Free-water volume fraction increases non-linearly with age in the white matter of the healthy human brain

The term free-water volume fraction (FWVF) refers to the cerebrospinal and interstitial fluids in the extracellular space of the white matter (WM) of the brain, which has been demonstrated as a sensitive biomarker that correlates with the cognitive performance and the neuropathological processes modifying the interstitial extracellular spaces. It can be quantified by properly fitting the isotropic compartment of the magnetic resonance (MR) signal in diffusion-sensitized sequences. Using N = 287 healthy subjects aged 25-94, this study examines in detail the evolution of the FWVF in the human brain WM across the adult lifespan, which has been previously reported to exhibit a positive trend. We found evidence of a noticeably non-linear gain after the sixth decade of life, with a region-specific variate and varying change rate of the FWVF parameter with age, at the same time a heteroskedastic pattern across the adult lifespan is suggested. On the other hand, the FW-compensated MR signal leads to a region-dependent flattened age-related evolution of the mean diffusivity (MD) and fractional anisotropy (FA), along with a considerable reduction in their variability, as compared to standard studies conducted over the raw MR signal. This way, our study provides a new perspective on the trajectory-based assessment of the brain and explains the source of the variations observed in FA and MD parameters across the lifespan with previous studies with the standard diffusion tensor imaging. ### Competing Interest Statement The authors have declared no competing interest.