Background and purposeOur objective was to apply multi-compartment T2 relaxometry in cognitively normal individuals aged 20–80 years to study the effect of aging on the parenchymal CSF fraction (CSFF), a potential measure of the subvoxel CSF space.Materials and methodsA total of 60 volunteers (age range, 22–80 years) were enrolled. Voxel-wise maps of short-T2 myelin water fraction (MWF), intermediate-T2 intra/extra-cellular water fraction (IEWF), and long-T2 CSFF were obtained using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) sequence and three-pool non-linear least squares fitting. Multiple linear regression analyses were performed to study the association between age and regional MWF, IEWF, and CSFF measurements, adjusting for sex and region of interest (ROI) volume. ROIs include the cerebral white matter (WM), cerebral cortex, and subcortical deep gray matter (GM). In each model, a quadratic term for age was tested using an ANOVA test. A Spearman’s correlation between the normalized lateral ventricle volume, a measure of organ-level CSF space, and the regional CSFF, a measure of tissue-level CSF space, was computed.ResultsRegression analyses showed that there was a statistically significant quadratic relationship with age for CSFF in the cortex (p= 0.018), MWF in the cerebral WM (p= 0.033), deep GM (p= 0.017) and cortex (p= 0.029); and IEWF in the deep GM (p= 0.033). There was a statistically highly significant positive linear relationship between age and regional CSFF in the cerebral WM (p< 0.001) and deep GM (p< 0.001). In addition, there was a statistically significant negative linear association between IEWF and age in the cerebral WM (p= 0.017) and cortex (p< 0.001). In the univariate correlation analysis, the normalized lateral ventricle volume correlated with the regional CSFF measurement in the cerebral WM (ρ = 0.64,p< 0.001), cortex (ρ = 0.62,p< 0.001), and deep GM (ρ = 0.66,p< 0.001).ConclusionOur cross-sectional data demonstrate that brain tissue water in different compartments shows complex age-dependent patterns. Parenchymal CSFF, a measure of subvoxel CSF-like water in the brain tissue, is quadratically associated with age in the cerebral cortex and linearly associated with age in the cerebral deep GM and WM.