Comparison Between Blood-Brain Barrier Water Exchange Rate and Permeability to Gadolinium-Based Contrast Agent in an Elderly Cohort

Background: Dynamic contrast-enhanced (DCE) MRI using intravenous injection of gadolinium-based contrast agents (GBCAs) is commonly used for imaging blood-brain barrier (BBB) permeability. Water is an alternative endogenous tracer with limited exchange rate across the BBB. A direct comparison between BBB water exchange rate and BBB permeability to GBCA is missing. The purpose of this study was to directly compare BBB permeability to GBCA (Ktrans and k(Gad) = Ktrans/Vp) and water exchange rate (kw) in a cohort of elderly subjects at risk of cerebral small vessel disease (cSVD). Methods: Ktrans/k(Gad) and kw were measured by DCE-MRI and diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL), respectively, at 3 Tesla in 16 elderly subjects (3 male, age = 67.9 ± 3.0 yrs) at risk of cSVD. The test-retest reproducibility of kw measurements was evaluated with repeated scans ~6 weeks apart. Mixed effects linear regression was performed in the whole brain, gray matter (GM), white matter (WM), and 6 subcortical brain regions to investigate associations between Ktrans/k(Gad) and test-retest kw. In addition, kw and Ktrans/k(Gad) were compared in normal appearing white matter (NAWM), white matter hyperintensity (WMH) lesions and penumbra. Results: Significant correlation was found between kw and Ktrans only in WM (β = 6.7 × 10(4), P = 0.036), caudate (β = 8.6 × 10(4), P = 0.029), and middle cerebral artery (MCA) perforator territory (β = 6.9 × 10(4), P = 0.009), but not in the whole brain, GM or rest 5 brain regions. Significant correlation was found between kw and k(Gad) in MCA perforator territory (β = 1.5 × 10(3), P = 0.049), medial-temporal lobe (β = 3.5 × 10(3), P = 0.032), and hippocampus (β = 3.4 × 10(3), P = 0.038), but not in the rest brain regions. Good reproducibility of kw measurements (ICC=0.75) was achieved. Ktrans was significantly lower inside WMH than WMH penumbra (16.2%, P = 0.026), and k(Gad) was significantly lower in NAWM than in the WMH penumbra (20.8%, P < 0.001). Conclusion: kw provides a measure of water exchange rate across the BBB with good test-retest reproducibility. The BBB mechanism underlying kw and Ktrans/k(Gad) is likely to be different, as manifested by correlations in only three brain regions for each pair of comparison between kw and Ktrans or k(Gad).