Synopsis

This is the syllabus for a Sunrise Educational Session presentation.

The introduction of what is now called [Dynamic-Contrast-Enhanced] DCE-MRI began to shift MRI from its anatomic era into [in this case] a vascular era. In 1991, at DCE-MRI’s beginning, it was asserted that the tissue longitudinal ¹H₂O relaxation rate constant [R₁ = 1/T₁] value is linearly related to Gd(III)‑based contrast agent tissue concentration, [CA_t].¹ The next year, 1992, radio-labeled Gd(III) was used to demonstrate the dependence is actually non-linear, curving downward with increasing [CR_t].² This was ascribed to the effect of equilibrium transcytolemmal water exchange,² since there had been NMR studies of the latter phenomenon in cell suspensions reported already for twenty years.

Soon it became clear that imposing the linear R₁ = f([CA]) constraint on the analysis is the DCE‑MRI manifestation of the tracer pharmacokinetic paradigm [TP]: for a classic tracer, one cannot distinguish whether the tracer molecule is present [in this case] in the parenchymal interstitium, the cellular cytoplasms, or both – the loci of almost all tissue water. The physical rationalization, explained in back-to-back papers, is the hope that water exchange kinetics are sufficiently fast to make CA compartmentalization as ambiguous as that of a classic tracer.^3,4 The TP application to DCE MRI has been comprehensively reviewed.⁵

If, however, the exchange kinetics are not sufficiently fast, we have shown in a number of papers the shutter-speed pharmacokinetic paradigm [SSP] can supersede the tracer method, and account for this possibility.^6-16 The shutter-speed approach marries the classic Bloch/McConnell MR exchange relaxation matrix to the classic Kety tracer extravasation rate law. It accounts for the exchange kinetics with only one parameter, the equilibrium cellular water molecule efflux rate constant, k_io [the reciprocal of the ROI or voxel average intracellular water lifetime, tau_i]. The TP is the SSP special case in the discrete limit when the transcytolemmal MR shutter-speed vanishes.¹⁷ An important advantage is that k_io magnitudes extracted from in vivo DCE-MRI data can be compared with those measured with high precision in more rigorous ex vivo cell suspension and perfused, functioning [heart, brain] tissue NMR studies. The good agreement in scale^6-17 provides an independent validation of the shutter-speed paradigm.

At first, SSP k_io determination was accomplished to remove systematic errors in the traditional DCE‑MRI parameters, K^trans and v_e, caused by its TP neglect [implicit assumption; k_io approaches infinity]. The CA extravasation transfer constant [K^trans] and the extracellular volume fraction [v_e] are not so readily independently validated as k_io. The screening of breast^10,11,13 and prostate^14-16 cancer is improved particularly by the SSP correction of K^trans. Furthermore, the k_io value itself provides important information: increases in the ROI-averaged value can be used to grade prostate cancer,¹⁶ and the decrease of the breast tumor-averaged value after the first neoadjuvant chemotherapy [NACT] cycle is a good predictor of favorable ultimate NACT outcome.¹⁸

Most importantly, however, it was recently discovered that k_io has a metabolically active component,^19,20 in addition to its passive pathway that had always been assumed exclusive. While changes in the k_io(passive) value are determined mainly by changes in the average cell diameter reciprocal [if the cell swells, k_io(p) decreases], alterations of the k_io(active) component are determined by changes in the cell membrane Na⁺,K⁺-ATPase [NKA] enzyme activity.^19,20 Changes in cell size and NKA activity usually occur simultaneously: one cannot be determined accurately without accounting for the other. The NKA pump is present in all animal cell membranes, and is responsible for the membrane potential, the trans-membrane [Na⁺] and [K⁺] gradients, and driving almost all secondary active membrane transporters. Thus, NKA is perhaps biology’s most vital enzyme. It has not before been possible to measure its on-going activity in vivo, let alone map this with high spatial-resolution. The k_io parameter has a supra-intensive²¹ nature: it is independent of the ROI or voxel cell density. Thus, given its basis in ¹H₂O MRI, the SSP promises the highest possible metabolic imaging resolution currently available – and of an enzyme kinetic biomarker of ubiquitous importance. The NKA enzyme is responsible for the majority of ATP consumption. This can move DCE-MRI forward into a new metabolic era.

Acknowledgements

References

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