4 TELSA MRI BOLUS CR STUDIES OF HUMAN BBB PERMEABILITY

描述（来自申请人摘要的逐字）：长期目标是 动态对比增强[团注跟踪（B-T）] MRI的进展-高 (time/空格）分辨率记录对比试剂（CR）通道， 团注。虽然适用于所有组织，但低分子量Gd（111）螯合物 特别是用于血脑屏障（BBB）完整性的良好探针。甚至轻微 限定血脑屏障紧密性的帕拉（内皮）细胞途径的妥协是 检测到基本B-T药代动力学参数（CR作为示踪剂）测量： 灌注CR输送，B）毛细血管壁CR渗透性，和c）CR可及性 （间隙）空间。这些导致有效的B-T研究， 硬化（MS）白色物质（WM）病变和脑肿瘤。通常的 根据与浓度的线性关系测定浓度[CR]， 测量的纵向组织“H2O弛豫时间（T”）的倒数要求 快速交换极限（FXL）用于平衡跨细胞膜水交换。但是， 新的结果表明，（虽然快）系统离开FXL非常低， 组织[CR]s（<100 μ M）。双位点交换（2SX）模型解释了这一点， 导致重要的结论：1）在临床领域[< 2 T]最常用的，它是 在系统离开FXL之前很难检测到CR， [CR]误差结果假设它，II）在更高的字段（4 T这里），T，和S/N 增加允许在低水平（容易地5 I1 M组织[CR]）下检测CR， 为了确保FXL，111）真实的（热力学的）间隙[CR]的时间过程 （直接来自2SX）和血浆[CR]（来自大血管的“输入功能”） 无法对所有三个药代动力学参数进行因子分解 一个传统的追踪器。三个具体目标将这些发现扩展到 定量4 T研究（约3 mm 3）：1）正常人脑，2） MS脑的正常外观区域，和3）MS病变。在正常的大脑中， 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），迄今认为MRI CR不可能。此外，FXL 获得，以及来自均衡的额外早期时程贡献 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 捐款.尽管在MS的正常WM中BBB渗透性加倍， 大脑，系统仍在FXL中。随着MS中CR摄取的增加， 病变边缘，在标准剂量后，系统大大偏离FXL。高4 T 灵敏度允许以超低剂量（可能 0.01 mmol/kg）。拟合这两个数据集产生了一个新的 测量ROI平均细胞膜透水性的参数 系数这项工作涉及物理学、物理化学、 生物物理学，生理学（所有正常组织），并涉及许多 病理学包括多发性硬化症和癌症。

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.