Hypothalamic integrity is associated with age, sex and cognitive function across lifespan: A comparative analysis of two large population-based cohort studies

Abstract

Background The hypothalamus is the body's principal homeostatic center. Emerging findings from animal studies suggest that the hypothalamus could also play a crucial role in the modulation of cognition. However, detailed assessments of age and sex effects on hypothalamic structural integrity and its cognitive correlates across the lifespan are still lacking. Therefore, we aimed to investigate hypothalamic structural integrity in relation to age, sex and cognitive performance across lifespan in the general population. Methods We used cross-sectional data from the Rhineland Study (RS) (N=5812, 55.2 ± 13.6 years, 58% women) and the UK Biobank Imaging Study (UKB) (N=45076, 64.2 ± 7.7 years, 53% women), two large-scale population-based cohort studies. Volumes of hypothalamic structures were obtained from 3T structural magnetic resonance images through application of a recently developed automatic parcellation procedure (FastSurfer-HypVINN). The standardized cognitive domain scores were derived from extensive neuropsychological test batteries. We employed multivariable linear regressions to assess age and sex effects on volumes of hypothalamic structures, and to evaluate the associations of these volumes with domain-specific cognitive function. Findings Mean (standard deviation) volumes of the total hypothalamus were 1124.2 mm3 (104.8) in RS and 1102.1 mm3 (119.9) in UKB. With increasing age, the volumes of the total, anterior and posterior hypothalamus, and mammillary bodies decreased (between -1.20 to -0.14 mm3/year in RS and between -3.82 to -0.49 mm3/year in UKB), and of the medial hypothalamus and tuberal region increased (between 0.33 to 0.65 mm3/year in RS and between 0.21 to 0.68 mm3/year in UKB). Volumes of all hypothalamic structures were larger in men compared to women. Larger total hypothalamus volumes were associated with better global cognition (β ± standard error (SE): 0.025 ± 0.017 [RS] and 0.026 ± 0.007 [UKB], both p<0.005), and total memory (0.030 ± 0.022 [RS] and 0.021 ± 0.009 [UKB], both p<0.007), while larger posterior hypothalamus volumes were associated with better global cognition (0.036 ± 0.014 [RS] and 0.028 ± 0.006 [UKB], both p<0.001), and total memory (0.038 ± 0.018 [RS] and 0.020 ± 0.008 [UKB], both p<0.001). Conclusion We found strong age and sex effects on hypothalamic structures, as well as robust associations between these structures and domain-specific cognitive functions. Overall, these findings thus implicate specific hypothalamic subregions as potential therapeutic targets against age-associated cognitive decline.