Mixed longitudinal and cross-sectional analyses of deep gray matter and white matter using diffusion weighted images in premanifest and manifest Huntington’s disease

•Deep gray matter showed more evident and earlier changes than deep white matter.•Superior and posterior areas of deep white matter changed earlier and more evidently.•Huntington’s disease may affect the microscopic brain structure in addition to aging.•White matter and deep gray matter in HD exhibits regional and temporal vulnerability. Changes in the brain of patients with Huntington's disease (HD) begin years before clinical onset, so it remains critical to identify biomarkers to track these early changes. Metrics derived from tensor modeling of diffusion-weighted MRIs (DTI), that indicate the microscopic brain structure, can add important information to regional volumetric measurements. This study uses two large-scale longitudinal, multicenter datasets, PREDICT-HD and IMAGE-HD, to trace changes in DTI of HD participants with a broad range of CAP scores (a product of CAG repeat expansion and age), including those with pre-manifest disease (i.e., prior to clinical onset). Utilizing a fully automated data-driven approach to study the whole brain divided in regions of interest, we traced changes in DTI metrics (diffusivity and fractional anisotropy) versus CAP scores, using sigmoidal and linear regression models. We identified points of inflection in the sigmoidal regression using change-point analysis. The deep gray matter showed more evident and earlier changes in DTI metrics over CAP scores, compared to the deep white matter. In the deep white matter, these changes were more evident and occurred earlier in superior and posterior areas, compared to anterior and inferior areas. The curves of mean diffusivity vs. age of HD participants within a fixed CAP score were different from those of controls, indicating that the disease has an additional effect to age on the microscopic brain structure. These results show the regional and temporal vulnerability of the white matter and deep gray matter in HD, with potential implications for experimental therapeutics.