Abstract
BACKGROUND: White matter hyperintensities (WMHs) are common in older adults and appear as abnormal signal on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). They are often linked to demyelination, axonal damage, and gliosis, as well as vascular changes. WMHs occur in both normal aging and mild cognitive impairment (MCI), where they may contribute to cognitive decline. OBJECTIVE: The study objectives were to determine whether advanced diffusion MRI (dMRI) techniques can detect distinct microstructural changes within WMHs in individuals with MCI compared to healthy controls and to evaluate relationships between these measures and cognitive performance. METHODS: Advanced dMRI techniques were used to assess WMH microstructural changes in normal aging (n = 55) and MCI (n = 46) participants from the ADNI database. WMHs and their surrounding penumbra were identified using an automated approach. Microstructural characteristics, derived from free-water (FW) diffusion tensor imaging and diffusion kurtosis imaging, were evaluated between groups and white matter regions. Associations between these measures and cognitive performance (assessed by the Mini-Mental State Exam) were examined. RESULTS: Across both groups, WMHs showed higher FW and lower FW-fractional anisotropy and kurtosis metrics compared to normal-appearing white matter, indicating widespread microstructural alterations. No groupwise microstructural differences were observed within corresponding tissue types. In the MCI group, kurtosis metrics within WMHs correlated with cognitive performance. CONCLUSIONS: These findings highlight the complexity of WMH-related microstructural changes and suggest that advanced dMRI biomarkers may offer valuable insights into the role of white matter changes in aging and cognitive decline.