Sex Differences in 6-Year Progression of White Matter Hyperintensities in Non-Demented Older Adults: Sydney Memory and Ageing Study

Objectives: To examine sex differences in the associations between vascular risk factors and 6-year changes in the volume of white matter hyperintensities (WMH), and between changes in WMH volumes and changes in cognitive performance, in a cohort of non-demented older adults. Methods: WMH volumes at 3 time-points (baseline, and 2- and 6-year follow-up) were automatically quantified in participants of Sydney Memory and Ageing Study (N = 605; age range = 70-92 years; 54.78% female). Linear mixed models were applied to examine the effects of vascular risk factors and cognitive consequences of the progression of WMH, as well as the sex moderation effects in the associations. Results: Total (TWMH), periventricular (PVWMH), and deep (DWMH) WMH volumes increased by 9.47%, 7.70%, and 11.78% per year, respectively. No sex differences were found in WMH progression rates. After Bonferroni correction, increases in PVWMH volumes over time were associated with decline in global cognition, especially in visuospatial and memory domains. Men with more increases in PVWMH volumes over time had greater declines in visuospatial abilities. Moreover, higher average TWMH volumes across time-points were associated with poorer average performance in processing speed and executive function domains across time. Higher average PVWMH volumes across time-points were also associated with worse average performance in the executive function domain over time, among women but not men. Conclusion: The findings highlighted sex differences in the associations between WMH progression and cognition decline over time, suggesting sex-specific strategies in managing WMH accumulations in ageing. Keywords: Cerebral small vessel disease, white matter hyperintensities, sex differences, brain ageing, cognitive decline.