Brain axial and radial diffusivity changes with age and gender in healthy adults

• Developmental changes in myelin and axons by sex were assessed in healthy adults.
• Myelin and axonal integrity declined with age, except in insular and occipital sites.
• Integrity declines were especially marked in hippocampus and posterior thalamus.
• Females showed more axonal and myelin changes in multiple structures than males.
• The findings show the need to control age and sex in fiber assessment of mixed groups.

White matter integrity changes with age, with the extent of variation dependent on attributes such as sex and oligodendrocyte health. Quantification of myelin and axonal integrity in healthy people would provide normative values necessary to determine pathology-related tissue characteristics with normal-aging and gender. We assessed white matter integrity with diffusion tensor imaging-based axial and radial diffusivity procedures (3.0-Tesla magnetic resonance imaging), which measure water diffusion parallel and perpendicular to axonal bundles, indicating axonal and myelin status, respectively, using region-of-interest (ROI) analyses, in 34 healthy adults (age, 46.5±6.0 years, 19 male). Sex differences in diffusion values were assessed with two-sample t-tests, and diffusion changes with age using Pearson's correlations; whole-brain effect sizes were examined with voxel-based procedures. Multiple brain areas showed increased axial and radial diffusivity values reflecting declines in axonal and myelin integrity with age, especially in mid-hippocampal and posterior thalamic areas. However, axonal and myelin integrity increased in insular and occipital cortex projections with maturity. Females showed reduced fiber and myelin integrity in substantially more structures than males, and those areas included limbic, basal ganglia, pontine, and cerebellar sites. A minority of structures, confined to cerebellar, temporal, and frontal cortices, showed reduced fiber and myelin integrity with age in males over females. Whole-brain effect sizes in diffusion values between sexes and age-related changes showed findings parallel to ROI analyses. The structural differences mandate partitioning of sex and age in adult white matter pathology assessment, and likely contribute to sex-based physiological and behavioral dysfunction in aging and in multiple pathologies.