Movement Disorders最新文献

{"title":"Movement Disorders: Volume 41, Number 9, September 2026","authors":"","doi":"10.1002/mds.70526","DOIUrl":"https://doi.org/10.1002/mds.70526","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027742","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":"September Infographic","authors":"","doi":"10.1002/mds.70558","DOIUrl":"https://doi.org/10.1002/mds.70558","url":null,"abstract":"<p>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 Greater Motor and Nonmotor Burden at Diagnosis Is Associated With Amyloid Copathology in Parkinson's Disease\u0000 </p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027755","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":"In Memoriam, Daniel Tarsy, MD (1940–2026)","authors":"Ludy C. Shih,&nbsp;David K. Simon,&nbsp;Clifford B. Saper,&nbsp;Stewart A. Factor","doi":"10.1002/mds.70506","DOIUrl":"10.1002/mds.70506","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 9","pages":"2249-2250"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148836233","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":"Deep Brain Stimulation of the Posterior Subthalamic Area and the Subthalamic Nucleus in Tremor-Dominant Parkinson's Disease: A Randomized, Crossover Trial","authors":"Zhengyu Lin MD, MSc,&nbsp;Zhitong Zeng MD,&nbsp;Yixin Pan MD,&nbsp;Peng Huang MD,&nbsp;Yuyan Tan MD,&nbsp;Chencheng Zhang PhD,&nbsp;Bomin Sun MD, PhD,&nbsp;Dianyou Li MD, PhD","doi":"10.1002/mds.70363","DOIUrl":"10.1002/mds.70363","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The posterior subthalamic area (PSA) is a familiarized target for Parkinson's disease (PD) in the lesioning era and has recently been reconsidered for deep brain stimulation (DBS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The aim of this study was to compare the therapeutic efficacy of PSA versus subthalamic nucleus (STN) DBS in tremor-dominant Parkinson's disease (TD-PD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This single-center, randomized, crossover trial was conducted at Ruijin Hospital, Shanghai, China, from June 2022 to August 2025. Patients with TD-PD received bilateral DBS implants via a single trajectory targeting both PSA and STN. Participants received 2 months of PSA stimulation followed by 2 months of STN stimulation or vice versa, with blinded programming and evaluation. The primary outcome was the difference in <i>off</i> medication improvement from baseline to the end of each stimulation period in the tremor subscore of the Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale Part III (MDS UPDRS-III; ClinicalTrials.gov, NCT05382858).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the 40 patients assessed for eligibility, 27 were randomly assigned and 19 completed the randomized crossover phase. Both PSA-DBS and STN-DBS significantly reduced the MDS UPDRS-III tremor subscore (baseline, 17.5 [3.3]; PSA, 4.5 [2.8]; STN, 8.0 [5.3]; <i>P</i> &lt; 0.001 for both). PSA-DBS achieved greater tremor suppression than STN-DBS (adjusted mean difference −3.3; 95% confidence interval [CI]: −5.4 to −1.3; <i>P</i> = 0.004). STN-DBS led to greater balance improvement (adjusted mean difference −1.7; 95% CI: −2.6 to −0.7; <i>P</i> = 0.002). Three cases of abnormal impedance occurred. Other adverse effects were mostly stimulation related and could be resolved with reprogramming.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Given the limited sample size and study attrition, these findings should be considered hypothesis generating. Nonetheless, PSA-DBS appears to be a safe and effective alternative or complementary target to STN in treating TD-PD and warrants further investigation in larger, definitive trials. © 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 9","pages":"2375-2385"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148020537","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":"Development and Validation of the 3PDQ: A Self-Reported Questionnaire for Diagnosing Primary Pain in Parkinson's Disease","authors":"Ana Marques MD, PhD,&nbsp;Estelle Harroch MSc,&nbsp;Bruno Pereira PhD,&nbsp;Nadine Attal MD, PhD,&nbsp;Caroline Giordana MD,&nbsp;Solène Frismand-Kryloff MD,&nbsp;David Maltête MD, PhD,&nbsp;Frédérique Fluchère MD,&nbsp;Tiphaine Rouaud MD,&nbsp;Christine Tranchant MD, PhD,&nbsp;Claire Thalamas MD,&nbsp;Margherita Fabbri MD, PhD,&nbsp;Nathalie Cantagrel MD,&nbsp;Fabienne Ory-Magne MD,&nbsp;Melissa Tir MD,&nbsp;Stéphane Thobois MD, PhD,&nbsp;Christian Geny MD,&nbsp;Sophie Drapier MD, PhD,&nbsp;Matthieu Béreau MD, PhD,&nbsp;Hayet Salhi MD,&nbsp;Olivier Rascol MD, PhD,&nbsp;Franck Durif MD, PhD,&nbsp;Didier Bouhassira MD, PhD,&nbsp;Xavier Moisset MD, PhD,&nbsp;Christine Brefel-Courbon MD","doi":"10.1002/mds.70364","DOIUrl":"10.1002/mds.70364","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pain is a frequent and heterogeneous non-motor symptom of Parkinson's disease (PD). Identifying its various underlying mechanisms remains challenging, while such mechanisms are likely to drive proper therapeutic management. Among the various PD-related pain subtypes, primary Parkinsonian pain (PPP) is particularly difficult to identify and differentiate from musculoskeletal pain, due to the absence of positive diagnostic criteria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The aim is to develop and validate the “Primary Parkinsonian Pain Diagnostic Questionnaire” (3PDQ), a self-reported tool for identifying PPP in PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The 3PDQ was developed through literature review and expert consensus, and refined based on patient feedback. In this multicentric study, 227 PD patients with chronic pain were recruited from 11 French Parkinson's Expert Centers; 179 were analyzed after cases were excluded where two independent expert raters made discordant types of pain diagnoses. Psychometric validation followed COSMIN standards, assessing acceptability, internal consistency, reproducibility, and diagnostic accuracy versus expert diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PPP was diagnosed in 36.3% of patients, whereas musculoskeletal pain was the most frequent pain subtype (42.5%). The final 11-item 3PDQ showed good acceptability (96.5% computable data), satisfactory internal consistency (Kuder–Richardson = 0.71), and excellent test–retest reliability (Lin's concordance = 0.82). The questionnaire demonstrated good discrimination between PPP and musculoskeletal pain (AUC = 0.82), with sensitivity = 82%, specificity = 74%, and a negative predictive value = 82%.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The 3PDQ is the first validated self-reported tool for diagnosing PPP in PD. It provides a reliable, clinically feasible tool to facilitate pain phenotyping and supports the development of mechanism-based treatment strategies. © 2026 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 9","pages":"2357-2374"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148153062","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":"Transcranial Pulse Stimulation Enhances Dexterity in Parkinson's Disease: A Randomized Sham-Controlled Trial","authors":"Eva Matt PhD,&nbsp;Nina Plischek MSc,&nbsp;Michael Mitterwallner PhD,&nbsp;Sonja Radjenovic PhD,&nbsp;Alexandra Weber MSc,&nbsp;Alina Domitner MSc,&nbsp;Gregor Dörl MSc,&nbsp;Anna Zettl MSc,&nbsp;Sarah Osou MSc,&nbsp;Anna Leitgeb BSc,&nbsp;Agnes Santer MD,&nbsp;Viktoria Winkler MD,&nbsp;Julia Mandelburger MD,&nbsp;Heidemarie Zach MD, PhD,&nbsp;Roland Beisteiner MD, MA","doi":"10.1002/mds.70365","DOIUrl":"10.1002/mds.70365","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ultrasound-based neuromodulation, capable of reaching deep brain areas with high precision, represents cutting-edge technology in non-invasive brain stimulation and is investigated as a novel treatment for neurological and psychiatric disorders, including Parkinson's disease (PD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To evaluate the effects of repeated transcranial pulse stimulation (TPS) applications on motor symptoms, brain structure, and functional activation in PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this randomized, sham-controlled, double-blind, crossover clinical trial, 30 participants with mild PD underwent six sessions of both verum and sham TPS targeting the sensorimotor network. Comprehensive clinical and magnetic resonance imaging (MRI) assessments were administered at baseline, 1 day, and 1 month post-stimulation for both conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Manual dexterity, measured via the coin rotation task, showed significantly larger improvement following verum compared with sham TPS (post-stimulation vs. baseline: <i>P</i>_corr = 0.048, ηp² = 0.14; 1-month post-stimulation vs. baseline: <i>P</i>_corr = 0.048, ηp² = 0.17). Gross motor symptoms, evaluated by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III), improved similarly after both verum and sham TPS. Functional MRI during a coin rotation task revealed increased activation in the sensorimotor network following verum stimulation compared with sham (<i>P</i> &lt; 0.001). Diffusion tensor imaging data indicated enhanced structural integrity in the primary somatosensory white matter following verum TPS compared with sham (<i>P</i> &lt; 0.05 family-wise error [FWE]-corrected). A total of 21 adverse events were reported, all mild and transient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings indicate that TPS produces behavioral, neurophysiological, and structural effects within the targeted sensorimotor network, and may represent a safe and effective adjunct to standard therapies in PD. © 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 9","pages":"2386-2398"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140646","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":"Healthy Dietary Patterns and Risk of Parkinson's Disease","authors":"Xiao Chen MPH,&nbsp;Hui Chen PhD,&nbsp;Peilu Wang MD, PhD,&nbsp;Michael A. Schwarzschild MD, PhD,&nbsp;Albert Y. Hung MD, PhD,&nbsp;Xiang Gao MD, PhD,&nbsp;Alberto Ascherio MD, DrPH,&nbsp;Mario H. Flores-Torres MD, PhD,&nbsp;Kjetil Bjornevik MD, PhD","doi":"10.1002/mds.70358","DOIUrl":"10.1002/mds.70358","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although healthy dietary patterns have been suggested to be associated with decreased Parkinson's disease (PD) risk, their protective role remains uncertain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To examine associations between eight dietary patterns and PD risk in two United States (US) cohorts followed for up to 32 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 70,973 women from the Nurses' Health Study and 45,820 men from the Health Professionals Follow-up Study. Dietary patterns were assessed every 4 years using food frequency questionnaires. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for PD across quintiles of cumulative average adherence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During follow-up, 579 women and 600 men developed PD. Higher adherence to dietary patterns was not associated with PD risk. Comparing the highest versus lowest quintile, HRs (95% CIs) were 1.01 (0.75–1.36) for the Alternative Healthy Eating Index-2010, 1.11 (0.91–1.35) for the Alternate Mediterranean Diet, 1.12 (0.69–1.79) for the Dietary Approaches to Stop Hypertension, 1.01 (0.84–1.22) for the healthful Plant-based Diet Index, 1.09 (0.90–1.32) for the Planetary Health Diet Index, 1.02 (0.84–1.24) for the Mediterranean-DASH Intervention for Neurodegenerative Delay diet score, 1.12 (0.90–1.38) for the reversed Empirical Dietary Inflammatory Pattern, and 0.99 (0.68–1.45) for the reversed Empirical Dietary Index for Hyperinsulinemia. In food-groups analyses, higher low-fat dairy intake was associated with higher PD risk (HR_Q5vsQ1: 1.37, 95% CI: 1.13–1.68).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In two US cohorts, adherence to eight healthy dietary patterns was not associated with PD risk. Although these patterns are associated with lower risk of several chronic diseases, they may be ineffective for PD prevention. © 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 9","pages":"2338-2348"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148160374","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":"Addressing the Challenges of Translating LRRK2 Biology into Disease-Modifying Therapies: The LRRK2 Investigative Therapeutics Exchange Initiative","authors":"Esther Sammler MD, PhD,&nbsp;Francesca Tonelli PhD,&nbsp;Michelle Durborow BS, Pharm,&nbsp;Jim McNasby JD,&nbsp;Todd Sherer PhD,&nbsp;Mahmood Ahmed PhD,&nbsp;Stevan W. Djuric PhD,&nbsp;Kalpana Merchant PhD,&nbsp;Alastair Reith PhD,&nbsp;Darryle Schoepp PhD,&nbsp;Christine Klein MD,&nbsp;Shalini Padmanabhan PhD,&nbsp;Dario R. Alessi PhD","doi":"10.1002/mds.70397","DOIUrl":"10.1002/mds.70397","url":null,"abstract":"&lt;p&gt;Parkinson's disease (PD) is a common and growing neurological disorder without a therapy that slows or halts progression, despite decades of investment and an increasingly sophisticated mechanistic understanding of its underlying biology. Among targets emerging from the genomic era, leucine-rich repeat kinase 2 (LRRK2) stands out for its robust genetic validation, mechanistic clarity, and pharmacological tractability. Importantly, a pipeline of LRRK2-targeted therapies has emerged. The first major efficacy readout from an LRRK2 kinase inhibitor program has now been reported: the Phase 2b LUMA study of BIIB122 (DNL151) did not demonstrate a clinical benefit in an unstratified cohort of early-stage PD patients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Rather than diminishing the rationale for targeting LRRK2, these findings highlight critical questions that remain unresolved, including the degree of target engagement required to achieve therapeutic benefit in the brain and the identification of patient populations most likely to respond to LRRK2-directed therapies. The results therefore reinforce the need for a coordinated, multidisciplinary strategy to develop next-generation LRRK2-targeted interventions, biomarkers, and patient stratification approaches.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The successful delivery of LRRK2-targeted therapies will depend on actively diversifying therapeutic strategies, refining trial design through biomarker integration, and advancing precision neurology approaches aligned with disease biology. The limiting factor is not the target but how it is being tested.&lt;/p&gt;&lt;p&gt;LRRK2 occupies a unique position in the PD landscape. It is one of the most common causes of autosomal dominant PD and a significant risk factor for sporadic disease.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The G2019S variant alone accounts for ~1% to 2% of PD cases globally, increasing to ~30% in certain North African Arab and Ashkenazi Jewish populations.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Beyond coding variants, genome-wide association studies implicate noncoding LRRK2 variants in modulating PD risk,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; whereas environmental exposures linked to PD activate the pathway.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Together, these data position LRRK2 at the intersection of genetic predisposition and environmental susceptibility across the PD spectrum.&lt;/p&gt;&lt;p&gt;Pathogenic LRRK2 variants converge on a shared functional consequence: kinase hyperactivation that disrupts endolysosomal biology, autophagy, and ciliogenesis across neuronal and peripheral compartments. This biological coherence is matched by pharmacological tractability.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; LRRK2 is currently being targeted by multiple therapeutic modalities in clinical trials, including ATP-competitive type I kinase inhibitors, targeted degradation strategies (PROTACs), and antisense oligonucleotides (ASO) (https://zenodo.org/records/15604012). However, the full therapeutic potential of LRRK2 targeting remains only partially realize","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 9","pages":"2280-2288"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148322667","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":"Systematic Review of the Huntington's Disease Drug Development Pipeline, 2014 to 2025","authors":"Pavlina Konstantinova PhD, MBA,&nbsp;Jenny Townhill PhD,&nbsp;Juliana Bronzova MD, DSc,&nbsp;Viktoria Andreeva PhD,&nbsp;Swati Sathe MD,&nbsp;Cristina Sampaio MD, PhD","doi":"10.1002/mds.70361","DOIUrl":"10.1002/mds.70361","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In the past decade, significant advances have improved our understanding of the mechanisms underlying HD pathobiology leading to several putative therapeutic targets for HD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The aim was to describe the Huntington's disease (HD) drug development clinical pipeline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed all HD clinical trials described in clinicaltrials.gov and the WHO International Clinical Trials Registry from January 1, 2014, to November 13, 2025. Studies were classified as interventional (pharmacological and nonpharmacological) or observational (natural history, biomarker, and other). Interventional trials were further categorized according to phase of development and type of intervention. Proposed mechanisms of action were classified according to adapted Common Alzheimer's and Related Dementias Research Ontology definitions, with huntingtin lowering assigned as a separate category.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 165 registered clinical studies for Huntington's disease (HD) were identified between 2014 and the index date, requiring 7501 participants. These included 54 observational studies and 111 interventional trials. Of the 69 pharmacological trials, 54.9% have been completed, 10.8% have been terminated, and 39.2% remain active. Over the past 11 years, 50 different pharmacological agents have been tested in 69 trials, with 21 agents currently being evaluated. Disease-modifying therapies now account for 90.5% of phase 1 trials, 61.8% of phase 2 trials, and 55.6% of phase 3 trials in the pipeline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Over the past decade, the HD clinical trial landscape has expanded and shifted toward disease-modifying strategies, with significant changes in trial design and a shift in the target population to an earlier stage of disease. © 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 9","pages":"2267-2277"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140608","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":"Rare-Variant Burden across Lysosomal Genes Implicates Sialylation and Ganglioside Metabolism in Parkinson's Disease","authors":"Konstantin Senkevich MD, PhD,&nbsp;Sitki Cem Parlar BSc,&nbsp;Cloe Chantereault,&nbsp;Lang Liu MBI,&nbsp;Eric Yu PhD,&nbsp;Uladzislau Rudakou MD, MSc,&nbsp;Jamil Ahmad PhD,&nbsp;Jennifer A. Ruskey MD,&nbsp;Farnaz Asayesh MSc,&nbsp;Dan Spiegelman MSc,&nbsp;Cheryl Waters MD,&nbsp;Oury Monchi PhD,&nbsp;Yves Dauvilliers MD, PhD,&nbsp;Nicolas Dupré MD, FRCP,&nbsp;Lior Greenbaum MD, PhD,&nbsp;Sharon Hassin-Baer MD,&nbsp;Irina Miliukhina MD, PhD,&nbsp;Alla Timofeeva MD, PhD,&nbsp;Anton Emelyanov PhD,&nbsp;Sofya Pchelina DrSci,&nbsp;Roy N. Alcalay MD, MSc,&nbsp;Ziv Gan-Or MD, PhD","doi":"10.1002/mds.70391","DOIUrl":"10.1002/mds.70391","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;Lysosomal dysfunction is central to Parkinson's disease (PD) pathogenesis, with &lt;i&gt;GBA1&lt;/i&gt; representing the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid, and ceramide metabolism have been proposed as contributors to PD, highlighting the need for genetic analyses across these pathways.&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 aim was to evaluate the contribution of rare variants across lysosomal genes to PD risk.&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 analyzed rare variants (minor allele frequency ≤0.01) across 36 lysosomal genes in 8267 individuals with PD and 68,208 controls, including 793 early-onset PD (≤50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3456 cases and 2664 controls) and combined with whole-genome sequencing data from the United Kingdom (UK) Biobank (2848 cases, 62,451 controls) and the Accelerating Medicines Partnership-PD cohort (1963 cases, 3093 controls). Associations were tested using Sequence Kernel Association Test-Optimal across variant classes (rare variants, nonsynonymous, loss-of-function, and predicted damaging variants with combined annotation-dependent depletion score &gt;20), followed by meta-analysis across cohorts. Domain-level analyses were performed for variants located within protein domains. False discovery rate (FDR) correction was applied.&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;Meta-analysis identified a significant association between rare variants in &lt;i&gt;ST3GAL3&lt;/i&gt; and Parkinson's disease (Pfdr = 0.04). Domain-based analyses showed enrichment of nonsynonymous variants within the β-acetyl-hexosaminidase–like domain of &lt;i&gt;HEXA&lt;/i&gt; (&lt;i&gt;P&lt;/i&gt; = 8.0 × 10&lt;sup&gt;−4&lt;/sup&gt;), although this signal did not survive correction (Pfdr = 0.154). In early-onset PD, domain-based analyses identified significant associations in &lt;i&gt;NAGLU&lt;/i&gt; (Pfdr = 7.3 × 10&lt;sup&gt;−6&lt;/sup&gt;) and &lt;i&gt;ST3GAL5&lt;/i&gt; (Pfdr = 0.03).&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;Rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to PD susceptibility beyond &lt;i&gt;GBA1&lt;/i&gt;, highlighting pathways for future replication and investigation. © 2026 The Author(s). &lt;i&gt;Movement Disorders&lt;/i&gt; published by Wiley Periodicals LLC on behalf of International Parkinson a","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"41 9","pages":"2349-2356"},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.70391","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148221685","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}