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

项目总结/摘要： 预计到2050年，阿尔茨海默病将影响超过1300万美国人。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的贡献， 老年痴呆症是国家研究重点。来自我们小组和其他人的数据表明， 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重要决定因素。 例如，由于动脉粥样硬化导致的脑动脉狭窄与风险增加有关。 老年痴呆症和血管性痴呆症。该领域长期以来一直专注于动脉粥样硬化和狭窄， 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模式， 这超出了动脉粥样硬化和/或狭窄，并结合脑动脉扩张作为一个独特的 病理表型我们假设，与许多拟人测量一样， 脑动脉是正常分布的，这种分布的极端是病态的。我们有 证实了这一假设。我们报告说，在脑动脉最大或最小的个体中， 直径越大，血管事件的风险越高。这些人中血管事件的风险增加 与极端的大脑表型的部分原因是共存的系统性，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以下因素有关： 阿尔茨海默病病理学独立于动脉粥样硬化和脑梗死。我们已经收集了初步数据 显示脑动脉直径与认知非线性相关，因此， 脑动脉狭窄或扩张的人的认知能力比那些 动脉直径由于脑动脉扩张研究不足，这将是我们建议的重点。大脑 动脉扩张可能发生在易患较弱结缔组织的遗传综合征的患者中， 但目前尚不清楚遗传易感因素是否存在于一般人群中。这是合理的， 脑动脉扩张对远端小动脉和毛细血管流动的机械作用可能会破坏脑动脉 自动调节，并解释与实质功能，如认知的关系。目前还不清楚 这些遗传因素是影响因素还是认知的直接贡献者。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遗传位点， 四项特征良好的、基于人群的纵向随访研究的参与者， 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后果 动脉扩张与脑血流速度和自动调节有关。在目标3中，我们将首先确认 脑动脉扩张与认知能力和痴呆风险之间的关系。然后我们将 使用与脑动脉扩张相关的遗传基因座进行修饰分析， 自动调节作为假定的效应调节剂。在这些研究结束时，我们将明确建立一个 脑动脉扩张在认知和痴呆中的作用。我们将鉴定遗传和生理特征， 将帮助我们确定机制，以进一步追求测序方法和功能测定， 这可能会发现新的治疗靶点。

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.