The long-term goal is to explore and demonstrate the applications of non-diamagnetic (here, paramagnetic) agent effects on the two strongest tissue NMR signals: 1H2O and 23Naaq (here, 1H2O). Projects proposed address the increasingly important dynamic- contrast-enhanced [bolus-tracking (B-T)] MRI approach: high spatiotemporal resolution recording of contrast reagent [CR; monomeric Gd(III) chelates] passage after bolus injection. B-T indications are found in cancer, myocardial ischemia, stroke, multiple sclerosis, and many other pathologies. Current grant period work has put us at the nexus of two major MRI trends: increasing CR usage, and increasing magnetic field strengths [B0, in Tesla (T)]. We have found that the threshold detection concentration, [CR], decreases with increasing B0. Quantitative B-T pharmacokinetics require the [CR] time-dependence, and a linear [CR] dependence on the measured 1H2O relaxation time (T1) reciprocal is universally assumed. However, we show that at clinical B0s (< 3 T) - precisely where this assumption is made - the CR level required is sufficiently high that significant errors are incurred. Equilibrium transcytolemmal water exchange kinetics are such that the system is not in the fast-exchange-limit (FXL,) required by the linear relationship. A new analysis, BOLERO (BOLus Enhanced Relaxation Overview), incorporating exchange kinetics into relaxation and pharmacokinetic rate laws, can handle the fast-exchange-regime (FXR) that does obtain at clinical B0s, and can yield (and map) accurate, absolute B-T parameters measuring: perfusion, vessel wall CR permeability, and extracellular volume fraction. However, preliminary studies and BOLERO simulations predict several unique high field experiments, which we propose here with rats at 7 T.
Our specific aims have two major categories: A. Non-brain ROIs, and B. Brain ROIs. With muscIe tissues in A, we will test the hypothesis that we can detect a CR dose -1/10 the standard (0.1 mmol/kg), after which the system is actually in the FXL. This will allow the first in vivo evaluation of CR relaxivity (coefficient relating [CR] and T1-1), with comparison of anionic and neutral CRs. A subsequent standard dose in the same preparation will yield novel parameters measuring mean cytolemmal water permeability and cell size, and cytosolic water fraction. We will also compare these in ischemic muscle. With B, we expect to detect slight CR blood-brain-barrier permeation. Though predicted by nuclear medicine CR tracer studies, the contrary conventional MRI hypothesis arises because the detection threshold at < 3 T is not low enough. We will also accurately measure the CR first-pass hyperfine BALD (Blood Agent Level Dependent) effect (not the dynamic-susceptibility-contrast at clinical B0s), yielding absolute measures of the microvascular arterial input function, the cerebral blood volume, and the mean vessel wall water permeability and diameter. We will compare these in gliosarcoma tumor growth and novel radiotherapeutic shrinking. This combines aspects of mathematics, physics, chemistry, biophysics, bioengineering, physiology, and biomedicine.
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