Human Brain Vascular Phenotyping with High-Field MRI:Water Permeability Mapping

项目概述：核磁共振在分子动力学和平衡交换测量方面有着悠久而丰富的历史。可以说，这是它最大的优势之一。这些方面与体内成像能力的结合是潜在的极其强大的，并且已经提供了重要的生理学见解。该项目的长期目标是改进MRI方法来绘制血脑屏障（BBB）平衡水分子交换。这一目标将通过fda批准的常规低分子量钆造影剂（CRs）在7特斯拉(T)的人脑中实现，并应用我们实验室开发的综合快门速度药代动力学模型来实现，该模型适当地考虑了多个组织间室之间的水交换以及CR外渗。本课题利用了组织水质子纵向弛豫时间常数和色散随磁场强度的同步增加；PI和调查人员广泛研究的课题。再加上随着磁场的增大，可以很好地识别出信噪比的增加，从而使CR的检测限大大提高，这对本项目至关重要。使用7 T MRI仪器有望显著提高人脑参数图的精度和准确性。在正常的大脑中，水和CR的跨血脑屏障渗透性系数（实际上，渗透性表面积产物）相差4个数量级（或更多），每一个都与小血管生理学的不同方面有关。这项工作的总体目标是：a)改进我们的MRI方法，以获得准确可靠的人脑血脑屏障水渗透性图；b)研究血脑屏障水渗透性的性别依赖性；c)研究血脑屏障水渗透性与多发性硬化症（MS）疾病表达之间的关系。与公共卫生的相关性：脑水含量的控制和调节在许多疾病的进展中很重要。本文提出的研究将探索新的、无创的MRI测量血液和大脑之间的水交换。这项研究将使我们更全面地了解正常大脑中的水稳态及其在多发性硬化症中是如何被扰乱的。新兴的多发性硬化症治疗已经针对血脑屏障水转运蛋白，该项目开发的方法将导致对这些干预措施效果的非侵入性评估。

DESCRIPTION (provided by applicant): Project Summary: NMR has contributed a long and rich history of molecular dynamics and equilibrium exchange measurements. Arguably, this is one of its greatest strengths. The combination of these aspects with in vivo imaging capabilities is potentially extremely powerful, and has already provided important physiological insights. The long-term objective of this project is to improve MRI methods to map equilibrium water molecular exchange across the blood-brain-barrier (BBB). This goal will be accomplished using conventional FDA-approved, low-molecular weight gadolinium contrast reagents (CRs) in human brain at 7 Tesla (T), and applying the comprehensive shutter-speed pharmacokinetic models developed in our laboratory that properly account for water exchanges between multiple tissue compartments as well as CR extravasation. This project takes advantage of the concurrent increase in the tissue water proton longitudinal relaxation time constant, and its dispersion, with magnetic field strength; a topic extensively studied by the PI and investigators. Taken together with the well-recognized S/N increases associated with increasing magnetic field, thus cause the CR detection limit to be greatly improved, which is crucial to this project. The use of a 7 T MRI instrument is expected to markedly improve the precision and accuracy of human brain parametric maps. In the normal brain, the trans-BBB permeability coefficients for water and CR (really, permeability surface area products) differ by four orders of magnitude (or more), and each is related to a different aspect of small vessel physiology. The overall goals of the proposed work are: a) to improve our MRI methods to obtain accurate and reliable human brain BBB water permeability maps, and b) to investigate sex dependences of BBB water permeability, and c) to investigate the association between BBB water permeability and multiple sclerosis (MS) disease expression. Relevance to Public Health: The control and regulation of brain water content is important in the progression of many diseases. The investigations proposed here will explore the novel, non-invasive MRI measurement of water exchange between blood and brain. This research will lead to a more complete understanding of water homeostasis in normal brain and how it is perturbed in MS. Emerging MS therapies have targeted BBB water transport proteins, and methods developed in this project will lead to non-invasive assessment of the efficacies of these interventions.