Lesley Y. Wu, Tessa du Toit, Tatiana Georgiades, Eleanor J. Stafford, Kristin Levine, Zih‐Hua Fang, Simona Jasaityte, Ana-Luisa Gil Martinez, Patrick Cullinane, Eduardo De Pablo‐Fernández, Cornelis Blauwendraat, Andrew B. Singleton, Sonja W. Scholz, Bryan J. Traynor, Nicholas Wood, John Hardy, Patrick Chinnery, Henry Houlden, Richard Cain, Claire Troakes, Viorica Chelban, Geidy E. Serrano, Djordje Gveric, Catriona McLean, Seth Love, A King, Andrew Robinson, Federico Roncaroli, Claire Shepherd, Glenda Halliday, Laura Parkkinen, Christopher M. Morris, Colin Smith, T Beach, Steve Gentleman, Thomas T. Warner, Tammaryn Lashley, Zane Jaunmuktane, Raquel Real, Huw R. Morris, Global Parkinson s Genetic Program (GP2), Yasser Mecheri, Bouchetara Mohamed Sofiane, Benhassine Traki, Emilia M Gatto, Marcelo Kauffman, Federico Capparelli, María Valentina Müller, Marcela Tela, Darío Sergio Adamec, César L. Ávila, Valentin Selvaggi, Nahuel Fonseca, Elena AVALE, Marcelo Merello, Griselda Judith Alvarado, Juan Pablo Diaz Rearte, Luciana Rojas Vazquez, Lucía Wang, Carlos Matias López Razquin, Andrea Bril, Florencia Nicole Wainberg, Maria Fernanda López, Samson Khachatryan, Zaruhi Tavadyan, Mariam Isayan, Claire E. Shepherd, Kishore Kumar, Melina Ellis, Miguel E. Rentería, Sulev Koks, Simon Rowe, Dennis Yeow, Carolyn Sue, Victor Flores Ocampo, Christine Wools, Keren Aliza Weiss, Ryan L. Davis, Amanda Willis, Steven He, Robert Arthur Wilcox, Denise Howting, Jack David Price, Pak Leng Cheong, Michel Tchan, Mary-Anne Young, Catriona McLean, Nicholas G. Martin, Hugo Morales Briceño, Thomas Kimber, Kathy H. C. Wu, John O'Sullivan, Lewis M. Singleton, Laura Ivete Rudaks, Luis M. García-Marín, Amanda Lim, Sue‐Faye Siow, Natalia Soledad Ogonowski, Santiago Díaz‐Torres, Fangyuan Cao
Importance: 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. Objective: To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multiancestry brain bank cohort. Design, Setting, and Participants: 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. Exposures: Genetic variant carrier status and clinical diagnostic category. Main Outcomes and Measures: Outcomes included clinical diagnostic accuracy, Lewy body and Alzheimer disease pathology burden, survival, association with genetic variants, and genetically inferred ancestry. Results: 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], 1.96; 95% CI, 1.30-3.04; P = 7.2 × 10-4). 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 GBA1 variant exhibited greater Lewy body burden compared with noncarriers (OR, 1.94; 95% CI, 1.24-3.03; P = .01) or carriers of the LRRK2 variant (OR, 7.44; 95% CI, 2.16-25.64; P = .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 (χ22 = 35.5; P < .001), independent of GBA1 and LRRK2 variant status. Conclusions and Relevance: 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.