Shutter-speed analysis of dynamic-contrast-agent (CA)-enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τb) and blood volume fraction (vb; capillary density-volume product (ρ†V)) in a high-resolution 1H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, kpo (τb-1), averages 3.2 and 2.9 s-1 in resting-state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) kpo differences are dominated by capillary water permeability (PW†), not size, differences. NWM and NGM voxel kpo and vb values are independent. Quantitative analyses of concomitant population-averaged kpo, vb variations in normal and normal-appearing MS brain ROIs confirm PW† dominance. (B) PW† is dominated (>95%) by a trans(endothelial)cellular pathway, not the PCA† paracellular route. In MS lesions and GBM tumors, PCA† increases but PW† decreases. (C) kpo tracks steady-state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional kpo correlates with literature MRSI ATP (positively) and Na+ (negatively) tissue concentrations. This suggests that the PW† pathway is metabolically active. Excellent agreement of the relative NGM/NWM kpovb product ratio with the literature 31PMRSI-MT CMRoxphos ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (kio) is proportional to plasma membrane P-type ATPase turnover, likely due to active trans-membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form "gliovascular units." We hypothesize that a chain of water cycling processes transmits brain metabolic activity to kpo, letting it report neurogliovascular unit Na+,K+-ATPase activity. Cerebral kpo maps represent metabolic (functional) neuroimages. The NGM 2.9 s-1 kpo means an equilibrium unidirectional water efflux of ~1015 H2O molecules s-1 per capillary (in 1 μL tissue): consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.
- High resolution
- Na,K pump
ASJC Scopus subject areas
- Molecular Medicine
- Radiology Nuclear Medicine and imaging