Early Longitudinal Brain Network Changes in Huntington's Disease Before Clinical Motor Onset

Longitudinal studies of seed-based functional connectivity (SBFC) in young adult Huntington's disease gene-expanded (HDGE) individuals are rare, and none, to our knowledge, have examined adult cohorts decades from predicted clinical motor diagnosis.

To examine longitudinal functional connectivity (FC) changes over ~4.8 years in adult HDGE individuals before clinical motor diagnosis compared with matched controls, all selected from the HD Young Adult Study (HD-YAS) cohort, focusing on bilateral caudate and putamen as seeds.

A subset of 71 right-handed individuals (43 HDGEs and 28 controls) from the HD-YAS underwent resting-state functional magnetic resonance imaging (fMRI) at two visits ~4.8 years apart. SBFC analyses focused on bilateral caudate and putamen seeds. Mixed-effects analysis of variance (ANOVA) tested main effects of group, time, and group × time interactions, with false discovery rate (FDR) correction. Post hoc tests explored significant findings.

HDGEs showed reduced FC between the putamen and cerebellar vermis/lobules and brainstem (P-FDR ≤ 0.01), alongside increased connectivity with precuneus (P-FDR = 0.04), supramarginal, and angular gyri (P-FDR = 0.04). Over ~4.8 years, HDGEs exhibited different FC trajectories compared with controls, displaying FC reductions between the right caudate and paracingulate, frontal (P-FDR = < 0.001), occipital (P-FDR = < 0.01), and striatal regions (P-FDR = ≤ 0.03).

These findings provide the first longitudinal evidence of early cortico-striatal and cerebellar functional network changes in adult HDGEs decades before clinical motor diagnosis, alongside possible compensatory processes in key hubs of the default mode network. These early FC changes likely reflect a dynamic interplay between neurodegenerative processes and adaptive reorganization, a balance that may ultimately fail as pathology progresses. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.