The long-term goal of this project is absolute quantification of (Dynamic-Contrast-Enhanced) DCE-MRI, the high spatiotemporal resolution recording of contrast reagent (CR) passage following bolus injection, via its effect on the tissue 1H2O MR signal longitudinal relaxation time constant (T1). Though applied to all tissues, the approved, low-MW Gd(III) chelate CRs are particularly sensitive probes of blood-brain-barrier (BBB) integrity. Even slight compromises of the para(endothelial)cellular pathway mainly defining BBB tightness are detected. In particular, this work exploits two recent developments - the increased availability of ultra-high magnetic field [BB0 e 7 Tesla (T)] whole-body MRI, and the introduction of the """"""""Shutter-Speed"""""""" DCE-MRI pharmacokinetic model (SSM). The former is important because it has recently been shown that CR detectability increases with BB0: i.e., the detection threshold CR concentration decreases with increasing BB0. One consequence is that, at least by 4T, it is possible to detect monomeric Gd(III) chelate extravasation across even the normal BBB. This is contrary to conventional wisdom only because it is not easily detectable at BB0 values [d 3T] currently used clinically: it occurs in all diagnostic CR MRI examinations. The SSM corrects a significant systematic error in the almost universally used Standard DCE-MRI pharmacokinetic Model (SM). SSM incorporates the effects of equilibrium intercompartmental water exchange kinetics, which are crucial since CR detection is indirect - via its effect on 1H2O. Large systematic errors in DCE-MRI pharmacokinetic parameters, Ktrans (volume-weighted CR trans-BBB rate constant), vb (blood volume fraction), and ve (interstitial volume fraction) can occur if shutter-speed effects are ignored. [For example, such SM errors negate very high (so far perfect) specificity in SSM DCE-MRI breast cancer screening.] The SSM recognizes that DCE-MRI is an intrinsically dual probe (CR and water) technique. It is proposed here that, at high BB0 (7T), SSM will allow high-resolution mapping of the permeability coefficient capillary surface area products for CR and water (PCRS and PWS) for the whole brain. Since S is an extensive property, it increases with vb. Thus, PS maps usually show greater intensity in gray matter (GM) than white matter because of the larger GM vb value. However, it is proposed that the ratio PCRS/PWS measures the intensive property PCR/PW. This new imaging biomarker has a very large dynamic range [>10-2 (musculature) to 10-5 (normal brain)], and should be exquisitely sensitive to normal brain anatomical variations and to BBB compromise, from subtle to major. The three specific aims are to: 1.) optimize DCE-MRI at 7T, and map PCR/PW in the entire 2.) normal brain, and in the entire 3.) normal-appearing, acute lesion-containing, and chronic lesion multiple sclerosis (MS) brain. [Comparison of neutral CR0 and anionic CR2- in the normal brain will probe the PCR molecular mechanism.] This work involves aspects of physics, physical chemistry, biophysics, physiology, and relates to a number of pathologies including MS, stroke, cancer, and myocardial disease.
This project involves (Dynamic-Contrast-Enhanced) DCE-MRI studies of the human brain at ultra-high magnetic field, 7 Tesla (T). The new """"""""Shutter-Speed"""""""" pharmacokinetic model (SSM) developed in the current period of this grant allows absolute quantitative analyses of DCE-MRI data. Though this project will study the normal and multiple sclerosis (MS) human brain, SSM DCE-MRI also applies to cancer in all areas of the body, to studies of normal and diseased human myocardium, and to many other pathologies.
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