Nondiamagnetic Agents in In Vivo 23Na and 1H2O MR

描述（由申请人提供）：长期目标是探索和证明非抗磁性（此处为顺磁性）试剂对两种最强组织NMR信号的作用：1H 2 O和23 Naaq（此处为1H 2 O）。提出的项目涉及日益重要的动态对比增强[团注跟踪（B-T）] MRI方法：团注后造影剂[CR;单体Gd（III）螯合物]通道的高时空分辨率记录。B-T适应症见于癌症、心肌缺血、中风、多发性硬化和许多其他病理。目前的资助期工作使我们处于两个主要MRI趋势的联系：CR使用增加和磁场强度增加[B 0，特斯拉（T）]。我们已经发现，阈值检测浓度，[CR]，随着B 0的增加而降低。定量B-T药代动力学需要[CR]时间依赖性，并且普遍假设[CR]对测量的1H 2 O弛豫时间（T1）倒数的线性依赖性。然而，我们表明，在临床B 0（< 3 T）-正是在这种假设-所需的CR水平是足够高的，导致重大错误。平衡跨细胞膜水交换动力学是这样的，即系统不处于线性关系所需的快速交换极限（FXL）。一种新的分析，BOLERO（BOLus增强舒张概述），将交换动力学纳入舒张和药代动力学速率定律，可以处理在临床B 0时获得的快速交换方案（FXR），并可以产生（和映射）准确的绝对B-T参数测量：灌注，血管壁CR渗透性和细胞外容积分数。然而，初步研究和BOLERO模拟预测了几个独特的高场实验，我们建议在这里与大鼠在7 T。我们的具体目标有两大类：A.非脑ROI，和B。脑ROI。使用A中的肌肉组织，我们将检验我们可以检测到CR剂量为标准剂量的约1/10（0.1 mmol/kg）的假设，之后系统实际上处于FXL中。这将允许首次在体内评价CR弛豫率（[CR]和T1-1相关系数），并比较阴离子和中性CR。在同一制剂中的后续标准剂量将产生测量平均细胞膜水渗透性和细胞大小以及细胞溶质水分数的新参数。我们也将在缺血性肌肉中比较这些。使用B，我们预期检测到轻微的CR血脑屏障渗透。虽然核医学CR示踪研究预测了相反的常规MRI假设，但由于< 3 T的检测阈值不够低，因此出现了相反的假设。我们还将准确测量CR首过超精细BALD（血液制剂水平依赖性）效应（而不是临床B 0时的动态敏感性对比），从而获得微血管动脉输入功能、脑血容量以及平均血管壁透水性和直径的绝对测量值。我们将比较这些在胶质肉瘤肿瘤生长和新的放射性萎缩。这结合了数学，物理，化学，生物物理学，生物工程，生理学和生物医学的各个方面。

DESCRIPTION (provided by applicant): 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.