F040 Cognition in far from onset young adult gene expansion carriers: insights from the Huntington’s disease young adult study (HD-YAS)

<h3>Background</h3> Cognitive impairments in Huntington’s Disease (HD) reflect neurodegeneration, initially affecting frontal-striatal networks and later becoming more widespread. <h3>Aims</h3> The HD Young Adult Study (HD-YAS) investigates cognition in gene expansion carriers (GECs) approximately 24 years from predicted onset, with longitudinal evaluations at two visits ~4.5 years apart. <h3>Methods</h3> 154 participants were recruited across two visits (V1: 2017–2019; V2: 2022–2024). V1 included 131 participants (64 GECs, 67 controls), and V2 added 23 participants (9 GECs, 14 controls), with 103 participants having longitudinal data. Participants completed neuropsychological tests from the CANTAB, EMOTICOM, and HD core battery, assessing attention, memory, cognitive flexibility, planning, executive function, and social and emotional cognition. General least-square linear models evaluated group differences cross-sectionally and longitudinally, with age and CAG-length associations analysed within the GEC group. <h3>Results</h3> Cross-sectional differences were found in the CANTAB Stop Signal Task (SST; p=0.011, FDR=0.131), Rapid Visual Processing Task (RVP; p=0.026, FDR=0.154), and semantic verbal fluency (p=0.039, FDR=0.154), with no detectable association with age and CAG. No longitudinal group differences were observed (FDR&gt;0.8). There were longitudinal associations with age and CAG in the CANTAB RVP (p=0.026, FDR=0.154), Paired Associate Learning (p=0.039, FDR=0.154), and symbol digit modalities test (p=0.011, FDR=0.131). <h3>Conclusions</h3> Our results showed subtle cognitive changes that occur early in HD, in very far from onset GECs. Importantly, both the CANTAB SST and RVP are subserved by a neural network involving the inferior frontal gyrus. The absence of longitudinal group differences suggests slow progression of cognitive impairments at this early disease stage.