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. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
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Jacobs, Tom P
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Allegheny-Singer Research Institute
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Yushmanov, Victor E; Kharlamov, Alexander; Yanovski, Boris et al. (2013) Correlated sodium and potassium imbalances within the ischemic core in experimental stroke: a 23Na MRI and histochemical imaging study. Brain Res 1527:199-208
Yushmanov, Victor E; Kharlamov, Alexander; Ibrahim, Tamer S et al. (2011) Kýýý dynamics in ischemic rat brain in vivo by ýýýýýýRb MRI at 7 T. NMR Biomed 24:778-83
Czambel, R Kenneth; Kharlamov, Alexander; Jones, Stephen C (2010) Variations of brain endothelial nitric oxide synthase concentration in rat and mouse cortex. Nitric Oxide 22:51-7
Kharlamov, Alexander; LaVerde, George C; Nemoto, Edwin M et al. (2009) MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain. J Neurosci Methods 182:205-10
Yushmanov, Victor E; Yanovski, Boris; Kharlamov, Alexander et al. (2009) Sodium mapping in focal cerebral ischemia in the rat by quantitative (23)Na MRI. J Magn Reson Imaging 29:962-6
Yushmanov, Victor E; Kharlamov, Alexander; Yanovski, Boris et al. (2009) Inhomogeneous sodium accumulation in the ischemic core in rat focal cerebral ischemia by 23Na MRI. J Magn Reson Imaging 30:18-24
Yushmanov, Victor E; Kharlamov, Alexander; Boada, Fernando E et al. (2007) Monitoring of brain potassium with rubidium flame photometry and MRI. Magn Reson Med 57:494-500
Yushmanov, Victor E; Kharlamov, Alexander; Simplaceanu, Elena et al. (2006) Differences between arterial occlusive and cortical photothrombosis stroke models with magnetic resonance imaging and microtubule-associated protein-2 immunoreactivity. Magn Reson Imaging 24:1087-93
Jones, Stephen C; Kharlamov, Alexander; Yanovski, Boris et al. (2006) Stroke onset time using sodium MRI in rat focal cerebral ischemia. Stroke 37:883-8
Kharlamov, Alexander; Jones, Stephen C; Kim, D Kyle (2002) Suramin reduces infarct volume in a model of focal brain ischemia in rats. Exp Brain Res 147:353-9

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