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The aim of this study was to investigate the distribution and the degree of asymmetric putaminal dopamine transporter availability in right-handed patients with Parkinson's disease and its association with the severity of lateralized motor signs. Asymmetry of motor symptoms was defined by the difference between right- and left-sided scores for lateralized items assessed by the Unified Parkinson's Disease Rating Scale Motor Score in a series of 68 patients with Parkinson's disease (disease duration 2.1 ± 1.5 years; Unified Parkinson's Disease Rating Scale Motor Score 22.7 ± 9). Putaminal dopamine transporter availability was measured with the radioligand [(123)I]β-carboxymethyoxy-3 -β-(4-iodophenyl) tropane ([(123)I]β-CIT) and single photon emission computed tomography. We found that in the right-handed Parkinson's disease cohort, the number of patients who had lower dopamine transporter uptake in the left posterior putamen was significantly greater compared with those with lower uptake in the right posterior putamen (Parkinson's disease-left group, n = 49; Parkinson's disease-right group, n = 19; P < 0.001). In addition, one-way analysis of variance revealed significant reductions of mean total putaminal [(123)I]β-CIT binding of the Parkinson's disease-right patients compared with Parkinson's disease-left patients (P < 0.05).The preponderance of reduced left putaminal dopamine transporter availability strengthens clinical observations of a greater proportion of right-handed patients with Parkinson's disease with predominantly right-sided motor signs and argues against a randomly distributed asymmetric vulnerability of substantia nigra dopaminergic neurons. The coexistence of a subgroup of right-handed patients with Parkinson's disease with more severe and predominant ipsilateral putaminal dopamine transporter decline suggests that asymmetry of dopaminergic denervation and motor dysfunction in Parkinson's disease cannot be fully explained by hemispheric dominance alone, but that other factors must be involved. [ABSTRACT FROM AUTHOR]

Objective: To develop and test a questionnaire for measuring quality of life in patients with craniocervical dystonia.Methods: A 29-item pool was developed based on semi-structured interviews of patients with cervical dystonia (CD) and blepharospasm (BSP). This preliminary questionnaire was administered to 203 consecutive patients with CD and BSP from Austrian dystonia and botulinum toxin outpatient clinics. For scale generation, a combination of exploratory factor and cluster analysis was applied. This resulted in the 24-item version of the instrument (CDQ-24) based on five subscales: Stigma, Emotional wellbeing, Pain, Activities of daily living, and Social/family life. The validity and reliability of the CDQ-24 was assessed in 231 consecutive patients with CD and BSP different from those examined with the preliminary questionnaire. This second survey included the CDQ-24, a generic QoL instrument (SF-36) and clinical rating scales. Sensitivity to change was analysed in 51 previously untreated (de novo) patients four weeks and one year following the first botulinum toxin treatment.Results: Internal consistency reliability was satisfactory for all subscales, with values of Cronbach's alpha ranging from 0.77 to 0.89. The CDQ-24 subscales showed moderate to high correlations with those SF-36 subscales measuring similar aspects (Pearson's correlation r = 0.50-0.73; p<0.001, each). Sensitivity to change was confirmed by highly significant improvements of all CDQ-24 subscores in the de novo patients from baseline to four week follow up. One year follow up data revealed a stable improvement.Conclusion: The CDQ-24 is the first fully validated and disease specific questionnaire to evaluate quality of life of patients with cervical dystonia and blepharospasm and we propose its use in clinical trials as well as in daily clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Although both orthostatic hypotension and urinary incontinence have been reported in a number of parkinsonian syndromes, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), differences in the evolution of these features have not been studied systematically in pathologically confirmed cases.Methods: 77 cases with pathologically confirmed parkinsonian syndromes (PD, n=11; MSA, n=15; DLB, n=14; CBD, n=13; PSP, n=24), collected up to 1994, formed the basis for a multicentre clinicopathological study organised by the NINDS to improve the differential diagnosis of parkinsonian disorders. The present study determined the time course-that is, latency to onset and duration from onset to death, of symptomatic orthostatic hypotension, and urinary incontinence in the NINDS series. Furthermore, the diagnostic validity of a predefined latency to onset within 1 year of disease onset of symptomatic orthostatic hypotension or urinary incontinence was analysed.Results: Significant group differences for latency, but not duration, of symptomatic orthostatic hypotension and urinary incontinence were found. Latencies to onset of either feature were short in patients with MSA, intermediate in patients with DLB, CBD, and PSP, and long in those with PD. Symptomatic orthostatic hypotension occurring within the first year after disease onset predicted MSA in 75% of cases; early urinary incontinence was less predictive for MSA (56%).Conclusion: Latency to onset, but not duration, of symptomatic orthostatic hypotension or urinary incontinence differentiates PD from other parkinsonian syndromes, particularly MSA. [ABSTRACT FROM AUTHOR]

Eighteen patients from three large multigenerational families with genetically established spinocerebellar ataxia type 2 (SCA2) were examined, with special attention to the presence of dystonic features. Cervical dystonia (CD) was diagnosed according to standardised clinical criteria. CD was scored using the Tsui score. Polymyography was performed in six cases using bilateral surface electrode recordings of the sternocleidomastoid and trapezius muscles together with needle electrode recordings of the splenius capitis muscles bilaterally. CD was found in 11 of 18 patients (61%), and was the presenting symptom in one case. Severity of CD was mild to moderate, with Tsui scores ranging from 5 to 12 points. Polymyography in 6 of 11 SCA2 patients with CD showed the typical pattern of dystonia with spontaneous, involuntary muscle activation at rest in at least one neck muscle with disturbed reciprocal inhibition of antagonistic neck muscles. CD appears to be a common clinical feature in SCA2 and may precede ataxia and gait disturbance. By contrast, none of the 18 patients had dystonic features in other body regions. CD has probably been underreported in patients with the ataxic SCA2 phenotype and should be considered as an additional clinical manifestation in patients with hereditary ataxia. [ABSTRACT FROM AUTHOR]

Multiple system atrophy is an adult-onset, sporadic, and progressive neurodegenerative disease. People with this disorder report a wide range of motor and non-motor symptoms. Overlap in the clinical presentation of multiple system atrophy with other movement disorders (eg, Parkinson's disease and progressive supranuclear palsy) is a concern for accurate and timely diagnosis. Over the past 5 years, progress has been made in understanding key pathophysiological events in multiple system atrophy, including the seeding of α-synuclein inclusions and the detection of disease-specific α-synuclein strains. Diagnostic criteria were revised in 2022 with the intention to improve the accuracy of a diagnosis of multiple system atrophy, particularly for early disease stages. Early signals of efficacy in clinical trials have indicated the potential for disease-modifying therapies for multiple system atrophy, although no trial has yet provided unequivocal evidence of neuroprotection in this rare disease. The advances in pathophysiology could play a part in biomarker discovery for early diagnosis as well as in the development of disease-modifying therapies., Competing Interests: Declaration of interests FK received personal fees from Institut de Recherches Internationales Servier, Takeda Pharmaceuticals, Sanofi, Teva, Bial, and the Austrian Society of Neurology in the past 36 months and he has ongoing grant support from the Austrian Science Fund, the National Institutes of Health, and the Michael J Fox Foundation, outside of the submitted work. AF reports grant support from the Austrian Science Fund, Multiple System Atrophy Coalition, Austrian Exchange Program, Medical University of Innsbruck, Tuba Stiftung; royalties from Springer and Thieme; and personal fees from Broadview Ventures, Theravance, Bial, Abbvie, GE Health Care, Austrian Neurology Society, Austrian Autonomic Society, International Parkinson Disease and Movement Disorders Society, and American Academy of Neurology, outside of the submitted work. WGM reports personal fees from Lundbeck, Teva, Takeda, Alterity, Inhibikase, Servier, GE, and UCB; and grant support from Fondation de France, Michael J Fox Foundation, Multiple System Atrophy Coalition, Bordeaux Initiative for Neurodegenerative Disordes, Programme Hospitalier de Recherche Clinique, and Agence Nationale de la Recherche. EC declares no competing interests. GKW died in February, 2024., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6-22 and HR: 3.6, 95% CI: 1.1-12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2-6), trouble swallowing (HR 2.5, 95% CI: 1.4-4.5) and changes in speech (HR:2.4, 95% CI:1.1-4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1-5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2-38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6-46), preserved olfaction (HR: 8.7, 95% CI: 1.7-45), anhidrosis (HR: 1.8, 95% CI: 1-3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1-2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., Competing Interests: Declaration of interests T.G.B. is a consultant for Aprinoia Therapeutics, Vivid Genomics, and Avid Radiopharmaceutical and is a scientific advisory board member for Vivid Genomics. J.A.H., H.R.M., B.J.T., and H.R.M. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. B.J.T. and S.W.S. receive research support from Cerevel Therapeutics. B.J.T. is an editorial and advisory board member for Brain, eClinicalMedicine, Journal of Neurology, Neurosurgery, and Psychiatry, and Neurobiology of Aging. H.R.M. reports paid consultancy from Biogen, Biohaven, Lundbeck, UCB, and Denali as well as lecture fees and honoraria from the Wellcome Trust and the Movement Disorders Society. H.R.M. received research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, the Drake Foundation, and the Medical Research Council. H.K. is editor-in-chief of Clinical Autonomic Research, serves as principal investigator (PI) of a clinical trial sponsored by Biogen MA Inc. (TRACK MSA, S19-01846), and received consultancy fees from Lilly USA LLC, Biohaven Pharmaceuticals Inc., Takeda Pharmaceutical Company Ltd., Ono Pharma UK Ltd., Lundbeck LLC, and Theravance Biopharma US Inc. A.F. reports royalties from Springer Verlag; speaker fees and honoraria from Theravance Biopharma, GE Health Care, Broadview Ventures, Austrian Autonomic Society, Stopp-HSP, and Elsevier; and research grants from the FWF-Austrian Science Fund, Medical University of Innsbruck, US MSA Coalition, Dr. Johannes and Hertha Tuba Foundation, and Austrian Exchange Program, outside of the present work. J.-A.P. is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. I.B. received consultancy fees from Theravance Biopharma US Inc., Amenal Pharmaceutics, Regeneron Pharmaceuticals, Takeda Pharmaceuticals, and Neurawell Therapeutics. S.W.S. serves on the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. is an editorial board member for the Journal of Parkinson’s Disease and JAMA Neurology. A.P. serves on the board of directors for CurePSP, has received research grants from the National Institutes of Health and the Michael J. Fox Foundation, and has received consultancy fees from AbbVie Inc., Biogen Inc., SciNeuro Pharmaceuticals, Ono Pharma, and Ferrer Internacional, S.A. A.T. serves on the scientific advisory board for Vivid Genomics. R.H.R. is currently employed by CoSyne Therapeutics; all work performed for this publication was performed on her own time and not as a part of her duties as an employee. Z.K.W. is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), the Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson's Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals Inc. (BHV4157-206) and Vigil Neuroscience Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research, as an external advisory board member for Vigil Neuroscience Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. F.K. received personal fees from Institut de Recherches Internationales Servier, Takeda Pharmaceuticals, Sanofi, Teva, Vial, and the Austrian Society of Neurology in the past 12 months, and he has ongoing grant support from the Austrian Science Fund (FWF) and the National Institutes of Health outside of the submitted work. W.G.M. has received fees for editorial activities with Elsevier and has served as an advisor for Lundbeck, Biohaven, Roche, Alterity, Servier, Inhibikase, Takeda, and Teva., (Published by Elsevier Inc.)

Background: Subthalamic deep brain stimulation (STN-DBS) reduces antiparkinsonian medications in Parkinson's disease (PD) compared with the preoperative state. Longitudinal and comparative studies on this effect are lacking., Objective: To compare longitudinal trajectories of antiparkinsonian medication in STN-DBS treated patients to non-surgically treated control patients., Methods: We collected retrospective information on antiparkinsonian medication from PD patients that underwent subthalamic DBS between 1999 and 2010 and control PD patients similar in age at onset and baseline, sex-distribution, and comorbidities., Results: In 74 DBS patients levodopa-equivalent daily dose (LEDD) were reduced by 33.9-56.0% in relation to the preoperative baseline over the 14-year observational period. In 61 control patients LEDDs increased over approximately 10 years, causing a significant divergence between groups. The largest difference amongst single drug-classes was observed for dopamine agonists., Conclusion: In PD patients, chronic STN-DBS was associated with a lower LEDD compared with control patients over 14 years., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: 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., Objectives: To replicate and improve the 4-item MSA-P score., Methods: 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., Results: 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., Conclusions: The 6-item MSA-P score is a cost-effective tool to pinpoint individuals with early-stage MSA-P., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© 2024. The Author(s).)

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.

Objective: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA)., Background: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion., Methods: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion., Results: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively., Conclusions: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe., Methods: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders., Results: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year., Conclusions: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design., (© 2023. The Author(s).)

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., (© 2022. The Author(s).)

Competing Interests: Competing interests: None declared.

Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and autonomic brain centres. It causes complex cumulative motor and non-motor disability with fast progression and effective therapy is currently lacking. The difficulties in the diagnosis and treatment of MSA are largely related to the incomplete understanding of the pathogenesis of the disease. The MSA pathogenic landscape is complex, and converging findings from genetic and neuropathological studies as well as studies in experimental models of MSA have indicated the involvement of genetic and epigenetic changes; α-synuclein misfolding, aggregation and spreading; and α-synuclein strain specificity. These studies also indicate the involvement of myelin and iron dyshomeostasis, neuroinflammation, mitochondrial dysfunction and other cell-specific aspects that are relevant to the fast progression of MSA. In this Review, we discuss these findings and emphasize the implications of the complexity of the multifactorial pathogenic cascade for future translational research and its impact on biomarker discovery and treatment target definitions., (© 2023. Springer Nature Limited.)

Background: An absent dorsolateral nigral hyperintensity (DNH) is a common finding in patients with neurodegenerative parkinsonism at high or ultra-high field susceptibility-weighted magnetic resonance imaging (SWI)., Objective: Despite increasing use of high field magnetic resonance imaging (MRI) in specialized centers, these scanners are still frequently unavailable in primary care or outpatient facilities and underdeveloped or emerging countries. Therefore, the aim of the present study was to evaluate the diagnostic utility of DNH assessment at 1.5 versus 3 T MRI to distinguish patients with neurodegenerative parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), from healthy controls (HC)., Methods: Absence of DNH was assessed on visual inspection of anonymized 1.5 T and 3.0 T SWI scans in a case-control study including 86 patients with neurodegenerative parkinsonism and 33 healthy controls (HC). All study participants were consecutively recruited to undergo 1.5 and 3 T MRI., Results: Overall correct classification was 81.7% (95% CI, 72.6-88.4%) for 1.5 T and 95.7% (95% CI, 89.1-98.7%) for 3 T MRI in discriminating neurodegenerative parkinsonism from controls. However, while DNH was bilaterally present in all but one of the HC at 3 T MRI, it was rated as abnormal (at least unilateral absence) in 15 of 22 HC at 1.5 T MRI, resulting in a specificity of 31.8%., Conclusions: The results of the present study demonstrate an insufficient specificity of visual assessment of DNH at 1.5 T MRI for the diagnosis of neurodegenerative parkinsonism., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: To investigate the impact of the coronavirus-disease-2019 (COVID-19) pandemic on European clinical autonomic practice., Methods: Eighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021., Results: Forty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every-third center reported major adverse events due to postponed examinations or visits. The most frequent newly-diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and recurrent vasovagal syncope, deemed likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new-onset of orthostatic intolerance, but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly-diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently POTS and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50-100% recovery rates at follow-up., Conclusions: Cardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, while the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints., (This article is protected by copyright. All rights reserved.)

Background and Purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences., Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey., Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021)., Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: The aim was to determine the extent of sudomotor dysfunction in people with neuromyelitis optica spectrum disorder (pwNMOSD) and to compare findings with a historical cohort of people with relapsing-remitting multiple sclerosis (pwRRMS)., Methods: Forty-eight pwNMOSD were enrolled from four clinical centers. All participants completed the Composite Autonomic Symptom Score 31 to screen for symptoms of sudomotor dysfunction. Sudomotor function was assessed using the quantitative sudomotor axon reflex test. The results were compared with a historical cohort of 35 pwRRMS matched for age, sex and disease duration., Results: Symptoms of sudomotor dysfunction, defined by a score in the Composite Autonomic Symptom Score 31 secretomotor domain &gt;0, were present in 26 (54%) of pwNMOSD. The quantitative sudomotor axon reflex test confirmed a sudomotor dysfunction in 25 (52.1%) of pwNMOSD; in 14 of them (29.2%) sudomotor dysfunction was moderate or severe. No difference was observed between pwNMOSD and pwRRMS in any of the studied parameters. However, symptomatic sudomotor dysfunction was more frequent in pwNMOSD (n = 8, 22.9%) compared to pwRRMS (n = 1, 3%; p = 0.028). In a multivariable logistic regression analysis, statistically significant predictors for symptomatic sudomotor failure were age and diagnosis of neuromyelitis optica spectrum disorder., Conclusions: Sudomotor dysfunction is common in pwNMOSD and more often symptomatic compared to pwRRMS., (© 2022 European Academy of Neurology.)

Background: The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver., Objectives: To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire., Methods: Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence., Results: At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%)., Conclusions: Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice., (© 2022 International Parkinson and Movement Disorder Society.)

Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients., (© 2022. Springer Nature Limited.)

Background: Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course., Objectives: The aims of this study were to develop a novel disease-progression model to estimate a population-level MSA progression trajectory and predict patient-specific continuous disease stages describing the degree of progress into the disease., Methods: The disease-progression model estimated a population-level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated., Results: The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA-parkinsonian (MSA-P) type patients having an accelerated rate of progression., Conclusions: The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well-founded predictions of patient-level future progressions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient., Objective: The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items., Methods: Data were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity-to-change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient-centricity was assessed through correlation of UMSARS items with quality-of-life measures., Results: Progression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient-centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking., Conclusion: The present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)