Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging

Abstract

Background and purpose: Transvascular water exchange plays a key role in the functional integrity of the blood-brain barrier (BBB). In white matter (WM), a variety of imaging modalities have demonstrated age-related changes in structure and metabolism, but the extent to which water exchange is altered remains unclear. Here, we investigated the cumulative effects of healthy aging on WM capillary water exchange.

Methods: A total of 38 healthy adults (aged 36-80 years) were studied using 7T dynamic contrast enhanced MRI. Blood volume fraction (v_b ) and capillary water efflux rate constant (k_po ) were determined by fitting changes in the ¹ H₂ O longitudinal relaxation rate constant (R₁ ) during contrast agent bolus passage to a two-compartment exchange model. WM volume was determined by morphometric analysis of structural images.

Results: R₁ values and WM volume showed similar trajectories of age-related decline. Among all subjects, v_b and k_po averaged 1.7 (±0.5) mL/100 g of tissue and 2.1 (±1.1) s^-1 , respectively. While v_b showed minimal changes over the 40-year-age span of participants, k_po declined 0.06 s^-1 (ca. 3%) per year (r = -.66; P < .0005), from near 4 s^-1 at age 30 to ca. 2 s^-1 at age 70. The association remained significant after controlling for WM volume.

Conclusions: Previous studies have shown that k_po tracks Na⁺ , K⁺ -ATPase activity-dependent water exchange at the BBB and likely reflects neurogliovascular unit (NGVU) coupled metabolic activity. The age-related decline in k_po observed here is consistent with compromised NGVU metabolism in older individuals and the dysregulated cellular bioenergetics that accompany normal brain aging.

Keywords: Aging; blood brain barrier, DCE-MRI, water cycling; white matter.

Figure 1.

Linear regression plots with age of ROI-averaged WM (a) ¹H₂O R₁ values, and (b) WM volume, normalized to total intracranial volume (ICV). Both R₁ and volume fraction are independent of age in subjects younger than ca. 60 years, but decline significantly thereafter. Arrows indicate the change points determined by numerical optimization. Outlying, influential R₁ values in two subjects are excluded. (c) Regression plot of R₁ values vs. WM volume fraction. Inset shows fit residuals.

Figure 2.

(a) Pixel-wise WM ¹H₂O R₁ values in a 68 year-old male. The horizontal axis shows R₁ values across the imaged slice, after skull removal and masking of gray matter and CSF regions. The vertical axis (removed for clarity) is proportional to the number of voxels and the scale is constant across the three plots. The time after CA injection is given at left. The median value of the R₁ distribution increases ca. 30 seconds (s) after injection as [CA] increases, and then decreases at longer times as CA washes out. The corresponding R₁ maps are shown at right, with identical grayscale applied to each.

Figure 3.

A representative WM ROI (yellow, upper left) R₁ vs. R_1b plot from a 69 year-old male. The solid curve represents the best fitting of the data to Eqn. [1]. Residual l₂-norm is 0.016 (0.020 ± 0.013, all datasets). The inset shows the blood (filled markers) and tissue (open) R₁ time-courses. A temporal correction of 2–3 sec (1 frame) has been applied to the blood data to account for delay in CA bolus arrival in the sagittal sinus (red voxel, upper left).

Figure 4.

Linear regression plots of v_b (inset) and k_po by age. The error bars (not all of which are visible on this scale) reflect standard deviation of ROI mean estimates for individual subjects based on Monte Carlo simulations. The solid lines represent the best linear fittings to the data.