Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

BACKGROUND: Whole‐brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). METHODS: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn‐HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24‐month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15‐month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract‐based spatial statistics. An optimized pipeline was employed to generate participant‐specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion‐carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). RESULTS: HD expansion‐carriers from TrackOn‐HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion‐carriers. CONCLUSION: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution.