4 TELSA MRI BOLUS CR STUDIES OF HUMAN BBB PERMEABILITY

4 TELSA MRI BOLUS CR 对人体血脑屏障通透性的研究

• 批准号: 6639713
• 负责人: CHARLES S. SPRINGER
• 金额: $ 39.28万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639713
• 关键词: bioimaging /biomedical imaging; biological fluid transport; blood brain barrier; blood volume; brain cell; clinical research; contrast media; gadolinium; human subject; magnetic resonance imaging; multiple sclerosis; pharmacokinetics; thermodynamics; tissue /cell culture; vascular endothelium permeability; water flow

DESCRIPTION (Verbatim from the Applicant's Abstract): The long-term goal is advancement of dynamic-contrast-enhanced [bolus-tracking (B-T)] MRI - the high (time/space) resolution recording of contrast reagent (CR) passage following bolus injection. Though applied to all tissues, the low-MW Gd(111) chelates are particularly good probes for blood-brain-barrier (BBB) integrity. Even slight compromises of the para(endothelial)cellular pathway defining BBB tightness are detected. Basic B-T pharmacokinetic parameters (CR as tracer) measure: a) perfusion CR delivery, b) capillary wall CR permeability, and c) CR-accessible (interstitial) space. These lead to efficacious B-T studies of multiple sclerosis (MS) white matter (WM) lesions and brain tumors. The usual determination of concentration, [CR], from a linear relationship with the measured longitudinal tissue 'H2O relaxation time (T') reciprocal requires the fast exchange limit (FXL) for equilibrium transcytolemmal water exchange. But, new results show that (though fast) the system departs the FXL at very low tissue [CR]s (<100 I1M). Two-site-exchange (2SX) modeling accounts for this and leads to important conclusions: 1) at clinical fields [< 2 T] most used, it is very difficult to detect CR before the system has departed the FXL and large [CR] errors result assuming it, II) at higher fields (4 T here), the T, and S/N increase allow CR detection at low levels (easily 5 I1M tissue [CR]) sufficient to insure the FXL, 111) time courses of real (thermodynamic) interstitial [CR] (directly from 2SX) and plasma [CR] ("input function" from a great vessel) allow the factorization of all three pharmacokinetic parameters not possible with a single traditional tracer. Three specific aims extend these findings to quantitative 4 T investigations ( about3 mm3) of: 1) the normal human brain, 2) normal-appearing regions of MS brains, and 3) MS lesions. In normal brain, one detects sufficiently low CR to observe actual WM uptake after a standard dose (0.1 mmol/kg), heretofore thought not possible with MRI CRs. Moreover, the FXL obtains, and an additional early time course contribution from equilibrium trans-BBB water exchange allows 2SX modeling with an ROI blood volume parameter facilitating further factoring the perfusion parameter into volume and velocity contributions. Despite a doubled BBB permeability in normal-appearing WM of MS brains, the system remains in the FXL. With the increased CR uptake in MS lesion rims, the system greatly departs the FXL after a standard dose. High 4 T sensitivity permits restudying the same lesion at an ultra-low dose (possibly 0.01 mmol/kg) sufficient for the FXL. Fitting both data sets yields a new parameter measuring the ROI average transcytolemmal water permeability coefficient. This work involves aspects of physics, physical chemistry, biophysics, physiology (all normal tissues), and relates to a number of pathologies including MS and cancer.

描述(逐字摘自申请者摘要)：长期目标是 动态增强[团注跟踪(B-T)]MRI的研究进展 对比剂(CR)通道的(时间/空间)分辨率记录 团注。虽然适用于所有组织，但低分子量Gd(111)螯合物是 尤其是血脑屏障(BBB)完整性的良好探头。即使是轻微的 定义血脑屏障紧密性的类(内皮)细胞途径的折衷是 检测到。基本B-T药代动力学参数(CR为示踪剂)测量：A) 灌注CR传递，b)毛细血管壁CR通透性，以及c)CR可达 (间隙)空间。这些都导致了有效的B-T研究 硬化症(MS)、白质(WM)病变和脑肿瘤。和往常一样 根据与浓度的线性关系测定浓度[CR] 测量的纵向组织的H2O松弛时间(T)的倒数要求 平衡跨细胞膜水分交换的快速交换极限(FXL)。但, 新的结果表明(尽管速度很快)系统在非常低的情况下离开FXL 纸巾[CR]S(&lt；100 I1m)。双站点交换(2SX)建模解释了这一点和 得出重要结论：1)在最常用的临床领域， 在系统离开FXL之前很难检测到CR [CR]假定会产生错误，ii)在更高的场(这里为4 T)、T和S/N 增加允许在低水平(轻松地5 I1M组织[CR])进行足够的CR检测 确保真实(热力学)间隙的时间进程[CR] (直接来自2SX)和血浆[CR](来自大型容器的“输入功能”) 允许因式分解所有三个药代动力学参数是不可能的 用单一的传统示踪剂。三个具体目标将这些发现扩展到 定量的4个T研究(约3mm3)：1)正常人脑，2) 多发性硬化症脑内正常区域；3)多发性硬化病变。在正常大脑中，一个 检测到足够低的CR，以观察标准剂量后的实际WM摄入量 (0.1 mmol/kg)，迄今为止认为MRI CRS是不可能的。此外，FXL ，并从平衡中获得额外的早期时间进程贡献 TRANS-BBB水交换允许使用ROI血容量参数进行2SX建模 便于将灌注参数进一步分解为体积和速度 贡献。尽管正常外观的MS的WM的血脑屏障通透性增加了一倍 大脑，系统仍保留在FXL中。多发性硬化症患者CR摄取增加 病变边缘，系统在标准剂量后极大地偏离FXL。高4 T 敏感性允许以超低剂量重新研究相同的病变(可能 0.01 mmol/kg)足以满足FXL的需要。对两个数据集进行拟合会产生一个新的 测定ROI平均跨细胞膜透水性的参数 系数。这项工作涉及到物理，物理化学， 生物物理学、生理学(所有正常组织)，并涉及许多 病理包括多发性硬化症和癌症。