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

年轻人脑微出血：危险因素、生物标志物和遗传学

基本信息

批准号：
9069721
负责人：
Jose Rafael Romero
金额：
$ 8.19万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069721
关键词：
Adult Age Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Anisotropy Anticoagulants Bioinformatics Biological Markers Blood Vessels Brain Brain Injuries Brain hemorrhage C-reactive protein Cardiovascular Diseases Cardiovascular system Cerebral Amyloid Angiopathy Cerebral small vessel disease Cerebrovascular Disorders Cerebrovascular Trauma Cerebrum Characteristics Cholesterol Clinical Clinical Trials Cognition Cognitive Communities Data Data Set Dementia Diffusion Diffusion Magnetic Resonance Imaging Disease Marker Early Diagnosis Epidemiology Framingham Heart Study Functional disorder Funding Generations Genetic Genetic Markers Genomics Grant Health Heart Hemorrhage Heritability Hippocampus (Brain)Hypertension Image Immunotherapy Impaired cognition Individual Inflammation Inflammatory Injury Ischemic Stroke Knowledge Life Lipids Lipoproteins Lobar Location Magnetic Resonance Imaging Measures Mentored Patient-Oriented Research Career Development Award Methods Nerve Degeneration Normal Range Outcome Participant Pathology Performance Persons Pharmaceutical Preparations Phospholipase A2 Plasma Prevalence Prevalence Study Prevention Process Reporting Request for Proposals Research Research Project Grants Risk Risk Factors Sampling Scanning Smoking Stroke Stroke prevention Structure Surrogate Markers Testing Vascular Diseases Vascular Endothelial Growth Factors White Matter Hyperintensity aging brain arterial stiffness associated symptom base beta amyloid pathology brachial artery cardiovascular risk factor cerebral microbleeds circulating biomarkers clinical Diagnosis cognitive function cognitive performance cognitive testing cohort endothelial dysfunction exome exome sequencing genetic risk factor genetic variant gray matter high risk improved men middle age novel offspring pre-clinical sulfated glycoprotein 2 tonometry young adult

项目摘要

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.

描述（由申请方提供）：使用脑MRI检测的亚临床脑血管疾病更常见，先于并预测临床明显的脑血管疾病和痴呆，其中脑微血管（CMB）是一个重要的未充分研究的组成部分。CMB主要归因于两种主要形式的易出血脑小血管病：高血压血管病和脑淀粉样血管病。CMB是卒中（缺血性和出血）、认知障碍和痴呆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、年轻至中年的患病率和遗传风险因素尚不清楚。心脏病研究（FHS）有大量关于心血管危险因素、遗传、生物标志物和亚临床心血管疾病指标的纵向数据。FHS第三代（Gen 3）受试者（N=1621;平均年龄45±8岁）接受了梯度回波序列脑MRI，并同时评估了认知能力。在拟议的补助金中，我们假设CMB最早将在第40个十年被检测到，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择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（张力测定法）以及与炎症、血管功能障碍和神经变性的新型循环生物标志物（LpPLA 2、VEGF、丛生蛋白、β-淀粉样蛋白）的关系。我们还将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（白色高信号体积，全脑和海马体积）和认知能力相关。最后，我们将使用{跨越3代的密集家族关系来评估CMB的遗传性，并使用单个变体和基于基因/区域的测试进行连锁和关联分析，使用可用的外显子组芯片和全外显子组测序数据进行生物信息学以搜索与CMB相关的遗传变体}。本项目将是K23奖“AG 038444：脑微出血的风险因素，遗传学和认知：Frachial研究（PI：Romero）”的附属项目，该项目正在调查第一代和第二代FHS参与者的CMB。在本提案中，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。除了将我们目前对CMB患病率和风险因素的了解扩展到比以前研究的更年轻的样本之外，本申请将研究3个主要的新方面：神经退行性变生物标志物之间关系（血浆聚集蛋白和β-淀粉样蛋白）与CMB的关系，CMB与脑完整性和衰老的新MRI测量的关系（DTI和灰质体积），以及与CMB相关的{常见和}罕见遗传变异的存在。拟议的研究项目将促进我们对年轻人CMB病理生理学的理解，并提高中风和痴呆的有效预防。