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

阿尔茨海默病血脑屏障通透性的非对比磁共振成像

• 批准号: 10390475
• 负责人: Hanzhang Lu
• 金额: $ 68.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390475
• 关键词: Affect; Albumins; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Amyloid Proteins; Animal Model; Area; Astrocytes; Autopsy; Bacteria; Benchmarking; Biochemical; Biological Assay; Blood; Blood - brain barrier anatomy; Bolus Infusion; Brain; Brain Diseases; Cells; Cerebrospinal Fluid; Cerebrovascular Circulation; Clinical; Clinical Trials; Cognition; Contrast Media; Development; Dextrans; Disease; Elderly; Extravasation; Foot Process; Gadolinium; Genetic Risk; Goals; Human; Imaging Techniques; Individual; Inflammatory Response; Injury; Label; Lead; Linear Algebra; Link; Literature; Magnetic Resonance Imaging; Measurement; Measures; Methods; Microscopy; Modality; Modeling; Monitor; Multicenter Trials; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotoxins; Outcome; Pathogenesis; Patients; Pericytes; Permeability; Persons; Phase; Physiologic pulse; Physiological; Procedures; Process; Proteins; Protocols documentation; Rattus; Research; Rest; Sampling; Scanning; Scheme; Senile Plaques; Signal Transduction; Site; Spinal Puncture; Surface; Techniques; Testing; Time; Tissues; Translating; Vascular Endothelial Cell; Vascular Endothelium; Veins; Venous; Water; Work; arterial spin labeling; base; blood-brain barrier crossing; blood-brain barrier function; blood-brain barrier permeabilization; cerebral atrophy; clinical application; cognitive function; contrast enhanced; design; in vivo; indexing; interest; macromolecule; new therapeutic target; novel; pathogen; screening; vascular injury; verification and validation; β-amyloid burden

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.

项目摘要/摘要： 由于最近对阿尔茨海默氏病抗淀粉样蛋白治疗的临床试验的结果令人失望 （AD），该领域在阐明替代性疾病机制方面越来越有趣，这可能导致新的 抗淀粉样蛋白治疗的治疗靶标。验尸的广泛文献 组织已经表明，对血脑屏障（BBB）的损害与 广告。此外，动物模型的最新研究表明，BBB损害与 淀粉样斑块的积累，淀粉样蛋白的聚集可能是炎症的一部分 大脑对病原体进入的反应，大概是在BBB泄漏之后的。 但是，AD中BBB的体内研究很少。一种通常用于评估BBB渗透率的方法 在人类中，是通过在测量和建模动态的同时管理基于Gadolinium（GD）的对比剂 对比增强（DCE）MRI信号。但是，对比增强MRI并不是AD中的常见程序 研究，尚未用于大规模或多站点研究。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 治疗的临床筛查和监测。 该应用的核心目的是开发一种MRI技术来测量BBB对水的渗透性， 不使用任何外源剂。 MRI可以通过确定哪一部分探测水BBB的渗透性 传入的动脉水进入大脑，并且在血管中保留了什么分数并将其排入静脉。这 项目由三个逻辑目标组成。 AIM 1将开发新的MRI脉冲序列以定量评估 BBB的全球和区域方式的渗透性 - 面积产品（PS）。 AIM 2将验证非 - 与人类基于GD对比的技术的对比方法以及动物中的荧光显微镜 BBB渗透开放后的模型。 AIM 3将在较早的 患有建立遗传风险的人患阿尔茨海默氏病（AD），即ApoE4-Carriers。我们 将将BBB渗透率与淀粉样蛋白伯嫩和认知功能进行比较，并研究其因果关系 通过中介模型分析。我们还将比较非对比度的渗透率结果 使用CSF采样的侵入性方法以及使用DCE MRI。 这项工作的影响是，我们将开发一种新型的非对比度技术来评估BBB的渗透性 在人类中。该技术可以在标准3T MRI上在5分钟内完成。结果 测量位于ML水/100克大脑/min的物理单位中，因此可以在跨站点或 方式。该技术将具有广泛的临床实用性，因为许多脑部疾病中隐含了BBB的损伤。 在此应用程序中，我们将在AD中演示该技术的实用性。