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: 10414070
• 负责人: Jose Gutierrez
• 金额: $ 69.45万
• 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/10414070
• 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; 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; 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; base; 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： 阿尔茨海默氏病的社会伯恩（AD）预计将上升，在没有有效的预防性的情况下 措施，预计到2050年将有1300万美国人的广告。 AD是大脑中淀粉样蛋白β（Aβ）沉积会导致AD，并且修改Aβ沉积可能会阻止， 缓慢或逮捕广告。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粥样硬化上 （ILAA），ILAA并不是与AD有关的唯一大脑大动脉表型。另一方面 是由扩张和/或 曲折。脑动脉扩张，多章促性症是其最病理性形式，与 一般人群中的高血压，结缔组织障碍，艾滋病毒和衰老。因此，我们提出了 超越动脉粥样硬化和/或狭窄的脑大动脉疾病的范式的变化，以及 将非动脉粥样硬化BAA纳入了一种不同的病理表型。我们已经证明了非 动脉粥样硬化的BAA与阿尔茨海默氏病有关，与动脉粥样硬化和脑相关。我们有 收集的初步数据表明，脑动脉直径与认知非线性相关，因此 与那些相比 平均动脉直径。该建议旨在阐明BAA是否修改了 通过小动脉/毛细血管功能障碍，神经/白质损伤和/或直接通过Aβ/TAU的痴呆症 代谢。目标1利用现有的基于人群的队列来获得非 - 动脉粥样硬化BAA，与神经退行性的同侧标记有关。 AIM 2专注于确定特定 迄今为止尚未获得与非动脉粥样硬化BAA相关的细胞和结构变化。 使用黄金标准的活人。在AIM 3中，使用转基因AD小鼠，我们将建模BAA以验证 非动脉粥样硬化BAA可能会导致盘状artiolos衰老并促进的生物学原理 副群变性，探索潜在的治疗靶标。这里提出的范式没有 在脑动脉重塑领域的先例。我们不仅建议以空前的深度研究BAA 和资源，也可以通过可翻译成像特征来将其进行环境化，从而进一步发展该领域。