{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:46:42Z","timestamp":1793249202502,"version":"4.5.0"},"reference-count":44,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"\n Importance<\/jats:title>\n Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features, and a delay in the emergence of pathognomonic features.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multiancestry brain bank cohort.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This was a multicenter, retrospective, autopsy-confirmed cross-sectional brain bank study on donors enrolled between 1985 and 2024. Included were donors from 11 academic brain banks in the UK, US, and Australia. Among brain donors with available genetic data from participating brain banks, included were individuals with clinical diagnoses of Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Genetic variant carrier status and clinical diagnostic category.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Outcomes included clinical diagnostic accuracy, Lewy body and Alzheimer disease pathology burden, survival, association with genetic variants, and genetically inferred ancestry.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 5648 brain donors with available genetic data, a total of 3353 eligible donors (mean [SD] age at death, 76.8 [10.6] years; 2072 male [61.8%]) were included. Misdiagnosis rates for movement disorders ranged approximately from 10% to 20%. Clinical diagnoses of dementia with parkinsonism (ie, Parkinson disease dementia and DLB) were more strongly associated with Lewy body pathology than Parkinson disease without dementia (odds ratio [OR],\u20091.96; 95% CI,\u20091.30-3.04;\n P<\/jats:italic>\n \u2009=\u20097.2\u2009\u00d7\u200910\n \u22124<\/jats:sup>\n ). Lewy pathology was identified in 33 of 745 of neurologically normal controls (4.4%). Alzheimer disease copathology was present in 426 of 1064 cases (40.0%) with Lewy body disease. Carriers of the\n GBA1<\/jats:italic>\n variant exhibited greater Lewy body burden compared with noncarriers (OR,\u20091.94; 95% CI,\u20091.24-3.03;\n P<\/jats:italic>\n \u2009=\u2009.01) or carriers of the\n LRRK2<\/jats:italic>\n variant (OR,\u20097.44; 95% CI,\u20092.16-25.64;\n P<\/jats:italic>\n \u2009=\u2009.01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (\u03c7\n 2<\/jats:sup>\n 2<\/jats:sub>\n = 35.5;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), independent of\n GBA1<\/jats:italic>\n and\n LRRK2<\/jats:italic>\n variant status.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Findings of this cross-sectional brain bank study highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimer disease copathology and ancestry-associated differences in pathology point to the need for biologically informed diagnostic tools. These results suggest supporting the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2026.1634","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T15:30:22Z","timestamp":1780932622000},"page":"798","source":"Crossref","is-referenced-by-count":5,"title":["Pathology and Genetics in a Global Cohort of Parkinsonian Disorders"],"prefix":"10.1001","volume":"83","author":[{"given":"Lesley Y.","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"du Toit","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Georgiades","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor J.","family":"Stafford","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Levine","sequence":"additional","affiliation":[{"name":"Data Tecnica International, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zih-Hua","family":"Fang","sequence":"additional","affiliation":[{"name":"The German Center for Neurodegenerative Diseases, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Jasaityte","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Luisa Gil","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Cullinane","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"De Pablo-Fernandez","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis","family":"Blauwendraat","sequence":"additional","affiliation":[{"name":"Global Parkinson\u2019s Genetics Program, Chevy Chase, Maryland"},{"name":"Coalition for Aligning Science (CAS), Chevy Chase, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Singleton","sequence":"additional","affiliation":[{"name":"Global Parkinson\u2019s Genetics Program, Chevy Chase, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja W.","family":"Scholz","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan J.","family":"Traynor","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland"},{"name":"Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hardy","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, Maryland"},{"name":"Department 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