7 Tesla MRI Bolus CR Studies of Human BBB Permeability

描述（由申请人提供）：该项目的长期目标是通过对组织1H2O MR信号纵向弛豫时间常数（T1）的影响，对（动态对比增强）DCE-MRI进行绝对量化，即注射造影剂（CR）通过后的高时空分辨率记录。虽然适用于所有组织，但经批准的低mw Gd（III）螯合CRs是血脑屏障（BBB）完整性的特别敏感的探针。甚至可以检测到主要决定血脑屏障紧密度的旁（内皮）细胞通路的轻微妥协。特别是，这项工作利用了两个最近的发展-超高磁场[BB0 e 7特斯拉(T)]全身MRI的可用性增加，以及“快门速度”DCE-MRI药代动力学模型（SSM）的引入。前者很重要，因为最近有研究表明，CR的可检测性随着BB0的增加而增加：即，检测阈值CR浓度随着BB0的增加而降低。结果之一是，至少通过4T，可以检测到单体Gd（III）螯合物外渗，甚至可以通过正常血脑屏障。这与传统观点相反，只是因为目前临床使用的BB0值[d 3T]不容易检测到：它发生在所有诊断性CR MRI检查中。SSM纠正了几乎普遍使用的标准DCE-MRI药代动力学模型（SM）中的一个重大系统误差。SSM包含平衡室间水交换动力学的影响，这是至关重要的，因为CR检测是间接的-通过它对1H2O的影响。如果忽略快门速度的影响，DCE-MRI药代动力学参数、Ktrans（体积加权CR反式血脑屏障速率常数）、vb（血容量分数）和ve（间质体积分数）可能出现较大的系统误差。例如，这种SM错误否定了SSM DCE-MRI乳腺癌筛查中非常高的（迄今为止完美的）特异性。SSM认识到DCE-MRI本质上是一种双探针（CR和水）技术。本文提出，在高BB0 （7T）下，SSM将允许全脑CR和水的渗透系数毛细管表面积产物（PCRS和PWS）的高分辨率映射。由于S是一个广泛的性质，它随vb增加。因此，PS图通常显示灰质（GM）比白质更强，因为GM的vb值更大。然而，有人建议用PCR/ PWS的比值来衡量PCR/PW的密集性。这种新的成像生物标志物具有非常大的动态范围[bbb10 -2（肌肉组织）到10-5（正常大脑）]，并且应该对正常大脑解剖变异和血脑屏障损害非常敏感，从细微到严重。三个具体目标是：1)优化7T时的DCE-MRI，绘制整个2)正常脑，以及整个3)外观正常、急性包含病变、慢性病变多发性硬化症（MS）脑的PCR/PW图谱。正常脑中性CR0和阴离子CR2-的比较将探讨PCR的分子机制。这项工作涉及物理学、物理化学、生物物理学、生理学的各个方面，并涉及许多病理学，包括多发性硬化症、中风、癌症和心肌疾病。公共卫生相关性：本项目涉及在7特斯拉(T)的超高磁场下对人脑进行（动态对比增强）DCE-MRI研究。新的“快门速度”药代动力学模型（SSM）在本拨款的当前阶段开发，允许对DCE-MRI数据进行绝对定量分析。虽然该项目将研究正常和多发性硬化症（MS）人类大脑，但SSM DCE-MRI也适用于身体所有部位的癌症，正常和患病人类心肌的研究，以及许多其他病理。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.