This study used advanced diffusion-weighted MRI (dMRI) to examine the association between exogenous sex-hormone exposure and the brain’s white matter aging trajectories in a large population-based sample of women. To investigate the effect of pre- and post-menopausal sex hormones on brain aging, cross-sectional brain dMRI data from the UK Biobank was analyzed using 3 diffusion models: conventional diffusion tensor imaging (DTI), the tensor distribution function (TDF), and neurite orientation dispersion and density imaging (NODDI). Mean skeletonized diffusivity measures were extracted and averaged across the whole brain, including fractional anisotropy, isotropic volume fraction, intracellular volume fraction and orientation dispersion index. We used general linear models and fractional polynomial regressions to characterize age-related trajectories in white matter measures following hormone therapy (HT) and oral contraceptive (OC) use in women (HT analysis: N=8,301; OC analysis: N=8,913). Sex hormone treatment (HT and OC) was statistically associated with the aging trends in white matter measures. Estrogen therapy alone appeared to exert a neuroprotective effect on age-related white matter processes, compared to HT containing both estrogen and progestin therapy - which was associated with accelerated aging-related processes in women. These results support the hypothesis that exogenous sex hormone exposure may impact white matter aging; white matter metrics may also be sensitive to sex hormone levels in women. Furthermore, we discuss the necessity to test alternative models for lifespan trajectories beyond popular linear and quadratic models, especially when dealing with large samples. Fractional polynomial models may provide a more adaptive alternative to linear or quadratic models.
The brain’s white matter microstructure, as assessed using diffusion-weighted MRI (DWI), changes significantly with age and also exhibits significant sex differences. Here we examined the ability of a traditional diffusivity metric (fractional anisotropy derived from diffusion tensor imaging, DTI-FA) and advanced diffusivity metrics (fractional anisotropy derived from the tensor distribution function, TDF-FA; neurite orientation dispersion and density imaging measures of intracellular volume fraction, NODDI-ICVF; orientation dispersion index, NODDI-ODI; and isotropic volume fraction, NODDI-ISOVF) to detect sex differences in white matter aging. We also created normative aging reference curves based on sex. Diffusion tensor imaging (DTI) applies a single-tensor diffusion model to single-shell DWI data, while the tensor distribution function (TDF) fits a continuous distribution of tensors to single-shell DWI data. Neurite orientation dispersion and density imaging (NODDI) fits a multi-compartment model to multi-shell DWI data to distinguish intra- and extracellular contributions to diffusion. We analyzed these traditional and advanced diffusion measures in a large population sample available through the UK Biobank (15,394 participants; age-range: 45-80 years) by using linear regression and fractional polynomials. Advanced diffusivity metrics (NODDI-ODI, NODDI-ISOVF, TDF-FA) detected significant sex differences in aging, whereas a traditional metric (DTI-FA) did not. These findings suggest that future studies examining sex differences in white matter aging may benefit from including advanced diffusion measures.
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