Biomarker Signatures for Delayed Cerebral Ischemia and Outcome Following Subarachnoid Hemorrhage

摘要 蛛网膜下腔出血(SAH)占所有卒中的5%，具有很高的死亡率和成本 社会类似于缺血性中风，因为受试者要年轻得多。尽管SAH的死亡率有所下降 在过去25年中，由于立即修复动脉瘤、改善医疗管理和 尼莫地平，近三分之一的SAH患者出现迟发性脑缺血(DCI)，常合并脑梗塞 这与糟糕的结果有关。虽然这被认为是由于迟发性脑血管痉挛， 最近的研究表明，减少或预防血管痉挛并不能改善预后。这导致了 到另一种假说，微血管血栓和血管痉挛 皮质弥漫性缺血以及外周和中枢性炎症可能导致DCI。因此，有一个很大的 未满足的需求评估人类SAH后导致DCI的潜在治疗目标，以及 可用于预测DCI以开始早期治疗，并预测结果以更好地分配资源。这个 该提议的前提是基于我们已经证明血液中的基因表达可以 预测SAH患者是否发生血管痉挛。这导致我们假设凝血和炎症 血液中的分子与脑微血管和其他因素相互作用导致大脑延迟 蛛网膜下腔出血后的脑缺血(DCI)和迟发性脑梗塞导致预后不良。我们建议 血液中的基因图谱将预测DCI，并使用改进的Rankin量表(MRS)预测结果。 R61阶段。具体目标#1a：对训练队列的全血进行RNA测序(RNAseq) 在SAH后1天、2天和3天但DCI之前的患者与匹配的血管危险因素对照组进行比较。 具体目标#1b。在1、2或3d确定血液中最显著受调控的基因和途径 将在4-14天内发生DCI的SAH患者与未发生DCI的SAH患者区分开来。特定的 目的#1c：使用WGCNA确定SAH后1、2或3d表达的关键HUB基因和上游基因 它们与4-14d发生DCI有关，可能是致病因素。具体目标#1D。使用支持 向量机(SVM)学习从目标#1b中识别最少数量的1、2或3d的基因 预测(1)SAH患者在4-14天发生DCI(2)，并在3个月时预测MRS为0、1-3、4-5和6。 具体目标#1e。用qRT-PCR确认RNAseq，并评估qRT-PCR的准确性和精密度。 R33期。具体目标#2：在SAH患者的单独验证队列中，对他们的 使用支持向量机测量外周血中AIM#1衍生的基因的表达以进行预测 (支持向量机)在第1天、第2天和/或第3天，哪些患者将在4-14天内发生DCI，哪些患者将 3个月时MRS=0(无缺陷)、1-2、3-5和MRS=6(死亡)。 使用的上下文。预测DCI和MRS的分子/途径可能作为未来的治疗或 DCI的预防目标。预测谁会发生DCI将使早期治疗DCI成为可能。在……里面 此外，未来预防SAH后DCI的临床试验将只招募那些预计会发生的患者。 SAH后的DCI。预测MRS结果可用于在未来的DCI试验中对患者进行分层。

Abstract Subarachnoid hemorrhage (SAH) accounts for 5% of all strokes, has a high mortality and the cost to society is similar to ischemic stroke since subjects are much younger. Though SAH fatality has decreased ~50% in the last 25 years due to immediate repair of aneurysms, improved medical management and nimodipine, nearly 1/3 of SAH patients develop delayed cerebral ischemia (DCI) often with cerebral infarction which is associated with poor outcomes. Though this was thought to be due delayed cerebral vasospasm, recent studies have shown that decreasing or preventing vasospasm does not improve outcomes. This has led to alternative hypotheses that combined effects of microvessel thrombosis and vasospasm combined with cortical spreading ischemia and peripheral and central inflammation may cause DCI. Thus, there is a great unmet need to assess potential treatment targets that contribute to DCI following SAH in humans and that could be used to predict DCI to begin early treatment and to predict outcome to better allocate resources. The premise of the proposal is based upon the findings that we have shown that gene expression in blood can predict SAH patients who develop vasospasm. This led us to Hypothesize that clotting and inflammatory molecules in blood interact with the brain microvasculature and other factors to cause Delayed Cerebral Ischemia (DCI) and delayed cerebral infarction following SAH which lead to poor outcomes. We propose that gene profiles in blood will predict DCI and predict outcomes using the modified Rankin Scale (mRS). R61 Phase. Specific Aim #1a: Perform RNA sequencing (RNAseq) on whole blood of a training cohort of patients 1, 2 and 3 days after a SAH but prior to DCI compared to matched vascular risk factor controls. Specific Aim #1b. Identify the most significantly regulated genes and pathways in blood at 1, 2 or 3d that distinguish SAH patients who develop DCI at 4-14 days from SAH patients who do not develop DCI. Specific Aim #1c: Use WGCNA to identify key hub genes and upstream genes expressed at 1, 2 or 3d after SAH and which are associated with developing DCI at 4-14d and might be causative. Specific Aim #1d. Use Support Vector Machine (SVM) learning to identify the least number of genes at 1, 2 or 3d from Aim #1b that best predict (1) SAH patients who develop DCI at 4-14 days (2) and predict mRS of 0, 1-3, 4-5, and 6 at 3 months. Specific Aim #1e. Confirm RNAseq with qRT-PCR and assess qRT-PCR accuracy and precision. R33 Phase. Specific Aim #2. In a separate validation cohort of SAH patients perform qRT-PCR on their peripheral blood to measure expression of genes derived in Aim #1 to predict using Support Vector Machine (SVM) on day 1, 2 and/or day 3 which patients will develop DCI at 4-14 days and which patients will have mRS=0 (no deficit), 1-2, 3-5 and mRS=6 (dead) at 3 months. Contexts of Use. The molecules/pathways that predict DCI and mRS could serve as future treatment or prevention targets of DCI. Predicting who will develop DCI would make it possible to treat DCI earlier. In addition, future clinical trials to prevent DCI following SAH would enroll just those patients predicted to develop DCI after SAH. Predicting mRS outcomes could be used to stratify patients in future DCI trials.