An atlas of age- and sex-related volumetric alterations of grey matter in subcortical regions: the case of 46,111 UK Biobank participants

Ageing is normally associated with neuroanatomical changes in brain structure, characterised by non-pathological neurodegeneration, which primarily manifests as a decline in cognitive functions. For early detection of neurodegenerative diseases, it is crucial to differentiate age-related structural changes from abnormal degeneration, however, a benchmark against which pathological alterations in brain volumetric structure could be detected has not yet been established, nor is the role of biological sex in such alterations during the ageing process comprehensively understood. In order to address the above-mentioned gaps in the state-of-the-art research, we employed high quality T1-weighted MRI images of 46,111 cognitively healthy individuals aged 44-83 from the largest-ever population representative UK Biobank cohort, and generated comprehensive maps of all the linear and non-linear trajectories of the volumetric alterations in the grey matter volumes of subcortical regions across males and females. According to our findings, the Brain Stem, and bilateral Amygdala and Hippocampus are the most susceptible subcortical regions to age-related atrophy, with males being generally more prone to such structural deterioration. However, ageing proves to have a dual function on brain grey matter volume as we also observed age-related inflammation in grey matter volume of the Pallidum and Caudate which accelerates during older ages and remain consistent across males and females. This indicates inflammation in these regions does not predispose one sex over the other in Dementia-related pathogenesis, given excessive inflammation in these regions is characteristic of pathological aging, although the moderating effect of biological sex and age has been evident in other subcortical regions. Our findings guide regenerative strategies and therapeutic interventions by locating subcortical regions most vulnerable to age- related atrophy and inflammation and establish a benchmark for sex-specific typical patterns of subcortical grey matter alterations due to ageing.