Delayed rt-PA Treatment in a Rat Embolic Stroke Model: Diagnosis and Prognosis of Ischemic Injury and Hemorrhagic Transformation with Magnetic Resonance Imaging

The authors characterized effects of late recombinant tissue plasminogen activator (rt-PA) administration in a rat embolic stroke model with magnetic resonance imaging (MRI), to assess potential MRI correlates, or predictors, or both, of rt-PA–induced hemorrhage. Diffusion-, perfusion-, and postcontrast T1 -weighted MRI were performed between 4 and 9 hours and at 24 hours after embolic stroke in spontaneously hypertensive rats. Treatment with either rt-PA or saline was started 6 hours after stroke. A spectrophotometric hemoglobin assay quantified hemorrhage severity. Before treatment, relative cerebral blood flow index (rCBFi) and apparent diffusion coefficient (ADC) in the ischemic territory were 30% ± 23% and 60% ± 5% (of contralateral), respectively, which increased to 45% ± 39% and 68% ± 4% 2 hours after rt-PA. After 24 hours, rCBFi and ADC were 27% ± 27% and 59 ± 5%. Hemorrhage volume after 24 hours was significantly greater in rt-PA–treated animals than in controls (8.7 ± 3.7 μL vs. 5.1 ± 2.4 μL, P < 0.05). Before rt-PA administration, clear postcontrast T1 -weighted signal intensity enhancement was evident in areas of subsequent bleeding. These areas had lower rCBFi levels than regions without hemorrhage (23% ± 22% vs. 36% ± 29%, P < 0.05). In conclusion, late thrombolytic therapy does not necessarily lead to successful reperfusion. Hemorrhage emerged in areas with relatively low perfusion levels and early blood–brain barrier damage. Magnetic resonance imaging may be useful for quantifying effects of thrombolytic therapy and predicting risks of hemorrhagic transformation.

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Analysis of Combined Treatment of Embolic Stroke in Rat with r-tPA and a GPIIb/IIIa Inhibitor

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600010 ◽

2005 ◽

Vol 25 (1) ◽

pp. 87-97 ◽

Cited By ~ 23

Author(s):

Guangliang Ding ◽

Quan Jiang ◽

Li Zhang ◽

Zheng Gang Zhang ◽

Lian Li ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Thrombolytic Therapy ◽

Combination Treatment ◽

Infarct Volume ◽

Embolic Stroke ◽

Control Group ◽

Resonance Imaging ◽

Cerebral Microvessels ◽

Magnetic Resonance Imaging Mri

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab′)2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated ( n = 12) and control ( n = 10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.

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Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

Brain Research ◽

10.1016/j.brainres.2007.06.039 ◽

2007 ◽

Vol 1165 ◽

pp. 135-143 ◽

Cited By ~ 15

Author(s):

Yoji Tanaka ◽

Hideto Ishii ◽

Megumi Hiraoka ◽

Naoyuki Miyasaka ◽

Toshihiko Kuroiwa ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Imaging Study ◽

Fibrinolytic Therapy ◽

Embolic Stroke ◽

Magnetic Resonance Imaging Study ◽

Stroke Model ◽

Resonance Imaging ◽

Annexin 2

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Magnetic Resonance Imaging Indexes of Therapeutic Efficacy of Recombinant Tissue Plasminogen Activator Treatment of Rat at 1 and 4 Hours after Embolic Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200001000-00005 ◽

2000 ◽

Vol 20 (1) ◽

pp. 21-27 ◽

Cited By ~ 36

Author(s):

Quan Jiang ◽

Rui Lan Zhang ◽

Zheng Gang Zhang ◽

James R. Ewing ◽

Ping Jiang ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Recombinant Tissue Plasminogen Activator ◽

Treated Group ◽

Untreated Group ◽

Embolic Stroke ◽

Resonance Imaging ◽

Tissue Plasminogen

With use of magnetic resonance imaging (MRI), the effects of early and delayed treatment of embolic stroke in rat with recombinant tissue plasminogen activator (rt-PA) were investigated. Rats with embolic stroke were treated with rt-PA at 1 (n = 9) or 4 (n = 7) hours after stroke onset or were untreated (n = 15). Diffusion-weighted imaging, perfusion-weighted imaging, and T2-weighted imaging were performed before and after embolization from 1 hour to 7 days. No significant differences were detected in the relative areas with low cerebral blood flow (CBF), apparent diffusion coefficient of water (ADCw), and T2 between the 4-hour treated group and the untreated group. Significant decreases in the average relative areas with low CBF were detected in the 1-hour treated group from 4 to 48 hours after embolization as compared with the untreated group. The increase in T2 in the 1-hour treated group was significantly lower than in the untreated and 4-hour treated groups. A significant increase in ADCw was detected in the 1-hour treated group at 3 and 24 hours after embolization as compared with the untreated and 4-hour treated groups. Secondary embolization was detected by both MRI and laser scanning confocal microscopy. The data suggest that MRI can detect the efficacy of rt-PA treatment and secondary ischemic damage.

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Magnetic Resonance Imaging Characterization of Hemorrhagic Transformation of Embolic Stroke in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200205000-00007 ◽

2002 ◽

Vol 22 (5) ◽

pp. 559-568 ◽

Cited By ~ 34

Author(s):

Quan Jiang ◽

Rui Lan Zhang ◽

Zheng Gang Zhang ◽

Robert A. Knight ◽

James R. Ewing ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Signal Intensity ◽

Critical Factor ◽

Hemorrhagic Transformation ◽

Magnetic Resonance Images ◽

Embolic Stroke ◽

Tissue Type ◽

Resonance Imaging ◽

Contrast Enhanced

Intracranial hemorrhage is a critical factor when considering efficacy and safety of thrombolytic intervention after thromboembolic stroke. This study tested whether magnetic resonance imaging could identify tissue for hemorrhagic transformation after the onset of embolic stroke. Rats subjected to embolic stroke with and without recombinant tissue-type plasmogen activator (rt-PA) treatment were followed-up with magnetic resonance imaging using the inverse of the apparent forward transfer rate for magnetization transfer (kinv), gadolinium-chelate contrast-enhanced magnetic resonance imaging, and diffusion-, perfusion-, and T2-weighted imaging. Rats with embolic stroke either were treated with rt-PA 1 (n = 16) or 4 hours (n = 13) after stroke onset or were not treated (n = 15). From these groups, at total of 17 rats had intracerebral hemorrhage. Tissue progressing to hemorrhage and adjacent to the site of hemorrhage was analyzed to identify magnetic resonance imaging markers that characterize hemorrhagic transformation. The parameter maps of kinv and contrast-enhanced magnetic resonance imaging showed greater sensitivity in the detection of tissue destined for hemorrhagic transformation compared with the apparent diffusion coefficient of water (ADCw) and CBF. In tissue not destined to undergo hemorrhagic transformation, kinv maps and contrast-enhanced magnetic resonance imaging exhibited small increases in kinv and contrast-enhanced magnetic resonance imaging signal intensity in the area encompassing the territory supplied by the middle cerebral artery. In contrast, large increases in kinv and in signal intensity in the contrast-enhanced magnetic resonance images were detected in the region where gross hemorrhage was confirmed histologically. The values of kinv, T2, and signal intensity in the contrast-enhanced magnetic resonance images were significantly higher in the region destined for hemorrhagic transformation (kinv, P ⩽ 0.033 3–24 hours after embolization; T2, P ⩽ 0.037 24–48 hours; contrast-enhanced magnetic resonance imaging, P < 0.05 4–7 hours) compared with the nonhemorrhagic transformation ischemic region or in the contralateral homologous regions after onset of ischemia. Of these methods, kinv shows the most sensitivity in the detection of hemorrhagic transformation soon after embolization. The authors' data suggest that kinv and contrast-enhanced magnetic resonance imaging are potentially important methodologies for detecting tissue destined for hemorrhagic transformation.

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