Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia

遗传对脑动脉扩张的影响及其在认知和痴呆中的作用

• 批准号: 10083526
• 负责人: Jose Gutierrez
• 金额: $ 9.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083526
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Arteries; Atherosclerosis; Atherosclerosis Risk in Communities; Biological Assay; Blood Flow Velocity; Blood Vessels; Blood capillaries; Brain; Brain Infarction; Caliber; Carbon Dioxide; Categories; Cerebral Atheroscleroses; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Clinical; Cognition; Communities; Connective Tissue; Connective Tissue Diseases; Data; Dementia; Dilatation - action; Disease; Distal; Event; Functional disorder; Future; General Population; Genes; Genetic; Genetic Determinism; Health; Homeostasis; Impaired cognition; Individual; Inherited; Ipsilateral; Link; Magnetic Resonance Angiography; Measurement; Measures; Mechanics; Mediating; Meta-Analysis; Modification; Outcome; Participant; Pathologic; Patients; Phenotype; Physiological; Population; Population Study; Predisposing Factor; Predisposition; Reporting; Research Priority; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Statistical Models; Stenosis; Syndrome; Testing; Uncertainty; Vascular Dementia; Vascular Diseases; Washington; base; brain health; cerebral hemodynamics; cerebrovascular health; cognitive function; cognitive performance; cognitive testing; dementia risk; epidemiology study; follow-up; genetic approach; genetic risk factor; genome wide association study; genomic locus; hemodynamics; imaging biomarker; middle cerebral artery; neuroimaging; new therapeutic target; novel; novel therapeutics; prospective; time use; trait; vascular contributions

PROJECT SUMMARY/ABSTRACT: Alzheimer disease is expected to affect over 13 million Americans by 2050. There is ample evidence that relates vascular disease to Alzheimer disease, and the vascular contributions to cognitive decline and dementia are a national research priority. Data from our group and others have demonstrated that brain large artery disease is an important determinant of cerebrovascular health and, consequently, of cognitive function. For example, narrowing of the brain arteries due to atherosclerosis has been associated with an increased risk of Alzheimer disease and vascular dementia. The field has long focused on atherosclerosis and stenosis as the sole contributors to cerebrovascular health, however. We believe that brain arterial dilatation may also be deleterious to brain health. Consequently, we propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct pathological phenotype. We postulated that, as with many anthropomorphic measurements, the diameters of brain arteries are normally distributed and that the extremes of this distribution are pathological. We have confirmed this hypothesis. We reported that among individuals with the largest or the smallest brain arterial diameters, the risk of vascular event is higher. The increased risk of vascular events among these individuals with extreme cerebral phenotypes is partially explained by the co-existence of systemic but not necessarily cerebral atherosclerosis. We have also demonstrated that non-atherosclerotic brain arterial aging 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. Because brain arterial dilatation is understudied, it will be the focus of our proposal. Brain arterial dilatation may occur among patients with genetic syndromes predisposing to weaker connective tissue, but it is unclear whether genetic predisposing factors exist in the general population. It is plausible that the mechanical effects of brain arterial dilatation over the distal arteriolar and capillary flow may disrupt cerebral autoregulation, and explain the relationship with parenchymal functions such as cognition. It remains unclear whether these genetic factors are effect modifiers or direct contributors to cognition. This proposal aims to address these uncertainties. In Aim 1, we will define genetic loci that relate to brain arterial dilatation in >5,000 participants of four well-characterized, population-based studies with longitudinal follow-up who also have neuroimaging and cognitive assessments. In Aim 2, we will establish the hemodynamic consequences of brain arterial dilatation by relating it to cerebral blood flow velocities and autoregulation. In Aim 3, we will first confirm the relationship between brain arterial dilatation with cognitive performance and risk of dementia. We will then perform a modification analysis using genetic loci related to brain arterial dilatation and measures of autoregulation as presumed effect modifiers. At the conclusion of these studies, we will definitively establish a role for brain arterial dilatation in cognition and dementia. We will identify genetic and physiological traits that will help us identify mechanisms to pursue further with sequencing approaches and functional assays, which in turn may enable discovery of novel therapeutic targets.

项目摘要/摘要： 到2050年，阿尔茨海默病预计将影响1300多万美国人。有充分的证据表明 将血管疾病与阿尔茨海默病联系起来，以及血管对认知能力下降和 痴呆症是国家研究的重点。来自我们团队和其他人的数据表明，大脑很大 动脉疾病是脑血管健康的重要决定因素，因此也是认知功能的决定因素。 例如，动脉粥样硬化导致的脑动脉狭窄与风险增加有关。 阿尔茨海默病和血管性痴呆症。长期以来，该领域一直专注于动脉粥样硬化和狭窄 然而，脑血管健康的唯一贡献者。我们认为脑动脉扩张也可能是 对大脑健康有害。因此，我们建议改变脑大动脉疾病的治疗模式。 它超越了动脉粥样硬化和/或狭窄，并将脑动脉扩张作为一种独特的 病理表型。我们假设，就像许多拟人化的测量一样， 脑动脉呈正态分布，这种分布的极端是病理性的。我们有 证实了这一假设。我们报告说，在大脑动脉最大或最小的个体中 直径越大，发生血管事件的风险越高。这些人发生血管事件的风险增加 具有极端大脑表型的部分原因是系统性的共存，但不一定 脑动脉粥样硬化。我们还证明了非动脉粥样硬化性脑动脉老化与 阿尔茨海默病的病理独立于动脉粥样硬化和脑梗塞。我们已经收集了初步数据 研究表明，脑动脉直径与认知能力呈非线性相关，因此患有脑血管疾病的人 大脑动脉狭窄或扩张的人的认知能力比平均水平的人差。 动脉直径。由于对脑动脉扩张的研究还不够深入，这将是我们提案的重点。脑区 动脉扩张可能发生在易患结缔组织较弱的遗传综合征的患者中， 但目前尚不清楚普通人群中是否存在遗传易感因素。看似合理的是， 脑动脉扩张对远端小动脉和毛细血管血流的机械影响可能会扰乱大脑 自我调节，并解释与认知等实质功能的关系。目前仍不清楚 这些遗传因素是影响认知的因素还是直接影响认知的因素。这项建议旨在 解决这些不确定性。在目标1中，我们将定义与5,000例脑动脉扩张相关的基因座 四项具有良好特征的、以人群为基础的研究的参与者，并进行了纵向随访，他们还 神经成像和认知评估。在目标2中，我们将建立脑血流动力学结果 通过将动脉扩张与脑血流速度和自身调节联系起来。在目标3中，我们将首先确认 脑动脉扩张与认知功能和痴呆风险的关系。到时候我们会的 使用与脑动脉扩张相关的遗传基因座进行修改分析，并测量 作为假定效应修饰物的自动调节。在这些研究结束后，我们将确定建立一个 脑动脉扩张在认知和痴呆中的作用。我们将确定基因和生理特征 将帮助我们确定进一步探索测序方法和功能分析的机制，这些机制在 TURN可能会发现新的治疗靶点。