Multimodal Characterization of Glymphatic-Related Magnetic Resonance Imaging Markers in Huntington's Disease: A Multi-Cohort Retrospective Study.

OBJECTIVE:To characterize magnetic resonance imaging (MRI)-based glymphatic surrogates in Huntington's disease (HD) using MRI measures of perivascular diffusivity and structural perivascular alterations across multiple large cohorts. METHODS:We analyzed 2,731 MRI sessions from 880 participants across 3 large retrospective HD cohorts. HD gene carriers were grouped by the HD Integrated Staging System into stage 0 to 3. We assessed the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and MRI-visible enlarged perivascular spaces (EPVS). Linear mixed-effects models examined group differences and associations with motor, cognitive, and functional measures. Likelihood ratio tests evaluated their added explanatory value beyond established imaging, genetic, and demographic variables. RESULTS:Left ALPS indices were lower at more advanced disease stages (stage 1: -3.71%, Cohen's d: -0.25; stage 2: -4.33%, Cohen's d: -0.31; Stage 3: -6.43%, Cohen's d: -0.46; all p < 0.05) compared with controls, independent of demographic and clinical variables. EPVS burden showed region-specific patterns, with subcortical EPVS volume fraction increased in HD (stage 1-3: +49.9% to +63.7%, Cohen's d: 0.47 to 0.55, p < 0.0001), whereas white matter EPVS volume fraction decreased at Stage 3 (-13.8%, Cohen's d: -0.21, p < 0.05). Lower ALPS indices correlated with higher motor impairment (p < 0.0001) and reduced functional capacity (p < 0.01). Both ALPS and EPVS improved prediction of composite HD progression beyond CAG-Age Product Score and striatal volume. INTERPRETATION:Multimodal MRI revealed stage-dependent alterations in MRI-based glymphatic surrogates with low to moderate effect sizes. These findings suggest that DTI-ALPS and EPVS metrics offer complementary, noninvasive indicators of HD pathology derivable from routine imaging protocols. ANN NEUROL 2026.