Biomarker Signatures for Delayed Cerebral Ischemia and Outcome Following Subarachnoid Hemorrhage

迟发性脑缺血的生物标志物特征和蛛网膜下腔出血后的结果

• 批准号: 10322173
• 负责人: Bradley Pearce Ander
• 金额: $ 64.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322173
• 关键词: 3-Dimensional; Affect; Age; Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Angiography; Arteries; Blood; Blood - brain barrier anatomy; Catheters; Cerebral Infarction; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrovascular Spasm; Cerebrum; Clinical; Clinical Trials; Coagulation Process; Cognitive; Complication; Derivation procedure; Diagnosis; Early treatment; Endothelin Receptor Antagonist; Enrollment; FDA approved; Future; Gene Expression; Genes; Hemorrhage; Human; Image; Inflammation; Inflammatory; Ischemia; Ischemic Stroke; Lead; Machine Learning; Measures; Medical; Meta-Analysis; Modeling; Morbidity - disease rate; Myocardial dysfunction; Neurologic; Nimodipine; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Placebos; Prevention; Pulmonary Edema; Quantitative Reverse Transcriptase PCR; Randomized Clinical Trials; Resources; Sensitivity and Specificity; Societies; Stroke; Subarachnoid Hemorrhage; Survivors; Systemic Inflammatory Response Syndrome; Thrombosis; Training; Validation; Vasospasm; Whole Blood; Work; base; biomarker signature; care costs; cerebral microvasculature; cohort; cost; improved; improved outcome; mortality; outcome prediction; patient stratification; peripheral blood; prevent; repaired; spreading depression; stroke patient; support vector machine; transcriptome; transcriptome sequencing; treatment trial; vascular risk factor; whole genome

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.

抽象的 蛛网膜下腔出血 (SAH) 占所有中风的 5%，死亡率高且治疗费用高 社会与缺血性中风相似，因为受试者要年轻得多。尽管 SAH 死亡率有所下降 过去 25 年约 50% 由于动脉瘤的立即修复、医疗管理的改善以及 尼莫地平，近1/3的SAH患者出现迟发性脑缺血（DCI），常伴有脑梗死 这与不良结果相关。虽然这被认为是由于迟发性脑血管痉挛所致， 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 另一种假设是微血管血栓形成和血管痉挛的综合作用 皮质扩散性缺血以及外周和中枢炎症可能导致 DCI。于是，就有了一个伟大的 评估可能导致人类蛛网膜下腔出血后 DCI 的潜在治疗目标的需求未得到满足，并且 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 该提案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 患者发生血管痉挛。这使我们假设凝血和炎症 血液中的分子与大脑微血管和其他因素相互作用，导致大脑迟发 SAH 后的缺血 (DCI) 和迟发性脑梗塞会导致预后不良。我们建议 血液中的基因谱将预测 DCI 并使用改良的 Rankin 量表 (mRS) 预测结果。 R61相。具体目标 #1a：对训练队列的全血进行 RNA 测序 (RNAseq) SAH 后 1、2 和 3 天但 DCI 之前的患者与匹配的血管危险因素对照进行比较。 具体目标#1b。确定 1、2 或 3 天时血液中受最显着调节的基因和通路 区分在 4-14 天发生 DCI 的 SAH 患者与未发生 DCI 的 SAH 患者。具体的 目标#1c：使用 WGCNA 识别 SAH 后 1、2 或 3 天表达的关键枢纽基因和上游基因，以及 这与 4-14 天发生 DCI 相关，并且可能是致病原因。具体目标#1d。使用支持 向量机 (SVM) 学习从目标 #1b 中识别 1、2 或 3d 时最少数量的基因 预测 (1) SAH 患者在 4-14 天时出现 DCI (2)，并预测 3 个月时 mRS 为 0、1-3、4-5 和 6。 具体目标#1e。使用 qRT-PCR 确认 RNAseq 并评估 qRT-PCR 的准确性和精密度。 R33相。具体目标#2。在 SAH 患者的单独验证队列中，对其进行 qRT-PCR 外周血测量目标 #1 中衍生的基因表达，使用支持向量机进行预测 (SVM) 在第 1、2 和/或第 3 天，哪些患者将在第 4-14 天出现 DCI，哪些患者将出现 DCI 3 个月时 mRS=0（无缺陷）、1-2、3-5 和 mRS=6（死亡）。 使用环境。预测 DCI 和 mRS 的分子/途径可以作为未来的治疗或 DCI 的预防目标。预测谁会患 DCI 将使更早治疗 DCI 成为可能。在 此外，未来预防 SAH 后 DCI 的临床试验将仅招募那些预计会发生 DCI 的患者 SAH 后 DCI。预测 mRS 结果可用于在未来的 DCI 试验中对患者进行分层。