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: 6911599
• 负责人: CHARLES S. SPRINGER
• 金额: $ 38.15万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911599
• 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（逐字研究申请人的摘要）：长期目标是 动态对比度增强[bolus-tracking（b-t）] MRI的进步 - 高 （时间/空间）对比试剂（CR）通过的分辨率记录以下 注射推注。虽然适用于所有组织，但低-MW GD（111）螯合物是 特别是血脑屏障（BBB）完整性的良好探针。甚至轻微 Para（内皮）细胞途径定义BBB紧密度的妥协是 检测到。基本的B-T药代动力学参数（CR为示踪剂）度量：A） 灌注CR递送，b）毛细管壁Cr渗透性，c）可访问 （间质）空间。这些导致有效的B-T研究 硬化症（MS）白质（WM）病变和脑肿瘤。通常 从与线性关系中确定浓度，[Cr] 测量的纵向组织'H2O松弛时间（T'）需要 快速交换极限（FXL），用于平衡的跨环甲水交换。但， 新结果表明（尽管很快）系统以非常低的方式离开FXL 组织[Cr] S（<100 i1m）。两场交换（2SX）建模为此说明 导致重要结论：1）在最常用的临床领域[<2 t]，它是 在系统离开FXL和大型之前，很难检测到CR [Cr]假设它的错误，ii）在较高的磁场（这里4 t），t和s/n 增加允许在低水平的CR检测（容易5 I1m组织[Cr]）足够 确保FXL，111）真实（热力学）间隙的时间课程[CR] （直接来自2SX）和等离子体[CR]（从大容器中的“输入函数”） 允许不可能分解所有三个药代动力学参数 带有单个传统示踪剂。三个具体目标将这些发现扩展到 定量4 t研究（约3 mm3）：1）正常人大脑，2） MS大脑的正常出现区域和3）MS病变。在正常的大脑中，一个 检测到足够低的Cr以观察标准剂量后的实际WM摄取 （0.1 mmol/kg），迄今为止，MRI CRS不可能。而且，FXL 获得，以及均衡的额外早期课程贡献 Trans-BBB水交换允许使用ROI血量参数2SX建模 促进将灌注参数分为体积和速度的进一步考虑 贡献。尽管MS的正常wm中BBB渗透性增加了一倍 大脑，系统保留在FXL中。随着MS的CR吸收增加 病变轮辋，该系统在标准剂量后大大离开了FXL。高4 t 敏感性允许在超低剂量下重新分配相同的病变（可能 0.01 mmol/kg）足够用于FXL。拟合两个数据集都会产生新的 参数测量ROI平均跨环膜水的渗透性 系数。这项工作涉及物理，物理化学的各个方面， 生物物理学，生理学（所有正常组织），与许多 包括MS和癌症在内的病理。