A Worldwide Study of White Matter Microstructural Alterations in People Living with Parkinson's Disease

Background: The progression of Parkinson disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies, particularly regarding the involvement of white matter (WM) tracts. Here we performed the largest diffusion MRI study of PD to date, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of WM differences. Methods: Diffusion-weighted MRI data from 1,654 participants diagnosed with PD (age range: 20-89 years; 33% female) and 885 controls (age range: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate regional microstructure in 21 white matter regions. Skeletonized maps of diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD) were analyzed and compared between Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter differences at different stages. Results: We found an enhanced, more widespread pattern of microstructural differences with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest (ROIs): Cohens d effect sizes reached d=-1.01 for FA differences in the fornix by PD HY Stage 4/5. The early PD signature in HY stages 1 and 2 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with clinical metrics of motor and non-motor clinical dysfunction. Conclusion: While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA in PD, which is consistent with early compensatory changes associated with the disorder. ### Competing Interest Statement NJ was MPI of a research grant from Biogen Inc for work unrelated to the contents of this manuscript. In the past 3 years, DS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, LOreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen ### Funding Statement TA: Health Research Council of New Zealand (20/538; 21/165); IA: São Paulo Research Foundation FAPESP BRAINN Grants# 2013075593 / FAPESP #2022 1178 4; FC: São Paulo Research Foundation FAPESP BRAINN Grant # 2013 07559 3; JDA: Health Research Council of New Zealand (20/538); Marsden Fund New Zealand (UOC2105), Neurological Foundation of New Zealand (2232 PRG); Research and Education Trust Pacific Radiology (MRIJDA); MD: Grant from ParkinsonNL (P2023 14); Honoraria from Movement Disorders Society Quebec; JD: R01NS107513; HE: Engineering and Physical Sciences Research Council (EPSRC) UK; MH: Parkinsons UK, Cure Parkinsons Trust, Oxford Biomedical Research Centre, GSK Oxford IMCM; NJ: R01AG059874, R01MH117601, R01NS107513, R01AG058854, P41EB015922; JK: is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), and the NIHR Oxford Health Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health; JK: F32MH122057 from NIMH; CM: U19 AG062418; TM: Health Research Council of New Zealand (20/538); Neurological Foundation of New Zealand (2232 PRG); Research and Education Trust Pacific Radiology (MRIJDA); TN: U.S. Alzheimers Association (AARG 23 1149996); COW: R01NS107513; LP: Salary: University of Manchester; Grants: EPSRC UK, MRC UK, GE medical systems, Academy of Medical Sciences UK; FP: Italian Ministry of Health, grant number RF 2019 2370182; TP: Health Research Council of New Zealand (21/165); PS: reports personal fees from Bial, AbbVie and Boston Scientific; DT: NIH/NIA; JW: National Science and Technology Council, Taiwan (109 2314 B 182 021 MY3,109 2221 E 182 009 MY3); CY: São Paulo Research Foundation FAPESP BRAINN Grant # 2013075593; CNPQ (#315953/2021 7) National Council for Scientific and Technological Development ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Open source datasets that support the findings of this study include PPMI and UK Biobank. Data for remaining cohorts are not openly available, but researchers are invited to register interest with the ENIGMA-PD Working Group in order to formally request site data through secondary proposals.