The hypothalamus serves as a critical neuroendocrine center, yet its specific topographical and microarchitectural vulnerabilities during the preclinical stages of Alzheimer’s disease remain poorly elucidated. This study aimed to comprehensively investigate the macroscopic volumetric and microstructural alterations within hypothalamic subregions in patients with mild cognitive impairment (MCI) and their associations with cognitive and functional decline. In this cross-sectional study, a total of 92 participants, comprising 47 MCI patients and 45 healthy controls (HC), underwent 3 T multimodal magnetic resonance imaging. The hypothalamus was automatically segmented into five bilateral subregions. Macroscopic volumetry (adjusted for estimated total intracranial volume) and diffusion tensor imaging (DTI) metrics—including fractional anisotropy (FA) and mean diffusivity (MD)—were extracted. Multiple regression models and sex-stratified correlation analyses were utilized to map structural trajectories against age, education, and clinical assessments. Hypothalamic alterations in MCI showed marked spatial heterogeneity and sexual dimorphism. Age-related volume loss was observed in HCs, whereas MCI patients exhibited sex-specific atrophic trajectories. MCI patients showed significantly reduced FA in the left anterior-inferior subregion compared with HCs. Microstructural disruption in the left tubular-superior subregion was significantly associated with lower MMSE scores and higher ADL scores. Higher educational attainment was independently associated with preserved microstructure in the posterior hypothalamus, supporting the cognitive reserve hypothesis. Hypothalamic degeneration in MCI is a spatially heterogeneous and sex-specific process. Localized microstructural disruption, especially in the left tubular-superior subregion, represents a sensitive imaging biomarker for early cognitive and functional impairment. • Subregional Profiling: Hypothalamic degeneration in MCI is not a uniform global process, but exhibits marked spatial heterogeneity and sexual dimorphism. • Microstructural Biomarker: Beyond macroscopic atrophy, high-resolution DTI identifies specific microstructural degradation (reduced FA) uniquely localized in the left anterior-inferior subregion of MCI patients. • Clinical Relevance: Microarchitectural disruption in the left tubular-superior subregion serves as a sensitive indicator, strongly correlating with both general cognitive decline and loss of functional independence. • Cognitive Reserve: Higher educational attainment acts as a protective factor, independently correlating with preserved microstructural integrity in the posterior hypothalamus.
Sun et al. (Fri,) studied this question.