Early Striatal-Cerebellar Connectivity Changes Tied to Huntington Disease, Decades Before Motor Onset

New longitudinal functional MRI data, published in Movement Disorders, showed that measurable changes in brain network connectivity occurred in Huntington disease gene-expanded (HDGE) individuals as much as 2 decades before predicted clinical motor diagnosis.¹ The study, conducted using the Huntington's Disease Young Adult Study (HD-YAS) cohort, is the first that applied longitudinal whole-brain seed-based functional connectivity (SBFC) analysis to an adult HDGE population this far from onset.

“These early FC changes likely reflect a dynamic interplay between neurodegenerative processes and adaptive reorganization, a balance that may ultimately fail as pathology progresses,” lead author Michela Leocadi, PhD, research fellow in the Department of Neurodegenerative Disease of the Huntington's Disease Centre at UCL Queen Square Institute of Neurology, and colleagues wrote.¹ The findings add functional evidence to a growing structural literature showing striatal atrophy decades before clinical motor signs in HD, and may help refine biomarkers for trials targeting the earliest, premanifest stages of disease.

Study Design and Findings

Investigators analyzed resting-state fMRI data from 71 right-handed participants (43 HDGE, 28 matched controls) drawn from the 131-person HD-YAS cohort, scanned at 2 visits roughly 4.8 years apart. Seed-based connectivity was assessed using bilateral caudate and putamen regions of interest, with mixed-effects ANOVA testing main effects of group, time, and group-by-time interaction, corrected using false discovery rate (FDR).

HDGE participants, who were clinically asymptomatic (Unified Huntington's Disease Rating Scale Total Motor Score ≤5) and estimated to be roughly 24 years from predicted motor diagnosis, showed significantly reduced connectivity between the putamen and cerebellar vermis, cerebellar lobules IV-V, and the brainstem bilaterally (P-FDR ≤ .01). Conversely, HDGE individuals showed increased connectivity between the putamen and default mode network hubs, including the precuneus (P-FDR = .04) and the supramarginal and angular gyri (P-FDR = .04).

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A significant group-by-time interaction emerged for the right caudate, indicating diverging trajectories between groups over the study period. HDGE participants showed progressive connectivity reductions between the right caudate and the paracingulate gyrus/frontal medial cortex (P-FDR < .001), lateral occipital cortex (P-FDR < .01), left caudate/putamen (P-FDR = .01), and right putamen (P-FDR = .03), while controls showed connectivity increases in the same regions over time.

Clinical Context

HD is a rare, autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the huntingtin gene, leading to loss of GABAergic medium spiny neurons in the striatum and progressive motor, cognitive, and psychiatric decline.² Striatal atrophy is a validated biomarker used to stage disease under the HD Integrated Staging System, but prior longitudinal resting-state fMRI studies in premanifest HDGE cohorts were limited to shorter follow-up windows (≤3 years) and largely reported no significant connectivity differences from controls, leaving a gap in understanding how and when functional network changes emerge relative to structural decline.³

Interpretation

The authors interpreted the pattern of reduced striatal-cerebellar/brainstem connectivity alongside increased striatal-parietal connectivity as evidence of early compensatory reorganization that may offset incipient neurodegeneration. They noted the right caudate findings, which showed initial hyperconnectivity to frontal and paracingulate regions followed by marked decline over the study period, could represent a compensatory mechanism that collapses as pathology advances, positioning the right caudate as a possible early hub of functional vulnerability.

The authors also pointed to converging neuropathological evidence of cerebellar involvement in HD, noting that Purkinje cell loss and deep cerebellar nuclei degeneration have been documented independent of striatal atrophy.

Limitations

The authors acknowledged that the final sample size, after strict quality control and exclusion of left-handed participants, was modest and may have limited power to detect subtler interaction effects. Resting-state fMRI also remainedsensitive to motion and physiological noise, and the SBFC approach focused specifically on caudate and putamen seeds rather than a whole-brain, extra-striatal analysis.

Since the cohort remained clinically and functionally normal throughout the study, the clinical significance of these connectivity changes is not yet established; the authors called for longer follow-up integrating structural, cognitive, and molecular biomarkers to determine whether these patterns predict future clinical decline.

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REFERENCES
1. Leocadi M, Hobbs NZ, Farag M, et al. Early Longitudinal Brain Network Changes in Huntington's Disease Before Clinical Motor Onset. Mov Disord. Published online August 9, 2026. doi:10.1002/mds.70461
2. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985;44(6):559-577. doi:10.1097/00005072-198511000-00003
3. Scahill RI, Zeun P, Osborne-Crowley K, et al. Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis. Lancet Neurol. 2020;19(6):502-512. doi:10.1016/S1474-4422(20)30143-5
4. Tabrizi SJ, Schobel S, Gantman EC, et al. A biological classification of Huntington's disease: the Integrated Staging System. Lancet Neurol. 2022;21(7):632-644. doi:10.1016/S1474-4422(22)00120-X