Nondiamagnetic Agents in In Vivo 23Na and 1H2O MR

体内非抗磁剂 23Na 和 1H2O MR

• 批准号: 6545074
• 负责人: CHARLES S. SPRINGER
• 金额: $ 54.18万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545074
• 关键词: Nondiamagnetic; Agents; Vivo; 23Na; 1H2O

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.

描述（由申请人提供）：长期目标是探索和演示非抗磁性（此处为顺磁性）剂对两种最强组织 NMR 信号的应用：1H2O 和 23Naaq（此处为 1H2O）。拟议的项目致力于解决日益重要的动态对比增强[推注跟踪（B-T）] MRI 方法：对比剂的高时空分辨率记录[CR；单体 Gd(III) 螯合物] 推注后通过。 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病症。目前的资助期工作使我们处于两个主要 MRI 趋势的结合点：增加 CR 使用和增加磁场强度 [B0，以特斯拉 (T) 为单位]。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，并且普遍假设线性 [CR] 依赖于测量的 1H2O 弛豫时间 (T1) 倒数。然而，我们表明，在临床 B0 (< 3 T) 处（正是做出这一假设），所需的 CR 水平足够高，以致会产生重大错误。平衡跨细胞膜水交换动力学使得系统不处于线性关系所需的快速交换极限（FXL）。一项新的分析 BOLERO（BOLus 增强松弛概述）将交换动力学纳入松弛和药代动力学速率定律中，可以处理在临床 B0 上获得的快速交换机制 (FXR)，并可以产生（并绘制）准确、绝对的 B-T 参数测量：灌注、血管壁 CR 渗透性和细胞外体积分数。然而，初步研究和 BOLERO 模拟预测了几个独特的高场实验，我们在这里建议用 7 T 的大鼠进行实验。我们的具体目标有两个主要类别：A. 非大脑 ROI 和 B. 大脑 ROI。对于 A 中的肌肉组织，我们将测试我们可以检测到标准 CR 剂量 -1/10 (0.1 mmol/kg) 的假设，之后系统实际上处于 FXL 中。这将能够通过阴离子 CR 和中性 CR 的比较，首次对 CR 弛豫率（[CR] 和 T1-1 相关系数）进行体内评估。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质水分数的新参数。我们还将在缺血性肌肉中比较这些。对于 B，我们期望检测到轻微的 CR 血脑屏障渗透。尽管核医学 CR 示踪剂研究预测，但由于 < 3 T 的检测阈值不够低，出现了相反的传统 MRI 假设。我们还将准确测量 CR 首过超精细 BALD（血液剂水平依赖性）效应（不是临床 B0 的动态磁敏度对比度），产生微血管动脉输入功能、脑血容量以及平均血管壁水渗透率和直径的绝对测量值。我们将在胶质肉瘤肿瘤生长和新型放射治疗缩小方面进行比较。它结合了数学、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。