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: 10615825
• 负责人: Jose Gutierrez
• 金额: $ 69.21万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615825
• 关键词: 3xTg-AD mouse; AD transgenic mice; Acceleration; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Amyloidosis; Animals; Arteries; Astrocytes; Astrocytosis; Atherosclerosis; Autopsy; Biological; Blood Vessels; Blood brain barrier dysfunction; Blood capillaries; Brain; Brain Diseases; Brain Infarction; Brain imaging; Clinical; Clinical Trials; Cognition; Connective Tissue Diseases; Data; Dementia; Deposition; Development; Diameter; Dilatation - action; Dimensions; Disease; Distal; Elastases; Elasticity; Elastin; Functional disorder; Future; General Population; Genetic; Goals; 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; Persons; Pharmaceutical Preparations; Phenotype; Population; Population Study; Positron-Emission Tomography; Predisposition; Preventive measure; Reporting; Resolution; Resources; Risk; Risk Factors; Role; Sampling; Signal Transduction; Stenosis; Tauopathies; Testing; Uncertainty; Vascular Diseases; abeta deposition; arterial remodeling; arteriole; brain cell; cerebrovascular; cisterna magna; cognitive performance; cohort; dementia risk; high risk; in vivo; multi-ethnic; multidisciplinary; neglect; neuroinflammation; new therapeutic target; novel; novel therapeutics; population based; prevent; tau Proteins; therapeutic target; trait; translational potential; 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.

项目摘要/摘要： 在缺乏有效的预防措施的情况下，阿尔茨海默病（AD）的社会负担预计将增加 如果采取措施，预计到 2050 年将有超过 1300 万美国人患有 AD。 AD 是大脑中β淀粉样蛋白 (Aβ) 沉积导致 AD，而改变 Aβ 沉积可以预防， 慢，还是抓AD。除了 Aβ 沉积外，AD 患者还经常患有血管疾病。 尽管大多数脑大动脉研究都集中在颅内大动脉动脉粥样硬化 (ILAA)，ILAA 并不是唯一与 AD 相关的脑大动脉表型。另一方面，多利科扩张症 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（脑动脉扩张是其最病理性的形式）与 普通人群的高血压、结缔组织疾病、艾滋病毒和衰老。因此我们提出一个 脑大动脉疾病范式的改变超出了动脉粥样硬化和/或狭窄的范围，以及 将非动脉粥样硬化 BAA 作为一种独特的病理表型。我们已经证明，非 动脉粥样硬化 BAA 与阿尔茨海默病病理学相关，独立于动脉粥样硬化和脑梗塞。我们有 收集的初步数据表明脑动脉直径与认知呈非线性相关，因此 与其他人相比，脑动脉狭窄或扩张的人的认知能力较差 与平均动脉直径。该提案旨在阐明 BAA 是否会改变对 通过小动脉/毛细血管功能障碍、神经元/白质损伤和/或直接通过 Aβ/tau 引起的痴呆 代谢。目标 1 利用现有的基于人群的队列来获取非 MRI 测量值 动脉粥样硬化 BAA 与同侧神经变性标志物相关。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无 使用金本位的活着的个人。在目标 3 中，使用转基因 AD 小鼠，我们将建模 BAA 来验证 非动脉粥样硬化性BAA可引起远端小动脉老化并促进其老化的生物学原理 实质变性，探索潜在的治疗靶点。这里提出的范式没有 脑动脉重塑领域的先例。我们建议不仅要以前所未有的深度研究BAA 和资源，还可以将其与可进一步发展该领域的可翻译成像特征结合起来。