Movement Disorders最新文献_第4页

When the Scale Drops: Pathways to Weight Loss in Parkinson's Disease and Future Directions. 当体重秤下降：帕金森氏症的减肥途径和未来方向。

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-03-04 DOI: 10.1002/mds.70258

Ellie D Gabriel,Robert S Eisinger,Joyce M Lee,Sarah Hamimi,Hope Kim,Susanna D Howard,Casey H Halpern

Although Parkinson's disease (PD) is classically defined by its motor features, non-motor symptoms exert a substantial and often under-recognized influence on disease trajectory. Among these, weight loss has long been observed in PD and other neurodegenerative disorders, yet the mechanisms remain incompletely understood. This limited mechanistic insight has left few treatment options for weight loss in PD. Emerging research highlights the role of metabolic regulation, neuroendocrine signaling, pharmacologic treatment, cognitive decline, gastrointestinal dysfunction, and brain stimulation in shaping weight trajectories in PD. In this review, we synthesize current evidence surrounding weight in PD, beginning with an overview of epidemiologic trends and their implications for morbidity and mortality. The sections that follow examine proposed mechanisms, clinical and treatment-related factors associated with weight change, and insights derived from deep brain stimulation studies. Finally, we summarize cross-mechanism interactions, current knowledge gaps and discuss practical recommendations for translating these insights into therapeutic strategies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

虽然帕金森病（PD）的经典定义是其运动特征，但非运动症状对疾病轨迹的影响很大，但往往未被认识到。其中，PD和其他神经退行性疾病长期以来一直观察到体重减轻，但其机制仍不完全清楚。这种有限的机制认识使得PD患者的减肥治疗选择很少。新兴研究强调了代谢调节、神经内分泌信号、药物治疗、认知能力下降、胃肠功能障碍和脑刺激在PD患者体重轨迹形成中的作用。在这篇综述中，我们从流行病学趋势及其对发病率和死亡率的影响的概述开始，综合了目前关于PD中体重的证据。接下来的部分将探讨与体重变化相关的机制、临床和治疗相关因素，以及从深部脑刺激研究中获得的见解。最后，我们总结了跨机制的相互作用，当前的知识差距，并讨论了将这些见解转化为治疗策略的实用建议。©2026作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

{"title":"When the Scale Drops: Pathways to Weight Loss in Parkinson's Disease and Future Directions.","authors":"Ellie D Gabriel,Robert S Eisinger,Joyce M Lee,Sarah Hamimi,Hope Kim,Susanna D Howard,Casey H Halpern","doi":"10.1002/mds.70258","DOIUrl":"https://doi.org/10.1002/mds.70258","url":null,"abstract":"Although Parkinson's disease (PD) is classically defined by its motor features, non-motor symptoms exert a substantial and often under-recognized influence on disease trajectory. Among these, weight loss has long been observed in PD and other neurodegenerative disorders, yet the mechanisms remain incompletely understood. This limited mechanistic insight has left few treatment options for weight loss in PD. Emerging research highlights the role of metabolic regulation, neuroendocrine signaling, pharmacologic treatment, cognitive decline, gastrointestinal dysfunction, and brain stimulation in shaping weight trajectories in PD. In this review, we synthesize current evidence surrounding weight in PD, beginning with an overview of epidemiologic trends and their implications for morbidity and mortality. The sections that follow examine proposed mechanisms, clinical and treatment-related factors associated with weight change, and insights derived from deep brain stimulation studies. Finally, we summarize cross-mechanism interactions, current knowledge gaps and discuss practical recommendations for translating these insights into therapeutic strategies. © 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":"245 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350295","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}

引用次数: 0

Heterozygous Loss-of-Function Variants of KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia. KCNJ10的杂合功能缺失变异导致阵发性运动障碍。

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-03-02 DOI: 10.1002/mds.70247

Wan-Bing Sun,Jiao-Jiao Xu,Yu-Lan Chen,Zhong-Chen Feng,Hong-Fu Li,Dian-Fu Chen,Zhi-Ying Wu

BACKGROUNDHeterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) were previously reported to be enriched in several patients with paroxysmal kinesigenic dyskinesia (PKD).OBJECTIVESThe aim was to confirm the pathogenesis of KCNJ10 variants and the relationship between KCNJ10 variants and PKD phenotypes.METHODSThe whole-exome sequencing followed by Sanger sequencing were used to screen the potential pathogenic KCNJ10 variants in a cohort of PKD patients. Functional studies were performed to check the pathogenicity of the variants. The clinical characteristics of KCNJ10-related PKD patients reported to date were reviewed.RESULTSFive heterozygous KCNJ10 variants including c.76C>T (p.R26*), c.436C>T (p.L146F), c.484A>G (p.T162A), c.524G>A (p.R175Q), and c.923del (p.G308Afs*17), were detected in five pedigrees and three sporadic patients. All variants had extremely low frequency in normal populations and were highly conserved between species. They influenced the location or expression of potassium inwardly rectifying channel (Kir) 4.1 and resulted in the Kir currents of cell decreased to varied degrees. Up to date, 31 KCNJ10 variants had been reported to manifest as PKD, and a significant majority (22/31, 71%) were in the cytoplasmic domain near the C-terminus. Notably, the KCNJ10-related PKD patients showed a pronounced male predominance.CONCLUSIONSThe study confirmed the correlation between PKD and the loss-of-function of Kir4.1 resulted from heterozygous KCNJ10 variants. The distribution bias of PKD-related KCNJ10 variants as well as the male predominance in affected individuals shed light on the mechanism investigation of this subtype of PKD. © 2026 International Parkinson and Movement Disorder Society.

背景钾内整流通道亚家族J成员10 （KCNJ10）的杂合变异体在一些阵发性运动障碍（PKD）患者中丰富。目的探讨KCNJ10变异的发病机制以及KCNJ10变异与PKD表型的关系。方法采用全外显子组测序和Sanger测序对PKD患者进行潜在致病性KCNJ10变异的筛选。进行功能研究以检查变异的致病性。回顾了迄今为止报道的kcnj10相关PKD患者的临床特征。结果在5个家系和3例散发患者中检测到5个KCNJ10杂合变异，分别为c.76C>T （p.R26*）、c.436C>T （p.L146F）、c.484A>G （p.T162A）、c.524G>A （p.R175Q）和c.923del （p.G308Afs*17）。所有变异在正常种群中出现的频率极低，并且在种间高度保守。它们影响钾内整流通道（Kir） 4.1的位置或表达，导致细胞Kir电流不同程度地降低。迄今为止，已经报道了31个KCNJ10变异表现为PKD，其中绝大多数（22/ 31,71%）位于c端附近的细胞质结构域。值得注意的是，kcnj10相关的PKD患者表现出明显的男性优势。结论本研究证实了KCNJ10杂合变异导致的Kir4.1功能缺失与PKD的相关性。PKD相关KCNJ10变异的分布偏倚以及男性在受影响个体中的优势，为研究该亚型PKD的发病机制提供了线索。©2026国际帕金森和运动障碍学会。

{"title":"Heterozygous Loss-of-Function Variants of KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia.","authors":"Wan-Bing Sun,Jiao-Jiao Xu,Yu-Lan Chen,Zhong-Chen Feng,Hong-Fu Li,Dian-Fu Chen,Zhi-Ying Wu","doi":"10.1002/mds.70247","DOIUrl":"https://doi.org/10.1002/mds.70247","url":null,"abstract":"BACKGROUNDHeterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) were previously reported to be enriched in several patients with paroxysmal kinesigenic dyskinesia (PKD).OBJECTIVESThe aim was to confirm the pathogenesis of KCNJ10 variants and the relationship between KCNJ10 variants and PKD phenotypes.METHODSThe whole-exome sequencing followed by Sanger sequencing were used to screen the potential pathogenic KCNJ10 variants in a cohort of PKD patients. Functional studies were performed to check the pathogenicity of the variants. The clinical characteristics of KCNJ10-related PKD patients reported to date were reviewed.RESULTSFive heterozygous KCNJ10 variants including c.76C>T (p.R26*), c.436C>T (p.L146F), c.484A>G (p.T162A), c.524G>A (p.R175Q), and c.923del (p.G308Afs*17), were detected in five pedigrees and three sporadic patients. All variants had extremely low frequency in normal populations and were highly conserved between species. They influenced the location or expression of potassium inwardly rectifying channel (Kir) 4.1 and resulted in the Kir currents of cell decreased to varied degrees. Up to date, 31 KCNJ10 variants had been reported to manifest as PKD, and a significant majority (22/31, 71%) were in the cytoplasmic domain near the C-terminus. Notably, the KCNJ10-related PKD patients showed a pronounced male predominance.CONCLUSIONSThe study confirmed the correlation between PKD and the loss-of-function of Kir4.1 resulted from heterozygous KCNJ10 variants. The distribution bias of PKD-related KCNJ10 variants as well as the male predominance in affected individuals shed light on the mechanism investigation of this subtype of PKD. © 2026 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"26 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329504","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}

引用次数: 0

Novel Variants in DCTN1 Associated with Perry Disease: A Case Series from a Chinese Parkinsonism Cohort 与Perry病相关的DCTN1新变异：来自中国帕金森病队列的病例系列

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-23 DOI: 10.1002/mds.70244

Yiying Zhang, Yiling Chen, Yixin Kang, Xinhui Chen, Jiaxiang Li, Xiaosheng Zheng, Bo Wang, Nan Jin, Chenxin Ying, Yaoting Wang, Zhidong Cen, Wei Luo

Background Perry disease is a rare autosomal dominant inherited neurodegenerative disorder caused by cytoskeleton‐associated protein glycine‐rich (CAP‐Gly) domain‐related variants in the DCTN1 gene, with characteristic TDP‐43 pathology. The typical manifestations are parkinsonism, psychiatric symptoms, weight loss, and central hypoventilation. Objective The aim of the study was to delineate the genotypic and phenotypic spectrum of Perry disease in a Chinese parkinsonism cohort. Methods We screened the DCTN1 CAP‐Gly domain‐related variants in 932 Chinese parkinsonism patients using next‐generation sequencing, and functional studies of the identified variants were conducted. Results Three variants were detected (two novel: p.Arg32Cys, p.Gly67Ser; one reported: p.Gly71Arg), indicating a rate of 0.32% (3/932). Clinical presentations mimicked progressive supranuclear palsy or early‐onset Parkinson's disease. Functional studies supported pathogenicity, revealing impaired localization of DCTN1 ‐encoded p150 Glued protein, TDP‐43 pathology, and altered lysosomal positioning. Conclusions Our study broadens the genetic and phenotypic spectrum of Perry disease. These findings support consideration of DCTN1 CAP‐Gly domain‐related variants in patients with parkinsonism to facilitate early recognition and management. © 2026 International Parkinson and Movement Disorder Society.

Perry病是一种罕见的常染色体显性遗传性神经退行性疾病，由DCTN1基因中细胞骨架相关蛋白-富甘氨酸（CAP - Gly）结构域相关变异引起，具有特征性的TDP - 43病理。典型表现为帕金森病、精神症状、体重减轻和中枢性低通气。目的研究中国帕金森病队列中Perry病的基因型和表型谱。方法利用下一代测序技术筛选932例中国帕金森病患者的DCTN1 CAP - Gly结构域相关变异，并对鉴定出的变异进行功能研究。结果共检出3个变异（2个新变异：p.Arg32Cys、p.Gly67Ser， 1个已报道变异：p.Gly71Arg），变异率为0.32%（3/932）。临床表现类似于进行性核上性麻痹或早发性帕金森病。功能研究支持致病性，揭示了DCTN1编码的p150粘合蛋白的定位受损，TDP - 43病理和溶酶体定位的改变。结论本研究拓宽了佩里病的遗传和表型谱。这些发现支持在帕金森病患者中考虑DCTN1 CAP - Gly结构域相关变异，以促进早期识别和管理。©2026国际帕金森和运动障碍学会。

{"title":"Novel Variants in DCTN1 Associated with Perry Disease: A Case Series from a Chinese Parkinsonism Cohort","authors":"Yiying Zhang, Yiling Chen, Yixin Kang, Xinhui Chen, Jiaxiang Li, Xiaosheng Zheng, Bo Wang, Nan Jin, Chenxin Ying, Yaoting Wang, Zhidong Cen, Wei Luo","doi":"10.1002/mds.70244","DOIUrl":"https://doi.org/10.1002/mds.70244","url":null,"abstract":"Background Perry disease is a rare autosomal dominant inherited neurodegenerative disorder caused by cytoskeleton‐associated protein glycine‐rich (CAP‐Gly) domain‐related variants in the DCTN1 gene, with characteristic TDP‐43 pathology. The typical manifestations are parkinsonism, psychiatric symptoms, weight loss, and central hypoventilation. Objective The aim of the study was to delineate the genotypic and phenotypic spectrum of Perry disease in a Chinese parkinsonism cohort. Methods We screened the DCTN1 CAP‐Gly domain‐related variants in 932 Chinese parkinsonism patients using next‐generation sequencing, and functional studies of the identified variants were conducted. Results Three variants were detected (two novel: p.Arg32Cys, p.Gly67Ser; one reported: p.Gly71Arg), indicating a rate of 0.32% (3/932). Clinical presentations mimicked progressive supranuclear palsy or early‐onset Parkinson's disease. Functional studies supported pathogenicity, revealing impaired localization of DCTN1 ‐encoded p150 Glued protein, TDP‐43 pathology, and altered lysosomal positioning. Conclusions Our study broadens the genetic and phenotypic spectrum of Perry disease. These findings support consideration of DCTN1 CAP‐Gly domain‐related variants in patients with parkinsonism to facilitate early recognition and management. © 2026 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"15 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146778386","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}

引用次数: 0

Comments on: “Bipolar Disorder as a LongTerm Risk Factor for Parkinson's Disease: A Nationwide Case–Control Study” 评论：“双相情感障碍是帕金森病的长期危险因素：一项全国病例对照研究”

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-16 DOI: 10.1002/mds.70214

Nengjun Xiang, Li Cai, Han Gao, Wentao Li

引用次数: 0

Reply to: “Comments on: “Bipolar Disorder as a Long‐Term Risk Factor for Parkinson's Disease: A Nationwide Case–Control Study”” 回复：对“双相情感障碍作为帕金森病的长期危险因素：一项全国病例对照研究”的评论

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-16 DOI: 10.1002/mds.70215

Elina Jaakkola, Marjaana Koponen, Valtteri Kaasinen, Jarmo Hietala, Sirpa Hartikainen, Anna‐Maija Tolppanen

引用次数: 0

Local Field Aperiodic Spectral Power Modulated by Deep Brain Stimulation in Parkinson's Disease 帕金森病深部脑刺激调制的局部场非周期频谱功率

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-13 DOI: 10.1002/mds.70232

Martin Lamoš, Aneta Žáčková, David Ulčák, Benjamin Gurka, Daniel Brzuchanski, Lucia Šmahovská, Martina Bočková

Background Aperiodic spectral broadband power has been described recently as reflecting Parkinson's disease (PD) severity. It has therefore become an increasing focus of research interest in the context of the new adaptive deep brain stimulation (DBS) approach. Objective We aimed to study the influence of DBS on the main parameters of the aperiodic spectral component of local field potentials (LFPs). Methods LFPs were recorded from the subthalamic nucleus (STN) in patients with PD (n = 22) during a simple experimental paradigm that included 5 minutes of resting state and a short gait task during DBS OFF and ON conditions ( off medication). Classical spectral analysis was performed using fast Fourier transform; the analysis of the aperiodic component was performed by fitting oscillations and a one‐over‐F approach. In a subset of the patients (n = 14), it was possible to evaluate the symptom progression over time after 1 year by analyzing the control measurement. Results The severity of hypokinetic/rigid symptomatology, measured by International Parkinson and Movement Disorders Society Unified Parkinson's Disease Rating Scale, correlated significantly with both of the aperiodic components characteristics of the STN LFPs: the slope and the offset. These parameters were significantly modified by DBS, as evaluated with a Wilcoxon signed‐rank test during the resting state and during the gait task. Aperiodic power remained stable over time during the control measurements. Conclusions The aperiodic component in LFPs may reflect pathological activity of the neuronal network and might serve as a new potential clinical marker in PD. The variable relation to conventional beta oscillopathy indicates the involvement of multiple neural mechanisms. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

非周期频谱宽带功率最近被描述为反映帕金森病（PD）的严重程度。因此，在新的适应性深部脑刺激（DBS）方法的背景下，它已成为越来越多的研究兴趣的焦点。目的研究脑起搏器对局部场电位（LFPs）非周期谱成分主要参数的影响。方法采用简单的实验模式，记录PD患者（n = 22）在DBS关闭和开（停药）状态下的5分钟静息状态和短步态任务下的丘脑下核（STN） lfp。经典光谱分析采用快速傅立叶变换；通过拟合振荡和1 - over - F方法对非周期分量进行分析。在一部分患者（n = 14）中，可以通过分析对照测量值来评估1年后症状的进展情况。结果由国际帕金森和运动障碍学会统一帕金森病评定量表测量的低运动/僵硬症状的严重程度与STN lfp的两种非周期成分特征：斜率和偏移量显著相关。在静息状态和步态任务期间，通过Wilcoxon签名秩检验评估，DBS显著改变了这些参数。在控制测量期间，非周期功率随时间保持稳定。结论lfp的非周期成分可能反映了神经网络的病理活动，可能作为PD新的潜在临床标志物。与常规β -示波器病变的变量关系表明涉及多种神经机制。©2026作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

{"title":"Local Field Aperiodic Spectral Power Modulated by Deep Brain Stimulation in Parkinson's Disease","authors":"Martin Lamoš, Aneta Žáčková, David Ulčák, Benjamin Gurka, Daniel Brzuchanski, Lucia Šmahovská, Martina Bočková","doi":"10.1002/mds.70232","DOIUrl":"https://doi.org/10.1002/mds.70232","url":null,"abstract":"Background Aperiodic spectral broadband power has been described recently as reflecting Parkinson's disease (PD) severity. It has therefore become an increasing focus of research interest in the context of the new adaptive deep brain stimulation (DBS) approach. Objective We aimed to study the influence of DBS on the main parameters of the aperiodic spectral component of local field potentials (LFPs). Methods LFPs were recorded from the subthalamic nucleus (STN) in patients with PD (n = 22) during a simple experimental paradigm that included 5 minutes of resting state and a short gait task during DBS OFF and ON conditions ( off medication). Classical spectral analysis was performed using fast Fourier transform; the analysis of the aperiodic component was performed by fitting oscillations and a one‐over‐F approach. In a subset of the patients (n = 14), it was possible to evaluate the symptom progression over time after 1 year by analyzing the control measurement. Results The severity of hypokinetic/rigid symptomatology, measured by International Parkinson and Movement Disorders Society Unified Parkinson's Disease Rating Scale, correlated significantly with both of the aperiodic components characteristics of the STN LFPs: the slope and the offset. These parameters were significantly modified by DBS, as evaluated with a Wilcoxon signed‐rank test during the resting state and during the gait task. Aperiodic power remained stable over time during the control measurements. Conclusions The aperiodic component in LFPs may reflect pathological activity of the neuronal network and might serve as a new potential clinical marker in PD. The variable relation to conventional beta oscillopathy indicates the involvement of multiple neural mechanisms. © 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":"28 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169757","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}

引用次数: 0

Cell‐Type‐Specific Causal Inference Unveils Novel Targets for Parkinson's Disease 细胞类型特异性因果推断揭示帕金森病的新靶点

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-13 DOI: 10.1002/mds.70223

Si‐Chun Gu, Qiao Yang Sun, Wei Zhang, Chang‐Yi Shen, Hang Su, Fang Xie, Can‐xing Yuan, Zhi‐dong Zhou, Eng King Tan, Qing Ye

Background Parkinson's disease (PD) involves heterogeneous neurodegenerative processes across brain cell types. The cell‐type‐specific effects of genetic risk remain unclear. Objective We aimed to identify cell‐type‐specific causal genes for PD and to link genetic risk to molecular mechanisms and therapeutic opportunities. Methods We performed the first cell‐stratified Mendelian randomization integrating single‐cell expression quantitative trait loci data from eight brain cell types with large PD genome‐wide association studies datasets, followed by validation, neuropathological correlation, and postmortem expression analyses. Results Thirteen significant causal associations for four genes ( ARL17A , ARL17B , KANSL1 , LRRC37A ) were identified across seven cell types, with consistent replication. ARL17A increased risk, whereas ARL17B , KANSL1 , and LRRC37A were protective. Gene expression correlated with disease severity and showed cell‐type‐specific dysregulation. Drug–gene interaction screen highlighted US Food and Drug Administration–approved agents including raloxifene and dorzolamide as potential therapeutic modulators. Conclusions This study contributed to cell‐type‐specific genetic mechanisms in PD , linking risk variants to molecular alterations and nominating therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.

帕金森氏病（PD）涉及跨脑细胞类型的异质神经退行性过程。遗传风险的细胞类型特异性影响尚不清楚。目的：我们旨在确定PD的细胞类型特异性致病基因，并将遗传风险与分子机制和治疗机会联系起来。方法：我们进行了第一次细胞分层孟德尔随机化，整合了来自8种脑细胞类型的单细胞表达数量性状位点数据，以及大型PD全基因组关联研究数据集，随后进行了验证、神经病理相关性和死后表达分析。结果在7种细胞类型中鉴定出4个基因（ARL17A、ARL17B、KANSL1、LRRC37A）的13个显著因果关联，且复制一致。ARL17A增加了风险，而ARL17B、KANSL1和LRRC37A具有保护作用。基因表达与疾病严重程度相关，并表现出细胞类型特异性失调。药物-基因相互作用筛选突出了美国食品和药物管理局批准的药物，包括雷洛昔芬和多唑胺作为潜在的治疗调节剂。结论：本研究揭示了PD中细胞类型特异性的遗传机制，将风险变异与分子改变联系起来，并指定了治疗靶点。©2026国际帕金森和运动障碍学会。

{"title":"Cell‐Type‐Specific Causal Inference Unveils Novel Targets for Parkinson's Disease","authors":"Si‐Chun Gu, Qiao Yang Sun, Wei Zhang, Chang‐Yi Shen, Hang Su, Fang Xie, Can‐xing Yuan, Zhi‐dong Zhou, Eng King Tan, Qing Ye","doi":"10.1002/mds.70223","DOIUrl":"https://doi.org/10.1002/mds.70223","url":null,"abstract":"Background Parkinson's disease (PD) involves heterogeneous neurodegenerative processes across brain cell types. The cell‐type‐specific effects of genetic risk remain unclear. Objective We aimed to identify cell‐type‐specific causal genes for PD and to link genetic risk to molecular mechanisms and therapeutic opportunities. Methods We performed the first cell‐stratified Mendelian randomization integrating single‐cell expression quantitative trait loci data from eight brain cell types with large PD genome‐wide association studies datasets, followed by validation, neuropathological correlation, and postmortem expression analyses. Results Thirteen significant causal associations for four genes ( ARL17A , ARL17B , KANSL1 , LRRC37A ) were identified across seven cell types, with consistent replication. ARL17A increased risk, whereas ARL17B , KANSL1 , and LRRC37A were protective. Gene expression correlated with disease severity and showed cell‐type‐specific dysregulation. Drug–gene interaction screen highlighted US Food and Drug Administration–approved agents including raloxifene and dorzolamide as potential therapeutic modulators. Conclusions This study contributed to cell‐type‐specific genetic mechanisms in PD , linking risk variants to molecular alterations and nominating therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"10 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169756","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}

引用次数: 0

Parkinson's Disease Patient‐Specific Striatum Organoids Show Hallmarks of Increased Inflammation 帕金森病患者特异性纹状体类器官显示炎症增加的特征

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-11 DOI: 10.1002/mds.70176

Kyriaki Barmpa, Claudia Saraiva, Alise Zagare, Mona Tuzza, Joseph Longworth, Elisa Zuccoli, Katrin Hufnagel, Florian Skwirblies, Ronny Schmidt, Dirk Brenner, Christoph Schröder, Jens C. Schwamborn

Background Dopaminergic neurons from the substantia nigra pars compacta project their axons into the dorsal striatum, forming the nigrostriatal pathway. In Parkinson's disease (PD), dopaminergic terminals degenerate in the striatum, leading to dopamine depletion, which in turn causes alterations in the basal ganglia circuits that are essential for movement control. However, the reasons for dopaminergic neuron terminal degeneration in the striatum are still not understood. The LRRK2 gene is highly expressed in the striatum, and the LRRK2‐G2019S mutation is one of the most common mutations associated with PD. It is therefore tempting to speculate that dysregulations in the striatal functionality can initiate or contribute to the dopaminergic neuron terminals' degeneration. Objectives We aimed to examine the phenotypic differences between healthy and patient striatum organoids carrying the LRRK2‐G2019S mutation to assess whether specific alterations in the striatum that are independent of dopaminergic input could contribute to the development of the disease. Methods Striatum organoids were generated using healthy and PD patient–induced pluripotent stem cell lines, and they were cultured until day 80. We evaluated the levels of striatum‐specific proteins, and we performed proteomics and kinase activity analysis. Results PD striatum organoids revealed increased abundance of DRD2, DARPP32, and CDK5. Proteomics and kinase activity analysis demonstrated an inflammatory phenotype, which was further validated by investigating the occurrence of reactive astrocytes. Conclusions Striatum organoids recapitulate PD‐relevant phenotypes autonomously, independent of dopaminergic input. This includes a significant inflammatory phenotype. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

来自黑质致密部的多巴胺能神经元将其轴突投射到背纹状体，形成黑质纹状体通路。在帕金森病（PD）中，纹状体中的多巴胺能末梢退化，导致多巴胺耗竭，进而导致对运动控制至关重要的基底神经节回路的改变。然而，纹状体多巴胺能神经元末梢变性的原因尚不清楚。LRRK2基因在纹状体中高度表达，LRRK2‐G2019S突变是与PD相关的最常见突变之一。因此，我们很容易推测纹状体功能失调可以引发或促成多巴胺能神经元末梢的退化。我们旨在研究携带LRRK2 - G2019S突变的健康和患者纹状体类器官之间的表型差异，以评估纹状体中不依赖于多巴胺能输入的特异性改变是否有助于疾病的发展。方法采用健康人诱导的多能干细胞和PD患者诱导的多能干细胞制备类纹状体，培养至第80天。我们评估了纹状体特异性蛋白的水平，并进行了蛋白质组学和激酶活性分析。结果PD纹状体类器官显示DRD2、DARPP32和CDK5的丰度增加。蛋白质组学和激酶活性分析证实了炎症表型，通过研究反应性星形胶质细胞的发生进一步证实了这一点。结论：纹状体类器官自主再现PD相关表型，独立于多巴胺能输入。这包括明显的炎症表型。©2026作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

{"title":"Parkinson's Disease Patient‐Specific Striatum Organoids Show Hallmarks of Increased Inflammation","authors":"Kyriaki Barmpa, Claudia Saraiva, Alise Zagare, Mona Tuzza, Joseph Longworth, Elisa Zuccoli, Katrin Hufnagel, Florian Skwirblies, Ronny Schmidt, Dirk Brenner, Christoph Schröder, Jens C. Schwamborn","doi":"10.1002/mds.70176","DOIUrl":"https://doi.org/10.1002/mds.70176","url":null,"abstract":"Background Dopaminergic neurons from the substantia nigra pars compacta project their axons into the dorsal striatum, forming the nigrostriatal pathway. In Parkinson's disease (PD), dopaminergic terminals degenerate in the striatum, leading to dopamine depletion, which in turn causes alterations in the basal ganglia circuits that are essential for movement control. However, the reasons for dopaminergic neuron terminal degeneration in the striatum are still not understood. The LRRK2 gene is highly expressed in the striatum, and the LRRK2‐G2019S mutation is one of the most common mutations associated with PD. It is therefore tempting to speculate that dysregulations in the striatal functionality can initiate or contribute to the dopaminergic neuron terminals' degeneration. Objectives We aimed to examine the phenotypic differences between healthy and patient striatum organoids carrying the LRRK2‐G2019S mutation to assess whether specific alterations in the striatum that are independent of dopaminergic input could contribute to the development of the disease. Methods Striatum organoids were generated using healthy and PD patient–induced pluripotent stem cell lines, and they were cultured until day 80. We evaluated the levels of striatum‐specific proteins, and we performed proteomics and kinase activity analysis. Results PD striatum organoids revealed increased abundance of DRD2, DARPP32, and CDK5. Proteomics and kinase activity analysis demonstrated an inflammatory phenotype, which was further validated by investigating the occurrence of reactive astrocytes. Conclusions Striatum organoids recapitulate PD‐relevant phenotypes autonomously, independent of dopaminergic input. This includes a significant inflammatory phenotype. © 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":"97 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153580","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}

引用次数: 0

The Cerebellar Cognitive‐Affective Syndrome Scale Reveals Consistent, Early, and Progressive Neuropsychological Deficits in Autosomal‐Recessive Spastic Ataxia of Charlevoix‐Saguenay: A Large International Cross‐Sectional Study 小脑认知-情感综合征量表揭示了常染色体隐性痉挛性共济失调患者一致、早期和进行性的神经心理缺陷：一项大型国际横断面研究

IF 8.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-11 DOI: 10.1002/mds.70201

Julie Fortin, Matthis Synofzik, Élyse‐Anne Pedneault‐Tremblay, Dominik Hermle, Andreas Thieme, Dagmar Timmann, Roberta La Piana, Bernard Brais, Justine Dolbec, Isabelle Côté, Cynthia Gagnon, Andreas Traschütz

Background Neuropsychological deficits have been observed in patients with cerebellar damage, but never thoroughly investigated in autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS). Objectives The goal is the characterization of presence, severity, and profile of neuropsychological deficits in ARSACS using the cerebellar cognitive‐affective syndrome (CCAS) scale. Methods Prospective study including a discovery cohort from Saguenay/Canada (n = 31, median [inter‐quartile range] age: 57 [54–62] years), and a validation cohort from Tübingen, Germany (n = 17, 35 [21–43] years) with matched controls (n = 19). Results All ARSACS patients failed in multiple CCAS‐related subtests and exceeded cutoffs for “definite CCAS.” Even the younger validation cohort failed more subtests than controls (5 [3–7] vs. 1 [1–2], P < 0.001) and had lower CCAS total scores (81 [67–86] vs. 101 [91–106], P < 0.001). Total scores worsened in the older discovery cohort (40 [25–52], P < 0.001) and correlated with age/disease duration (ρ = −0.575, P < 0.001) and ataxia severity (Scale for the Assessment and Rating of Ataxia: ρ = −0.527, P = 0.003). Conclusions Neuropsychological deficits consistent with CCAS are consistent in ARSACS, present early, and progress in the disease course. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

背景在小脑损伤患者中观察到神经心理缺陷，但从未对常染色体隐性痉挛性共济失调（ARSACS）进行过彻底的研究。目的是使用小脑认知情感综合征（CCAS）量表来描述ARSACS中神经心理缺陷的存在、严重程度和特征。方法前瞻性研究包括来自加拿大Saguenay的发现队列（n = 31，中位年龄：57[54-62]岁）和来自德国t宾根的验证队列（n = 17, 35[21-43]岁）和匹配对照（n = 19）。结果：所有ARSACS患者在多个CCAS相关亚测试中均未通过，并且超过了“明确CCAS”的临界值。甚至更年轻的验证队列也比对照组失败了更多的亚测试（5[3-7]对1 [1 - 2]，P < 0.001）， CCAS总分更低（81[67-86]对101 [91-106]，P < 0.001）。在年龄较大的发现队列中，总得分更差（40 [25-52],P < 0.001），并与年龄/病程（ρ = - 0.575, P < 0.001）和共济失调严重程度（共济失调评估和评分量表：ρ = - 0.527, P = 0.003）相关。结论与CCAS相一致的神经心理缺陷在ARSACS中是一致的，表现较早，并在病程中进展。©2026作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

{"title":"The Cerebellar Cognitive‐Affective Syndrome Scale Reveals Consistent, Early, and Progressive Neuropsychological Deficits in Autosomal‐Recessive Spastic Ataxia of Charlevoix‐Saguenay: A Large International Cross‐Sectional Study","authors":"Julie Fortin, Matthis Synofzik, Élyse‐Anne Pedneault‐Tremblay, Dominik Hermle, Andreas Thieme, Dagmar Timmann, Roberta La Piana, Bernard Brais, Justine Dolbec, Isabelle Côté, Cynthia Gagnon, Andreas Traschütz","doi":"10.1002/mds.70201","DOIUrl":"https://doi.org/10.1002/mds.70201","url":null,"abstract":"Background Neuropsychological deficits have been observed in patients with cerebellar damage, but never thoroughly investigated in autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS). Objectives The goal is the characterization of presence, severity, and profile of neuropsychological deficits in ARSACS using the cerebellar cognitive‐affective syndrome (CCAS) scale. Methods Prospective study including a discovery cohort from Saguenay/Canada (n = 31, median [inter‐quartile range] age: 57 [54–62] years), and a validation cohort from Tübingen, Germany (n = 17, 35 [21–43] years) with matched controls (n = 19). Results All ARSACS patients failed in multiple CCAS‐related subtests and exceeded cutoffs for “definite CCAS.” Even the younger validation cohort failed more subtests than controls (5 [3–7] vs. 1 [1–2], P < 0.001) and had lower CCAS total scores (81 [67–86] vs. 101 [91–106], P < 0.001). Total scores worsened in the older discovery cohort (40 [25–52], P < 0.001) and correlated with age/disease duration (ρ = −0.575, P < 0.001) and ataxia severity (Scale for the Assessment and Rating of Ataxia: ρ = −0.527, P = 0.003). Conclusions Neuropsychological deficits consistent with CCAS are consistent in ARSACS, present early, and progress in the disease course. © 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":"6 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153562","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}

引用次数: 0

Movement Disorders: Volume 41, Number 1, January 2026 运动障碍：第41卷，第1号，2026年1月

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders

Pub Date : 2026-02-07 DOI: 10.1002/mds.70225

引用次数: 0