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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by DZNE institutional funds, the Federal Ministry of Education and Research of Germany (031L0206, 01GQ1801), an Alzheimer Association Research Grant (Award Number: AARG-19-616534), the Chan Zuckerberg Initiative (Project FastSurfer, Grant Number: EOSS5 2022-252594), the Helmholtz-AI project DeGen (ZT-I-PF-5-078), and NIH (R01 LM012719, R01 AG064027, R56 MH121426, and P41 EB030006). Peng Xu is supported by a scholarship from China Scholarship Council, and N. Ahmad Aziz is supported by a European Research Council Starting Grant (Number: 101041677). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committee of the University of Bonn Medical Faculty approved the Rhineland Study. The ethics committee of the National Information Governance Board for Health and Social Care and the National Health Service North West Centre for Research approved the UK Biobank Imaging Study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The Rhineland Study's dataset is not publicly available because of data protection regulations. Access to data can be provided to scientists in accordance with the Rhineland Study's Data Use and Access Policy. Requests for further information or to access the Rhineland Study's dataset should be directed to rs-duac@dzne.de. All individual level data from the UK Biobank Imaging Study used in the current manuscript are available through the UK Biobank Resource (https://www.ukbiobank.ac.uk). This research has been conducted using the UK Biobank Resource under Application Number 82056.