Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging

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 (τ(b)) and blood volume fraction (v(b); capillary density-volume product (ρ(†)V)) in a high-resolution (1)H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, k(po) (τ(b)(-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) k(po) differences are dominated by capillary water permeability (P(W)(†)), not size, differences. NWM and NGM voxel k(po) and v(b) values are independent. Quantitative analyses of concomitant population-averaged k(po), v(b) variations in normal and normal-appearing MS brain ROIs confirm P(W)(†) dominance. (B) P(W)(†) is dominated (>95%) by a trans(endothelial)cellular pathway, not the P(CA)(†) paracellular route. In MS lesions and GBM tumors, P(CA)(†) increases but P(W)(†) decreases. (C) k(po) tracks steady-state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k(po) correlates with literature MRSI ATP (positively) and Na(+) (negatively) tissue concentrations. This suggests that the P(W)(†) pathway is metabolically active. Excellent agreement of the relative NGM/NWM k(po)v(b) product ratio with the literature (31)PMRSI-MT CMR(oxphos) ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k(io)) 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 k(po), letting it report neurogliovascular unit Na(+),K(+)-ATPase activity. Cerebral k(po) maps represent metabolic (functional) neuroimages. The NGM 2.9 s(-1) k(po) means an equilibrium unidirectional water efflux of ~10(15) H2O molecules s(-1) per capillary (in 1 μL tissue): consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.