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

项目摘要/摘要： 由于最近抗淀粉样蛋白治疗阿尔茨海默病的临床试验结果令人失望 (Ad)，该领域对阐明可能导致新疾病的替代机制越来越感兴趣 作为抗淀粉样蛋白治疗的补充的治疗靶点。大量使用尸检的文献 组织研究表明，血脑屏障(BBB)的破坏与糖尿病的发病机制密切相关。 广告。此外，最近在动物模型中的研究表明，血脑屏障损伤和 淀粉样斑块的堆积，在淀粉样蛋白的聚集可能是炎症的一部分 脑部对病原体进入的反应，推测是在血脑屏障渗漏之后。 然而，关于AD中血脑屏障的体内研究很少。一种常用的评价血脑屏障渗透性的方法 在人体内是通过在测量和建模动态过程中使用基于Gd的造影剂 增强(DCE)MRI信号。然而，增强MRI并不是AD的常见检查方法 研究，尚未用于大规模或多地点研究。因此，一种非对比技术可以 评估血脑屏障通透性在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。 该应用的中心目标是开发一种MRI技术来测量血脑屏障对水的渗透性， 而不使用任何外源物质。核磁共振可以通过确定水中血脑屏障渗透性的比例来探测 进入的动脉水进入大脑，其中的一部分残留在血管中，并流入静脉。这 项目由三个合乎逻辑的目标组成。AIM 1将开发新的MRI脉冲序列以定量评估 渗透率-全球和地区BBB的表面积乘积(PS)。AIM 2将验证非 人体Gd造影法和动物荧光显微镜造影法 血脑屏障渗透性开放的模型。目标3将在老年人中进行该技术的临床应用 已确定有患阿尔茨海默病(AD)遗传风险的个人，即APOE4携带者。我们 将比较血脑屏障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。我们还将比较非对比渗透率结果与 使用侵入性脑脊液采样方法和DCE MRI。 这项工作的影响是，我们将开发一种新的非对比技术来评估血脑屏障通透性 在人类身上。在标准的3T磁共振成像上，这项技术可以在5分钟内完成。选举的结果是 测量的生理单位是毫升水/100g脑/分钟，因此可以进行跨地点或 医疗模式。这项技术将具有广泛的临床应用，因为血脑屏障的损伤与许多脑部疾病有关。 在本应用程序中，我们将演示此技术在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.