Accelerated non-atherosclerotic brain arterial aging relationship to Alzheimer's disease

加速非动脉粥样硬化性脑动脉老化与阿尔茨海默病的关系

• 批准号: 9891713
• 负责人: Jose Gutierrez
• 金额: $ 55.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891713
• 关键词: 3xTg-AD mouse; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Amyloidosis; Animals; Arteries; Astrocytes; Astrocytosis; Atherosclerosis; Autopsy; Biological; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Infarction; Caliber; Cellular Structures; Cerebrovascular Disorders; Clinical; Clinical Trials; Cognition; Connective Tissue Diseases; Data; Dementia; Deposition; Development; Dilatation - action; Disease; Distal; Elastases; Elastin; Functional disorder; Future; General Population; Genetic; Goals; Gold; HIV; Human; Hypertension; Image; Immunofluorescence Immunologic; Immunohistochemistry; Impaired cognition; Individual; Intervention; Ipsilateral; MMP2 gene; Magnetic Resonance Imaging; Measures; Mediating; Metabolism; Metalloproteases; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Participant; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Population Study; Positron-Emission Tomography; Predisposition; Preventive measure; Reporting; Resolution; Resources; Risk; Risk Factors; Role; Sampling; Signal Transduction; Stenosis; Structure; Tauopathies; Testing; Transgenic Organisms; Uncertainty; Vascular Diseases; abeta deposition; arterial remodeling; arteriole; base; brain cell; cerebrovascular; cisterna magna; cognitive performance; cohort; dementia risk; high risk; in vivo; multidisciplinary; neglect; neuroinflammation; new therapeutic target; novel; novel therapeutics; population based; prevent; tau Proteins; therapeutic target; trait; white matter damage

PROJECT SUMMARY/ABSTRACT: The societal burden of Alzheimer's disease (AD) is expected to rise, and in the absence of effective preventive measures, more than 13 million Americans are projected to have AD by 2050. The prevailing understanding of AD is that amyloid beta (Aβ) deposition in the brain leads to AD and that modifying Aβ deposition may prevent, slow, or arrest AD. In addition to Aβ deposition, individuals with AD often suffer from vascular disease. Although the majority of brain large artery studies have focused on intracranial large artery atherosclerosis (ILAA), ILAA is not the only brain large artery phenotype that relates to AD. Dolichoectasia, on the other hand, is a form of non-atherosclerotic brain arterial aging (BAA) phenotype that consists of dilatation and/or tortuosity. Brain arterial dilatation, dolichoectasia being its most pathological form, is associated with hypertension in the general population, connective tissue disorders, HIV, and aging. We thus propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates non-atherosclerotic BAA as a distinct pathological phenotype. We have demonstrated that non- atherosclerotic BAA relates to Alzheimer pathology independent of atherosclerosis and brain infarcts. We have gathered preliminary data showing that brain arterial diameters are associated non-linearly with cognition, so that individuals with narrowed or dilated brain arteries have poorer cognitive performance compared with those with average arterial diameters. This proposal aims to elucidate whether BAA modifies the susceptibility to dementia via arteriolar/capillary dysfunction, neuronal/white matter damage, and/or directly via Aβ/tau metabolism. Aim 1 leverages an existing population-based cohort to obtain an MRI measure of non- atherosclerotic BAA and relate to ipsilateral marker of neurodegeneration. Aim 2 focuses on identifying specific cellular and structural changes that relate to non-atherosclerotic BAA with a precision so far not available in living individuals using the gold standard. In Aim 3, using transgenic AD mice, we will model BAA to validate the biological principle that non-atherosclerotic BAA can cause aging of distal arterioles and promote parenchymal degeneration, exploring potential therapeutic targets. The paradigm presented here has no precedent in the field of brain arterial remodeling. We propose not only to study BAA with unprecedented depth and resources but also to contextualize it with translatable imaging traits that may further evolve this field.

项目总结/摘要： 阿尔茨海默病（AD）的社会负担预计将上升，在缺乏有效预防措施的情况下， 据估计，到2050年，超过1300万美国人将患有AD。普遍的理解是 AD是脑中淀粉样蛋白β（Aβ）沉积导致AD，改变Aβ沉积可以预防， 慢，或逮捕AD。除了Aβ沉积外，AD患者还经常患有血管疾病。 虽然大多数脑大动脉的研究集中在颅内大动脉粥样硬化 虽然脑大动脉表型与AD相关，但脑大动脉表型并不是唯一与AD相关的表型。另一方面， 是一种非动脉粥样硬化性脑动脉老化（BAA）表型，包括扩张和/或 曲折脑动脉扩张，长扩张是其最常见的病理形式， 一般人群中的高血压、结缔组织疾病、HIV和老龄化。因此，我们提出一个 脑大动脉疾病范式的变化超出动脉粥样硬化和/或狭窄，以及 将非动脉粥样硬化BAA作为独特的病理表型。我们已经证明，非- 动脉粥样硬化BAA与阿尔茨海默病病理学有关，与动脉粥样硬化和脑梗塞无关。我们有 收集的初步数据显示，脑动脉直径与认知呈非线性相关， 脑动脉狭窄或扩张的人的认知能力比那些 平均动脉直径该提案旨在阐明BAA是否改变了对 通过小动脉/毛细血管功能障碍、神经元/白色物质损伤和/或直接通过Aβ/tau蛋白引起的痴呆 新陈代谢.目的1利用现有的基于人群的队列，获得非- 动脉粥样硬化BAA和与同侧神经变性标志物有关。目标2侧重于确定具体的 与非动脉粥样硬化BAA相关的细胞和结构变化，其精确度迄今为止尚不适用于 使用黄金标准的人。目的3：利用转基因AD小鼠，建立BAA模型，以验证其有效性 非动脉粥样硬化性BAA可引起远端小动脉老化并促进动脉粥样硬化的生物学原理 实质变性，探索潜在的治疗靶点。这里提出的范例没有 脑动脉重塑领域的先例。我们不仅建议以前所未有的深度研究BAA 和资源，而且还将其与可能进一步发展这一领域的可翻译成像特征相结合。