| Magnetic resonance imaging (MRI) techniques employing contrast reagents (CRs) have been developed to probe tissue vascular properties. Most techniques involve serially acquiring T1-weighted images before, during, and after administration of a paramagnetic CR which passes from the intravascular spaces into the interstitia of most tissues, thereby enhancing parenchymal image contrast. In the pharmacokinetic analysis of such data, the CR is treated as a tracer and its concentration, [CR], time-course is crucial. Unlike nuclear medicine, the CR is detected indirectly, via its effect on some property of the 1H2O NMR signal. For quantitative CR bolus tracking (B-T) analysis, the property often chosen is the longitudinal 1H2O relaxation rate constant, R1 (≡ 1/T 1). Universally, a linear dependence such as R1 = r 1[CR] + R10 is assumed, where r1 is the longitudinal relaxivity, and R10 is the pre-CR rate constant. While true for a homogeneous solution, the use of such a relationship for tissue presupposes that equilibrium transcytolemmal water exchange is effectively infinitely fast---what is commonly referred to as the fast exchange limit (FXL) of the NMR time-scale. Quantitative pharmacokinetic analysis of CR B-T data reported in the literature employ exclusively the FXL assumption. However, recent results demonstrate that water exchange is generally not sufficiently frequent to prevent significant departure from the FXL at rather typical in vivo [CR] values.;We present a theory, BOLERO (BOLus Enhanced Relaxation Overview), featuring a two-site exchange model combined with Kety pharmacokinetic theory which encompasses the FXL, the fast exchange regime (FXR), and the slow exchange regime (SXR). BOLERO permits modeling of MRI CR B-T data while either constrained to the FXL, or allowed access to the FXR and SXR to extract the physiologically relevant pharmacokinetic parameters K trans (extravasation transfer constant), ve (extracellular water fraction), and taui (average intracellular water lifetime). We show with simulated data, rodent data, and human data that major underestimations (up to 200%) of these parameters can result when one is analyzing a system with the FXL model while the system does, in reality, sortie into the FXR. BOLERO analysis shows promise for in vivo vascular phenotyping in pathophysiology. |
