Free Water as a Marker of Early Small Vessel Disease in Healthy Aging

Background Brain aging is associated with cerebrovascular changes and related microstructural pathology. In this context, research indicates that small vessel disease (SVD) is characterized by increases in extracellular free water (FW). Methods We examined 94 individuals with early signs of small vessel disease (eSVD; Mage = 69.47 years, SDage = 8.27; 59.6% female) and 94 age‐matched controls (CON; Mage = 70.80 years, SDage = 8.59, 59.6% female). Individuals with eSVD were defined by having a white matter hyperintensity (WMH) score ≥ 2 or showing the presence of lacunes or microbleeds. We examined differences in the diffusion MRI measures between both groups. In addition, we assessed the association between age and the diffusion MRI measures averaged across the entire normal‐appearing white matter (NAWM). To test if FW mediates the association of FW‐uncorrected DTI measures and age, we applied simple mediation models. Results Differences between individuals with eSVD and CON were identified for FW in NAWM and FW‐uncorrected DTI, but not for FW‐corrected DTI measures. Both FW and FW‐uncorrected DTI measures in NAWM were significantly associated with age across the total sample (rrange = −0.24 to 0.44) and across each group (rrange = −0.36 to 0.48). In addition, the association between FW‐uncorrected DTI measures and age was mediated by FW. Conclusions Even in subjects with subtle, clinically silent, cerebral white matter changes, increases in FW could be observed compared to individuals without those changes. Therefore, FW might act as a sensitive marker at the earliest signs of SVD.