Gray matter blood-brain barrier water exchange dynamics are reduced in progressive multiple sclerosis

Abstract

Background and purpose: To compare transcapillary wall water exchange, a putative marker of cerebral metabolic health, in brain T₂ white matter (WM) lesions and normal appearing white and gray matter (NAWM and NAGM, respectively) in individuals with progressive multiple sclerosis (PMS) and healthy controls (HC).

Methods: Dynamic-contrast-enhanced 7T MRI data were obtained from 19 HC and 23 PMS participants. High-resolution pharmacokinetic parametric maps representing tissue microvascular and microstructural properties were created by shutter-speed (SS) paradigm modeling to obtain estimates of blood volume fraction (v_b ), water molecule capillary efflux rate constant (k_po ), and the water capillary wall permeability surface area product (P_w S ≡ v_b *k_po ). Linear regression models were used to investigate differences in (i) k_po and P_w S between groups in NAWM and NAGM, and (ii) between WM lesions and NAWM in PMS.

Results: High-resolution parametric maps were produced to visualize tissue classes and resolve individual WM lesions. Normal-appearing gray matter k_po and P_w S were significantly decreased in PMS compared to HC (p ≤ .01). Twenty-one T₂ WM lesions were analyzed in 10 participants with PMS. k_po was significantly decreased in WM lesions compared to PMS NAWM (p < .0001).

Conclusions: Transcapillary water exchange is reduced in PMS NAGM compared to HC and is further reduced in PMS WM lesions, suggesting pathologically impaired brain metabolism. k_po provides a sensitive measure of cerebral metabolic activity and/or coupling, and can be mapped at higher spatial resolution than conventional imaging techniques assessing metabolic activity.

Keywords: DCE-MRI; blood-brain barrier; cerebral metabolism; neurodegeneration; progressive multiple sclerosis.

FIGURE 1

Single‐voxel normal appearing gray matter (NAGM; yellow, inset) and sagittal sinus (red, inset) R ₁ (≡1/T₁) data from a 61‐year‐old with progressive multiple sclerosis (maps shown in Figure 2). Panel A illustrates the temporally aligned tissue (blue circles) and blood (red diamonds) response curves as a function of time during the shutter‐speed dynamic‐contrast‐enhanced MRI acquisition (note left and right y‐axes for tissue and blood, respectively). The corresponding R _1b versus R _1t (R ₁ in tissue) plot and associated Shutter‐Speed Paradigm fitted curve (solid black line) obtained from Equation (1) are shown in panel B

FIGURE 2

Parametric maps and group comparisons. Voxelwise parametric maps (left) from a 64‐year‐old healthy control (mean normal appearing white matter [NAWM] R _1exv = 0.89, k _po = 3.71, v _b = 0.016, P _w S = 0.063) and a 61‐year‐old with progressive multiple sclerosis (PMS, 37‐year disease duration; mean NAWM R _1exv = 0.81, k _po = 2.73, v _b = 0.017, P _w S = 0.048), and corresponding group box plots (right). Color bars illustrate parametric map scales. Arrows on PMS maps highlight two hypointense WM lesions demonstrating conspicuously reduced R _1exv and k _po, suggesting permanent tissue damage (eg, potentially axonal and/or myelin loss) and a hypometabolic state, respectively. NAWM R _1exv, k _po, and P _w S are appreciably decreased in this participant with PMS. Boxplots illustrate average WM (left), WM lesions (middle), and GM (right) for all participants. Note that unscaled p _b (and P _w S′ = k _po*p _b) maps are shown for ease of visualization, and scaled v _b (≡p _b*f _w, and P _w S = k _po*v _b) values are reported for each tissue. Outliers are illustrated with “+” symbols. *p < .05; **p ≤ .01; ***p ≤ .0001. GM, gray matter; HC, healthy control; k _po, water molecule capillary efflux rate constant; p_b, mole fraction of tissue water in blood; P _w S, water capillary wall permeability surface area product (≡v _b*k _po); R _1exv, extravascular ¹H₂O relaxation rate constant; v _b, blood volume fraction; WM, white matter