Movement Disorders最新文献

{"title":"The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder","authors":"Zhongbo Chen MRCP, PhD,&nbsp;Pilar Alvarez Jerez MSc,&nbsp;Claire Anderson PhD,&nbsp;Martin Paucar MD, PhD,&nbsp;Jasmaine Lee MSc,&nbsp;Daniel Nilsson PhD,&nbsp;Hannah Macpherson MSc,&nbsp;Annarita Scardamaglia BSc,&nbsp;Kylie Montgomery BSc,&nbsp;John Hardy FMedSci, PhD,&nbsp;Andrew B. Singleton PhD,&nbsp;Arianna Tucci MD, PhD,&nbsp;Katherine D. Mathews MD, PhD,&nbsp;Ying-Hui Fu PhD,&nbsp;Martin Engvall MD, PhD,&nbsp;José Laffita-Mesa MD, PhD,&nbsp;Inger Nennesmo MD, PhD,&nbsp;Anna Wedell MD, PhD,&nbsp;Louis J. Ptáček MD, PhD,&nbsp;Cornelis Blauwendraat PhD,&nbsp;Emil K. Gustavsson PhD,&nbsp;Per Svenningsson MD, PhD,&nbsp;Mina Ryten MD, PhD,&nbsp;Henry Houlden MD, PhD","doi":"10.1002/mds.30077","DOIUrl":"10.1002/mds.30077","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The identification of a heterozygous exonic GGC repeat expansion in <i>ZFHX3</i> underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Given that the pathogenic repeat expansion is rare on a population level, we proposed a common ancestor across all families. Here, we employed targeted long-read sequencing through adaptive sampling, enriching for the chr16q22 region of interest.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Using phased sequencing results from individuals from Utah, Iowa, and Southern Sweden, we confirmed a common ~2000-year-old ancestral haplotype harbouring the repeat expansion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study provides further insight into the genetic architecture of SCA4. © 2024 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":"40 2","pages":"363-369"},"PeriodicalIF":7.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.30077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782518","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":"Clinical Outcome Assessments for Spasticity: Review, Critique, and Recommendations","authors":"Ota Gal PhD,&nbsp;Marjolaine Baude MD,&nbsp;Thierry Deltombe MD,&nbsp;Alberto Esquenazi MD, FAAPMR,&nbsp;Jean-Michel Gracies MD, PhD,&nbsp;Martina Hoskovcova MD, PhD,&nbsp;Carmen Rodriguez-Blazquez PhD,&nbsp;Raymond Rosales MD, PhD,&nbsp;Lalith Satkunam MBBS, FRCPC,&nbsp;Jörg Wissel MD, FRCP,&nbsp;Tiago Mestre MD, PhD,&nbsp;Álvaro Sánchez-Ferro MD, PhD,&nbsp;Matej Skorvanek MD, PhD,&nbsp;Michelle Hyczy de Siqueira Tosin MHS, PhD,&nbsp;Robert Jech MD, PhD,&nbsp;the members of the MDS Clinical Outcome Assessments Scientific Evaluation Committee and MDS Spasticity Study group","doi":"10.1002/mds.30062","DOIUrl":"10.1002/mds.30062","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Spasticity is a common feature in patients with disruptions in corticospinal pathways. However, the term is used ambiguously. Here, spasticity is defined as enhanced velocity-dependent stretch reflexes and placed within the context of deforming spastic paresis encompassing other forms of muscle overactivity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This scoping review aims at evaluating the clinimetric quality of clinical outcome assessments (COAs) for spasticity across different pathologies and to make recommendations for their use.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A literature search was conducted to identify COAs used to assess spasticity. An international expert panel evaluated the measurement properties in the included COAs. Recommendations were based on the MDS-COA program methodology based on three criteria: if the COA was (1) applied to patients with spastic paresis, (2) used by others beyond the developers, and (3) determined to be reliable, valid, and sensitive to change in patients with spasticity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 72 COAs of which 17 clinician-reported outcomes (ClinROs) and 6 patient-reported outcomes (PROs) were reviewed. The Tardieu Scale was the only ClinRO recommended for assessing spasticity. One ClinRO—Composite Spasticity Index—and two PROs—Spasticity 0–10 Numeric Rating Scale and 88-Item Multiple Sclerosis Spasticity Scale—were recommended with caveats. The Ashworth-derived COAs were excluded after evaluation due to their focus on muscle tone rather than spasticity, as defined in this review.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The Tardieu Scale is recommended for assessing spasticity, and two PROs are recommended with caveats. Consistent terminology about the various types of muscle overactivity is necessary to facilitate their assessment and treatment. © 2024 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":"40 1","pages":"22-43"},"PeriodicalIF":7.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764832","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":"Ira Shoulson, MD (1946–2024)","authors":"David G. Standaert MD, PhD,&nbsp;Karl D. Kieburtz MD, MPH","doi":"10.1002/mds.30078","DOIUrl":"10.1002/mds.30078","url":null,"abstract":"&lt;p&gt;On May 12, 2024, our community lost a tireless champion of innovation for patients and families with movement disorders. Ira Shoulson, MD, was a source of inspiration, hope, and solace for clinicians, investigators, study participants, colleagues, and, always, his patients.&lt;/p&gt;&lt;p&gt;Ira's training, after an undergraduate degree at the University of Pennsylvania, began at the University of Rochester School of Medicine &amp; Dentistry, where he fell under the influence of George Engel, MD, an internist/psychiatrist and the father of the biopsychosocial model of medicine, a patient-centered approach that considers psychological and social as well as biological factors as contributors to health. Dr. Engel was renowned for his perceptive and revealing interviewing skills, and Ira carried that ability throughout his career. After 2 years of internal medicine training in Rochester, he spent 2 years at the NIH, primarily with Tom Chase, MD (a pioneer in the neuropharmacology of Parkinson's disease), and then another 2 years back in Rochester as a neurology resident, followed by a year as chief resident in both medicine and neurology. He then introduced the Movement Disorders program at Rochester under the acronym (he had a penchant for them) the MIND (Movement and Inherited Neurological Disorders) Unit. His first recruit to help in caring for outpatients was a registered nurse, a first for the institution. The hospital restrictions confined her official duties to obtaining weights and blood pressures, values Ira prized above all other data save the history. We never observed Ira engage with a patient, whether in the clinic or hospital, without a warm, direct handshake, a set of postural blood pressures, and an assessment of weight. After that, the engaging conversation began, always in an unhurried and illuminating fashion. Ira used to joke that early on the nurse was allowed to take only blood pressures and weights, and once he was a professor that was all anyone let him do.&lt;/p&gt;&lt;p&gt;Ira was a relentless innovator. In 1987 he was awarded the first NINDS grant for a multicenter, randomized controlled trial of putative neuroprotective agents in Parkinson's disease: deprenyl (now called selegiline) and tocopherol (vitamin E), a project that became the DATATOP study. To facilitate the work he founded a nonprofit, academic collaboration, the Parkinson Study Group (PSG), whose core tenets were the free and unrestricted right to publish (facilitated by holding the database), democratic governance, and disclosure of conflicts of interest (a novel idea for the time). DATATOP and the PSG became engines for progress in Parkinson's disease. In the course of the design and execution of the trial, the PSG developed the methods, rating scales, and outcome measures that continue to drive the field today. The PSG also built a novel culture of inclusion among investigators and coordinators in Parkinson research studies; research coordinators were always included in both the","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 1","pages":"3-4"},"PeriodicalIF":7.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.30078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764880","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":"Sustained Clinical Benefit of Adaptive Deep Brain Stimulation in Parkinson's Disease Using Gamma Oscillations: A Case Report","authors":"Stephanie Cernera PhD,&nbsp;Carina R. Oehrn MD, PhD,&nbsp;Lauren H. Hammer MD, PhD,&nbsp;Maria Shcherbakova BS,&nbsp;Jiaang Yao MS,&nbsp;Amelia Hahn BS,&nbsp;Sarah Wang PhD,&nbsp;Jill L. Ostrem MD,&nbsp;Simon Little MBBS, PhD,&nbsp;Philip A. Starr MD, PhD","doi":"10.1002/mds.30076","DOIUrl":"10.1002/mds.30076","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Adaptive deep brain stimulation (aDBS) dynamically adjusts stimulation parameters according to patient needs. We recently showed that chronic aDBS utilizing invasive neural signals for feedback control is superior to conventional DBS (cDBS) during normal daily life in a 2-month trial. The stability of aDBS over longer periods remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To assess the effects of aDBS on motor symptoms and quality of life (QoL) in one individual with Parkinson's disease over 8 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used stimulation-entrained cortical gamma oscillations as a control signal for aDBS in the subthalamic nucleus and quantified benefits using motor diary ratings, QoL scales, and wearable metrics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that aDBS delivered superior and consistent benefits compared with baseline cDBS in measures of bradykinesia and QoL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>aDBS can achieve prolonged, stable improvement over clinically optimized cDBS. The neural signal remains stable, and aDBS parameters remain appropriate over extended periods. © 2024 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 2","pages":"345-350"},"PeriodicalIF":7.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764796","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":"Validation of Parkinson's Disease Ascertainment in the Veterans Administration Electronic Medical Record","authors":"Samuel M. Goldman MD, MPH,&nbsp;Frances M. Weaver PhD,&nbsp;Lishan Cao MS,&nbsp;Beverly Gonzalez PhD,&nbsp;Kevin T. Stroupe PhD,&nbsp;Kalea Colletta DO,&nbsp;Shamil Jugnundan MD, MPH,&nbsp;Ethan G. Brown MD,&nbsp;Caroline M. Tanner MD, PhD","doi":"10.1002/mds.30075","DOIUrl":"10.1002/mds.30075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Electronic medical record (EMR)–based studies hold great potential for epidemiologic investigations of Parkinson's disease (PD) causal factors and phenomenology, but diagnostic misclassification may obscure or bias inferences.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The aims were to determine the validity of PD diagnostic codes in the Veterans Administration (VA) national electronic medical databases and develop recommendations for maximizing ascertainment accuracy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated a cohort of 146,776 veterans who utilized VA healthcare between 1999 and 2021. We reviewed the medical records of individuals with a PD International Classification of Diseases (ICD) code in outpatient, inpatient, or community care encounters to assign a gold-standard diagnosis. We determined diagnostic accuracy based on provider type, coding frequency, medications, and potentially exclusionary ICD codes overall and by race.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 377 of 810 (46.5%) with a PD ICD code had PD. Veterans whose PD was coded by a PD-specialist neurologist were most likely to have PD (83.6%), but sensitivity was low (15.0%). Diagnostic accuracy decreased for PD coded by any neurologist (66.9%), but sensitivity improved (69.4%). Requiring two or more PD codes in combination with two or more levodopa prescriptions improved accuracy, particularly among nonneurologists. Neuroleptic-induced parkinsonism was the most frequent diagnosis in those without PD (15.6%). Accuracy was lower in Black (29.0%) than White (50.5%) veterans regardless of provider type (miscoding odds ratio 2.5, 95% confidence interval 1.7–3.6).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results highlight the limitations of EMR-based PD ascertainment. Researchers can maximize accuracy by considering provider specialty, coding frequency, pharmacy data, and exclusionary diagnoses, but some degree of record review is required to ensure high accuracy. Higher miscoding among Black veterans warrants further study. © 2024 The Author(s). <i>Movement Disorders</i> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 2","pages":"245-253"},"PeriodicalIF":7.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.30075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764797","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":"Genetic Mutations in Cell Junction Proteins Associated with Brain Calcification","authors":"Dehao Yang, Zihan Jiang, Honghao Huang, Lebo Wang, Chenxin Ying, Yiqun Chen, Yangguang Lu, Tingxuan Zhang, Yusheng Zhu, Shiyue Wang, Yaoting Wang, Yuru Guo, Haoyu Wang, Zhidong Cen, Wei Luo","doi":"10.1002/mds.30068","DOIUrl":"https://doi.org/10.1002/mds.30068","url":null,"abstract":"Intracerebral calcium deposition, classified into primary familial brain calcification (PFBC) and secondary brain calcification, occurs within the brain parenchyma and vasculature. PFBC manifests with progressive motor decline, dysarthria, and cognitive impairment, with limited treatment options available. Recent research has suggested a link between dysfunction of the blood–brain barrier (BBB) and PFBC, with certain genetic variants potentially affecting neurovascular unit (NVU) function, thereby contributing to BBB integrity disruption and brain calcification. Cell junctions play an indispensable role in maintaining the function of NVUs. The pathogenic mechanisms of PFBC‐causative genes, such as <jats:italic>PDGFRB, PDGFB, MYORG,</jats:italic> and <jats:italic>JAM2,</jats:italic> involve NVU disruption. Cell junctions, such as tight junctions, gap junctions, adherens junctions, desmosomes, hemidesmosomes, and focal adhesions, are vital for cell–cell and cell–extracellular matrix connections, maintaining barrier function, cell adhesion, and facilitating ion and metabolite exchange. Several recent studies have highlighted the role of mutations in genes encoding cell junction proteins in the onset and progression of brain calcification and its related phenotypes. This emerging body of research offers a unique perspective for investigating the underlying mechanisms driving brain calcification. In this review, we conducted an examination of the literature reporting on genetic variants in cell junction proteins associated with brain calcification to delineate potential molecular pathways and investigate genotype–phenotype correlations. This approach not only reinforces the rationale for molecular subtyping of brain calcification but also lays the groundwork for the discovery of novel causative genes involved in pathogenesis. © 2024 International Parkinson and Movement Disorder Society.","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"65 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758496","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":"Digital Outcomes as Biomarkers of Disease Progression in Early Parkinson's Disease: A Systematic Review","authors":"Pablo Rábano-Suárez MD,&nbsp;Natalia del Campo PhD,&nbsp;Isabelle Benatru MD,&nbsp;Caroline Moreau MD, PhD,&nbsp;Clément Desjardins MD,&nbsp;Álvaro Sánchez-Ferro MD, PhD,&nbsp;Margherita Fabbri MD, PhD","doi":"10.1002/mds.30056","DOIUrl":"10.1002/mds.30056","url":null,"abstract":"<p>Outcomes derived from digital health technologies (DHTs) are promising candidate markers for monitoring Parkinson's disease (PD) progression. They have the potential to represent a significant shift in clinical research and therapeutic development in PD. However, their ability to track disease progression is yet to be established. This systematic review aimed to identify digital biomarkers capable of tracking early PD progression (disease duration &lt;5 years) by reviewing longitudinal studies (minimum follow-up of 6 months). We evaluated study design and quality, population features, reported DHTs and their performance to track progression. Of 1507 records screened, 15 studies were selected, published between 2009 and 2023, with the majority coming from the last 5 years. Of the 15, 11 were observational and four were interventional trials (follow-up range: 6–60 months). Twelve different DHTs were used (8 required active tests, 8 in-hospital use), capturing features related to motor function and daily activities, including five DHTs focused on gait/posture. Rating scales were used as comparators in all but one study. Three DHTs detected longitudinal changes when scales did not, with one study showing larger effect sizes for change over time of selected DHT features compared to rating scales. Four studies showed longitudinal correlations among DHT features and rating scales. Preliminary promising data suggest that DHT-derived outcomes may help reduce sample sizes in disease-modifying trials. There is a need to standardize study methodologies and facilitate data sharing to confirm these results and further validate the sensitivity of DHTs to track disease progression in PD. © 2024 The Author(s). <i>Movement Disorders</i> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 2","pages":"184-203"},"PeriodicalIF":7.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.30056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753676","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":"Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).","authors":"Skandha Ramakrishnan, Neha Mohan, Zhangji Dong, Mei Liu, Liang Qiang","doi":"10.1002/mds.30072","DOIUrl":"https://doi.org/10.1002/mds.30072","url":null,"abstract":"<p><p>Spastic Paraplegia 4 (SPG4) is a debilitating neurodegenerative disorder characterized by progressive muscle weakness and spasticity in the lower limbs, often leading to gait impairment. Central to SPG4 pathology is the die-back degeneration of corticospinal tracts, primarily driven by mutations in the spastin protein encoded by the SPAST gene. SPAST gives rise to two major spastin isoforms, M1- and M87-spastin, which are generated from distinct translation initiation sites. Although spastin is implicated in various cellular functions, the specific roles of each isoform in the pathogenesis of SPG4 remain poorly understood. This review offers an overview of the genetic and structural organization of the M1- and M87-spastin isoforms, highlighting their distinct and overlapping functions, and exploring their potential roles in the haploinsufficiency and gain-of-toxicity mechanisms underlying SPG4. We also present a novel perspective on the evolutionary emergence of M1-spastin and its potential unique involvement in the pathogenesis of SPG4. Drawing upon the latest research, we propose an intriguing hypothesis regarding the hetero-oligomerization of M1- and M87-spastin, exploring how their interaction may drive disease progression and open new avenues for therapeutic intervention. By integrating the current research with these fresh insights, we seek to illuminate the complex molecular mechanisms driving SPG4 and foster the development of innovative therapeutic strategies. This review not only incorporates existing knowledge but also lays the groundwork for future studies aimed at uncovering the isoform-specific roles of spastin in SPG4, with the ultimate goal of advancing targeted treatments for this challenging neurodegenerative disorder. © 2024 International Parkinson and Movement Disorder Society.</p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754387","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":"Cortical Functional Connectivity Changes in the Body-First and Brain-First Subtypes of Parkinson's Disease","authors":"Matteo Conti MD,&nbsp;Valentina D'Onofrio MD,&nbsp;Roberta Bovenzi MD,&nbsp;Valerio Ferrari MD,&nbsp;Francesca Di Giuliano MD, PhD,&nbsp;Rocco Cerroni MD, PhD,&nbsp;Mariangela Pierantozzi MD, PhD,&nbsp;Tommaso Schirinzi MD, PhD,&nbsp;Nicola Biagio Mercuri MD, PhD,&nbsp;Angelo Antonini MD, PhD,&nbsp;Andrea Guerra MD, PhD,&nbsp;Alessandro Stefani MD, PhD","doi":"10.1002/mds.30071","DOIUrl":"10.1002/mds.30071","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Rapid eye movement (REM) sleep behavior disorder (RBD) may precede motor symptoms in Parkinson's disease (PD) by years. According to a recent hypothesis, premotor RBD (pRBD) is a marker of the PD body-first subtype, where synucleinopathy originates from the peripheral autonomic nervous system. Conversely, in the brain-first subtype, pathology would arise in the brain. Functional connectivity (FC) could provide additional insight into the neurodegenerative process of these putative PD subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aim to analyze the possible FC differences between early-stage PD patients with (PD^pRBD+) and without (PD^pRBD−) pRBD using high-density electroencephalography (EEG).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We enrolled 28 PD^pRBD+, 35 PD^pRBD−, and 35 healthy controls (HC). Data were recorded with a 64-channel EEG system, and a source-reconstruction method was used to identify brain-region activity. FC was calculated using the weighted phase-lag index in θ, α, β, and low-γ bands. Statistical analysis was conducted using network-based statistic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found a significant trend of decreased α-FC across PD^pRBD+, PD^pRBD−, and HC, mainly in prefrontal and temporal areas. The altered α-FC correlated with Montreal Cognitive Assessment scores in PD^pRBD+ and, to a lesser extent, PD^pRBD− and with gait/postural disturbances in PD^pRBD+ patients only. PD^pRBD+ and PD^pRBD− had similarly increased FC than HC in a β band network, predominantly involving sensorimotor and limbic areas. The increased β network FC was related to bradykinesia severity in both PD subgroups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Compared to PD^pRBD− (brain-first subtype), PD^pRBD+ group (body-first subtype) demonstrates specific EEG-FC dysfunctions in the α band, which may reflect early involvement of the cholinergic ascending system. © 2024 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 2","pages":"254-265"},"PeriodicalIF":7.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749505","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":"Environmental Risk Factors for Parkinson's Disease: A Critical Review and Policy Implications","authors":"Kajsa Atterling Brolin PhD,&nbsp;Eva Schaeffer MD,&nbsp;Ashvin Kuri MBBS,&nbsp;Isabell Katharina Rumrich PhD,&nbsp;Artur Francisco Schumacher Schuh MD, PhD,&nbsp;Sirwan K.L. Darweesh MD, PhD,&nbsp;Valtteri Kaasinen MD, PhD,&nbsp;Anna-Maija Tolppanen PhD,&nbsp;Lana M. Chahine MD, MS,&nbsp;Alastair J. Noyce FRCP, PhD","doi":"10.1002/mds.30067","DOIUrl":"10.1002/mds.30067","url":null,"abstract":"<p>The age-standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes the need to identify modifiable risk factors of PD, which could form a logical entry point for the prevention of PD. The World Health Organization (WHO) has recommended reducing exposure to specific environmental factors that have been reported to be associated with PD, in particular pesticides, trichloroethylene (TCE), and air pollution. In this review we critically evaluate the epidemiological and biological evidence on the associations of these factors with PD and review evidence on whether these putative associations are causal. We conclude that when considered in isolation, it is difficult to determine whether these associations are causal, in large part because of the decades-long lag between relevant exposures and the incidence of manifest PD. However, when considered in tandem with evidence from complementary research lines (such as animal models), it is increasingly likely that these associations reflect harmful causal effects. Fundamentally, whilst we highlight some evidence gaps that require further attention, we believe the current evidence base is sufficiently strong enough to support our call for stronger policy action. © 2024 The Author(s). <i>Movement Disorders</i> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"40 2","pages":"204-221"},"PeriodicalIF":7.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.30067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724558","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}