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： 预计到2050年，阿尔茨海默氏病预计将影响超过1300万美国人。有足够的证据表明 将血管疾病与阿尔茨海默氏病有关，以及对认知能力下降和 痴呆症是国家研究的重点。我们小组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，因此是认知功能。 例如，由于动脉粥样硬化而导致的大脑动脉变窄与风险增加有关 阿尔茨海默氏病和血管性痴呆。该领域长期以来一直关注动脉粥样硬化和狭窄 但是，唯一造成了脑血管健康的因素。我们认为大脑动脉扩张也可能是 对大脑健康有害。因此，我们提出了大脑大动脉疾病范式的变化 这超出了动脉粥样硬化和/或狭窄，并将脑动脉扩张纳入独特 病理表型。我们假设，与许多拟人化测量一样， 脑动脉是正态分布的，并且该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，血管事件的风险更高。这些人之间血管事件的风险增加 具有极端的脑表型的部分是由全身性共存的部分解释，但不一定是 脑动脉粥样硬化。我们还证明了非动脉粥样硬化脑动脉衰老与 阿尔茨海默氏病理学独立于动脉粥样硬化和脑梗塞。我们收集了初步数据 表明脑动脉直径与认知无线性相关，因此 与平均水平相比 动脉直径。由于脑动脉扩张不足，因此这将是我们建议的重点。脑 遗传综合征患者可能发生动脉扩张，易于结缔组织， 但是目前尚不清楚一般人群中是否存在遗传易感因素。合理的是 脑动脉扩张在远端小动脉和毛细血管流动的机械作用可能破坏大脑 自动调节，并解释与实质功能（例如认知）的关系。目前尚不清楚 这些遗传因素是效应修饰剂还是认知的直接贡献者。该建议旨在 解决这些不确定性。在AIM 1中，我们将定义> 5,000中与脑动脉扩张相关的遗传基因座 具有纵向随访的四个特征良好的，基于人群的研究的参与者 神经影像学和认知评估。在AIM 2中，我们将建立大脑的血液动力学后果 通过将动脉扩张与脑血流速度和自动调节有关。在AIM 3中，我们将首先确认 脑动脉扩张与认知能力和痴呆症风险之间的关系。然后我们会 使用与脑动脉扩张相关的遗传基因座进行修饰分析和测量 自动调节作为假定的效应修饰符。在这些研究的结论下，我们将确定建立一个 脑动脉扩张在认知和痴呆中的作用。我们将确定遗传和生理特征 将帮助我们确定通过测序方法和功能测定的机制进一步追求的机制， 转弯可能会发现新型治疗靶标。