Cerebral Microbleeds in Young Adults: risk factors, biomarkers and genetics

 描述(申请人提供)：用脑MRI发现的亚临床脑血管疾病，其中脑微出血(CMB)是一个重要的未被研究的组成部分，更常见，先于和预测临床明显的脑血管疾病和痴呆。CMB主要归因于两种主要形式的出血性脑血管疾病：高血压血管病和淀粉样脑血管病。CMB是中风(缺血和出血)、认知障碍和痴呆症风险增加的预测因子。它们的存在使缺血性中风和阿尔茨海默病的预防、治疗和研究工作(免疫疗法)复杂化。然而，CMB的潜在病理生理学、在中青年中的患病率和遗传危险因素尚不清楚。弗雷明翰心脏研究(FHS)拥有丰富的关于心血管危险因素、遗传、生物标记物和亚临床心血管疾病测量方法的纵向数据。FHS第三代(Gen 3)参与者(N=1621；平均年龄45±8岁)接受了梯度回波序列的脑MRI检查，并同时评估认知能力。在建议的拨款中，我们假设CMB最早将在第四个十年被发现，患病率将随着年龄的增长而增加，并与心血管危险因素和选定的心血管药物使用有关。我们将研究CMB与血管功能障碍的亚临床指标(眼压测量)的关系，以及与炎症、血管功能障碍和神经退变的新的循环生物标志物(LpPLA2、血管内皮生长因子、聚集素、β-淀粉样蛋白)的关系。我们还将把CMB与脑损伤和衰老的新MRI测量(扩散张量成像，灰质体积)、衰老和血管损伤的传统MRI测量(白质高信号体积、大脑和海马体总体积)以及认知能力联系起来。最后，我们将利用三代间密集的家系关系来评估CMB的遗传力，并使用单个变异体和基于基因/区域的测试进行连锁和关联分析，利用现有的外显子芯片和整个外显子组测序数据进行生物信息学搜索与CMB相关的遗传变异。本项目将是K23奖项“AG038444：脑微出血的风险因素、遗传学和认知：弗雷明翰研究(PI：Romero)”的附加项目，该奖项正在调查第一代和第二代FHS参与者中的CMB。在目前的提案中，我们要求适度的资金来创建和分析第三代CMB数据的新数据集。除了将我们目前关于CMB患病率和风险因素的知识扩展到比以前研究过的更年轻的样本之外，本申请还将研究三个主要的新方面：神经退行性变的生物标记物(血浆聚集素和β-淀粉样蛋白)与CMB的关系，CMB与新的大脑完整性和衰老的MRI指标(DTI和灰质体积)的关系，以及与CMB相关的{常见的和罕见的遗传变异的存在。建议的研究项目将增进我们对年轻人CMB病理生理学的了解，并改善对中风和痴呆的有效预防。

 DESCRIPTION (provided by applicant): Subclinical cerebrovascular disease detected using brain MRI, of which cerebral microhemorrhages (CMB) is an important understudied component, is more frequent, precedes and predicts clinically evident cerebrovascular disease and dementia. CMB are attributed mainly to two major forms of hemorrhage prone cerebral small vessel disease: hypertensive vasculopathy and cerebral amyloid angiopathy. CMB are predictors of increased risk of stroke (ischemic and hemorrhage), cognitive impairment and dementia. Their presence complicates prevention, treatment and research efforts (immunotherapy) for ischemic stroke and Alzheimer's disease. However the underlying pathophysiology, prevalence in young to middle age and genetic risk factors of CMB are unclear. The Framingham Heart Study (FHS) has a wealth of longitudinal data on cardiovascular risk factors, genetic, biomarker and subclinical cardiovascular disease measures readily available. FHS third generation (Gen 3) participants (N=1621; mean age 45±8 years) had brain MRI with gradient echo sequences, and simultaneous assessment of cognitive performance. In the proposed grant we hypothesize that CMB will be detected as early as the 4th decade, prevalence will increase with age, and be related to cardiovascular risk factors and select cardiovascular medication use. We will investigate the relation of CMB to subclinical measures of vascular dysfunction (tonometry), and to novel circulating biomarkers of inflammation, vascular dysfunction and neurodegeneration (LpPLA2, VEGF, clusterin, beta-amyloid). We will also relate CMB to novel MRI measures of brain injury and aging (diffusion tensor imaging, gray matter volumes), traditional MRI measures of aging and vascular injury (white matter hyperintensity volume, total brain and hippocampal volumes) and cognitive performance. Finally, we will use {the dense familial relationships across the 3 generations to assess heritability of CMB, and perform linkage and association analyses using single variants and gene/region based tests, bioinformatics to search for genetic variants associated with CMB using available exome chip and whole exome sequencing data}. The present project will be an adjunct to a K23 award "AG038444: Risk Factors, Genetics and Cognition in Cerebral Microbleeds: Framingham Study (PI: Romero)", that is investigating CMB in the 1st and 2nd generation of FHS participants. In the present proposal we request modest funds to create and analyze a new dataset of CMB data in Gen 3. In addition to expanding our current knowledge of CMB prevalence and risk factors to a younger sample than has previously been studied, the present application will study 3 major novel aspects: the relation of biomarkers of neurodegeneration (plasma clusterin and beta-amyloid) to CMB, the relation of CMB to novel MRI measures of brain integrity and aging (DTI and gray matter volumes), and the existence of {common and} rare genetic variants associated with CMB. The proposed research project will advance our understanding of the pathophysiology of CMB in young adults, and improve effective prevention of stroke and dementia.