Abstract
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 kGad = Ktrans/Vp) and water exchange rate (kw) in a cohort of elderly subjects at risk of cerebral small vessel disease (cSVD).Methods: Ktrans/kGad 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/kGad and test-retest kw. In addition, kw and Ktrans/kGad 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 × 104, P = 0.036), caudate (β = 8.6 × 104, P = 0.029), and middle cerebral artery (MCA) perforator territory (β = 6.9 × 104, P = 0.009), but not in the whole brain, GM or rest 5 brain regions. Significant correlation was found between kw and kGad in MCA perforator territory (β = 1.5 × 103, P = 0.049), medial-temporal lobe (β = 3.5 × 103, P = 0.032), and hippocampus (β = 3.4 × 103, 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 kGad 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/kGad is likely to be different, as manifested by correlations in only three brain regions for each pair of comparison between kw and Ktrans or kGad.
Highlights
The blood-brain barrier (BBB) plays important roles in regulating the exchange of substances between blood and brain parenchyma, and protecting the central nervous system (CNS) from neurotoxic substances circulating in the blood (Sweeney et al, 2019)
The highest BBB leakage to gadolinium-based contrast agents (GBCAs) was found in the hippocampus (7.6 × 10−4 min−1), which was significantly higher than the whole-brain average Ktrans
To the best of our knowledge, this is the first time that water exchange rate across the BBB was directly compared with BBB permeability to GBCAs
Summary
The blood-brain barrier (BBB) plays important roles in regulating the exchange of substances between blood and brain parenchyma, and protecting the central nervous system (CNS) from neurotoxic substances circulating in the blood (Sweeney et al, 2019). The BBB becomes increasingly permeable to large molecules with advancing age, in patients with vascular dementia and cerebral small vessel disease (cSVD) (Farrall and Wardlaw, 2009; Montagne et al, 2015), while water exchange rate across the BBB shows a reverse trend and declines with aging (Li et al, 2005; Anderson et al, 2020). Dynamic contrast-enhanced MRI (DCE-MRI), which uses gadolinium-based contrast agents (GBCAs), has been widely used to study a broad spectrum of CNS disorders associated with BBB disruption, including multiple sclerosis (MS), ischemic stroke, and brain tumor (Heye et al, 2014; Montagne et al, 2016). Dynamic contrast-enhanced (DCE) MRI using intravenous injection of gadolinium-based contrast agents (GBCAs) is commonly used for imaging blood-brain barrier (BBB) permeability.
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