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

Abstract

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 (′†·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 {parenthesized} 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† para-cellular 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. These suggest the PW† pathway is metabolically active. Excellent agreement of the relative NGM/NWM kpo·vb product ratio with the literature 31PMRSI-MT CMRoxphos ratio confirms the flux property.} We have previously shown 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 co-operativities, polar brain endothelial, neuroglial, and neuronal cells form “gliovascular units.” We hypothesize 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/capillary [in 1 μL tissue]: consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.

Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling

“…As long as the AIF time-course curve shape can be well captured, k io and k ep should be the more reproducible parameters than K trans and v e . With the recent discovery that k io is a measure of on-going Na + ,K + -ATPase turnover [7], the capability to quantify k io using the SSP model potentially ushers DCE-MRI into the emerging field of high-resolution metabolic imaging [8], in addition to its well-known function of quantifying microvascular properties. The parameter k ep could be a better measure of capillary CR permeation than K trans .…”

“…The parameter k ep could be a better measure of capillary CR permeation than K trans . The parameter K trans usually well-approximates the permeability coefficient capillary surface area product, P CR † •S [8,27]. Thus, it can have a significant contribution from the voxel blood volume surface area.…”

“…It provides high-resolution anatomical [lesion size, shape], microvascular [tumor blood volume, capillary permeability] [1–6] and, potentially metabolic [Na + ,K + ATPase activity] information [7,8]. The quantitative estimation of DCE-MRI pharmacokinetic parameters requires knowledge of the time-dependences of the plasma and interstitial compartmental contrast reagent (CR) concentrations, [CR p ](t) and [CR o ](t), respectively.…”

Toward 20 T magnetic resonance for human brain studies: opportunities for discovery and neuroscience rationale

“…From the kinetics, the mean intra-capillary water molecule lifetime can be inferred, with a spatial resolution ≤1 mm. Its reciprocal is proportional to Na + , K + -ATPase (NKA) turnover, a process involving active trans-membrane water cycling [71]. NKA is the brain’s most vital enzyme, consuming over 50 % of ATP per unit time.…”

“…The first normal human resting-state brain k po map (Fig. 7) has been obtained at 7 T [71]. It is interesting that NKA activity per capillary is greater in white matter (WM) than in gray matter in the awake patient.…”