Free water in healthy aging

Brain aging is associated with cerebrovascular changes and related microstructural pathology, which can be examined by measures of diffusion tensor imaging (DTI) such as fractional anisotropy or mean diffusivity. However, it was suggested that small vessel disease (SVD) is mainly driven by increases in extracellular free water (FW) rather than alterations of white matter fibre organization. The aim of this study was to examine the association of FW, FW-uncorrected and FW-corrected DTI measures with aging, and to determine if there are differences in FW and DTI measures between individuals with incipient signs of small vessel disease (iSVD) and elderly controls (CON).

We examined 188 age-matched individuals (mean age = 70.14, SD = 8.44; 59.6% female) with incipient signs of SVD and CON of the Austrian Stroke Prevention Family Study. Individuals with iSVD were defined by white matter hyperintensities (WMH) scores ≥ 2, presence of lacunes and/or microbleeds, whereas CON did not show any signs of lacunes, microbleeds and exhibited WMH scores < 2. We assessed the association of FW across the entire normal appearing white matter (NAWM), FW-uncorrected and FW-corrected DTI with age. To test if FW mediates the association of FW-uncorrected DTI measures and age, we applied simple mediation models. Lastly, we examined differences in FW and FW-corrected DTI parameters between groups.

FW in NAWM and FW-uncorrected DTI measures in NAWM were significantly associated with age in both the total sample (rrange = -.24 - .44) and subgroups (rrange = -.36 - .48). For the correlation between FW-corrected DTI parameters and age, predominantly non-significant results were observed. Mediation analyses revealed that the association between FW-uncorrected DTI measures and age is mediated by FW in the total sample as well as in both subgroups. Differences between individuals with iSVD and CON were identified for FW in NAWM and FW-uncorrected DTI, but not for FW-corrected DTI measures.

The association between FW-uncorrected diffusion measures and age appears to be driven by FW. Even in subjects with subtle, clinically silent, cerebral white matter changes, significant increases in FW could be observed. Therefore, FW might act as a sensitive marker at earliest, clinically silent, signs of SVD.