MRI‐Based Water Exchange Rate Across the Blood‐Brain‐Barrier is Associated with Diffusion MRI Free Water in Older Adults

Abstract

AbstractBackgroundThe blood brain barrier (BBB) tightly regulates the clearance of waste from the central nervous system. Changes in BBB function may disrupt such clearance mechanisms, resulting in increased waste and unrestricted fluid, or free water (FW), which can be measured using diffusion‐weighted imaging. Here, we explored whether MRI‐based BBB water exchange rate (kw; measure of BBB function) is associated with FW within white matter tracts connecting the executive control network (ECN). We further explored whether FW within the ECN would likewise be associated with executive function performance.MethodFifty‐three older adults (ages 65‐85) without dementia were scanned using a 3‐Tesla MRI Siemens Magnetom Prisma with a 64‐channel head coil. A 3D gradient‐and‐spin‐echo diffusion‐prepared arterial spin labeling (DP‐ASL) sequence and a 126‐direction main diffusion MRI sequence using 4 b‐values (0, 500, 1000, and 2000 s/mm2) were acquired. Each participant’s mean kw values averaged over the entire brain were calculated from the DP‐ASL data. FW maps were calculated, registered to FMRIB space, and skeletonized using FSL’s tract‐based spatial statistics (TBSS). Skeletonized FW values were averaged across the white matter tracts connecting the ECN using a previously defined fMRI template. All participants completed the cognitive assessment from the Uniform Data Set Version 3 within one year of the scan date. Executive function was assessed for each participant based on a composite measure including digit span backwards and trails making part B test minus part A. A multivariate linear regression model first tested the association between whole brain kw values (predictor) and FW in the ECN as the dependent variable. A second multivariate linear regression model then tested the association between FW in the ECN (predictor) and EF performance as the dependent variable. Models controlled for age and sex.ResultsWhole brain kw values were negatively associated with FW in the ECN (r = ‐0.338, p = 0.031). FW in the ECN was negatively associated with EF performance (r = ‐0.318, p = 0.024).ConclusionOur results suggest that BBB dysfunction is associated with free water in large‐scale cognitive networks. Subsequent free water changes in these networks are linked with associated decreases in cognitive performance.