Microglial, Inflammatory and Omics Markers of Cerebral Small Vessel Disease in the CHARGE Consortium

CHARGE 联盟中脑小血管疾病的小胶质细胞、炎症和组学标记

• 批准号: 9272153
• 负责人: MYRIAM FORNAGE
• 金额: $ 103.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272153
• 关键词: Accounting; Age; Aging; Albumins; Amyloid beta-Protein; Anisotropy; Astrocytes; Atherosclerosis; Biological; Biological Markers; Biology; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Cerebral small vessel disease; Clinical; Communities; Coronary Artery Risk Development in Young Adults Study; DNA Methylation; Data; Dementia; Development; Diffusion Magnetic Resonance Imaging; Environment; Epidemiology; Epigenetic Process; Fibrinogen; Framingham Heart Study; Functional disorder; GDF15 gene; Gelatinase B; Gene Expression; Genes; Genetic; Genetic study; Genomics; Glial Fibrillary Acidic Protein; Gold; Heart; IL6 gene; Image; Impaired cognition; Incidence; Infarction; Inflammation; Inflammatory; Injury; Intervention; Ischemic Stroke; Lacunar Infarctions; Magnetic Resonance Imaging; Measures; Microvascular Dysfunction; Minority; Modeling; National Institute of Neurological Disorders and Stroke; Neurocognitive; Neuroglia; Neurological outcome; Outcome; Participant; Performance; Persons; Predictive Value; Predisposition; Prevention; Prevention trial; Randomized; Research; Risk; Risk Factors; Role; Sampling; Serum; Serum Markers; Staging; Stroke; TNF gene; Troponin I; Urine; Vascular Endothelial Growth Factors; White Matter Hyperintensity; aging gene; base; biomarker panel; candidate marker; cardiovascular health; cerebral atrophy; cerebral microbleeds; circulating biomarkers; clinical risk; cognitive function; cohort; data space; disorder risk; genome wide association study; imaging biomarker; improved; neurovascular; novel; novel marker; population based; pre-clinical; predictive marker; sulfated glycoprotein 2; transcriptomics; vascular risk factor; white matter; whole genome

Cerebral Small Vessel Disease (SVD) is an important, potentially modifiable factor for clinical dementia. Recent data suggest that the age-specific incidence of dementia may be decreasing, partly as a result of better management of vascular risk factors, lending urgency to dementia prevention trials but a major impediment is the absence of circulating biomarkers for tracking onset and progression of SVD. Brain MRI imaging markers are the current gold standard for SVD but are too expensive and burdensome for repeated assessments. Recent genetic studies, including from the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) consortium, implicate microglial inflammation and astroglia in the biology of SVD and dementia. We propose to measure 2 circulating biomarkers of microglial inflammation (sCD-14 and YKL-40) and a marker of astroglial injury (GFAP) in ~17,000 persons (including 4000 minority participants, 6000 with >2 MRI) across 5 CHARGE population-based cohorts. Specifcally, we will (1) examine the association of the novel biomarkers with (a) previously collected MRI-defined SVD (white matter hyperintensities, lacunar infarcts and cerebral microbleeds), and in persons under age 70, sensitive MRI measures of early, preclinical SVD such as fractional anisotropy on diffusion- weighted imaging, regional cortical thinning and perivascular spaces; (b) previously collected measures of cognitive function; and (c) neurocognitive and vascular consequences of SVD (dementia and stroke). We will use a Mendelian Randomization framework and existing genetic data to examine causal relationships between the novel biomarkers and MRI, neurocognitive, and clinical outcomes. (2) We will assess the incremental predictive utility of the novel biomarkers over (a) vascular risk factor profiles such as the Framingham Stroke Risk Prediction score; (b) over a panel of previously measured `candidate' biomarkers for SVD including CRP, IL6, TNF-alpha, fibrinogen, BNP, urine albumin, tHcy, ST2, GDF15, TnI, BDNF, VEGF, MMP-9, beta-amyloid, clusterin and APOE and (c) we will identify a parsimonious set of biomarkers that best predict presence of SVD and risk of cognitive decline, stroke and dementia. (3) We will (a) validate the prediction models developed in Aim 2 in independent samples, (b) extend the biological associations and improve clinical prediction models through hypothesis-free exploration of multi-dimensional omics (whole genome, GWAS, epigenetic and gene expression) and (c) investigate the added predictive value of risk models that combine genetic, epigenetic, transcriptomic information over models that consider only risk factor and serum biomarker information. In summary we propose to leverage extensive available data to identify and validate a novel circulating biomarker profile of glial cell dysfunction that will improve our understanding of SVD biology and help in the prediction of SVD and its associated adverse neurological outcomes.

脑小血管疾病（SVD）是临床痴呆的一个重要的、潜在可改变的因素。 最近的数据表明，痴呆症的特定年龄发病率可能正在下降，部分原因是改善 血管危险因素的管理，给痴呆症预防试验带来了紧迫性，但一个主要障碍是 缺乏用于追踪 SVD 发病和进展的循环生物标志物。脑 MRI 成像标记 是当前 SVD 的黄金标准，但对于重复评估来说过于昂贵且繁重。 最近的遗传学研究，包括基因组流行病学心脏与衰老研究队列 (CHARGE) 联盟，将小胶质细胞炎症和星形胶质细胞与 SVD 和痴呆的生物学联系起来。 我们建议测量小胶质细胞炎症的 2 种循环生物标志物（sCD-14 和 YKL-40）和 约 17,000 人的星形胶质细胞损伤标志物 (GFAP)（包括 4000 名少数族裔参与者，6000 名患有 >2 MRI）跨越 5 个基于 CHARGE 人群的队列。 具体来说，我们将 (1) 检查新型生物标志物与 (a) 之前收集的相关性 MRI 定义的 SVD（白质高信号、腔隙性梗塞和脑微出血）以及人体 70 岁以下，早期临床前 SVD 的敏感 MRI 测量，例如扩散各向异性分数 加权成像、局部皮质变薄和血管周围空间； (b) 先前收集的措施 认知功能； (c) SVD 的神经认知和血管后果（痴呆和中风）。 我们将使用孟德尔随机化框架和现有的遗传数据来检查因果关系 新型生物标志物与 MRI、神经认知和临床结果之间的关系。 (2) 我们将评估新型生物标志物对 (a) 血管风险的增量预测效用 因素概况，例如弗雷明汉中风风险预测评分； (b) 在先前测量的面板上 SVD 的“候选”生物标志物包括 CRP、IL6、TNF-α、纤维蛋白原、BNP、尿白蛋白、tHcy、ST2、 GDF15、TnI、BDNF、VEGF、MMP-9、β-淀粉样蛋白、簇蛋白和 APOE，并且 (c) 我们将确定一个简约的 一组最能预测 SVD 存在以及认知能力下降、中风和痴呆风险的生物标志物。 (3) 我们将 (a) 在独立样本中验证目标 2 中开发的预测模型，(b) 扩展 生物关联并通过无假设探索改进临床预测模型 多维组学（全基因组、GWAS、表观遗传和基因表达）以及 (c) 研究 结合遗传、表观遗传、转录组信息的风险模型增加了模型的预测价值 仅考虑危险因素和血清生物标志物信息。 总之，我们建议利用广泛的可用数据来识别和验证正在流传的小说 神经胶质细胞功能障碍的生物标志物谱将提高我们对 SVD 生物学的理解并有助于 SVD 及其相关不良神经学结果的预测。