Geometric properties of caudate and putamen mark the progression of Huntington’s disease

Abstract

Volumetric MRI of the caudate and putamen is a robust biomarker of striatal degeneration in Huntington’s disease (HD). Striatal degeneration may be reflected beyond volume alone, in additional shape and intensity alterations. We evaluated five novel morphometric biomarkers of the caudate and putamen – curvature, flatness, eccentricity, elongation, and focal assessment of divergence estimation (FADE; T1-weighted signal shift) – using cross-sectional and longitudinal MRI data from healthy controls (N = 100), individuals with premanifest HD (preHD; N = 100), and individuals with early manifest HD (earlyHD; N = 100). Geometric measures showed significant cross-sectional group differences with large effect sizes, although volume remained the most sensitive individual biomarker. Longitudinally, most geometric measures detected abnormal rates of change, particularly in the caudate, with medium-to-large effect sizes. The direct comparison between preHD and earlyHD proved challenging for all biomarkers; however, elongation yielded the largest effect size and outperformed volume in this comparison. FADE detected abnormal signal increases in HD groups at baseline but not longitudinally. Power analyses confirmed that volume retains the highest sensitivity, while geometric measures follow closely. Combining volume and geometric measures improved the cross-validated classification accuracy starting at low sample sizes. Correlations between scores and results from atrophy simulations confirmed that HD leaves two signatures on the striatum: loss of volume and loss of shape. While volume remains the strongest standalone biomarker, geometric measures provide complementary information that sharpens disease detection and may enhance biomarker frameworks in future HD clinical trials.