas no corresponding item is established for women. In this study, we aimed to investigate sexual dysfunction in women with multiple system atrophy. METHODS: We administered the Female Sexual Function Index questionnaire and interviewed women with multiple system atrophy and age-matched controls regarding the presence of "genital hyposensitivity." RESULTS: We recruited 25 women with multiple system atrophy and 42 controls. Female Sexual Function Index scores in sexually active women with multiple system atrophy were significantly lower (multiple system atrophy = 10; 15.4, 95% CI [10.1, 22.1], controls = 37; 26.1 [24.1, 28.1], p = 0.0004). The lowest scores concerned the domains of desire, arousal and lubrication. Genital hyposensitivity was reported by 56% of the patients with multiple system atrophy and 9% controls (p < 0.0001). CONCLUSIONS: Sexual dysfunction is highly prevalent in women with multiple system atrophy. Screening for disturbances in specific sexual domains should be implemented in the clinical evaluation of women with suggestive motor symptoms.

CGRP-antibodies, topiramate and botulinum toxin type A in episodic and chronic migraine: A systematic review and meta-analysis.

BACKGROUND: The approval of monoclonal antibodies for prevention of migraine has revolutionized treatment for patients. Oral preventatives are still considered first line treatments as head-to-head trials comparing them with antibodies are lacking. METHODS: The main purpose of this study was to provide a comparative overview of the efficacy of three commonly prescribed migraine preventative medication classes. For this systematic review and meta-analysis, we searched the databases CENTRAL, EMBASE, and MEDLINE until 20 March 2020. We included RCTs reporting the 50% response rates for topiramate, Botulinum Toxin Type A and monoclonal antibodies against CGRP(r). Studies were excluded if response rates were not reported, treatment allocation was unclear, or if study quality was insufficient. Primary outcome measure were the 50% response rates. The pooled odds ratios with 95% confidence intervals were calculated with the random effects model. The study was registered at PROSPERO (CRD42020222880). FINDINGS: We identified 6552 reports. Thirty-two were eligible for our review. Studies assessing monoclonal antibodies included 13,302 patients and yielded pooled odds ratios for the 50% response rate of 2.30 (CI: 2.11-2.50). Topiramate had an overall effect estimate of 2.70 (CI: 1.97-3.69) with 1989 included patients and Botulinum Toxin Type A achieved 1.28 (CI: 0.98-1. 67) with 2472 patients included. INTERPRETATION: Topiramate, botulinum toxin type A and monoclonal antibodies showed higher odds ratios in achieving a 50% response rate compared to placebo. Topiramate numerically demonstrated the greatest effect size but also the highest drop-out rate.

Characterization of gait variability in multiple system atrophy and Parkinson's disease.

BACKGROUND: Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls. OBJECTIVES: We compared gait variability at different walking velocities between and within groups of patients with Parkinson-variant multiple system atrophy, idiopathic Parkinson's disease, and a control group of older adults. METHODS: Gait metrics were recorded in 11 multiple system atrophy, 12 Parkinson's disease patients, and 18 controls using sensor-based gait analysis. Gait variability was analyzed for stride, swing and stance time, stride length and gait velocity. Values were compared between and within the groups at self-paced comfortable, fast and slow walking speed. RESULTS: Multiple system atrophy patients displayed higher gait variability except for stride time at all velocities compared with controls, while Parkinson's patients did not. Compared with Parkinson's disease, multiple system atrophy patients displayed higher variability of swing time, stride length and gait velocity at comfortable speed and at slow speed for swing and stance time, stride length and gait velocity (all P < 0.05). Stride time variability was significantly higher in slow compared to comfortable walking in patients with multiple system atrophy (P = 0.014). Variability parameters significantly correlated with the postural instability/gait difficulty subscore in both disease groups. Conversely, significant correlations between variability parameters and MDS-UPDRS III score was observed only for multiple system atrophy patients. CONCLUSION: This analysis suggests that gait variability parameters reflect the major axial impairment and postural instability displayed by multiple system atrophy patients compared with Parkinson's disease patients and controls.

Case Report: Secondary bilateral parkinsonism and dystonia treated with dronabinol.

Drug abuse may damage basal ganglia that are essential for planning and execution of movements. We report a 38-year old patient with ischemic lesions of the basal ganglia presenting with bilateral painful dystonia and parkinsonism caused by polyintoxication. Dronabinol resulted in improvement of pain and gait disturbance, suggesting a novel therapeutic strategy in these challenging patients.