Movement Disorders最新文献

{"title":"Cortical Cholinergic Pathway Degeneration Reflects Cognitive Impairment and Dementia in Parkinson's Disease","authors":"Nicola M. Slater, Daniel J. Myall, Reza Shoorangiz, Wassilios G. Meissner, Ian J. Kirk, Ross J. Keenan, Rebecca M. Lee, Kyla‐Louise Horne, Michael R. MacAskill, Campbell J. Le Heron, Toni L. Pitcher, Tim J. Anderson, Tracy R. Melzer, John C. Dalrymple‐Alford","doi":"10.1002/mds.70584","DOIUrl":"https://doi.org/10.1002/mds.70584","url":null,"abstract":"Background Cognitive impairment is a prevalent and debilitating feature of Parkinson's disease (PD). Increasing evidence from postmortem and in vivo positron emission tomography imaging studies supports cholinergic dysfunction in PD. There is, however, little evidence regarding the influence of the structural integrity of cortical cholinergic pathways that emanate from the nucleus basalis of Meynert (NBM). Objectives To investigate the association between cognition and the structural integrity of medial and lateral cortical cholinergic projection pathways in PD. Methods Neuropsychological assessment, T1 imaging, and high angular resolution diffusion imaging (HARDI) were acquired from 108 participants with PD (41 female, mean age 71.3 years) and 41 control participants (22 female, mean age 70.6 years). Streamlines representing three cortical cholinergic pathways (one medial and two lateral) from the NBM were extracted from anatomically constrained tractography. Structural integrity was compared across controls and cognitive subgroups (PD with normal cognition [PD‐N], with mild cognitive impairment [PD‐MCI], and with dementia [PDD]) and using a continuous global measure of cognition. Results In PD, we found evidence that lower cognitive performance was associated with increased mean diffusivity across all pathways, especially the perisylvian component of the lateral pathway. In those individuals with dementia, increased free water fraction and decreased fractional anisotropy and fiber density and cross‐section was detected across all pathways. Conclusions Degeneration of the cortical cholinergic system is associated with cognitive decline in PD. Future work should determine whether pathway degeneration predicts future cognitive decline and dementia. © 2026 The Author(s). <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"5 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221394","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":"Habitual Diet, Gut Microbiome Dysbiosis, and α‐Synucleinopathy Conversion in Isolated Rapid Eye Movement ( REM) Sleep Behavior Disorder","authors":"Suyi Xie, Yuhua Yang, Shi Tang, Li Zhou, Jing Wang, Joey W.Y. Chan, Brian Or, Ningning Li, Siyi Gong, Zhixuan He, Jianzhang Ni, Yaping Liu, Jihui Zhang, Paul K.S. Chan, Zigui Chen, Sunny Hei Wong, Vincent C.T. Mok, Ngan Yin Chan, Steven W.H. Chau, Yun Kwok Wing, Bei Huang","doi":"10.1002/mds.70562","DOIUrl":"https://doi.org/10.1002/mds.70562","url":null,"abstract":"Background Accumulating evidence indicates that habitual diet, including plant‐based dietary patterns, is associated with neurodegenerative α‐synucleinopathy risk. However, the role of diet and its correlation with the gut microbiome in prodromal α‐synucleinopathy, specifically among patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), remains unclear. Objective To evaluate dietary patterns, their interplay with gut microbial dysbiosis, and longitudinal effects on neurodegenerative progression in iRBD patients. Methods We recruited 287 iRBD patients and 208 age‐ and sex‐matched controls. Plant‐based diet indices (PDIs) were derived from food frequency questionnaires. Shotgun metagenomic sequencing was performed in 456 subjects for diet–microbiome analyses. After a median follow‐up of 4.2 years, 45 (15.7%) iRBD patients converted to α‐synucleinopathies. Cox proportional hazards models assessed the associations between diet and neurodegenerative outcomes. Results We found that iRBD patients exhibited lower healthful PDIs (adjusted odds ratio [aOR] 95% confidence interval [95% CI]: 0.48 [0.29–0.80], <jats:italic>P</jats:italic> = 0.005) but higher consumption of unhealthful plant‐based foods (refined grains, sweets, and sweeteners). Diet–microbiome interaction analysis identified dietary associations for 84.3% of iRBD‐related gut microbes, including co‐occurrence between healthful PDI and <jats:italic>Clostridium sp. AF20‐17LB</jats:italic> . Longitudinally, four dietary factors and five iRBD‐related microbes were associated with neurodegenerative outcomes; specifically, higher coffee consumption was linked to a lower risk of progression to α‐synucleinopathy (aHR [95% CI]: 0.30 [0.11–0.78], <jats:italic>P</jats:italic> = 0.01). Furthermore, mediation analyses indicated that the iRBD‐enriched species <jats:italic>Ruthenibacterium lactatiformans</jats:italic> mediated the association between unhealthful PDI and dementia‐first conversion. Conclusions Habitual diet in iRBD is associated with gut microbiome dysbiosis and predicts neurodegenerative progression. These findings highlight diet–microbiome interactions as modifiable targets for intervention in prodromal α‐synucleinopathy. © 2026 The Author(s). <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"26 6 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198938","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":"TGF ‐β Inhibition Attenuates Tau Accumulation and Neurodegeneration in Progressive Supranuclear Palsy Patient‐Derived Organoids","authors":"Mariagrazia Talarico, Andrea Quattrone, Giorgia Lucia Benedetto, Raffaele Covello, Maurizio Martini, Valeria Zuccalà, Giovanni Cuda, Elvira Immacolata Parrotta, Aldo Quattrone","doi":"10.1002/mds.70574","DOIUrl":"https://doi.org/10.1002/mds.70574","url":null,"abstract":"Background Progressive supranuclear palsy (PSP) is a devastating 4‐repeat tauopathy with no approved disease‐modifying treatments. Recent evidence showed increased transforming growth factor‐β (TGF‐β) levels in PSP patient‐derived ventral midbrain organoids (vMOs) and serum neuronally derived exosomes. Objective This study investigated whether TGF‐β pharmacological inhibition could mitigate PSP pathology in vMOs. Methods Ninety‐six vMOs were generated from induced pluripotent stem cells from two PSP‐Richardson's syndrome patients and two healthy control donors (HCs). From day 60 to day 90, PSP organoids were (1) exposed to TGF‐β receptor I inhibitor (SB431542); (2) exposed to recombinant TGF‐β1, TGF‐β2, and TGF‐β3; or (3) untreated. At day 90, several tau species were assessed by immunoblotting; neurodegeneration was evaluated through TUNEL assay and immunofluorescence (tyrosine hydroxylase [TH], neurofilament light chain [NfL]); astrocytic activation (glial fibrillary acidic protein [GFAP]) marker was evaluated by immunofluorescence, and histopathological hallmarks were evaluated by immunohistochemistry. An HC‐derived organoid subgroup was exposed to the treatment conditions to assess potential toxicity. Results At day 90, untreated PSP‐derived vMOs exhibited increased phosphorylated tau levels (Ser396, Thr181, Ser202/Ser205 [AT8]) compared with HC‐derived vMOs, dopaminergic neuron loss (reduced TH, increased NfL), and astrocytic reactivity (increased GFAP), along with PSP characteristic tau deposition. Tau hyperphosphorylation, neurodegeneration, and astrocytic reactivity were all markedly reduced in PSP‐derived vMOs treated with TGF‐β receptor I inhibitor. Conversely, exposure to TGF‐β exacerbated these features. No toxic effects were observed in HC vMOs exposed to treatment conditions. Conclusions Pharmacological inhibition of TGF‐β signaling prevented key PSP molecular alterations in patient‐derived organoids. These findings support further research and pave the way for future investigation of TGF‐β–targeting strategies in clinical trials in patients with PSP. © 2026 The Author(s). <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"2 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198939","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":"Severe Parkinson's Disease Linked to SNCA Locus Triplication Is Associated with Expression Changes in Platelets: A Case Report","authors":"Susanna Jiménez‐Román, David Adamuz, Jorge Mena, Abril Tuset, Mar Mallo, Alex Menendez, Daniela Samaniego, Lourdes Ispierto, Dolores Vilas, Pau Pastor, Katrin Beyer","doi":"10.1002/mds.70529","DOIUrl":"https://doi.org/10.1002/mds.70529","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"5 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172914","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":"Reply to “Evaluation of Rare MCOLN1 Variants in a Large Cohort of α‐Synucleinopathies”","authors":"Chenxin Ying, Xinhui Chen, Zhidong Cen, Xinghua Feng, Nan Jin, Jiaxiang Li, Xinchen Wang, Wei Luo","doi":"10.1002/mds.70569","DOIUrl":"https://doi.org/10.1002/mds.70569","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"31 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172916","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":"Evaluation of Rare MCOLN1 Variants in a Large Cohort of α‐Synucleinopathies","authors":"Yuan Gao, Ruwei Ou, Dejiang Pang, Yi Xiao, Qirui Jiang, Shichan Wang, Jiyong Liu, Yushan Tan, Xiaokai Zhou, Qianqian Wei, Wei Song, Xueping Chen, Chunyu Li, Jing Yang, Yiyuan Cui, Bi Zhao, Junyu Lin, Huifang Shang","doi":"10.1002/mds.70568","DOIUrl":"https://doi.org/10.1002/mds.70568","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"7 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172917","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":"Vitamin B6 Deficiency and Status Epilepticus: A Preventable Cause of Death in People with Parkinson's Disease","authors":"Karlo J. Lizarraga, Andres M. Kanner, Anthony E. Lang","doi":"10.1002/mds.70580","DOIUrl":"https://doi.org/10.1002/mds.70580","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"10 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172915","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":"Cerebellar Network Organization in Parkinson's Disease: Functional Connectivity across Motor and Cognitive Circuits","authors":"Chi‐Ying R. Lin,Thamires N.C. Magalhães,Shayla S. Yonce,Ihika Rampalli,Rory Mahabir,Jessica A. Bernard,and the Parkinson's Precision Medicine Initiative","doi":"10.1002/mds.70564","DOIUrl":"https://doi.org/10.1002/mds.70564","url":null,"abstract":"Abstract Background The cerebellum is increasingly recognized as a key contributor to cognitive reserve and network organization in Parkinson's disease (PD). However, the relationship of cerebello‐cortical and cerebello‐basal ganglia connectivity with cognitive status and nigrostriatal integrity remains incompletely understood. Methods Resting‐state functional magnetic resonance imaging (fMRI) data from 172 participants with PD in the Parkinson's Precision Medicine Initiative were analyzed. Cerebello‐basal ganglia and cerebello‐cortical connectivity were investigated using region of interest (ROI)‐to‐ROI and seed‐to‐voxel approaches. Cerebellar connectivity was examined in relation to cognitive status, age, disease duration, motor severity, dopaminergic medication exposure, and contralateral putaminal striatal binding ratio (SBR). Results PD participants demonstrated robust positive cerebello‐basal ganglia connectivity, particularly between lobule VI/vermis VI and the pallidum. Greater age was associated with widespread reductions in cerebello‐basal ganglia coupling. Longer disease duration was associated with stronger connectivity within cerebellar and basal ganglia circuits, and among cognitively unimpaired participants, stronger lobule V connectivity with temporal regions. After adjustment for contralateral putaminal SBR, cognitively unimpaired participants generally demonstrated greater connectivity between left cerebellar regions and frontal networks, whereas cognitively impaired participants showed greater connectivity from posterior cerebellar and vermal regions, including regions implicated in cognitive processing, to temporal, parahippocampal, occipital, parietal, and somatosensory regions. Conclusions Cerebellar functional connectivity in PD shows region‐specific differences across cognitive status rather than uniform network loss with cognitive impairment. These findings support further investigation of cerebellar functional connectivity as a candidate biomarker of cognitive resilience and network adaptation in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"10 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149959","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":"The Gut–Brain Axis in Parkinson's Disease: From Clinical Observation toward Mechanism‐Based Precision Medicine","authors":"Filip Scheperjans, Per Borghammer, Ronald F. Pfeiffer, Silke Appel‐Cresswell, Ali Keshavarzian","doi":"10.1002/mds.70566","DOIUrl":"https://doi.org/10.1002/mds.70566","url":null,"abstract":"Gastrointestinal dysfunction is increasingly recognized as a core feature of Parkinson's disease (PD), affecting quality of life, nutrition, medication response, and potentially the earliest stages of pathogenesis. This perspective traces the evolution of the gut from a neglected source of non‐motor symptoms to a central component of biological models of PD. Gastrointestinal manifestations are physiologically heterogeneous and require objective phenotyping to distinguish dysphagia, gastroparesis, slow transit, defecatory dysfunction, and overlapping mechanisms. The body‐first/brain‐first framework further suggests that Lewy pathology may follow distinct anatomical trajectories, with early enteric and autonomic involvement defining a subgroup in which gut‐directed biomarkers and therapies may be especially relevant. Alterations of the gut microbiome are reproducibly associated with PD, although geography, constipation, medication, diet, disease stage, and reverse causation complicate interpretation. Emerging work is shifting from taxonomy toward microbial functions and host pathways, including barrier integrity, immune and enteroendocrine signaling, short‐chain fatty acids, glucagon‐like peptide‐1 (GLP‐1), host genetic susceptibility, α‐synuclein aggregation and propagation, and microbial levodopa metabolism. Trials of probiotics, fecal microbiota transplantation, and dietary interventions remain heterogeneous and have not established disease‐modifying efficacy. Progress will require longitudinal studies in prodromal and subtype‐defined populations, objective gastrointestinal measurements, integrated microbial, host‐genetic and other multi‐omics, mechanistic human and animal models, and clinical trials combining target‐engagement markers with meaningful outcomes. Such an approach may enable precision gut‐brain medicine for appropriately selected patients with PD. © 2026 The Author(s). <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"78 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123832","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":" KCNA2 ‐Associated Hereditary Spastic Paraplegia: Clinical Characteristics and Rationale for Targeted Treatment","authors":"Christian M. Boßelmann, Martin Vyhnalek, Zuzana Blichova, Ludmila Novotna, Anna Uhrova Meszarosova, Petra Havránková, Elena Kuster, Robert J. Lauerer, Ulrike B.S. Hedrich, Hang Lyu, Mayke Oosterloo, Michael Alber, Ludger Schöls, Karen Müller‐Schlüter, Almut Turid Bischoff, Thomas Klopstock, Georgios Koutsis, Georgia Karadima, Stephanie Efthymiou, Henry Houlden, Ainara Salazar‐Villacorta, Colin A. Ellis, Anna Scheper, Dieter Gläser, Tobias B. Haack, Matias Wagner, Michael Zech, Konrad Platzer, Pasquale Striano, Steffen Syrbe, Rebecca Schüle, Holger Lerche","doi":"10.1002/mds.70555","DOIUrl":"https://doi.org/10.1002/mds.70555","url":null,"abstract":"Background A single recurrent variant, NM_004974.4( <jats:italic>KCNA2</jats:italic> ):c.881G&gt;A:p.(Arg294His), causes hereditary spastic paraplegia (HSP) through a unique variant‐specific mechanism. Data from paralogous variants suggest that this may be a druggable mechanism. Objective The objective of this work is to give an overview of the clinical spectrum and course of <jats:italic>KCNA2</jats:italic> ‐p.(Arg294His)‐associated HSP (HSP‐ <jats:italic>KCNA2</jats:italic> ) and report treatment with eplerenone, a potassium‐sparing diuretic. Methods In this retrospective study, we recruited individuals with the variant of interest through international rare disease networks. Treatment with eplerenone was done as off‐label use, and outcome measures were recorded during routine clinical care. Results We report the clinical characteristics of 23 individuals from 17 families with HSP‐ <jats:italic>KCNA2</jats:italic> . We observed a consistent core phenotype of abnormal evoked potentials (100%), cerebellar ataxia (83%), and lower limb spasticity (70%). Childhood‐onset was more commonly associated with epilepsy (odds ratio, 4.16; <jats:italic>P</jats:italic> = 0.042), and 52% had developmental delay. Progression of motor disability was slow even in childhood onset. We observed full (100%) penetrance and estimated the prevalence to be 0.18 to 0.69 case per million. Treatment with eplerenone was associated with a decrease on the Scale for the Assessment and Rating of Ataxia (Cohen's <jats:italic>d</jats:italic> = −1.8; −7.9% change from baseline, <jats:italic>P</jats:italic> = 0.015), but not on the Spastic Paraplegia Rating Scale, whereas stopping treatment was associated with worsening symptoms. At 2‐year follow‐up, four of five (80%) individuals chose to remain on treatment. Conclusions HSP‐ <jats:italic>KCNA2</jats:italic> is a syndrome with a recognizable variant‐specific core phenotype. Our exploratory analyses on eplerenone may serve as rationale for future investigations on targeted treatments. © 2026 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"12 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123682","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}