Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure across the lifespan in patients with genetic FTD and whether these changes related to sleep dysfunction. Data from the observational multisite Genetic Frontotemporal Dementia Initiative (GENFI) study were used. GENFI participants were adult members of a family with known pathogenic variants in the microtubule-associated protein tau (MAPT) or progranulin (GRN) genes or an expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Family members without a pathogenic variant served as controls. GENFI participants were followed annually, with up to 7 visits, and underwent clinical characterization, neuropsychological testing, biological sampling, and brain MRI. For our analyses, participants were included if they had at least 1 T1-weighted structural MRI scan available. Linear mixed-effect models were used to examine changes in sleep dysfunction, measured using the Cambridge Behavioural Inventory-Revised sleep subscale, volumetric changes in hypothalamic regions, and the associations between cortical and hypothalamic atrophy and sleep dysfunction. Participants included 491 adults with pathogenic genetic variants of FTD (27.9% symptomatic; median age: 49.4 years, 56.4%F) and 321 controls (median age: 44.2 years, 57.3%F). Pathogenic variant carriers showed greater sleep dysfunction across the adult lifespan (β = [0.25-0.34], q < 0.005) with MAPT carriers alone showing presymptomatic sleep changes (β = 0.34, q = 0.005). Cortical thinning in frontal and parietal regions was associated with greater sleep disturbances in C9orf72 and GRN carriers (q < 0.05). MAPT carriers showed consistently significant volume loss over time across all sleep-relevant hypothalamic subunits (β = [-0.56 to -0.39], q < 0.005), and reduced volumes in these subunits were related to increased sleep dysfunction (β = [-0.20 to -0.16], q < 0.05). These findings suggest that sleep dysfunction in patients with genetic FTD may be attributable to atrophy in sleep-relevant hypothalamic subunits, with the most severe and consistent deficits observed in MAPT carriers. While biologically plausible, our statistical approach cannot confirm a causal link between atrophy and sleep disturbances.
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