Multimodal MRI insights into glymphatic clearance and blood-brain barrier integrity in healthy aging

Aging is associated with impaired CSF clearance in preclinical models, but its impact on blood-brain barrier (BBB) health and glymphatic function in humans remains unclear. The BBB and glymphatic functions are complementary and may partially overlap, yet their interaction is yet to be fully elucidated. In this study, we aimed to compare BBB integrity, extracellular free water, and glymphatic function between healthy young and older adults, and to examine mechanistic relationships among these measures using multimodal MRI techniques. 30 healthy participants with no known neurological or psychiatric disorders, including 12 younger (26 ± 3 years) and 18 older individuals (75 ± 7 years), underwent MRI scans on a 3T Siemens Prisma scanner. Multimodal MRI techniques were used, including diffusion-prepared arterial spin labeling to measure the water exchange rate (Kw) across the blood-brain barrier (BBB); free water (FW) imaging to quantify extracellular free water in white matter; and diffusion tensor imaging along perivascular spaces (DTI-ALPS) to assess glymphatic function. These measures were compared between younger and older individuals. Mediation analysis was performed to assess the mechanistic relationship between BBB integrity and glymphatic function and to test whether this relationship was mediated by free water. Older individuals showed reduced whole-brain Kw (p = 0.021), increased white matter FW (p = 0.002), and reduced DTI-ALPS (p < 0.001) compared to younger adults. Kw was positively associated with DTI-ALPS (β = 0.402 × 10^-2, p = 0.022) and negatively associated with FW (β = -0.676 × 10^-3, p = 0.008). DTI-ALPS was negatively associated with FW (β = -3.487, p = 0.001). Significantly reduced Kw was also observed in the cortical grey matter of older adults. Reduced Kw may reflect impaired BBB function, while reduced DTI-ALPS and increased FW indicate impaired glymphatic clearance. FW mediated the relationship between Kw and DTI-ALPS (95% CI [0.00014, 0.00404], p = 0.035), suggesting a potential mechanistic link between BBB function, extracellular water content, and glymphatic clearance efficiency. Overall, this study provides novel multimodal MRI insights into BBB and glymphatic alterations in healthy aging and may inform the development of MRI biomarkers to preserve cognitive health.