Predictors of spontaneous cerebral AVM hemorrhage

描述（由申请人提供）：准确平衡介入治疗和自然病史（主要是颅内出血（ICH））的竞争风险，对于脑动静脉畸形（bavm）患者的最佳管理是必要的。该项目的首要主题是开发新的风险分层生物标志物，并为其使用提供决策分析框架。作为一个类别，未破裂患者发生治疗相关损伤的风险较高，但发生脑出血的风险较低。因此，治疗未破裂的脑脊髓瘤（占所有病例的一半）正变得越来越有争议。正在进行的随机临床试验（NCT00389181），一项未破裂脑avm （ARUBA）的随机试验，比较了最佳干预（手术，栓塞和/或放射手术）与非干预。如果发现不干预优于甚至不优于未破裂病例，那么将有更大的需求对未破裂病例进行风险分层，因为在这一组中缺乏良好的脑出血风险预测指标。综上所述，迫切需要改进风险评估。目的1将证明无症状的病灶内微出血（SIM）是一个新的危险因素的bAVM破裂。我们将表明，显微镜下的证据，含铁血黄素（含铁血黄素阳性）在切除的bAVM组织与脑出血指数（脑出血的临床表现）相关。此外，我们将证明巨噬细胞浸润与含铁血黄素阳性高度相关，这代表了另一种潜在的生物标志物。除了用作风险标志物外，SIM和巨噬细胞浸润也可以作为临床试验的替代终点。Aim 2将开发一种用于SIM的MR生物标志物，显示切除组织中含铁血黄素阳性与预处理铁敏感成像（ISI）的敏感性效应相关。使用平均随访2.5年的前瞻性队列，我们将估计SIM发生率，并将其与已知症状性脑出血发生率进行比较。一个潜在的额外标记，巨噬细胞浸润，也可以在患者中使用阿魏木糖醇成像，一种超小颗粒氧化铁（USPIO）；阿魏木糖醇摄取的MR成像可以预测切除组织中组织巨噬细胞的负荷。在Aim 3中，我们将证明(a) IL1ss和TNF的遗传变异是诊断后新脑出血的预测因素；(b)内啡肽（ENG）基因型与ICH后预后恶化相关；(c) BDNF基因型与未破裂病例手术切除后功能预后恶化相关；(d)使用我们现有的全基因组关联研究数据集，我们将确定新的脑出血风险预测因素，脑出血后的结果和切除后的结果。我们将对新的基因座进行测序，以确定与这些结果相关的变异，并在我们的整个队列中进行测试。目标4将构建一个实用的系统来平衡风险和收益，以最佳地为bAVM管理提供信息，并在情境中评估和结合目标1-3的新知识与已建立的风险标记。我们假设新的风险因素的加入将进一步改善风险的区分。拟议的项目将加强未来多中心的努力，以改善对bAVM患者的护理。

DESCRIPTION (provided by applicant): Accurately balancing the competing risks of interventional treatment and natural history - primarily intracranial hemorrhage (ICH) - is necessary for optimal management of patients harboring brain arteriovenous malformations (bAVMs). The overarching theme of this project is to develop novel risk-stratification biomarkers and provide a decision-analysis framework for their use. As a class, unruptured patients are at higher risk for treatment-related injury but at lower risk for ICH. Accordingly, treatment of unruptured bAVMs-half of all cases- is becoming increasingly controversial. The ongoing randomized clinical trial (NCT00389181), A Randomized Trial of Unruptured Brain AVMs (ARUBA), is comparing best intervention (either surgery, embolization and/or radiosurgery) vs. non-intervention. If non-intervention is found superior-or even non- inferior-then there will be even greater demand to risk-stratify unruptured cases, as good ICH risk predictors are lacking in this group. Taken together, there is a pressing need to improve risk assessment. Aim 1 will demonstrate that Silent Intralesional Microhemorrhage (SIM) is a novel risk factor for bAVM rupture. We will show that microscopic evidence of hemosiderin (hemosiderin positivity) in resected bAVM tissue is associated with index ICH (clinical presentation with ICH. Further we will show that macrophage infiltration is highly correlated with hemosiderin positivity, which represents an additional potential biomarker. In addition to use as risk markers, both SIM and macrophage infiltration might also serve as surrogate endpoints for clinical trials. Aim 2 will develop a MR biomarker for SIM, showing that hemosiderin positivity in resected tissue is correlated with susceptibility effect on pre-treatment iron-sensitive imaging (ISI). Using a prospective cohort with a mean follow-up of 2.5 years, we will estimate SIM incidence and compare it to known symptomatic ICH rates. A potential additional marker, macrophage infiltration, can also be imaged in patients using ferumoxytol, an UltraSmall Particles of Iron Oxide (USPIO); MR imaging of ferumoxytol uptake will predict tissue macrophages burden in resected tissue. In Aim 3, we will demonstrate that (a) genetic variants in IL1ss and TNF are predictors of new ICH after diagnosis; (b) endoglin (ENG) genotype is associated with worsened outcome after index ICH; (c) BDNF genotype is associated with worsened functional outcome after surgical resection in unruptured cases; and (d) Using our existing Genome-Wide Association Study dataset, we will identify novel risk predictors for new ICH, outcome after ICH and outcome after resection. We will sequence novel loci to identify variants associated with these outcomes and test in our entire cohort. Aim 4 will construct a practical system to balance risks and benefits to optimally inform bAVM management and contextually evaluate and combine new knowledge from Aims 1-3 with established risk markers. We hypothesize that addition of novel risk factors will provide further improvement in discrimination of risk. The proposed project will undergird future multi-center efforts to improve care for bAVM patients.