Brain K+ Dynamics, BBB Breakdown & Hemorrhagic Transformation in Ischemic Stroke

描述（申请人提供）：多模式CT和MRI可用于研究和诊断卒中病理进展，可排除出血性卒中，并可能用于延长溶栓时限，但无法确定溶栓再灌注增加卒中后出血性转化（HT）发生的时限。利用实验性缺血，我们提出了一种方法来估计个人的溶栓时限。这种方法将提供一个目前还没有的关键信息：在没有出血性中风的情况下，预测溶栓是否会导致HT的能力。我们的假设是，当血脑屏障（BBB）最初破裂后给予血栓溶解剂时，HT的频率会增加。该建议的基本原理是基于我们观察到闭塞后3-4小时缺血皮质中脑组织钾[K+]br突然下降75%。我们认为，这种[K+]br的突然减少，即“K+下降”，表明血脑屏障开始破裂，最终导致再灌注后的HT。我们将用K/Rb替代MRI观察这个[K+]分支。铷-87，而不是K，可以有效地观察到与MRI，作为一个同源物的K+，并可以取代K（18%）通过喂养。我们将在大鼠脑中使用Rb MRI对[K+]br的下降进行计时，并将研究其与三种不同再灌注缺血模型（包括在不同时间给予tPA的栓子模型和再灌注后添加tPA的机械模型）中HT频率的关系，作为中风模型和严重程度以及不同侧支血流潜力的函数。我们预测，当再灌注发生在[K*]^下降之后而不是之前时，HT的发生增加，并且BBB渗透性变化将与K+下降一致。此外，我们将评估缺血核心中[K+]br下降与其他MRI参数（T1、T2、ADC、AST CBF、[Na+]br）的关系，并预测其将发生在[Na+]br的特定水平，但与除Gd-DTPA外渗外的任何其他参数无关。这些结果将与放射自显影CBF和K、Rb和Na的组织分析相结合。间接因素（包括温度和血清电解质）将用于改变K+下降的时间：假设BBB变化也会发生变化。该提案对血脑屏障破坏与HT关系的研究可能直接导致急性缺血性卒中评估和管理的额外诊断和治疗进展。

DESCRIPTION (provided by applicant): Multimodal CT and MRI are available to study and diagnose stroke pathological progression, can rule out hemorrhagic stroke, and possibly can be used to extend the time limit for thrombolysis, but there is no way to determine the time limit after which reperfusion with thrombolysis increases the occurrence of post-stroke hemorrhagic transformation (HT). Using experimental ischemia, we propose a method to estimate the individual time limit for thrombolysis. This method would provide a crucial piece of information that is not currently available: the ability to predict whether thrombolysis, in the absence of hemorrhagic stroke, will cause HT. Our hypothesis is that the frequency of HT will increase when a thrombolytic agent is administered after the initial breakdown of the blood-brain barrier (BBB). The rationale for this proposal is based on our observation of a sudden fall of 75% in brain tissue potassium, [K+]br, in ischemic cortex 3-4 h after occlusion. We propose that this abrupt decrease in [K+]br, the "K+ drop," indicates the start of BBB breakdown, which eventually leads to HT after reperfusion. We will use K/Rb substitution MRI to observe this [K+]brfall. Rubidium-87, but not K, can be effectively observed with MRI, acts as a congener of K+, and can be substituted for K (18%) by feeding. We will time this drop in [K+]br using Rb MRI in the rat brain, and will investigate its relation to the frequency of HT in three different reperfusion ischemic models (including an embolus model with tPA administered at various times and a mechanical model with added tPA after reperfusion), as a function of stroke model and severity, and varying collateral blood flow potential. We predict the increased occurrence of HT when reperfusion occurs after, but not before, this fall in [K*]^, and that BBB permeability changes will coincide with the K+ drop. In addition, we will assess this [K+]br drop in relation to other MRI parameters (T1, T2, ADC, AST CBF, [Na+]br) in the ischemic core and predict that it will occur at a specific level of [Na+]br but will not be related to any other parameter except for Gd-DTPA extravasation. These results will be combined with autoradiographic CBF and tissue analysis for K, Rb, and Na. Indirect factors (including temperature and serum electrolytes) will be used to change the time of the K+ drop: BBB changes are hypothesized to follow suit. This proposal's investigation of the relation of BBB breakdown to HT could lead directly to additional diagnostic and therapeutic advances in the assessment and management of acute ischemic stroke.