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 2 A 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 2 B 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038540-03
Application #
6351882
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Jacobs, Tom P
Project Start
1999-06-15
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2001
Total Cost
$229,944
Indirect Cost
Name
Henry Ford Health System
Department
Neurology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Nagaraja, Tavarekere N; Ewing, James R; Karki, Kishor et al. (2011) MRI and quantitative autoradiographic studies following bolus injections of unlabeled and (14)C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants. NMR Biomed 24:547-58
Knight, Robert A; Nagaraja, Tavarekere N; Ewing, James R (2011) Letter by Knight et al regarding article, ""Validation of in vivo magnetic resonance imaging blood-brain barrier permeability measurements by comparison with gold standard histology"". Stroke 42:e568
Nagaraja, Tavarekere N; Knight, Robert A; Ewing, James R et al. (2011) Multiparametric magnetic resonance imaging and repeated measurements of blood-brain barrier permeability to contrast agents. Methods Mol Biol 686:193-212
Nagaraja, Tavarekere N; Karki, Kishor; Ewing, James R et al. (2010) The MRI-measured arterial input function resulting from a bolus injection of Gd-DTPA in a rat model of stroke slightly underestimates that of Gd-[14C]DTPA and marginally overestimates the blood-to-brain influx rate constant determined by Patlak plots. Magn Reson Med 63:1502-9
Knight, Robert A; Karki, Kishor; Ewing, James R et al. (2009) Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[(14)C]DTPA. J Cereb Blood Flow Metab 29:1048-58
Nagaraja, Tavarekere N; Karki, Kishor; Ewing, James R et al. (2008) Identification of variations in blood-brain barrier opening after cerebral ischemia by dual contrast-enhanced magnetic resonance imaging and T 1sat measurements. Stroke 39:427-32
Nagaraja, Tavarekere N; Keenan, Kelly A; Fenstermacher, Joseph D et al. (2008) Acute leakage patterns of fluorescent plasma flow markers after transient focal cerebral ischemia suggest large openings in blood-brain barrier. Microcirculation 15:1-14
Nagaraja, Tavarekere N; Nagesh, Vijaya; Ewing, James R et al. (2007) Step-down infusions of Gd-DTPA yield greater contrast-enhanced magnetic resonance images of BBB damage in acute stroke than bolus injections. Magn Reson Imaging 25:311-8
Nagaraja, Tavarekere N; Keenan, Kelly A; Brown, Stephen L et al. (2007) Relative distribution of plasma flow markers and red blood cells across BBB openings in acute cerebral ischemia. Neurol Res 29:78-80
Cao, Y; Brown, S L; Knight, R A et al. (2005) Effect of intravascular-to-extravascular water exchange on the determination of blood-to-tissue transfer constant by magnetic resonance imaging. Magn Reson Med 53:282-93

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