Non-contrast MR imaging of blood-brain-barrier permeability in Alzheimer's disease

项目概要/摘要： 由于最近阿尔茨海默病抗淀粉样蛋白治疗的临床试验结果令人失望， (AD)，该领域对阐明替代疾病机制越来越感兴趣，这可能会导致新的 与抗淀粉样蛋白治疗互补的治疗靶点。大量文献使用死后 组织已经表明，血脑屏障（BBB）的损伤复杂地参与了脑缺血的发病机制。 AD.此外，最近在动物模型中的研究表明，BBB损伤与 淀粉样蛋白斑块的积累，淀粉样蛋白的聚集可能是炎症反应的一部分。 脑对病原体进入的反应，推测是在BBB渗漏之后。 然而，在AD中BBB的体内研究很少。通常用于评估BBB渗透性的方法 在人类中的应用是通过施用基于钆（Gd）的造影剂，同时测量和建模动态 对比增强（DCE）MRI信号。然而，对比增强MRI在AD中并不是一种常见的方法 研究，尚未用于大规模或多地点研究。因此，一种非对比技术， 评估BBB渗透性在AD研究中特别重要，如果成功，可以可行地转化为 临床筛查和治疗监测。 本申请的中心目标是开发一种MRI技术来测量BBB对水的渗透性， 而不使用任何外源性试剂。MRI可以探测水BBB渗透性，通过确定什么分数的 进入的动脉水进入大脑，并且哪一部分留在血管中并排出到静脉。这 该项目包括三个逻辑目标。目标1将开发新的MRI脉冲序列， 在全球和区域的方式BBB的渗透率表面积积（PS）。目标2将验证非 在人类中使用基于Gd对比的技术和在动物中使用荧光显微镜的对比方法 BBB渗透性开放模型。目的3为该技术在老年人中的临床应用提供指导 具有发展阿尔茨海默病（AD）的既定遗传风险的个体，即APOE 4携带者。我们 将比较BBB通透性与淀粉样蛋白负荷和认知功能，并研究它们之间的因果关系 通过中介模型分析。我们还将比较无造影剂渗透率结果与 使用侵入性CSF采样方法以及使用DCE MRI。 这项工作的影响是，我们将开发一种新的非造影技术来评估血脑屏障通透性 在人类身上。该技术可以在标准3 T MRI上在5分钟内完成。的结果 测量的生理单位为ml水/100 g脑/min，因此可以在不同部位进行可行的比较，或 方式。这种技术将具有广泛的临床实用性，因为BBB损伤与许多脑部疾病有关。 在这个应用程序中，我们将展示这种技术在AD中的实用性。

Project Summary/Abstract: Because of disappointing outcomes of recent clinical trials of anti-amyloid therapy in Alzheimer’s Disease (AD), the field is increasingly interested in elucidating alternative disease mechanisms which may lead to new therapeutic targets that are complementary to anti-amyloid treatment. Extensive literature using post-mortem tissue has suggested that damage to the blood-brain-barrier (BBB) is intricately involved in the pathogenesis of AD. Furthermore, recent studies in animal models suggested a direct link between BBB damage and accumulation of amyloid plaques, in that aggregation of the amyloid protein may be part of an inflammatory response of the brain to pathogen entry, presumably following BBB leakage. However, in vivo studies of BBB in AD are scarce. A method commonly used to evaluate BBB permeability in humans is by administering Gadolinium (Gd) based contrast agent while measuring and modeling dynamic contrast-enhanced (DCE) MRI signal. However, contrast-enhanced MRI is not a common procedure in AD research and has not been used in large-scale or multi-site studies. Therefore, a non-contrast technique to assess BBB permeability is of particular importance in AD research and, if successful, can feasibly translate to clinical screening and monitoring of treatment. The central goal of this application is to develop an MRI technique to measure BBB permeability to water, without using any exogenous agent. MRI can probe water BBB permeability by determining what fraction of the incoming arterial water enters the brain and what fraction remains in the vessel and drains to the vein. This project consists of three logical aims. Aim 1 will develop novel MRI pulse sequences to quantitatively evaluate permeability-surface-area product (PS) of BBB in both global and regional fashion. Aim 2 will validate the non- contrast method with Gd-contrast based technique in humans and with fluorescent microscopy in animal models following osmotic opening of BBB. Aim 3 will conduct clinical application of the technique in elderly individuals who have an established genetic risk to develop Alzheimer’s Disease (AD), i.e. APOE4-carriers. We will compare BBB permeability with amyloid burden and cognitive function, and study their causal relationship through a mediational model analysis. We will also compare the non-contrast permeability results to those using an invasive method of CSF sampling as well as using DCE MRI. The impact of this work is that we will develop a novel non-contrast technique to evaluate BBB permeability in humans. The technique can be completed within 5 minutes on a standard 3T MRI. The outcome of the measurement is in physiological unit of ml water/100g brain/min, thus can be feasibly compared across sites or modalities. This technique will have broad clinical utility, as injury of BBB is implicated in many brain diseases. In this application, we will demonstrate the utility of this technique in AD.