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

描述（申请人提供）：多模态CT和MRI可用于研究和诊断脑卒中病理进展，可排除出血性脑卒中，并可能用于延长溶栓时限，但无法确定溶栓再灌注增加脑卒中后出血转化（HT）发生的时限。利用实验性缺血，我们提出了一种估计个体溶栓时限的方法。这种方法将提供目前无法获得的关键信息：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，在血脑屏障（BBB）初始破坏后使用溶栓剂时，HT的频率会增加。这一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”，表明血脑屏障开始分解，最终导致再灌注后的HT。我们将使用K/Rb取代MRI来观察这种[K+]变化。MRI可以有效地观察到铷-87，而不是K，它是K+的同系物，可以通过进料取代K（18%）。我们将使用Rb MRI对大鼠脑中的[K+]br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的栓塞模型和在再灌注后添加tPA的力学模型）中HT频率的关系，作为卒中模型和严重程度的函数，以及不同的侧支血流量电位。我们预测，在[K*]^下降之后再灌注时，而不是在[K*]^下降之前再灌注时，血脑屏障通透性的变化将与K+下降一致。此外，我们将评估这种[K+]br下降与缺血核心其他MRI参数（T1、T2、ADC、AST CBF、[Na+]br）的关系，并预测它将发生在特定水平的[Na+]br，但与Gd-DTPA外渗以外的任何其他参数无关。这些结果将与放射自成像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）将被用来改变K+下降的时间：血脑屏障的变化假设也会随之改变。本研究对血脑屏障破坏与HT之间关系的研究将直接导致急性缺血性脑卒中的诊断和治疗的进一步进展。

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.