Brain tissue cerebrospinal fluid fraction increases quadratically in normal aging

Background and Purpose: Our 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 cerebrospinal fluid fraction (CSFF), a measure of the microscopic-scale CSF space. Materials and Methods: A total of 66 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 analysis with correction for multiple comparisons was performed to study the association between age and regional MWF, IEWF, and CSFF measurements, adjusting for sex and region of interest (ROI) volume. The cerebral white matter (WM), cerebral cortex, and subcortical deep gray matter (GM) were considered as ROIs. 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. Results: In the multiple regression analysis, we found a statistically significant quadratic relationship between age and regional CSFF for all three ROIs (all p-values < 0.001). A statistically significant quadratic relationship with age was also found for MWF in the deep GM (p = 0.004) and IEWF in the cortex (p = 0.012). There was a statistically significant linear relationship between age and regional IEWF in the cerebral WM (p = 0.006) and deep GM (p = 0.002). In the univariate correlation analysis, the normalized lateral ventricle volume was found to correlate moderately with the regional CSFF measurement in the cerebral WM (ρ = 0.43, p < 0.001), cortex (ρ = 0.43, p < 0.001), and deep GM (ρ = 0.49, p < 0.001). Conclusion: Brain tissue water residing in different water compartments shows complex changing patterns with age. Parenchymal CSFF, a biomarker of microscopic-scale CSF-like water, shows a quadratic increase in both GM and WM, starting approximately at the age of 50. ### Competing Interest Statement The authors have declared no competing interest.