Movement Disorders最新文献

{"title":"Divergent Glymphatic Dysfunction and Free Water Pathology Underpin Distinct Mechanisms and Enable Differential Diagnosis in Parkinson's Disease and Multiple System Atrophy","authors":"Ruinan Shen MD, PhD,&nbsp;Zexuan Meng MD,&nbsp;Xue Zhu MD,&nbsp;Haiying Lyu MD,&nbsp;Sijia Huang MBBS,&nbsp;Xiaojin Wang PhD,&nbsp;Yuhong Fu MD, PhD,&nbsp;Woojin S. Kim PhD,&nbsp;Yong Lu PhD,&nbsp;Bingshun Wang PhD,&nbsp;Yuyan Tan PhD,&nbsp;Liche Zhou MD,&nbsp;Jun Liu MD, PhD","doi":"10.1002/mds.70293","DOIUrl":"10.1002/mds.70293","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Parkinson's disease (PD) and multiple system atrophy (MSA) show overlapping clinical features, posing diagnostic challenges. This study investigates whether distinct patterns of glymphatic dysfunction and free water (FW) accumulation can differentiate their underlying mechanisms and serve as discriminatory biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to evaluate glymphatic function and FW pathology in PD and MSA, and to develop an integrated biomarker panel for differential diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a cross-sectional and longitudinal neuroimaging study involving 231 participants: 74 healthy control subjects (HCs), 79 patients with PD, and 78 patients with MSA. Glymphatic function (diffusion tensor image analysis along the perivascular space [DTI-ALPS] index and choroid plexus volume [CPV]) and FW distribution were derived from magnetic resonance imaging. Diagnostic performance was evaluated using receiver operating characteristic curves. Mediation analyses explored relationships among glymphatic impairment, FW accumulation, and clinical symptoms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Both PD and MSA showed reduced DTI-ALPS and enlarged CPV versus HC. FW accumulation exhibited disease-specific patterns: cortical/midline in PD and cerebellar in MSA. Longitudinal analysis confirmed progressive FW accumulation in these regions. Spatial coupling between glymphatic dysfunction and FW was strong in PD but absent in MSA. FW mediated the relationship between glymphatic impairment and motor/autonomic symptoms in PD, but not MSA. The integrated model combining neuroimaging and clinical metrics showed excellent discriminatory power for PD and MSA (area under the curve = 0.994).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>PD and MSA exhibit distinct glymphatic-FW pathological profiles. The coupled mechanism in PD contrasts with the uncoupled pathology in MSA, reflecting divergent pathogenesis. Multimodal imaging biomarkers demonstrate high diagnostic accuracy, showing strong potential for differential diagnosis in clinical practice. © 2026 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1812-1824"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Memoriam Regina Katzenschlager (1964–2026)","authors":"Susan H. Fox MD,&nbsp;Cristina Sampaio MD,&nbsp;Andrew Lees FRCP,&nbsp;Werner Poewe MD","doi":"10.1002/mds.70382","DOIUrl":"10.1002/mds.70382","url":null,"abstract":"&lt;p&gt;We are deeply saddened to announce the sudden death of Dr. Regina Katzenschlager on April 21, 2026, in a car accident while holidaying in New Zealand.&lt;/p&gt;&lt;p&gt;Regina was Head of the Department of Neurology at the Danube-City Hospital and of the Karl Landsteiner Institute for neuro-immunological and neurodegenerative disorders in Vienna, Austria. She also served as president of both the Austrian PD and Movement Disorder Society (MDS) and the Austrian Society of Neurology and played a major role in shaping movement disorder training and research in her country. Her role as a leader within the field of movement disorders extended far beyond Austria.&lt;/p&gt;&lt;p&gt;After completing her training in Neurology and Psychiatry in Vienna, Regina moved to the United Kingdom (UK) and was a Research Fellow with Andrew Lees at University College London from 1999 to 2002. During her time there, she co-authored the seminal UK Parkinson Disease Research group clinical trial, which showed that early use of a dopamine agonist, bromocriptine, did not result in any long-term benefit on risk of motor fluctuations, compared to use of selegiline or levodopa. She also published on the antidyskinetic effects of subcutaneous apomorphine pump therapy for Parkinson's disease (PD). A decade later she went on to lead the double blind randomized controlled trial (RCT) (TOLEDO) study confirming benefit of infusions of apomorphine on motor fluctuations in PD.&lt;/p&gt;&lt;p&gt;Regina was an integral and active member of the International Parkinson and MDS. She served as a member of the International Executive Committee (2021–2025) and was secretary of the MDS-European Section (2023–2025); as well as a member of the website editorial board and Movement Disorders journal editorial board and membership committee.&lt;/p&gt;&lt;p&gt;Regina served as member of the MDS-Evidence Based Medicine (EDM) group from the beginnings in 2000, alongside Cristina Sampaio and later succeeded Cristina as chair of MDS EBM committee. Her first publication was the initial Cochrane review on use of anticholinergics for PD, which was a huge undertaking reviewing RCTs published from 1927 to 2003. This publication, which for the non-initiated might seem almost medieval, was a major landmark in establishing the evidence-based medicine movement within the MDS. At this time, we were in the very beginning of EBM, when it was thought individual expertise was what counted most to affirm treatment efficacy. Many people had assignments to review classes of drugs for PD using the evidence-based methodology. Regina completed her assignment with aplomb and established herself as a reliable and knowledgeable “EBMER.” Regina went on to participate in all subsequent EBM updates on motor and non-motor treatments for PD and led the MDS EBM committee during the transition to the Grading of Recommendations Assessment, Development, and Evaluation system from 2017 to 2021 and in recent years as a member of the MDS EBM advisory committee.&lt;/p&gt;&lt;p&gt;On a personal ","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1621-1622"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70382","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148285839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) Characterizes Neurodegeneration Levels Across the α-Synucleinopathy Continuum","authors":"Beatrice Orso PhD,&nbsp;Ignacio Roura PsyD,&nbsp;Pietro Mattioli MD,&nbsp;Francesco Famà BSc,&nbsp;Federico Massa MD, PhD,&nbsp;Luigi Lorenzini PhD,&nbsp;Andrea Brugnolo PhD,&nbsp;Nicola Girtler PsyD,&nbsp;Mattia Losa MD,&nbsp;Stefano Raffa MD,&nbsp;Luca Sofia MD,&nbsp;Monica Roascio PhD,&nbsp;Gabriele Arnulfo PhD,&nbsp;Silvia Morbelli MD, PhD,&nbsp;Matteo Pardini MD, PhD,&nbsp;Dario Arnaldi MD, PhD","doi":"10.1002/mds.70301","DOIUrl":"10.1002/mds.70301","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;[&lt;sup&gt;18&lt;/sup&gt;F]Fluorodeoxyglucose positron emission tomography ([&lt;sup&gt;18&lt;/sup&gt;F]FDG PET) represents an endorsed neurodegeneration biomarker in neuronal &lt;i&gt;α-&lt;/i&gt;synucleinopathies. Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents a prodromal stage of such disorders.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To assess [&lt;sup&gt;18&lt;/sup&gt;F]FDG PET as a neurodegeneration biomarker, using published brain metabolic disease-related patterns, and a regional-based approach, across the prodromal to overt &lt;i&gt;α-&lt;/i&gt;synucleinopathy continuum.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We included 83 prodromal subjects with iRBD, comprising non-converters (n = 56) and converters (n = 27) to an overt &lt;i&gt;α-&lt;/i&gt;synucleinopathy (either Parkinson's disease [PD] or dementia with Lewy bodies [DLB]) according to the last available follow-up, and 85 subjects with PD (n = 40) and DLB (n = 45). For comparison, we enrolled a group of healthy subjects (n = 41). Participants underwent brain [&lt;sup&gt;18&lt;/sup&gt;F]FDG PET at baseline. Analysis of covariance was used to test the ability of previously published [&lt;sup&gt;18&lt;/sup&gt;F]FDG PET disease-related patterns in characterizing neurodegeneration levels along the prodromal to overt &lt;i&gt;α-&lt;/i&gt;synucleinopathy continuum, and across the motor-predominant (parkinsonism-first) and the cognitive-predominant (dementia-first) clinical trajectories. We further assessed metabolic changes using a regional-based approach.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;All disease-related patterns effectively discriminated clinical stages, from prodromal to overt &lt;i&gt;α&lt;/i&gt;-synucleinopathies, with comparable performance. [&lt;sup&gt;18&lt;/sup&gt;F]FDG PET significantly distinguished all groups along the cognitive-predominant pathway; whereas in the motor-predominant pathway, converter patients were not significantly discriminated from non-converters. Regionally, the inferior parietal, precuneus, and middle frontal areas exhibited the most prominent decrease in [&lt;sup&gt;18&lt;/sup&gt;F]FDG uptake with progression, alongside relative parallel progressive increases in the cerebellum, pons, parahippocampal areas, putamen, and pallidum.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;[&lt;sup&gt;18&lt;/sup&gt;F]FDG PET disease-related patterns efficiently characterize neurodegeneration from prodromal to overt &lt;i&gt;α&lt;/i&gt;-synucleinopathy, best assessing the cognitive-predominant (dementia-first) pathway. © 2026","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1786-1797"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collaborative Genomics for Dystonia in Central and Eastern Europe: Successes Achieved, New Frontiers Ahead","authors":"Robert Jech MD, PhD,&nbsp;Petra Havránková MD, PhD,&nbsp;Eugenia Tsoma MD,&nbsp;Lukáš Kunc MD,&nbsp;Tomáš Krajča MD,&nbsp;Ján Necpál MD,&nbsp;Olga Ulmanová MD, PhD,&nbsp;Aleksandra Tomic MD,&nbsp;Ivana Dzinovic PhD,&nbsp;Irena Rektorová MD, PhD,&nbsp;Marek Baláž MD,&nbsp;Tereza Serranová MD,&nbsp;Stanislava Jaselska MD,&nbsp;Maria Giertlova MD,&nbsp;Kristina Kulcsarova MD,&nbsp;Alexandra Lackova MD,&nbsp;Denisa Harvanova MD,&nbsp;Miriam Ostrozovicova MD,&nbsp;Vladimir Han MD,&nbsp;GenDy Collaborators,&nbsp;Matej Škorvánek MD, PhD,&nbsp;Michael Zech MD","doi":"10.1002/mds.70300","DOIUrl":"10.1002/mds.70300","url":null,"abstract":"&lt;p&gt;The application and clinical utility of genomic analyses are well established in the field of movement disorders, where high-throughput molecular tests have revolutionized the rate, speed, and precision of diagnosis.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Nevertheless, there is a wide appreciation of inequitable access to genomic programs with maldistribution of enrollment into precision-medicine studies for individuals living with a movement disorder in “underrepresented” geographical regions.&lt;span&gt;&lt;sup&gt;2-4&lt;/sup&gt;&lt;/span&gt; Although successes in diversifying cohorts and overcoming diagnostic disparities have been shown for some forms of movement disorders, most notably for Parkinson's disease,&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; significant room for improvement of inclusion and investigation remains for other patient groups, such as individuals with dystonia. Lim and colleagues&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; recently proposed a seminal definition of underrepresented populations in genomic research, highlighting patients from Eastern European countries as an important portion of underserved individuals who face barriers to systematic genetic characterization. The investigation of the impact of state-of-the-art genomic testing approaches in such disadvantaged populations has often started to focus on more common conditions, exacerbating the issue of underrepresentation of patients with rare genetic dystonias from these regions.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; In this Viewpoint article, we aim to summarize our experiences in building a roadmap for narrowing disparities in genomic research among dystonia-affected individuals from underrepresented European countries. Through the perspective of the “Mapping Genomic Diversity of Dystonia in Central and Eastern Europe” (GenDy) project, we report accomplishments and provide examples on a 10-year timescale,&lt;span&gt;&lt;sup&gt;8-10&lt;/sup&gt;&lt;/span&gt; fostering more equitable advantages from genomics for diverse patients with dystonia.&lt;/p&gt;&lt;p&gt;GenDy has so far applied genomic sequencing to 961 families using different analytical designs (250 trio analyses). The overall diagnostic yield from the main employed sequencing method—WES—within GenDy is 22%,&lt;span&gt;&lt;sup&gt;8, 10&lt;/sup&gt;&lt;/span&gt; which accounts for 118 different rare monogenic diagnoses (most common diagnosis: &lt;i&gt;SGCE&lt;/i&gt;). An analysis of all WES-based genetic diagnoses across participating countries, detailed in Table S1, revealed a broad spectrum of causal genomic findings without evidence of significant regional enrichments. Instead, the genetic landscape appeared to be characterized by a few recurrently affected genes alongside a large number of ultra-rare conditions identified only once,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; reflecting the rarity of these disorders rather than population-specific structures or referral biases. However, regional differences in diagnostic yield were observed; for instance, the higher yield in the Slovakian subcohort likely reflects an enrichment for complex pediatric cases compared wit","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1666-1672"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk Factors for the Diagnosis of Progressive Supranuclear Palsy in the UK Biobank","authors":"Charlie Weige Zhao MD,&nbsp;Marian Dale MD,&nbsp;Alexander Pantelyat MD,&nbsp;Maria Carmela Tartaglia MD,&nbsp;Ruth B. Schneider MD,&nbsp;David G. Coughlin MD, MTR,&nbsp;Federico Rodriguez-Porcel MD,&nbsp;Zbigniew Wszolek MD,&nbsp;Tao Xie MD, PhD,&nbsp;Lawrence I. Golbe MD,&nbsp;James B. Rowe MD, PhD,&nbsp;Anne-Marie Wills MD, MPH","doi":"10.1002/mds.70287","DOIUrl":"10.1002/mds.70287","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Progressive supranuclear palsy (PSP) is a tauopathy for which there is limited understanding of epidemiological risk factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to identify premorbid nonmedical and medical risk factors for PSP diagnosis in a large prospective population-based cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a matched nested case–control study using the UK Biobank (UKB) cohort consisting of &gt;500,000 adults aged 37 to 73 years. PSP diagnoses were identified from 2007 to censor date (August 2025) and matched 1:10 by age and sex to control subjects without parkinsonism or dementia diagnoses. We derived risk factors using an iterative logistic regression approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were 240 incident PSP diagnoses in the UKB. In the fully adjusted model, premorbid depression (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.30–4.50; <i>P</i> &lt; 0.001), delirium (OR, 6.76; 95% CI, 4.08–11.19; <i>P</i> &lt; 0.001), and functional gastrointestinal disorders (OR, 1.91; 95% CI, 1.39–2.63; <i>P</i> &lt; 0.001) were associated with increased risk. Heavy alcohol consumption was associated with higher risk compared with moderate consumption (OR, 1.65; 95% CI: 1.21–2.26; <i>P</i> = 0.0017). Body mass index (BMI) and alcohol consumption had nonlinear risk profiles. Cancer diagnosis was inversely associated with PSP (OR, 0.56; 95% CI, 0.40–0.79; <i>P</i> &lt; 0.001). Depression and delirium diagnoses remained significant 5 to 10 years before diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this large prospective cohort, PSP was associated with premorbid lifestyle practices and neuropsychiatric diagnoses years before diagnosis. This suggests a long premotor phase and highlights opportunities for earlier diagnosis and further mechanistic investigation. The inverse association with cancer mirrors the relationship seen in other neurodegenerative conditions and may point toward shared mechanisms. © 2026 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1727-1739"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147518901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indirect Striatal Projection Neurons Drive a D2 Receptor-Dependent Pathway to Dyskinesia and Dystonia","authors":"Laura Andreoli PhD,&nbsp;Teodor Nyman MSc,&nbsp;Elena Espa PhD,&nbsp;Johan Jakobsson PhD,&nbsp;Osama F. Elabi PhD,&nbsp;Maria Angela Cenci MD, PhD","doi":"10.1002/mds.70299","DOIUrl":"10.1002/mds.70299","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>L-DOPA-induced dyskinesia is attributed to opposite activity changes mediated by D1 and D2 dopamine receptors in the two striatal output pathways. Whereas the causal role of direct-pathway D1 receptors is well established, the specific involvement of indirect-pathway D2 receptors in dopaminergic dyskinesias has remained elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We used conditional knockout approaches in mice to determine whether indirect-pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Studies were conducted in mice with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway receiving subchronic treatments with L-DOPA or D2/D1-selective agonists. A conditional knockout of indirect-pathway D2 receptors was produced either through the entire striatum (double-transgenic <i>Adora2a</i>-Cre/<i>Drd2</i>^loxP/loxP mice) or selectively in the dopamine-denervated dorsal striatum (proenkephalin promoter-driven Cre vector delivery to <i>Drd2</i>^loxP/loxP mice).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The severity of L-DOPA-induced abnormal involuntary movements and dystonia was halved in both knockout models compared with control mice, whereas the treatment effect on normal motor behaviors was either not reduced or improved. All dyskinetic and dystonic features induced by the D2-selective receptor agonist sumanirole were completely abolished, whereas those induced by the D1-class agonist SKF38393 were largely unaffected. Using phosphorylated ribosomal protein S6 as an activity marker, we detected a treatment-induced recruitment of prototypical parvalbumin-positive neurons in the external globus pallidus (a target of indirect-pathway projections). This effect was inhibited in both knockout models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We provide experimental evidence that indirect-pathway D2 receptors significantly contribute to the expression of dyskinesia during L-DOPA treatment and mediate D2 agonist-dependent dystonic features. © 2026 The Author(s). <i>Movement Disorders</i> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1690-1703"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4","authors":"Philip Harrer MD, PhD,&nbsp;Volker Kittke PhD,&nbsp;Alice Saparov MSc,&nbsp;Alexej Knaus MD,&nbsp;Shimriet Zeidler MD,&nbsp;Rachel Schot MD,&nbsp;Florian Kraft MD,&nbsp;Matthias Begemann MD,&nbsp;Suzanna Koudijs MD,&nbsp;Ugo Sorrentino MD,&nbsp;Chen Zhao PhD,&nbsp;Ivana Dzinovic PhD,&nbsp;Martin Pavlov MSc,&nbsp;Elisabeth Graf PhD,&nbsp;Antonia M. Stehr MD,&nbsp;Peter M. Krawitz MD,&nbsp;Christian Wilhelm PhD,&nbsp;Saskia Biskup MD,&nbsp;Fahd Alsalloum MD,&nbsp;Steffen Berweck MD,&nbsp;Juliane Winkelmann MD,&nbsp;Konrad Oexle MD,&nbsp;Ingo Kurth MD,&nbsp;G. Christoph Korenke MD,&nbsp;Michael Zech MD","doi":"10.1002/mds.70297","DOIUrl":"10.1002/mds.70297","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p><i>SRRM4</i> is an exclusively neural-expressed splicing-factor gene not yet associated with a monogenic condition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We sought to delineate movement disorders caused by <i>SRRM4</i> variants. De novo splice-donor-site variants at position +2 of intron 5 of <i>SRRM4</i> (c.464+2T&gt;C, c.464+2T&gt;A) occurred in three unrelated patients with dystonia and chorea. We present detailed phenotypic information on these individuals and characterize the effect of the splice-site alteration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Exome and genome sequencing were used to identify <i>SRRM4</i> variants. To assess the consequence of a mutant +2 residue at the affected splice donor of <i>SRRM4</i>, we performed transcriptomic analyses using short-read and long-read RNA-sequencing in patient fibroblasts in which <i>SRRM4</i> expression was induced by genome editing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clinical presentations were characterized by infantile combined dystonic and choreatic syndromes or chorea-predominant disease. Studies in <i>SRRM4</i> expression-activated cells revealed two variant-specific <i>SRRM4</i>-mRNA isoforms including one that was characterized by a 69-nucleotide in-frame insertion without creation of a premature termination codon, suggestive of a mechanism other than loss-of-function. Additionally, we uncovered altered splicing patterns of known <i>SRRM4</i> downstream mRNA-substrates in patient cells compared to <i>SRRM4</i> expression-activated control fibroblasts, such as a conserved <i>AP1S2</i> microexon. <i>AP1S2</i> is linked to a monogenic syndrome with abnormal movements and missplicing of its microexon is a well-established outcome in neural models of <i>SRRM4</i> disruption.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We conclude that the patients' phenotypes are caused by a previously undiagnosed <i>SRRM4</i>-related disorder, offering a basis for improved understanding of mechanistic convergence in genetic movement disorders and potential therapeutic targeting of the misregulated splicing events. © 2026 The Author(s). <i>Movement Disorders</i> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1704-1715"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147641611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson's Disease","authors":"Tzi Shin Toh BSc,&nbsp;Lei Cheng Lit PhD,&nbsp;Shen-Yang Lim MD,&nbsp;Jia Wei Hor PhD,&nbsp;Choey Yee Lew MB, BCh, BAO,&nbsp;Anis Nadhirah Khairul Anuar MMedSc,&nbsp;Yi Wen Tay PhD,&nbsp;Kirsten Black BSc,&nbsp;Jia Lun Lim PhD,&nbsp;Jannah Zulkefli BSc,&nbsp;Kai Shi Lim BSc,&nbsp;Hans Xing Ding BSc,&nbsp;Shalini Padmanabhan PhD,&nbsp;Azlina Ahmad-Annuar PhD,&nbsp;Eng King Tan MD,&nbsp;Dario R. Alessi PhD,&nbsp;Esther Sammler MD, PhD,&nbsp;Ai Huey Tan MD, PhD","doi":"10.1002/mds.70314","DOIUrl":"10.1002/mds.70314","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Leucine-rich repeat kinase 2 (LRRK2) kinase inhibition is a promising therapeutic strategy for Parkinson's disease (PD), but the functional impact of Asian-prevalent &lt;i&gt;LRRK2&lt;/i&gt; p.G2385R and p.R1628P variants remains unclear. Robust patient stratification and target engagement markers are needed for global LRRK2-targeted trials.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The aim of this study was to characterize ex vivo LRRK2 activation status and its clinical correlates in patients with PD carrying &lt;i&gt;LRRK2&lt;/i&gt; p.G2385R and/or p.R1628P variants and in patients with idiopathic PD (iPD).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We recruited 242 participants: patients with PD carrying &lt;i&gt;LRRK2&lt;/i&gt; p.G2385R (PD-G2385R; n = 57), p.R1628P (PD-R1628P; n = 61), or both (n = 5); patients with iPD (n = 61); and healthy control subjects (HCs; n = 58). Monocyte LRRK2 activity markers (pRab10&lt;sup&gt;Thr73&lt;/sup&gt; and pLRRK2&lt;sup&gt;Ser935&lt;/sup&gt;) were analyzed using multiplexed quantitative immunoblotting. Clinical severity was assessed using the International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Clinical Impression of Severity Index for PD, and Montreal Cognitive Assessment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Compared with HCs, pRab10&lt;sup&gt;Thr73&lt;/sup&gt; was elevated (indicative of LRRK2 kinase hyperactivation) in PD-G2385R (~1.2-fold, &lt;i&gt;P&lt;/i&gt; = 0.011) and in double-variant carriers (~2.8-fold, &lt;i&gt;P&lt;/i&gt; = 0.008), but not in PD-R1628P or iPD. Inversely correlated with pRab10&lt;sup&gt;Thr73&lt;/sup&gt; (&lt;i&gt;r&lt;/i&gt;&lt;sub&gt;&lt;i&gt;s&lt;/i&gt;&lt;/sub&gt; = −0.611, &lt;i&gt;P&lt;/i&gt; &lt; 0.001), pLRRK2&lt;sup&gt;Ser935&lt;/sup&gt; was reduced (indicative of a more active LRRK2 conformation) in all PD subgroups (lowest in double-variant carriers). All double-variant carriers, the majority of single-variant carriers, and one-third of participants with iPD had pRab10&lt;sup&gt;Thr73&lt;/sup&gt; greater than the control median. Higher pRab10&lt;sup&gt;Thr73&lt;/sup&gt; correlated with better cognition.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;LRRK2 kinase activity is enhanced in patients with PD carrying &lt;i&gt;LRRK2&lt;/i&gt; p.G2385R, with further elevation observed in a small group of double-variant carriers. Elevated kinase activity in a subset of iPD underscores the relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed interindividual variability indicates additional genetic or environmental modifiers and highlights the","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1750-1761"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and Volumetric Alterations in the Basal Ganglia and the Cerebellum in Dopa-Responsive Dystonia in Symptomatic and Asymptomatic GCH1 Mutation Carriers","authors":"Jannik Prasuhn MD,&nbsp;Leon van Well MS,&nbsp;Marta M. Pokotylo MSc,&nbsp;Feline Hamami MS,&nbsp;Joke-Lina Aßmann MS,&nbsp;Katja Lohmann PhD,&nbsp;Maximilian G. Ködderitzsch-Mertins MS,&nbsp;Julia Henkel MD,&nbsp;Jan Uter MD,&nbsp;Alexander Münchau MD,&nbsp;Christine Klein MD,&nbsp;Anne Weissbach MD,&nbsp;Norbert Brüggemann MD","doi":"10.1002/mds.70332","DOIUrl":"10.1002/mds.70332","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Dopa-responsive dystonia is caused by pathogenic variants in the &lt;i&gt;GCH1&lt;/i&gt; gene. Although its clinical features and reduced penetrance are known, in vivo metabolic and structural alterations in symptomatic (sMC) and asymptomatic mutation carriers (aMC) remain poorly understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The aims were to characterize the volumetric and neurometabolic brain changes in &lt;i&gt;GCH1&lt;/i&gt; mutation carriers (MC) and explore their relationship with clinical severity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We studied 20 sMCs, 5 aMCs, and 25 mutation-free healthy controls (HC) using volumetric magnetic resonance imaging (MRI) combined with &lt;sup&gt;31&lt;/sup&gt;phosphorus magnetic resonance spectroscopy imaging (&lt;sup&gt;31&lt;/sup&gt;P-MRSI) of the basal ganglia and cerebellum. Analysis of covariance (ANCOVA) was used for group comparisons, and correlations were assessed using clinical symptom severity rating scales.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Volumetric analyses revealed enlarged globus pallidus (16.6%, &lt;i&gt;P&lt;/i&gt; = 0.0010) and putamen (7.2%, &lt;i&gt;P&lt;/i&gt; = 0.0310) volumes in sMCs and increased cerebellar gray matter in aMCs (8.0%, &lt;i&gt;P&lt;/i&gt; = 0.0500). Nicotinamide adenine dinucleotide (NAD) levels were significantly reduced in the basal ganglia of carriers (NAD/Pi [inorganic phosphate]: −14.7%, &lt;i&gt;P&lt;/i&gt; = 0.0460; NAD/ATP-α: −15.5%, &lt;i&gt;P&lt;/i&gt; = 0.0180). In the cerebellum, aMCs demonstrated elevated high-energy phosphate ratios ([ATP-α + PCr]/Pi: 23.7%, &lt;i&gt;P&lt;/i&gt; = 0.0170; ATP-α/Pi: 21.3%, &lt;i&gt;P&lt;/i&gt; = 0.0460; PCr [phosphocreatine]/Pi: 25.2%, &lt;i&gt;P&lt;/i&gt; = 0.0090) compared with sMCs and HCs. Smaller cerebellar volumes correlated with greater dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale, ρ = −0.557, &lt;i&gt;P&lt;/i&gt; = 0.0133), whereas lower basal ganglia NAD ratios correlated with higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III (ρ = −0.527, &lt;i&gt;P&lt;/i&gt; = 0.0204), and Toronto Western Spasmodic Torticollis Rating Scale scores (ρ = −0.475, &lt;i&gt;P&lt;/i&gt; = 0.0398).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Volumetric MRI and &lt;sup&gt;31&lt;/sup&gt;P-MRSI reveal region- and subgroup-specific metabolic and structural alterations in &lt;i&gt;GCH1&lt;/i&gt; MCs, linking basal ganglia vulnerability and cerebellar adaptation to clinical severity. © 2026 The Author(s). &lt;i&gt;Movement Disorders&lt;/i&gt; published by Wiley Periodicals LLC on behalf of International Parkinson and Movement D","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1716-1726"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70332","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seeing Invisible Oligomers: Rethinking α-Synuclein Pathology Through Proximity Ligation Assay","authors":"Hiroaki Sekiya MD, PhD,&nbsp;Nanna Møller Jensen PhD,&nbsp;Dennis W. Dickson MD,&nbsp;Poul Henning Jensen MD, PhD","doi":"10.1002/mds.70335","DOIUrl":"10.1002/mds.70335","url":null,"abstract":"<p>Parkinson's disease (PD) and multiple system atrophy are defined by α-synuclein (αSYN)-positive inclusions – Lewy bodies (LBs) and glial cytoplasmic inclusions – yet mounting evidence indicates that these inclusions represent only a fraction of disease-relevant pathology. αSYN exists in dynamic conformational states, and soluble oligomeric assemblies, often undetectable by conventional immunohistochemistry, are increasingly implicated as key neurotoxic species. The αSYN proximity ligation assay (αSYN-PLA) enables in situ detection of widespread non-inclusion oligomeric pathology across synucleinopathies. Notably, PLA studies in <i>LRRK2</i>-associated PD demonstrate abundant oligomeric αSYN even in cases lacking LBs, challenging the centrality of inclusions in defining disease. In this Perspective, we outline the principles of αSYN-PLA, discuss antibody strategies and structural implications of detected species, review current evidence – including LB-negative <i>LRRK2</i>-PD – and consider temporal dynamics and clinical applications of PLA-positive aggregates as biomarkers and therapeutic targets. © 2026 The Author(s). <i>Movement Disorders</i> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 7","pages":"1680-1689"},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}