Discovery of disrupted sustained attention and altered functional connectivity in far-from-onset Huntington's disease gene-expanded young adults.

BACKGROUND: Cognitive impairments are a hallmark of Huntington's disease (HD). METHODS: Seventy-one participants (43 HD gene-expanded [HDGE], 28 healthy controls) from the HD-Young Adult Study at two timepoints ≈ 4.7 years apart, completed the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing task and underwent resting-state functional magnetic resonance imaging. We focused on predefined regions of interest that are involved in sustained attention. RESULTS: HDGE individuals showed significantly poorer sustained attention than controls (padj = 0.007), with no significant change over time. Functional connectivity (FC) analyses revealed group differences in attention-related networks, including the occipital-operculum and lentiform-orbitalis pathways. Time and group × time effects were also observed in frontal and parietal regions. DISCUSSION: These findings demonstrate early and persistent attention deficits in HDGE, linked to altered FC in attention-related circuits. This supports the presence of early cognitive dysfunction in HD and highlights potential compensatory and pathological changes in brain networks prior to the onset of clinical motor symptoms. HIGHLIGHTS: We detail the discovery of early sustained attention deficits in Huntington's disease (HD) gene-expanded (HDGE) young adults. These sustained attention deficits do not measurably decline over a 4.7-year period. Altered functional connectivity was observed in attention-related brain networks. Alterations in regions include occipital, opercular, lentiform, and frontal areas. Findings support attention as an early cognitive biomarker in HDGE young adults.