Subcortical correlates of sleep in aging and Alzheimer's disease: an in vivo study.

Abstract

Sleep disturbances are frequently observed in patients with neurodegenerative diseases, but in vivo evidence linking subcortical sleep-wake structures to sleep phenotypes is limited. We aim to examine associations between MRI-derived measures of subcortical sleep-wake regulating regions and polysomnographic sleep parameters in individuals with Alzheimer's disease and cognitively healthy controls. Fifty-seven adults (45 with biomarker-confirmed Alzheimer's disease and 12 cognitively healthy controls with normal pTau217 plasma levels) were recruited at the Hospital Clínic de Barcelona. All participants completed overnight polysomnography and 3T brain MRI, including a neuromelanin-sensitive sequence. MRI-derived measures of wake-promoting structures [locus coeruleus (LC), posterior hypothalamus and basal forebrain] and sleep-promoting regions (anterior hypothalamus) were obtained. We estimated the association between nocturnal polysomnographic variables [including total sleep time, sleep efficiency, time in rapid eye movement (REM) and non-REM sleep stages, REM sleep latency, wake after sleep onset and arousals] and MRI-derived measures. Then, a principal component analysis (PCA) was used to obtain derived patterns of sleep-wake regulation. Among sleep-promoting regions, higher anterior hypothalamic volumes correlated with greater time in bed (ρ = 0.19, P < 0.05), increased sleep period time (SPT) (ρ = 0.25, P < 0.01), and decreased REM over SPT (ρ = -0.22, P < 0.05). Within wake-promoting structures, higher posterior hypothalamic volume and LC integrity were associated with higher arousals (ρ = 0.32, P < 0.05 and ρ = 0.18, P < 0.05, respectively), and higher basal forebrain volume was associated with less REM over SPT (ρ = -0.25, P < 0.05). Control anatomic regions showed no associations with sleep parameters. The first two principal components of the PCA explain 47.7% of the variance. Anterior hypothalamic volumes clustered with longer, more efficient sleep, whereas LC integrity aligned with increased wakefulness and REM sleep latency. Alzheimer's disease participants showed a shift towards the latter pattern, indicating disrupted sleep-wake regulation. MRI-derived measures of subcortical sleep-wake regions were associated with clinical sleep phenotypes in Alzheimer's disease and ageing. These in vivo findings align with prior post-mortem research, reinforcing the role of subcortical structures in sleep disturbances and highlighting these circuits as potential targets to alleviate sleep symptoms and modify disease progression.