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: 10621142
• 负责人: Hanzhang Lu
• 金额: $ 63.04万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621142
• 关键词: Acceleration; 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; Central Nervous System; 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; Link; Literature; Magnetic Resonance Imaging; Measurement; Measures; Methods; Microscopy; Modality; Modeling; Monitor; Multicenter Trials; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Osmosis; 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; apolipoprotein E-4; arterial spin labeling; 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： 由于最近抗淀粉样蛋白疗法治疗阿尔茨海默病的临床试验结果令人失望 （AD），该领域越来越有兴趣阐明替代疾病机制，这可能会导致新的疾病机制 使用尸检的大量文献来补充抗淀粉样蛋白治疗的治疗目标。 组织表明，血脑屏障（BBB）的损伤与以下疾病的发病机制密切相关 此外，最近的动物模型研究表明 BBB 损伤与 AD 之间存在直接联系。 淀粉样斑块的积累，因为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，大概是在血脑屏障渗漏之后。 然而，AD 中 BBB 的体内研究很少有常用来评估 BBB 通透性的方法。 在人类中，通过使用基于钆 (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 并不是 AD 的常见手术。 研究尚未在大规模或多地点研究中使用，因此，需要采用非对比技术。 评估 BBB 渗透性在 AD 研究中尤为重要，如果成功，可以切实转化为 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 BBB 对水的渗透性， MRI 无需使用任何外源性试剂即可通过确定 BBB 的比例来探测水 BBB 的渗透性。 流入的动脉水进入大脑，剩下的部分留在血管中并排入静脉。 项目由三个逻辑目标组成，目标 1 将开发新颖的 MRI 脉冲序列来定量评估。 全球和区域 BBB 的渗透性表面积乘积 (PS) 将验证非-。 在人类中使用基于 Gd 对比技术的对比方法以及在动物中使用荧光显微镜的对比方法 Aim 3 渗透开放后的模型将在老年人中开展该技术的临床应用。 具有罹患阿尔茨海默病 (AD) 的既定遗传风险的个体，即 APOE4 携带者。 将比较血脑屏障通透性与淀粉样蛋白负荷和认知功能，并研究它们的因果关系 我们还将通过中介模型分析将非对比渗透率结果与这些结果进行比较。 使用侵入性脑脊液取样方法以及 DCE MRI。 这项工作的影响是我们将开发一种新颖的非对比技术来评估 BBB 渗透性 该技术可以在标准 3T MRI 上 5 分钟内完成。 测量的生理单位为毫升水/100克脑/分钟，因此可以在不同地点或地区进行可行的比较 该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。 在此应用中，我们将演示该技术在 AD 中的实用性。