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

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 (vb ) and capillary water efflux rate constant (kpo ) 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, vb and kpo averaged 1.7 (±0.5) mL/100 g of tissue and 2.1 (±1.1) s-1 , respectively. While vb showed minimal changes over the 40-year-age span of participants, kpo 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 kpo 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 kpo observed here is consistent with compromised NGVU metabolism in older individuals and the dysregulated cellular bioenergetics that accompany normal brain aging.

Longitudinal relaxographic imaging of white matter hyperintensities in the elderly.

BACKGROUND: Incidental white matter hyperintensities (WMHs) are common findings on T2-weighted magnetic resonance images of the aged brain and have been associated with cognitive decline. While a variety of pathogenic mechanisms have been proposed, the origin of WMHs and the extent to which lesions in the deep and periventricular white matter reflect distinct etiologies remains unclear. Our aim was to quantify the fractional blood volume (vb) of small WMHs in vivo using a novel magnetic resonance imaging (MRI) approach and examine the contribution of blood-brain barrier disturbances to WMH formation in the deep and periventricular white matter. METHODS: Twenty-three elderly volunteers (aged 59-82 years) underwent 7 Tesla relaxographic imaging and fluid-attenuated inversion recovery (FLAIR) MRI. Maps of longitudinal relaxation rate constant (R1) were prepared before contrast reagent (CR) injection and throughout CR washout. Voxelwise estimates of vb were determined by fitting temporal changes in R1 values to a two-site model that incorporates the effects of transendothelial water exchange. Average vb values in deep and periventricular WMHs were determined after semi-automated segmentation of FLAIR images. Ventricular permeability was estimated from the change in CSF R1 values during CR washout. RESULTS: In the absence of CR, the total water fraction in both deep and periventricular WMHs was increased compared to normal appearing white matter (NAWM). The vb of deep WMHs was 1.8 ± 0.6 mL/100 g and was significantly reduced compared to NAWM (2.4 ± 0.8 mL/100 g). In contrast, the vb of periventricular WMHs was unchanged compared to NAWM, decreased with ventricular volume and showed a positive association with ventricular permeability. CONCLUSIONS: Hyperintensities in the deep WM appear to be driven by vascular compromise, while those in the periventricular WM are most likely the result of a compromised ependyma in which the small vessels remain relatively intact. These findings support varying contributions of blood-brain barrier and brain-CSF interface disturbances in the pathophysiology of deep and periventricular WMHs in the aged human brain.