Tau‐associated neuronal loss in the intermediate nucleus of the human hypothalamus, a putative VLPO analog, in progressive supranuclear palsy and Alzheimer's disease

BACKGROUND: Sleep phenotypes differ in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). The human intermediate nucleus (IntN), a putative ventrolateral preoptic analog, promotes non-rapid eye movement (NREM) sleep, but its disease-specific vulnerability is unclear. METHODS: Post mortem hypothalami (n = 30; baseline [Braak stage I-II] n = 6; PSP n = 9; Braak III-IV n = 4; Braak V-VI n = 11) underwent marker-guided IntN delineation, galanin/phospho-tau (T231) immunohistochemistry, and stereology. RESULTS: Advanced PSP showed profound IntN degeneration (84% neuron reduction vs baseline). In AD neuropathologic change, IntN neuronal loss and phospho-tau burden were greater in higher Braak stages and preferentially affected galanin-positive neurons (≈77% reduction in late AD); phospho-tau burden was higher in galanin-positive neurons. CONCLUSIONS: The IntN is a disease-sensitive node, with near-ablation in PSP and progressive, preferential loss of detectable galaninergic neurons in AD. Although longitudinal observations and premortem sleep/wake measurements were not available for this sample, these findings are consistent with disease-level differences in NREM/ slow-wave sleep disturbance reported in PSP and AD.