Nondiamagnetic Agents in In Vivo 23Na and 1H2O MR

描述（由申请人提供）：长期目标是探索和展示非抗磁性（这里是顺磁性）剂对两种最强组织核磁共振信号：1H2O和23Naaq（这里是1H2O）的应用。提出的项目解决日益重要的动态对比增强[丸跟踪（B-T）] MRI方法：造影剂的高时空分辨率记录[CR；单分子Gd（III）螯合物在注射后通过。B-T适应症见于癌症、心肌缺血、中风、多发性硬化症和许多其他疾病。目前的拨款期工作使我们处于两个主要MRI趋势的联系：CR使用的增加和磁场强度的增加[B0，在特斯拉(T)]。我们发现阈值检测浓度[CR]随着B0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]与测量的1H2O弛豫时间（T1）倒数呈线性依赖关系。然而，我们表明，在临床B0s (< 3t) -正是在这个假设的地方-所需的CR水平足够高，导致显著的错误。平衡的经细胞乳水交换动力学使得该系统不在线性关系所要求的快速交换极限（FXL）内。一项新的分析，BOLERO (BOLus Enhanced Relaxation Overview)，将交换动力学纳入松弛和药代动力学速率定律，可以处理快速交换机制（FXR），可以获得临床B0s，并且可以产生（和绘制）准确的，绝对的B-T参数测量：灌注，血管壁CR渗透率和细胞外体积分数。然而，初步研究和BOLERO模拟预测了几个独特的高场实验，我们在这里提出了7岁大鼠的实验。我们的具体目标有两大类：A.非大脑roi， B.大脑roi。对于A中的肌肉组织，我们将测试假设，我们可以检测到CR剂量-标准的1/10 (0.1 mmol/kg)，之后系统实际上处于FXL中。这将允许首次在体内评估CR的弛豫度（与[CR]和T1-1相关的系数），并比较阴离子和中性CR。在相同的制剂中，随后的标准剂量将产生新的参数，测量平均细胞膜水渗透性和细胞大小，以及细胞质水分数。我们也将在缺血肌肉中比较这些。对于B，我们希望检测到轻微的CR血脑屏障渗透。虽然核医学CR示踪剂研究预测，但由于< 3 T的检测阈值不够低，因此出现了与传统MRI相反的假设。我们还将准确测量CR首过超细BALD（血药水平依赖）效应（而不是临床B0s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、平均血管壁水渗透性和直径的绝对测量值。我们将比较这些在胶质瘤肿瘤生长和新的放射治疗萎缩。它结合了数学、物理、化学、生物物理、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.