Whole-Brain Connectivity in a Large Study of Huntington's Disease Gene Mutation Carriers and Healthy Controls

Huntington's disease (HD) is an inherited brain disorder characterized by progressive motor, cognitive, and behavioral dysfunctions. It is caused by abnormally large trinucleotide cytosine-adenine-guanine (CAG) repeat expansions on exon 1 of the Huntingtin gene. CAG repeat length (CAG-RL) inversely correlates with an earlier age of onset. Region-based studies have shown that HD gene mutation carrier (HDgmc) individuals (CAG-RL ≥36) present functional connectivity alterations in subcortical (SC) and default mode networks. In this analysis, we expand on previous HD studies by investigating associations between CAG-RL and connectivity in the whole brain, as well as between CAG-dependent connectivity and motor and cognitive performances. We used group-independent component analysis on resting-state functional magnetic resonance imaging scans of 261 individuals (183 HDgmc and 78 healthy controls) from the PREDICT-HD study, to obtain whole-brain resting state networks (RSNs). Regression analysis was applied within and between RSNs connectivity (functional network connectivity [FNC]) to identify CAG-RL associations. Connectivity within the putamen RSN is negatively correlated with CAG-RL. The FNC between putamen and insula decreases with increasing CAG-RL, and also shows significant associations with motor and cognitive measures. The FNC between calcarine and middle frontal gyri increased with CAG-RL. In contrast, FNC in other visual (VIS) networks declined with increasing CAG-RL. In addition to observed effects in SC areas known to be related to HD, our study identifies a strong presence of alterations in VIS regions less commonly observed in previous reports and provides a step forward in understanding FNC dysfunction in HDgmc.