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

脑小血管疾病(SVD)是临床痴呆的一个重要的、潜在的可改变因素。 最近的数据表明，特定年龄的痴呆症发病率可能正在下降，部分原因是更好的 血管危险因素的管理，为痴呆症预防试验提供了紧迫性，但一个主要障碍是 缺乏追踪SVD发生和发展的循环生物标志物。脑MRI成像标记物 是目前SVD的黄金标准，但对于重复评估来说过于昂贵和繁重。 最近的遗传学研究，包括来自基因组流行病学中心脏和衰老研究的队列 (指控)联合体，涉及SVD和痴呆的生物学中的小胶质炎症和星形胶质细胞。 我们建议检测两个小胶质细胞炎症的循环生物标志物(SCD-14和YKL-40)和一个 约17,000人的星形胶质损伤(GFAP)标志物(包括4,000名少数民族参与者，6,000名星形胶质损伤患者 核磁共振)覆盖了5个基于人群的队列。 具体地说，我们将(1)检查新的生物标记物与(A)先前收集的关联 MRI定义的SVD(脑白质高信号、腔隙性脑梗塞和脑微出血)，以及 在70岁以下，早期临床前SVD的敏感MRI指标，如弥散各向异性分数- 加权成像、局部皮质变薄和血管周围间隙；(B)以前收集的测量 认知功能；和(C)SVD(痴呆症和中风)的神经认知和血管后果。 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 新的生物标记物与核磁共振、神经认知和临床结果之间的关系。 (2)我们将评估新生物标记物对(A)血管风险的增量预测效用 因素概况，如Framingham卒中风险预测评分；(B)一组先前测量的 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、血管内皮生长因子、基质金属蛋白酶-9、β-淀粉样蛋白、聚集素和载脂蛋白和(C)我们将确定节俭的 一组生物标志物，最好地预测SVD的存在以及认知能力下降、中风和痴呆症的风险。 (3)我们将(A)在独立样本中验证在目标2中开发的预测模型，(B)扩展 通过无假说的探索建立生物学关联并改进临床预测模型 多维组学(全基因组、GWA、表观遗传学和基因表达)和(C)研究 增加了风险模型的预测价值，这些模型结合了遗传、表观遗传、转录信息而不是模型 仅考虑危险因素和血清生物标志物信息。 总之，我们建议利用大量可用的数据来识别和验证一种新的循环 神经胶质细胞功能障碍的生物标志物图谱将提高我们对SVD生物学的理解，并有助于 SVD及其相关不良神经结局的预测。

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.