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

View Article: PubMed Central - PubMed

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 (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 kpoand 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 kpocorrelates 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−1kpo 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. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd.

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Capillary property space. A plot of biomarker inter‐relationships for population‐averaged NGM and NAGM ROI values in Table 1. Thus, ⟨τb(NAGM)⟩−1/⟨τb(NGM)⟩−1 = 0.80, and vb(NAGM)/vb(NGM) = 1.5, where τb−1 ≡ kpo (τb is the mean capillary water lifetime) and vb the capillary volume fraction. The red curve is the trace of points that satisfy these experimental relationships simultaneously, in a 3D space of brain tissue microvascular properties. The vertical axis is PW†(NGM)/PW†(NAGM), the capillary water permeability coefficient ratio. The oblique axes are the inverse capillary radius ratio, rNGM−1/rNAGM−1 (=rNAGM/rNGM), and the capillary density ratio, ρ†NAGM/ρ†NGM. The coordinates of the curve in regions of reasonable rNAGM/rNGM (gray shading) are consistent only with τb being dominated by the PW† factor. When rNAGM = rNGM (black point), ρ†NAGM = 1.44ρ†NGM, and PW†(NGM) = 1.25PW†(NAGM). PW† is reduced in resting‐state NAGM from its value in resting‐state NGM.
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nbm3294-fig-0008: Capillary property space. A plot of biomarker inter‐relationships for population‐averaged NGM and NAGM ROI values in Table 1. Thus, ⟨τb(NAGM)⟩−1/⟨τb(NGM)⟩−1 = 0.80, and vb(NAGM)/vb(NGM) = 1.5, where τb−1 ≡ kpo (τb is the mean capillary water lifetime) and vb the capillary volume fraction. The red curve is the trace of points that satisfy these experimental relationships simultaneously, in a 3D space of brain tissue microvascular properties. The vertical axis is PW†(NGM)/PW†(NAGM), the capillary water permeability coefficient ratio. The oblique axes are the inverse capillary radius ratio, rNGM−1/rNAGM−1 (=rNAGM/rNGM), and the capillary density ratio, ρ†NAGM/ρ†NGM. The coordinates of the curve in regions of reasonable rNAGM/rNGM (gray shading) are consistent only with τb being dominated by the PW† factor. When rNAGM = rNGM (black point), ρ†NAGM = 1.44ρ†NGM, and PW†(NGM) = 1.25PW†(NAGM). PW† is reduced in resting‐state NAGM from its value in resting‐state NGM.

Mentions: Briefly, we use the relationships kpo(A)/kpo(B) = [PW†(A)/PW†(B)] (rB/rA), and [vb(B)/vb(A)]1/2 = (ρB†/ρA†)1/2(rB/rA), for ROIs A and B. For example, for A = NAGM and B = NGM we plot in 3D capillary property space the trace of all points that simultaneously satisfy the experimental population‐averaged kpo(A)/kpo(B) and [vb(B)/vb(A)]1/2 ratios (Fig. A1). The experimental data are incompatible with the mean capillary radius and density simultaneously remaining invariant from NGM to NAGM. The brain literature generally indicates it more likely that chronic vb differences are due to capillary density (ρ†) differences than to capillary dilation or constriction (r changes) 38, 39, 40, 41. (Even in an acute hypercapnic perturbation, the microvascular radii for the dominant capillary volume fraction remain unchanged 41. The very smallest capillaries, normally effectively occluded, are opened during the hypercapnia – there is some “recruitment” – but in most capillaries there is a blood velocity increase 41.) Therefore, the Figure 1A results clearly indicate that the mean capillary water permeability in MS NAGM is reduced from its value in NGM (the NGM → NAGM transition). For equal mean capillary radii, PW†(NAGM) = 0.8PW†(NGM), PW† is reduced by 20%. Recall that r is the average for a large number of capillaries. Only 100 capillaries μL−1 means 4000 per 40 μL voxel. The Table 1 ROIs represent 80–100 voxels. 100 voxel ROIs in six subjects yield averages over 2 400 000 capillaries.


Mapping human brain capillary water lifetime: high ‐ resolution metabolic neuroimaging
Capillary property space. A plot of biomarker inter‐relationships for population‐averaged NGM and NAGM ROI values in Table 1. Thus, ⟨τb(NAGM)⟩−1/⟨τb(NGM)⟩−1 = 0.80, and vb(NAGM)/vb(NGM) = 1.5, where τb−1 ≡ kpo (τb is the mean capillary water lifetime) and vb the capillary volume fraction. The red curve is the trace of points that satisfy these experimental relationships simultaneously, in a 3D space of brain tissue microvascular properties. The vertical axis is PW†(NGM)/PW†(NAGM), the capillary water permeability coefficient ratio. The oblique axes are the inverse capillary radius ratio, rNGM−1/rNAGM−1 (=rNAGM/rNGM), and the capillary density ratio, ρ†NAGM/ρ†NGM. The coordinates of the curve in regions of reasonable rNAGM/rNGM (gray shading) are consistent only with τb being dominated by the PW† factor. When rNAGM = rNGM (black point), ρ†NAGM = 1.44ρ†NGM, and PW†(NGM) = 1.25PW†(NAGM). PW† is reduced in resting‐state NAGM from its value in resting‐state NGM.
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nbm3294-fig-0008: Capillary property space. A plot of biomarker inter‐relationships for population‐averaged NGM and NAGM ROI values in Table 1. Thus, ⟨τb(NAGM)⟩−1/⟨τb(NGM)⟩−1 = 0.80, and vb(NAGM)/vb(NGM) = 1.5, where τb−1 ≡ kpo (τb is the mean capillary water lifetime) and vb the capillary volume fraction. The red curve is the trace of points that satisfy these experimental relationships simultaneously, in a 3D space of brain tissue microvascular properties. The vertical axis is PW†(NGM)/PW†(NAGM), the capillary water permeability coefficient ratio. The oblique axes are the inverse capillary radius ratio, rNGM−1/rNAGM−1 (=rNAGM/rNGM), and the capillary density ratio, ρ†NAGM/ρ†NGM. The coordinates of the curve in regions of reasonable rNAGM/rNGM (gray shading) are consistent only with τb being dominated by the PW† factor. When rNAGM = rNGM (black point), ρ†NAGM = 1.44ρ†NGM, and PW†(NGM) = 1.25PW†(NAGM). PW† is reduced in resting‐state NAGM from its value in resting‐state NGM.
Mentions: Briefly, we use the relationships kpo(A)/kpo(B) = [PW†(A)/PW†(B)] (rB/rA), and [vb(B)/vb(A)]1/2 = (ρB†/ρA†)1/2(rB/rA), for ROIs A and B. For example, for A = NAGM and B = NGM we plot in 3D capillary property space the trace of all points that simultaneously satisfy the experimental population‐averaged kpo(A)/kpo(B) and [vb(B)/vb(A)]1/2 ratios (Fig. A1). The experimental data are incompatible with the mean capillary radius and density simultaneously remaining invariant from NGM to NAGM. The brain literature generally indicates it more likely that chronic vb differences are due to capillary density (ρ†) differences than to capillary dilation or constriction (r changes) 38, 39, 40, 41. (Even in an acute hypercapnic perturbation, the microvascular radii for the dominant capillary volume fraction remain unchanged 41. The very smallest capillaries, normally effectively occluded, are opened during the hypercapnia – there is some “recruitment” – but in most capillaries there is a blood velocity increase 41.) Therefore, the Figure 1A results clearly indicate that the mean capillary water permeability in MS NAGM is reduced from its value in NGM (the NGM → NAGM transition). For equal mean capillary radii, PW†(NAGM) = 0.8PW†(NGM), PW† is reduced by 20%. Recall that r is the average for a large number of capillaries. Only 100 capillaries μL−1 means 4000 per 40 μL voxel. The Table 1 ROIs represent 80–100 voxels. 100 voxel ROIs in six subjects yield averages over 2 400 000 capillaries.

View Article: PubMed Central - PubMed

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 (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 kpoand 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 kpocorrelates 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−1kpo 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. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd.

No MeSH data available.


Related in: MedlinePlus