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（由适用提供）：使用脑MRI检测到的亚临床脑血管疾病，其中脑微毛发（CMB）是一个重要的成分，是更频繁的，在临床上证据并预测临床上的脑疾病和痴呆症。 CMB主要归因于两种主要形式的出血易于脑血管疾病：高血压血管病和脑淀粉样血管病。 CMB是中风风险增加（缺血和出血），认知障碍和痴呆症的预测指标。它们的存在使缺血性中风和阿尔茨海默氏病的预防，治疗和研究工作（免疫疗法）复杂化。然而，尚不清楚基本的病理生理学，年轻人到中年的患病率和CMB的遗传危险因素尚不清楚。 Framingham心脏研究（FHS）拥有大量有关心血管危险因素，遗传，生物标志物和亚临床心血管疾病措施的纵向数据。 FHS第三代（Gen 3）参与者（n = 1621;平均年龄45±8岁）具有带有梯度回声序列的脑MRI，并简单地评估了认知性能。在拟议的赠款中，我们假设将在第4个十年之前检测到CMB，患病率将随着年龄的增长而增加，并且与心血管危险因素和选择的心血管药物使用有关。我们将研究CMB与血管功能障碍（Tonometry）的亚临床测量以及炎症，血管功能障碍和神经变性的新型生物标志物（LPPLA2，VEGF，VEGF，clusterin，beta-Amyloid）。我们还将将CMB与脑损伤和衰老的新型MRI测量（扩散张量成像，灰质体积），传统的衰老和血管损伤的MRI测量值（白质高强度体积，总脑和海马体积）和认知性能。最后，我们将使用{3代的密集家庭关系来评估CMB的遗传力，并使用基于单个变体和基于基因/区域的测试，生物信息学进行连锁和关联分析，以搜索使用可用的外科体芯片和整个Exome测序数据}的遗传变异。本项目将是K23奖“ AG038444：脑微粒的危险因素，遗传学和认知：Framingham研究（PI：ROMERO）”的危险因素，遗传学和认知”，该研究正在研究FHS参与者的第一和第二代参与者中的CMB。 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 young sample than has previously been studied, the present application will study 3 major novel aspects: the relationship of biomarkers of neurodegeneration (plasma clusterin and beta-amyloid) to CMB, the relationship of CMB to novel MRI measures of brain完整性和衰老（DTI和灰质体积），以及与CMB相关的{common and}稀有遗传变异的存在。拟议的研究项目将提高我们对年轻人中CMB病理生理学的理解，并改善中风和痴呆症的有效预防。