Traumatic brain injury associated with altered corpus callosum microstructure in females: Exploring the roles of menopause timing and hormone therapy in UK biobank.

BackgroundTraumatic brain injury (TBI) has lasting effects on white matter, yet sex-specific factors such as menopause timing and hormone replacement therapy (HRT) may modulate these outcomes in females.ObjectivesTo investigate how TBI, menopause timing, HRT use, and reproductive history relate to corpus callosum white matter microstructure in female UK Biobank participants.DesignCross-sectional analysis of UK Biobank diffusion MRI data using propensity score matching to compare females with TBI to controls.MethodsWe analyzed diffusion MRI data from females with and without TBI. Corpus callosum fractional anisotropy (FA), mean diffusivity (MD), and isotropic volume fraction (ISOVF) were assessed. TBI effects were examined across pre- and postmenopausal groups, accounting for HRT use, duration, and reproductive factors.ResultsFemales with TBI (n=363) exhibited widespread corpus callosum alterations compared to propensity-matched controls (n=10,128), with reduced FA and elevated MD across multiple sub-regions (all FDR p<0.05). Among TBI cases, those who sustained injury before menopause (n=30) showed significantly lower splenium FA and higher body MD compared with those injured after menopause (n=333) and controls (n=10,128). HRT use did not modify TBI-related alterations in primary analyses. However, among HRT users (n=3,108), a significant TBI×duration interaction emerged for genu MD (p=0.030), indicating that the effect of HRT duration on white matter microstructure differed between TBI cases and controls. Reproductive factors independently predicted some white matter measures but did not confound TBI, menopause timing, or HRT associations.ConclusionsTBI-associated white matter changes in females are related to menopause timing and hormonal exposure, with HRT effects dependent on duration and injury context. These findings highlight the importance of sex- and hormone-specific approaches in TBI research and the need for longitudinal studies to clarify mechanisms and potential interventions.