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）是临床痴呆症的重要，可能改变的因素。 最近的数据表明，痴呆症的特定年龄特异性发生率可能正在降低，部分原因是 管理血管危险因素，贷款施加紧迫的预防痴呆试验，但主要障碍是 缺乏用于跟踪SVD发作和进展的循环生物标志物。脑MRI成像标记 目前是SVD的黄金标准，但对于重复评估而言太昂贵且负担重。 最近的遗传研究，包括基因组流行病学的心脏与衰老研究的同类研究 （收费）财团，暗示了SVD和痴呆症生物学中的小胶质细胞炎症和星形胶质细胞。 我们建议测量2个小胶质细胞炎症（SCD-14和YKL-40）的循环生物标志物和A 大约17,000人的星形胶质损伤标记（GFAP）（包括4000名少数族裔参与者，6000人，> 2 MRI）在5个基于人群的同伙中。 特异性，我们将（1）检查新型生物标志物与先前收集的（a）的关联 MRI定义的SVD（白质超强度，lacunar梗塞和脑微孔），并且 70岁以下的早期临床前SVD的敏感MRI度量，例如扩散的分数各向异性 加权成像，区域皮质稀疏和血管周空间； （b）先前收集的措施 认知功能； （c）SVD（痴呆和中风）的神经认知和血管后果。 我们将使用Mendelian随机框架和现有遗传数据来检查因果关系 在新型的生物标志物和MRI，神经认知和临床结果之间。 （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Framingham中风风险预测评分； （b）在一系列先前测量的面板上 SVD的“候选”生物标志物，包括CRP，IL6，TNF-Alpha，纤维蛋白原，BNP，尿白蛋白，THCY，ST2， GDF15，TNI，BDNF，VEGF，MMP-9，β-淀粉样蛋白，簇和APOE，以及（c）我们将确定一个简约的 一组最佳预测SVD存在和认知能力下降，中风和痴呆症风险的生物标志物。 （3）我们将（a）验证在独立样本中AIM 2中开发的预测模型，（b）扩展 通过假设的探索，生物学关联并改善了临床预测模型 多维的OMICS（全基因组，GWAS，表观遗传和基因表达）和（c）研究 在模型上结合了遗传，表观遗传学，转录组信息的风险模型的预测价值 仅考虑危险因素和血清生物标志物信息。 总而言之，我们建议利用广泛的可用数据来识别和验证新颖的循环 神经胶质细胞功能障碍的生物标志物概况，这将提高我们对SVD生物学的理解并有助于 SVD的预测及其相关的不良神经系统结果。