NMR STUDIES OF HEMORRHAGIC TRANSFORMATION IN ISCHEMIA

描述：（逐字从申请人的摘要）治疗进展 使用溶栓药物的人类急性中风的发病率增加， 在再灌注的出血性转化（HT）的管理的兴趣 缺血性梗塞临床试验表明，溶栓药物 rt-PA可改善某些缺血性卒中患者的预后，但 并伴有症状性HT的风险增加。更多使用 因此，急性卒中的溶栓治疗将取决于临床医生的 识别有发生HT风险的患者的能力和技术， 尽量减少这种风险。在这个项目中，我们将测试三个具体目标， 假设目的1建立大鼠大脑中动脉闭塞模型 （MCAO）模型，并建立缺血持续时间（1-2 小时），在术后24小时产生25%、50%和75%的HT发生率 再灌注我们假设MCAO后HT的发展取决于 缺血发作和再灌注之间的时间。目标2A将是 研究急性血脑屏障（BBB）破坏与脑缺血的关系。 缺血性脑组织的演变HT（使用HT的大鼠MCAO模型产生 目标1）中通过跟踪Gd-DTPA摄取确定的3 HT发生率 使用磁共振成像（MRI）。放射性标记化学品，14 C标记 Gd-DTPA和55 Fe标记的红细胞将用于确认MRI 通过定量放射自显影测量并建立血浆Gd-DTPA 时间-浓度曲线目标2A的假设是，HT的发生是由于 导致血脑屏障破坏的急性内皮损伤。共振增强成像 使用Gd-DTPA的缺血脑组织可以显示急性BBB损伤， 在HT的发展之前，并提供BBB的定量估计 Gd-DTPA渗透性表面产物（PS产物）和分布空间， 可能为HT提供一个有用的危险指数。目标2B将是调查 血压、脑灌注、脑血流量（CBF）和 急性Gd-DTPA摄取和随后HT的梗死面积来检验假设 Gd-DTPA摄取的频率和程度以及随后的HT将 受组织的灌注状态和更大、更严重的 缺血性梗塞目的3将是检查是否溶栓剂 rt-PA增加了拟定大鼠HT的频率和/或严重程度 MCAO模型目标3的假设是rt-PA将影响 出血，因此增强区域的大小和/或Gd-DTPA的比率 在缺血和再灌注的急性期摄取，但不会增加 在我们的大鼠MCAO模型中HT的频率。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Advances in the treatment of acute stroke in humans using thrombolytic agents have prompted an increased interest in the management of hemorrhagic transformation (HT) in reperfused ischemic infarction. Clinical trials have shown that the thrombolytic drug rt-PA improves the outcome of certain patients with ischemic stroke, but is accompanied by an increased risk of symptomatic HT. Increased utilization of thrombolytic therapy in acute stroke, therefore, will depend on the clinician's ability to identify patients at risk of developing HT and techniques to minimize such risks. In this project, we will test three specific aims and hypotheses. Aim 1 will be to develop a rat middle cerebral artery occlusion (MCAO) model of Ht in ischemic stroke and establish ischemic durations (1-2 hours) that produce 25%, 50% and 75% HT incidence rates at 24 hours post reperfusion. We hypothesize that the development of HT after MCAO will depend on the time between the onset of ischemia and reperfusion. Aim 2A will be to study the relationship of acute blood brain barrier (BBB) disruption to evolving HT of ischemic brain tissue (produced using the rat MCAO model of HT with the 3 HT incidence rates established in Aim 1) by tracking Gd-DTPA uptake using magnetic resonance imaging (MRI). Radiolabeled chemicals, 14C-labeled Gd-DTPA and 55Fe-labeled red blood cells, will be used to validate MRI measurements by quantitative autoradiography and to establish plasma Gd-DTPA time-concentration curves. The hypothesis for Aim 2A is that HT occurs due to acute endothelial damage that causes BBB disruption. Contrast enhanced MRI of ischemic brain tissue using Gd-DTPA can demonstrate acute BBB injury, which precedes the development of HT, and provide quantitative estimates for BBB Gd-DTPA permeability surface product (PS product) and distribution space that may provide a useful risk index for HT. Aim 2B will be to investigate the effects of blood pressure, cerebral perfusion, cerebral blood flow (CBF) and infarct size on acute Gd-DTPA uptake and subsequent HT to test the hypothesis that the frequency and degree of Gd-DTPA uptake and subsequent HT will be affected by the perfusion status of the tissue and by larger, more severe ischemic infarcts. Aim 3 will be to examine whether the thrombolytic agent rt-PA increases the frequency and/or the severity of HT in the proposed rat MCAO model. The hypothesis for Aim 3 is that rt-PA will affect the severity of bleeding, and hence the size of the enhancing region and/or rate of Gd-DTPA uptake in acute phases of ischemia and reperfusion, but will not increase the frequency of HT in our rat MCAO model.