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

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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 indi- vidual time limit for thrombolysis. This method would provide a crucial piece of information that is notcur- rently 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 obser- vation 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 even- tually 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 di- agnostic and therapeutic advances in the assessment and management of acute ischemic stroke.