Movement Disorders最新文献

{"title":"Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia","authors":"Daniela Scarabino PhD,&nbsp;Liana Veneziano PhD,&nbsp;Suran Nethisinghe PhD,&nbsp;Elide Mantuano MSc,&nbsp;Alessia Fiore MSc,&nbsp;Giulia Granata MSc,&nbsp;Nita Solanky PhD,&nbsp;Ginevra Zanni MD, PhD,&nbsp;Francesca Cavalcanti MD,&nbsp;Rosa Maria Corbo MD,&nbsp;Paola Giunti MD, PhD","doi":"10.1002/mds.29976","DOIUrl":"10.1002/mds.29976","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the <i>FXN</i> gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age-matched healthy subjects (n = 87).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>LTL was measured by real-time polymerase chain reaction quantitative analysis (qPCR).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)-like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 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":"39 11","pages":"2058-2066"},"PeriodicalIF":7.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29976","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131386","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":"A Homozygous Variant in NAA60 Is Associated with Primary Familial Brain Calcification.","authors":"Xinhui Chen, Yihua Shi, Feng Fu, Lebo Wang, Hongying Yu, Dehao Yang, Xinchen Wang, Chenxin Ying, Haoyu Wang, Zhiru Lin, Haotian Wang, Fan Zhang, Xiaosheng Zheng, Yuru Guo, Yaoting Wang, YiHeng Zeng, Miao Zhao, Yiling Chen, Jiaxiang Li, Haibin Xia, Jiawen Chen, Bo Wang, Sheng Wu, Fei Xie, Jianhua Feng, Zhidong Cen, Wei Luo","doi":"10.1002/mds.30004","DOIUrl":"https://doi.org/10.1002/mds.30004","url":null,"abstract":"<p><strong>Background: </strong>Primary familial brain calcification (PFBC) is a monogenic disorder characterized by bilateral calcifications in the brain. The genetic basis remains unknown in over half of the PFBC patients, indicating the existence of additional novel causative genes. NAA60 was a recently reported novel causative gene for PFBC.</p><p><strong>Objective: </strong>The aim was to identify the probable novel causative gene in an autosomal recessive inherited PFBC family.</p><p><strong>Methods: </strong>We performed a comprehensive genetic study on a consanguineous Chinese family with 3 siblings diagnosed with PFBC. We evaluated the effect of the variant in a probable novel causative gene on the protein level using Western blot, immunofluorescence, and coimmunoprecipitation. Possible downstream pathogenic mechanisms were further explored in gene knockout (KO) cell lines and animal models.</p><p><strong>Results: </strong>We identified a PFBC co-segregated homozygous variant of c.460_461del (p.D154Lfs*113) in NAA60. Functional assays showed that this variant disrupts NAA60 protein localization to Golgi and accelerated protein degradation. The mutant NAA60 protein alters its interaction with the PFBC-related proteins PiT2 and XPR1, affecting intracellular phosphate homeostasis. Further mass spectrometry analysis in NAA60 KO cell lines revealed decreased expression of multiple brain calcification-associated proteins, including reduced folate carrier (RFC), a folate metabolism-related protein.</p><p><strong>Conclusions: </strong>Our study replicated the identification of NAA60 as a novel causative gene for autosomal recessive PFBC, demonstrating our causative variant leads to NAA60 loss of function. The NAA60 loss of function disrupts not only PFBC-related proteins (eg, PiT2 and XPR1) but also a wide range of other brain calcification-associated membrane protein substrates (eg, RFC), and provided a novel probable pathogenic mechanism for PFBC. © 2024 International Parkinson and Movement Disorder Society.</p>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124379","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":"IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA","authors":"Sunita Venkateswaran MD,&nbsp;Jean Michaud MD,&nbsp;Yoko Ito PhD,&nbsp;Michael Geraghty MD, MSc,&nbsp;Evan C. Lewis MD,&nbsp;Benjamin Ellezam MD, PhD,&nbsp;Kym M. Boycott MD, PhD,&nbsp;David A. Dyment MD, PhD,&nbsp;Kristin D. Kernohan PhD,&nbsp;Care4Rare Canada Consortium","doi":"10.1002/mds.29938","DOIUrl":"10.1002/mds.29938","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Childhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of <i>interferon regulatory factor 2 binding protein like</i> (<i>IRF2BPL</i>)-related disorder.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at <i>ATN1</i> was non-diagnostic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Subsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo <i>IRF2BPL</i> variant. The <i>IRF2BPL</i> c.562C&gt;T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide the first detailed pathological description for <i>IRF2BPL</i>-related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic-ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 11","pages":"2102-2109"},"PeriodicalIF":7.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118570","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":"Rest Tremor in Parkinson's Disease Is Associated with Ipsilateral Striatal Dopamine Transporter Binding","authors":"Kalle J. Niemi MD,&nbsp;Juha Sunikka MD,&nbsp;Hamid Soltanian-Zadeh PhD,&nbsp;Esmaeil Davoodi-Bojd PhD,&nbsp;Arman Rahmim PhD,&nbsp;Valtteri Kaasinen MD, PhD,&nbsp;Juho Joutsa MD, PhD","doi":"10.1002/mds.29997","DOIUrl":"10.1002/mds.29997","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;The cardinal motor symptoms of Parkinson's disease (PD) include rigidity, bradykinesia, and rest tremor. Rigidity and bradykinesia correlate with contralateral nigrostriatal degeneration and striatal dopamine deficit, but association between striatal dopamine function and rest tremor has remained unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The aim of this study was to investigate the possible link between dopamine function and rest tremor using Parkinson's Progression Markers Initiative dataset, the largest prospective neuroimaging cohort of patients with PD.&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;Clinical, [&lt;sup&gt;123&lt;/sup&gt;I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([&lt;sup&gt;123&lt;/sup&gt;I]FP-CIT) single photon emission computed tomography (SPECT), and structural magnetic resonance imaging data from 354 early PD patients and 166 healthy controls were included in this study. We employed a novel approach allowing nonlinear registration of individual scans accurately to a standard space and voxelwise analyses of the association between motor symptoms and striatal dopamine transporter (DAT) binding.&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;Severity of both rigidity and bradykinesia was negatively associated with contralateral striatal DAT binding (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;FWE&lt;/sub&gt; &lt; 0.05 [FWE, family-wise error corrected]). However, rest tremor amplitude was positively associated with increased ipsilateral DAT binding (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;FWE&lt;/sub&gt; &lt; 0.05). The association between rest tremor and binding remained the same controlling for Hoehn &amp; Yahr stage, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, bradykinesia–rigidity score, or motor phenotype. The association between rest tremor and binding was independent of bradykinesia-rigidity and replicated using 2-year follow-up data (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;FWE&lt;/sub&gt; &lt; 0.05).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In agreement with the existing literature, we did not find a consistent association between rest tremor and contralateral dopamine defect. However, our results demonstrate a link between rest tremor and increased or less decreased ipsilateral DAT binding. Our findings provide novel information about the association between dopaminergic function and parkinsonian rest tremor. © 2024 The Author(s). &lt;i&gt;Movement Disorders&lt;/i&gt; published by Wiley Periodicals LLC on behalf of Internati","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 11","pages":"2014-2025"},"PeriodicalIF":7.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29997","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118571","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 Cost of Illness of Parkinson's Disease from a Societal Perspective","authors":"Anke Wijers MD,&nbsp;Anirudhan Ravi MSc,&nbsp;Silvia M.A.A. Evers PhD,&nbsp;Gerrit Tissingh MD, PhD,&nbsp;Ghislaine A.P.G. van Mastrigt PhD","doi":"10.1002/mds.29995","DOIUrl":"10.1002/mds.29995","url":null,"abstract":"<p>Previous reviews on the cost of illness (COI) of Parkinson's disease (PD) have often focused on health-care costs due to PD, underestimating its effects on other sectors. This systematic review determines the COI of PD from a societal perspective. The protocol was registered in PROSPERO (ID: CRD42023428937). Embase, Medline, and EconLit were searched up to October 12, 2023, for studies determining the COI of PD from a societal perspective. From 2812 abstracts, 17 studies were included. The COI of PD averaged €20,911.37 per patient per year, increasing to almost €100,000 in the most severely affected patients. Health-care costs accounted for 46.1% of total costs, followed by productivity loss (37.4%) and costs to patient and family (16.4%). The COI of PD strongly varied between different geographical regions, with costs in North America 3.6 times higher compared to Asia. This study is the first to identify the relative importance of different cost items. Most important were reduced employment, government benefits, informal care, medication, nursing homes, and hospital admission. There was strong variety in the cost items that were included, with 55.2% of cost items measured in fewer than half of articles. Our review shows that PD-COI is high and appears in various cost sectors, with strong variety in the cost items included in different studies. Therefore, a guideline for the measurement of COI in PD should be developed to harmonize this. This article provides a first step toward the development of such a tool by identifying which cost items are most relevant. © 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":"39 11","pages":"1938-1951"},"PeriodicalIF":7.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29995","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102712","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 Primary Familial Brain Calcification Mechanisms: Are NAA60 and SLC20A2 Partners in Crime?","authors":"Max Brand MSc,&nbsp;Ana Westenberger PhD","doi":"10.1002/mds.30000","DOIUrl":"10.1002/mds.30000","url":null,"abstract":"","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 10","pages":"1731"},"PeriodicalIF":7.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102713","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":"Skin Tau Quantification as a Novel Biomarker in Huntington's Disease","authors":"Iñigo Ruiz-Barrio MD,&nbsp;Anna Vázquez-Oliver PhD,&nbsp;Arnau Puig-Davi MSc,&nbsp;Elisa Rivas-Asensio BSc,&nbsp;Jesus Perez-Perez MD,&nbsp;Cristina Fernandez-Vizuete BSc,&nbsp;Andrea Horta-Barba PhD,&nbsp;Gonzalo Olmedo-Saura MD,&nbsp;Nil Salvat-Rovira BSc,&nbsp;Frederic Sampedro MD, PhD,&nbsp;Elena Vacchi PhD,&nbsp;Giorgia Melli MD, PhD,&nbsp;Javier Pagonabarraga MD, PhD,&nbsp;Jaime Kulisevsky MD, PhD,&nbsp;Saul Martinez-Horta PhD","doi":"10.1002/mds.29989","DOIUrl":"10.1002/mds.29989","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this cross-sectional study, we measured skin tau levels using enzyme-linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel-based morphometry approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG-Age-Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease-related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 11","pages":"2067-2074"},"PeriodicalIF":7.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078666","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":"Metagenomic Analysis Reveals Large-Scale Disruptions of the Gut Microbiome in Parkinson's Disease","authors":"Avril Metcalfe-Roach PhD,&nbsp;Mihai S. Cirstea PhD,&nbsp;Adam C. Yu MSc,&nbsp;Hena R. Ramay PhD,&nbsp;Olabisi Coker PhD,&nbsp;Seti Boroomand PhD,&nbsp;Faezeh Kharazyan MSc,&nbsp;Davide Martino MD,&nbsp;Laura K. Sycuro PhD,&nbsp;Silke Appel-Cresswell MD,&nbsp;B. Brett Finlay PhD","doi":"10.1002/mds.29959","DOIUrl":"10.1002/mds.29959","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Parkinson's disease (PD) has been consistently linked to alterations within the gut microbiome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Our goal was to identify microbial features associated with PD incidence and progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Metagenomic sequencing was used to characterize taxonomic and functional changes to the PD microbiome and to explore their relation to bacterial metabolites and disease progression. Motor and non-motor symptoms were tracked using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and levodopa equivalent dose across ≤5 yearly study visits. Stool samples were collected at baseline for metagenomic sequencing (176 PD, 100 controls).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PD-derived stool samples had reduced intermicrobial connectivity and seven differentially abundant species compared to controls. A suite of bacterial functions differed between PD and controls, including depletion of carbohydrate degradation pathways and enrichment of ribosomal genes. <i>Faecalibacterium prausnitzii</i>-specific reads contributed significantly to more than half of all differentially abundant functional terms. A subset of disease-associated functional terms correlated with faster progression of MDS-UPDRS part IV and separated those with slow and fast progression with moderate accuracy within a random forest model (area under curve = 0.70). Most PD-associated microbial trends were stronger in those with symmetric motor symptoms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide further evidence that the PD microbiome is characterized by reduced intermicrobial communication and a shift to proteolytic metabolism in lieu of short-chain fatty acid production, and suggest that these microbial alterations may be relevant to disease progression. We also describe how our results support the existence of gut-first versus brain-first PD subtypes. © 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":"39 10","pages":"1740-1751"},"PeriodicalIF":7.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29959","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078665","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":"Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinson's Disease in Patients with Type 2 Diabetes: A Population-Based Cohort Study","authors":"Huilin Tang MSc,&nbsp;Ying Lu BA,&nbsp;Michael S. Okun MD,&nbsp;William T. Donahoo MD,&nbsp;Adolfo Ramirez-Zamora MD,&nbsp;Fei Wang PhD,&nbsp;Yu Huang PhD,&nbsp;Melissa Armstrong MD, MSc,&nbsp;Mikael Svensson PhD,&nbsp;Beth A. Virnig PhD, MPH,&nbsp;Steven T. DeKosky MD,&nbsp;Jiang Bian PhD,&nbsp;Jingchuan Guo MD, PhD","doi":"10.1002/mds.29992","DOIUrl":"10.1002/mds.29992","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a disease-modifying effect in the development of Parkinson's disease (PD), but population studies yielded inconsistent results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The aim was to compare the risk of PD associated with GLP-1RAs compared to dipeptidyl peptidase 4 inhibitors (DPP4i) among older adults with type 2 diabetes (T2D).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using U.S. Medicare administrative data from 2016 to 2020, we conducted a population-based cohort study comparing the new use of GLP-1RA with the new use of DPP4i among adults aged ≥66 years with T2D. The primary endpoint was a new diagnosis of PD. A stabilized inverse probability of treatment weighting (sIPTW)–adjusted Cox proportional hazards regression model was employed to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for PD between GLP-1RA and DPP4i users.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This study included 89,074 Medicare beneficiaries who initiated either GLP-1RA (n = 30,091) or DPP4i (n = 58,983). The crude incidence rate of PD was lower among GLP-1RA users than DPP4i users (2.85 vs. 3.92 patients per 1000 person-years). An sIPTW-adjusted Cox model showed that GLP-1RA users were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95% CI, 0.63–0.95). Our findings were largely consistent across different subgroup analyses such as sex, race, and molecular structure of GLP-1RA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Among Medicare beneficiaries with T2D, the new use of GLP-1RAs was significantly associated with a decreased risk of PD compared to the new use of DPP4i. © 2024 International Parkinson and Movement Disorder Society.</p>\u0000 </section>\u0000 </div>","PeriodicalId":213,"journal":{"name":"Movement Disorders","volume":"39 11","pages":"1960-1970"},"PeriodicalIF":7.4,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071611","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":"Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy","authors":"Shawna R. Cook PhD,&nbsp;Cleo Schwarz MedVet,&nbsp;Julien Guevar DVM, MVM, DECVN, MRCVS,&nbsp;Charles-Antoine Assenmacher DVM, Msc, DACVP,&nbsp;Maeve Sheehy BS,&nbsp;Nathan Fanzone VMD,&nbsp;Molly E. Church MS, VMD, PhD,&nbsp;Leonardo Murgiano PhD,&nbsp;Margret L. Casal DVM, PhD,&nbsp;Vidhya Jagannathan PhD,&nbsp;Rodrigo Gutierrez-Quintana MVZ, MVM,&nbsp;Mark Lowrie MA, VetMB, MVM, DECVN, MRCVS,&nbsp;Frank Steffen DECVN,&nbsp;Tosso Leeb PhD,&nbsp;Kari J. Ekenstedt DVM, PhD","doi":"10.1002/mds.29977","DOIUrl":"10.1002/mds.29977","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical and postmortem evaluations, together with a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1-bp (base pair) deletion in <i>RNF170</i> encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine <i>RNF170</i> variant was estimated at ~30 years, before the reproductive isolation of the MAS breed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p><i>RNF170</i> variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 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":"39 11","pages":"2049-2057"},"PeriodicalIF":7.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mds.29977","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034713","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}