Movement Disorders最新文献

{"title":"Reversing Autophagy Inhibition Ameliorates Neurodegeneration in Hereditary Spastic Paraplegia Caused by a Degradation‐Resistant SPAST Mutation","authors":"Dingyi Zhang, Yang Hu, Jianhe Guo, Dongmei Wu, Yifan Zhang, Lingzi Yang, Yuxi Wang, Nong Xiao, Jinhua Fan, Yanling Dong, Min Zhong, Tongfei Liu","doi":"10.1002/mds.70150","DOIUrl":"https://doi.org/10.1002/mds.70150","url":null,"abstract":"Background Hereditary spastic paraplegias (HSPs) are monogenic neurodegenerative disorders, and <jats:italic>SPAST</jats:italic> mutations causing spastic paraplegia type 4 (SPG4) represent the most common form of HSP. <jats:italic>SPAST</jats:italic> mutations elevate SPASTIN protein levels beyond haploinsufficiency, but the mechanisms and downstream consequences are unclear. Methods We identified a de novo <jats:italic>SPAST</jats:italic> missense variant (p.I344E) in a young Chinese female with SPG4. Wild‐type (WT) and mutant (I344E/K) <jats:italic>SPAST</jats:italic> constructs were expressed in HEK293 for biochemical and functional assays including cycloheximide chase, ubiquitination analysis, and immunofluorescence. Leveraging somatic cell reprogramming and CRISPR‐based gene editing, we generated patient‐derived induced pluripotent stem cells (iPSCs) and their isogenic controls. Both lines were differentiated into cerebral organoids. Results I344E/K‐SPASTIN exhibited markedly higher steady‐state levels than WT‐SPASTIN owing to impaired ubiquitin‐proteasome‐mediated degradation; the I344E variant showed the greatest accumulation. Mutant SPASTIN mislocalized in cells, displayed diminished microtubule‐severing activity, and elevated acetylated tubulin—phenotypes that were rescued by overexpression of WT‐SPASTIN. In patient cerebral organoids, the I344E mutation led to increased p62/SQSTM1 aggregates, reduced autophagic flux, and enhanced neuronal death. Rapamycin restored autophagy, decreased p62 levels, and reduced cell death. Conclusions Our study provides evidence linking autophagy dysfunction to SPG4 pathogenesis and demonstrates that the I344E mutation acts through a gain‐of‐function mechanism. These findings challenge the prevailing haploinsufficiency model and implicate autophagy modulation as a potential therapeutic strategy for SPG4 and possibly other HSPs. © 2025 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"157 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765240","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":"December Infographic","authors":"","doi":"10.1002/mds.29863","DOIUrl":"10.1002/mds.29863","url":null,"abstract":"<p>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 Prediction of pathological subthalamic nucleus beta burst occurrence in Parkinson's disease</p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765237","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":"Movement Disorders: Volume 40, Number 12, December 2025","authors":"","doi":"10.1002/mds.70154","DOIUrl":"10.1002/mds.70154","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://movementdisorders.onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765236","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":"Author Response to Comment on “Neuropsychological Tests of Memory, Visuospatial, and Language Function in Parkinson's Disease: Review, Critique, and Recommendations”","authors":"Ondrej Bezdicek PhD,&nbsp;Roberta Biundo PhD,&nbsp;Matej Skorvanek MD, PhD,&nbsp;Daniel Weintraub MD,&nbsp;Gert J. Geurtsen PhD","doi":"10.1002/mds.70149","DOIUrl":"10.1002/mds.70149","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759763","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":"Comment on “Neuropsychological Tests of Memory, Visuospatial, and Language Function in Parkinson's Disease: Review, Critique, and Recommendations”","authors":"Joshua P. Woller MSc,&nbsp;Alireza Gharabaghi MD","doi":"10.1002/mds.70148","DOIUrl":"10.1002/mds.70148","url":null,"abstract":"&lt;p&gt;We commend Bezdicek and colleagues for a rigorous, consensus-based evaluation of neuropsychological tests for memory, language, visuospatial function, and premorbid intelligence in Parkinson's disease (PD).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Their tiered recommendations provide practical guidance for level-II assessment across Parkinson's Disease Mild Cognitive Impairment (PD-MCI) and PD dementia (PDD) and for outcome selection in trials.&lt;/p&gt;&lt;p&gt;The panel's core messages are clear. Word-list and story-recall measures show acceptable validity, reliability, and sensitivity to change in PD. The Boston Naming Test is a practical reference for language, matrix reasoning is the current visuospatial choice, and National adult reading test (NART) or NAART improves adjudication through premorbid-ability estimates. These points, including the stated limitations for early-stage sensitivity and motor confounds, provide a strong foundation for standardized workflows.&lt;/p&gt;&lt;p&gt;We suggest three additions that support the authors' framework.&lt;/p&gt;&lt;p&gt;First, reliability should also be treated as a design constraint of subsequent analyses. The maximum observable association between two variables is limited by their reliabilities. When studies compare or pool correlations across outcomes with unequal reliability, attenuation biases estimate toward zero and can be mistaken for weak construct associations.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Explicit reporting of reliability for each selected measure, and correction for attenuation in secondary analyses where justified, would reduce interpretive variability and improve cross-cohort comparability.&lt;/p&gt;&lt;p&gt;Second, sensitivity to change should use complementary thresholds. Minimal detectable change quantifies the smallest difference beyond measurement error, and minimal clinically important difference reflects patient-perceived benefit.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The latter is, therefore, often used when assessing outcomes of clinical trials.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; If responder classification is applied, minimally detectable change (MDC) and minimal clinically important difference (MCID) should shape that split. When MCID is smaller than MDC, individual change scores that exceed MCID but fall below MDC remain indeterminate and should not be interpreted as true change. This differentiation is especially relevant given the substantial day-to-day variability of PD symptoms, which may surpass MCID values.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Third, measurement invariance should be established before comparing groups, subtypes, therapy states, or time points.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Without item-level invariance, observed score differences may be driven by a subset of items that function differentially, which decouples scores from the intended construct. Given the paper's critique about uneven domain sensitivity and executive contamination of visuospatial measures, routine checks for differential item functioning and factorial stability would strengthen in","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 1","pages":"281-282"},"PeriodicalIF":7.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://movementdisorders.onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759727","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":"LRRK2 as a Potential Disease‐Modifying Target in Sporadic Parkinson's Disease","authors":"Anthony E. Lang, Robert A. Hauser, Lorraine V. Kalia, Bonnie Hersh, Zdenek Berger, Roy Llorens Arenas, Coro Paisan‐Ruiz, Kyle Fraser, Danna Jennings, Jillian H. Kluss, Sarah Huntwork‐Rodriguez, Anastasia G. Henry, J. Timothy Greenamyre","doi":"10.1002/mds.70100","DOIUrl":"https://doi.org/10.1002/mds.70100","url":null,"abstract":"A growing understanding of the role that leucine‐rich repeat kinase 2 (LRRK2) plays in Parkinson's disease (PD) supports continued focus on this enzyme as a therapeutic target for PD. Accumulating evidence suggests that there are phenotypic, neuropathologic, and biological similarities between sporadic PD (sPD) and familial forms in which <jats:italic>LRRK2</jats:italic> variants are inherited in an autosomal‐dominant pattern with variable penetrance (LRRK2‐PD). Further, genome‐wide association studies have found specific non‐coding variants that are risk factors for sPD. In this review, we describe the current state of knowledge as it relates to LRRK2's role in sPD, with a focus on comparing the physiology and pathology of sPD with LRRK2‐PD. As in LRRK2‐PD, LRRK2 activity may also be increased in sPD, possibly through interactions between genetics and the environment. Increased activity of LRRK2 and associated endolysosomal dysfunction have been observed in sPD patients, including evidence from postmortem brains of patients with sPD and animal models showing increased LRRK2 activity. Additionally, beneficial effects of LRRK2 inhibitors, such as improved lysosomal function, reduced α‐synuclein accumulation, and amelioration of neurodegeneration, have been demonstrated in animal models of sPD. Therefore, inhibition of LRRK2 kinase activity may be a promising approach to disease modification for sPD and LRRK2‐PD. Ongoing and future clinical studies examining LRRK2 kinase inhibitors will aim to elucidate their clinical efficacy in PD and to assess their potential effects on lysosomal function. © 2025 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":"11 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730690","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":"It Is Personal: What People with Parkinson's Disease Say Matters Most for Quality of Life","authors":"Samantha Dorrance, Richa Patel, Glenn T. Stebbins, Jamie Adams, Allison M. Allen, Tara Hastings, Soania Mathur, Onanong Phokaewvarangkul, Gary Rafaloff, Rajasumi Rajalingam, Anette Schrag, Christine Sun, Jennifer Mammen, Connie Marras","doi":"10.1002/mds.70134","DOIUrl":"https://doi.org/10.1002/mds.70134","url":null,"abstract":"Background Little is known about what matters most for quality of life in people with Parkinson's disease and how much it varies between individuals. Objective The goal was to define the relative impact of quality of life determinants in people with Parkinson's disease, including variation across individuals and by disease severity, gender, age, and ethnicity. Methods Sixty‐one factors potentially associated with quality of life in people with Parkinson's disease were identified from the literature and nominated by participants with Parkinson's disease. Forty‐four participants then rated their degree of impact on quality of life from “a lot” to “not at all,” and identified their “top 3 most important” factors. Results At the individual level, determinants of utmost importance varied greatly, with 39 of 61 factors being reported at least once in the “top 3.” There were 17 factors that at least 50% of the sample agreed affected quality of life “a lot,” and only two were symptoms of the disease. Twelve (all positive experiences) retained at least 50% agreement across subgroups defined by disease severity, age, gender and ethnicity. Symptom‐related factors of high importance varied markedly in mild disease subgroup in particular. Conclusions Factors that are not direct consequences of the disease, but may be highly personal and interfere with what one finds meaningful, emerged as highly relevant. Symptoms also greatly impacted quality of life for most individuals, but specific symptoms varied across individuals. Quality of life determinants in people with Parkinson's disease appear highly individualized, and currently used measurement tools with fixed items may not be optimal. © 2025 The Author(s). <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2025 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":"35 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730689","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 Impact of Calcitriol on Frataxin Levels in Friedreich's Ataxia Patients: Insights and Future Directions","authors":"Nie Zhang, Yahui Xu","doi":"10.1002/mds.29933","DOIUrl":"https://doi.org/10.1002/mds.29933","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"1 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730691","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":"Longitudinal Dynamics of Plasma Neurofilament Light Chain in Hereditary Spastic Paraplegia Type 11 (HSP-SPG11) and Type 15 (HSP-ZFYVE26).","authors":"Habibah A P Agianda,Julian E Alecu,Amy Tam,Hyo-Min Kim,Joshua Rong,Nicole Battaglia,Kaitlyn Warren,Rebekah Mannix,Nunzio Setola,Melissa Barghigiani,Grace Yoon,Yoshihisa Takiyama,Jangsup Moon,Katerina Bernardi,Kathryn Yang,Luca Schierbaum,Filippo Maria Santorelli,Darius Ebrahimi-Fakhari","doi":"10.1002/mds.70142","DOIUrl":"https://doi.org/10.1002/mds.70142","url":null,"abstract":"BACKGROUNDHSP-SPG11 and HSP-ZFYVE26 are autosomal-recessive forms of hereditary spastic paraplegias (HSPs). As therapeutic trials emerge, validated biomarkers are critically needed.OBJECTIVESTo evaluate plasma neurofilament light chain (pNfL) as a biomarker for neurodegeneration and disease progression.METHODSWe analyzed pNfL levels in 57 patients (36 HSP-SPG11, 21 HSP-ZFYVE26) and matched controls using single-molecule array technology. Longitudinal clinical and biomarker data were collected over 5 years.RESULTSBaseline pNfL levels were significantly elevated in patients: 33.85 pg/mL (IQR 25.15-47.38) in HSP-SPG11, 46.70 pg/mL (IQR 29.95-54.84) in HSP-ZFYVE26, and 4.90 pg/mL (IQR 3.48-6.90) in controls (P < 0.001). No significant difference was observed between HSP-SPG11 and HSP-ZFYVE26. In matched pair analysis, pNfL showed inverse correlation with age (ρ = -0.463, P < 0.001). Baseline pNfL did not predict future clinical progression.CONCLUSIONSElevated pNfL reflects early neuroaxonal injury in HSP-SPG11 and HSP-ZFYVE26; however, it could not be used as a surrogate for disease progression. © 2025 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"5 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710871","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":"Oligodendrocyte Inclusion Pathology in Fragile X‐Associated Tremor/Ataxia Syndrome","authors":"Yingratana McLennan, Hassan Aliashrafzadeh, Faith Zirkelbach‐Ngai, Forrest McKenzie, Brett D. Dufour, Lina V. Becerra‐Hernández, Adolfo Sanchez Escobar, Flora Tassone, Paul Hagerman, Randi Hagerman, Veronica Martínez‐Cerdeño","doi":"10.1002/mds.70145","DOIUrl":"https://doi.org/10.1002/mds.70145","url":null,"abstract":"Background Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder marked by white matter degeneration and intranuclear inclusions. While astrocytic and neuronal inclusions are well‐documented, oligodendrocytes were previously thought to lack such pathology. Objective To demonstrate that oligodendrocytes in the prefrontal cortex of FXTAS patients do harbor intranuclear inclusions, with significantly higher burden in white matter than gray matter. Methods Ubiquitin and p62 immunofluorescence and enzymatic staining were employed to confirm the presence of intranuclear inclusions in oligodendrocytes across multiple brain regions. Results Oligodendrocytes contain inclusions and inclusion burden is correlated with <jats:italic>FMR1</jats:italic> CGG repeat length ( <jats:italic>ρ</jats:italic> = 0.97, <jats:italic>P</jats:italic> &lt; 0.001) in white matter. Conclusions These findings implicate oligodendrocyte dysfunction in FXTAS pathogenesis which may contribute to demyelination and white matter degeneration. Our data emphasize the need to consider cell type‐specific mechanisms in FXTAS and support future therapeutic efforts aimed at restoring glial proteostasis. © 2025 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"127 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680154","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}