Growth of White Matter Signal Aberrations and Cortical Changes in Men and Women: A 9‐Year Multiple‐Time‐Point Longitudinal MRI Study in Older Adults

ABSTRACT

In aging, white matter hyperintensities (WMH) or white matter signal aberrations (WMSA), a proxy for cerebral small vessel disease, are the most common age‐related finding on brain MRI scans, with women reported to have a greater burden. Previous studies found that WMH/WMSA were linked to lower cortical volume and thickness. However, no study has investigated the connection between WMSA and both cortical thickness and area using multiple assessments over 9 years. We hypothesized that increasing WMSA was associated with a decrease in both cortical thickness and area over time, compounding the age‐typical decrease, and that the effect was more pronounced in women than men. Our cohort consisted of 104 older adults from the general population, born between 1936 and 1942, scanned at the same 3T scanner at baseline (mean age 72.4 years), and followed up at 1‐, 3‐, 5, and 9 years. We analyzed the 3D MPRAGE scans in FreeSurfer's longitudinal pipeline and extracted the volume of WMSA, cortical thickness and area, grey matter‐white matter intensity ratio, plus hippocampal and intracranial volume. Linear mixed‐effects models included the interaction between sex and WMSA on cortical thickness and area, and hippocampal volume. We also performed sex‐specific analyses. Finally, complete case and sensitivity analyses with known confounders were run. In both men and women, baseline WMSA volume was 3.6 cm ³ (95% CI, 2.1–6.2), followed by an average annual growth rate of 7.2% (95% CI, 6.1–8.3). Increasing WMSA over time was associated with accelerated cortical thinning. In men, the association between WMSA and cortical thinning was more pronounced and present in more lobes than in women, despite similar WMSA volume and growth in both sexes. In the lobes with accelerated cortical thinning, increasing WMSA was also associated with an increase in cortical area present only in men. The sex‐specific analyses revealed even more pronounced differences in the relationships between WMSA growth and cortical features over time. The changes in cortex associated with WMSA volume were superimposed on the changes related to aging in both sexes. Change in WMSA over time was not directly associated with change in hippocampal volume. Complete case and sensitivity analyses supported the main findings. Thus, contrary to our hypothesis, WMSA change over 9 years was connected to greater cortical thinning alongside a surprising increase in cortical area in men, despite men and women having similar WMSA volume and growth. Our results underscore the presence of marked sex differences in cortical plasticity in the aging brain in the presence of WMSA. WMSA, the most common age‐related proxy for small vessel disease, contributed significantly and above that related to aging, to cortical changes, more so in men than women.