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

Abstract Background The progression of Parkinson’s 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): Cohen’s 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.