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: 10018644
• 负责人: Jose Gutierrez
• 金额: $ 54.45万
• 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/10018644
• 关键词: 3xTg-AD mouse; AD transgenic mice; 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 - 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; 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.

项目摘要/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 据测算，到2050年，预计将有超过1300万美国人患有阿尔茨海默病。普遍存在的对 AD是大脑中淀粉样β蛋白(Aβ)的沉积导致AD，而修改Aβ沉积可能会阻止， 慢点，要不就逮捕广告。除了Aβ沉积，阿尔茨海默病患者还经常患有血管疾病。 虽然大多数脑大动脉研究都集中在颅内大动脉粥样硬化方面 (IlAA)，ilAA并不是唯一与AD相关的脑大动脉表型。另一方面，拇指扩张症， 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，是其最病理的形式，与 普通人群中的高血压、结缔组织疾病、艾滋病毒和老龄化。因此，我们提出一项 超越动脉粥样硬化和/或狭窄的大脑大动脉疾病范式的变化，以及 合并非动脉粥样硬化性BAA作为一种独特的病理表型。我们已经证明了非 动脉粥样硬化性BAA与阿尔茨海默病相关，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，大脑动脉直径与认知能力之间存在非线性关联，因此 大脑动脉狭窄或扩张的人的认知能力比那些 平均动脉直径。这一建议旨在阐明BAA是否改变了对 由小动脉/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 新陈代谢。AIM 1利用现有的基于人群的队列来获得非 动脉粥样硬化性BAA，与同侧神经退行性变的标志物有关。目标2侧重于确定特定的 与非动脉粥样硬化性BAA相关的细胞和结构变化，其精度是迄今在 使用金本位的活着的个体。在目标3中，使用转基因AD小鼠，我们将建立BAA模型以验证 非动脉粥样硬化性BAA可引起远端小动脉衰老并促进其发生的生物学机制 实质变性，探索潜在的治疗靶点。这里给出的范例没有 这是脑动脉重塑领域的先例。我们建议不仅对BAA进行前所未有的深度研究 不仅是为了使它与可翻译的成像特征联系在一起，还可能进一步发展这一领域。