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(Stroke. 1995;26:1453-1458.)
© 1995 American Heart Association, Inc.

Articles

Perfusion and Diffusion-Weighted MR Imaging for In Vivo Evaluation of Treatment With U74389G in a Rat Stroke Model

Tomm B. Müller, MD; Olav Haraldseth, MD, PhD; Richard A. Jones, PhD; Giovanni Sebastiani, MSc; Christian F. Lindboe, MD, PhD; Geirmund Unsgård, MD, PhD Audun N. Øksendal, MD, PhD

From the MR-Center, SINTEF/UNIMED (T.B.M., O.H., R.A.J.); the Department of Mathematical Sciences, The Norwegian Institute of Technology (G.S.); the Departments of Pathology (C.F.L.) and Neurosurgery (T.B.M., G.U.), University Hospital of Trondheim, Trondheim; and Nycomed Imaging (A.N.Ø.), Oslo, Norway.

Correspondence to Tomm B. Müller, Department of Neurosurgery, University Hospital of Trondheim, N-7006 Trondheim, Norway.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose The present study was performed to examine the potential of diffusion-weighted (DW) imaging and dynamic first-passage bolus tracking of susceptibility contrast agents (perfusion imaging) for early in vivo evaluation of the effects of treatment with the free radical scavenger U74389G in a rat model of temporary focal ischemia.

Methods After 45 minutes of middle cerebral artery occlusion, the treatment group (n=9) received an infusion of U74389G, and the control group (n=9) received the identical volume of the vehicle. Reperfusion was instituted in both groups after 120 minutes of middle cerebral artery occlusion. The DW images were collected during middle cerebral artery occlusion and reperfusion and were compared with histologically assessed areas of tissue injury after 2 hours of reperfusion. The dynamic perfusion series were processed on a pixel-to-pixel basis to produce parametric maps reflecting the maximum reduction in the signal obtained during the first passage of the contrast agent and the time delay between the arrival of the bolus and the point of maximum contrast-agent effect.

Results The area of ischemic injury, as assessed from the DW imaging at 60 minutes of reperfusion, was significantly smaller in the treatment group: 9±8% of ipsilateral hemisphere compared with 19±8% in the control group. The histological examination after 2 hours of reperfusion demonstrated an area of ischemic injury of 10±8% for the treatment group compared to 25±10% in the control group. In the treatment group, the perfusion imaging showed a reduction in time delay to maximum effect of the contrast agent in the ischemic hemisphere compared with the control group.

Conclusions The DW imaging during early reperfusion showed a protective effect of postocclusion treatment with the free radical scavenger U74389G. The improvement of time delay to maximum effect of the contrast agent observed in the perfusion imaging of the treatment group may reflect an improvement in the collateral flow to the ischemic tissue.


Key Words: cerebral ischemia, focal • free radicals • magnetic resonance imaging • rats


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Magnetic resonance perfusion imaging using dynamic image acquisition to depict the first passage of a bolus of an intravenously administered susceptibility contrast agent has been used to demonstrate deficits in the cerebral blood flow (CBF) after the onset of an ischemic insult in animal models of experimental stroke1 2 3 4 5 and in stroke patients.6 7 In an attempt to quantify regional CBF, tracer kinetic theory has been applied to signal-intensity changes during first-passage bolus tracking.5 8 9 10 11 However, some controversy exists as to the validity of these methods,12 13 especially in the case of reduced perfusion and pathophysiology of focal ischemia.5 14 Another possibility is to use simple parameters to characterize the changes in the signal intensity versus time curve during bolus passage and use these parameters to describe relative changes in perfusion.14 The method of diffusion-weighted (DW) MR imaging has proved to be sensitive to early ischemic tissue injury in the brain.1 3 5 14 15 16 17 18 19 The hyperintensity in DW images is caused by reduced translational movement of water in the ischemic tissue, probably reflecting intracellular edema20 21 22 and/or reduced water transport across cellular membranes23 after energy failure.24 25 Studies have shown that these changes are reversible after ischemia of short duration.3 14 The combination of DW and perfusion MR imaging has the potential of providing important information on the development of both tissue damage and the changes in flow during an ischemic attack,5 14 and thus it may be well suited for the in vivo evaluation of the effect of cerebroprotective therapy. In a recent study by Minematsu et al,26 DW imaging was used to demonstrate a beneficial effect of a novel N-methyl-D-aspartate antagonist.

To further investigate the possibilities of DW and perfusion MR imaging in the evaluation of cerebroprotective treatment in the acute phase of an ischemic stroke, we tested the free radical scavenger U74389G in a rat model of reversible middle cerebral artery (MCA) occlusion. U74389G is structurally similar to tirilazad mesylate and possesses similar pharmacodynamic and pharmacokinetic profiles. Free radical–induced damage is believed to be important in the development of ischemic tissue injury, particularly in the case of sustained ischemia followed by recirculation.27 The results of treatment with the free radical scavenger tirilazad mesylate in experimental ischemia have been mixed, with results depending on both the species and the type of animal model.28 29 30 31 32 33 In studies using rat MCA occlusion models, neuroprotection has been found with temporary focal ischemia,33 but the results with permanent focal ischemia have not been conclusive.33 34 35 In this study, the early effects of postocclusion treatment with U74389G on perfusion changes and ischemic tissue injury during 2 hours of MCA occlusion and 2 hours of reperfusion were monitored, using both first-pass bolus tracking of susceptibility contrast agent and DW imaging.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The surgical procedures were approved by the Norwegian Committee for Animal Experiments. Eighteen male Wistar rats (Møllegaard Breeding Center) weighing 320 to 350 g were randomly assigned to treatment with U74389G (n=9) or vehicle (n=9). Anesthesia was induced with isoflurane, and the rats were intubated, connected to a respirator, and ventilated with 1.5% isoflurane in a mixture of 70% nitrogen and 30% oxygen during surgery. The right femoral artery and vein were cannulated, and systemic arterial blood pressure was monitored continuously during the experiment. Arterial blood gases were measured before and after ischemia. Rectal temperature was monitored throughout the experiment and was maintained at 37°C with a heating blanket during surgery and with circulating heated fluorocarbons in a closed chamber in the animal cradle during the MR imaging. Occlusion of the MCA was achieved by the intraluminal filament technique originally described by Koizumi et al36 and later modified by various groups.37 38 39 After preparative surgery, the rats were placed in a home-built animal cradle for MR imaging, and the isoflurane was reduced to 1.0% for the rest of the experiment. During the experiment, intravenous injections of 150 IU/kg heparin to avoid secondary thrombosis in the MCA and intramuscular injections of 2 mg/kg pancuronium for muscle relaxation were administered at hourly intervals.

All rats were subjected to 2 hours of MCA occlusion and 2 hours of reperfusion. In the treatment group, infusion of U74389G was started after 45 minutes of ischemia at 0.2 mg/kg per minute during the first 15 minutes and then 0.05 mg/kg per minute for 1 hour. The control group received an infusion of an equal volume of the vehicle during the same period. At the end of the experiment, the animals were killed and transcardiac perfusion-fixed with formalin for histological examination.

Imaging was performed on a 2.35-T Bruker Biospec using a home-built saddle coil with an inner diameter of 4 cm. The first passage of a 1-second bolus of 0.5 mmol/kg Sprodiamide injection (dysprosium diethylenetriaminepentaacetic acid-bis[methylamide]; Dy-DTPA-BMA, Nycomed Imaging AS and Sanofi Winthrop) injected into the femoral vein was monitored via continuous acquisition of 30 images in one slice with a gradient-echo sequence using k-space substitution4 with an acquisition time of 0.6 second per image, echo time of 10 milliseconds, a slice thickness of 2.5 mm, a field of view of 6.4 cm, and a matrix of 128x128. DW imaging was performed with a spin-echo sequence with a scan time of 20 minutes, diffusion gradients in the z direction, and a "b" value of approximately 1400 s/mm2 in three slices with slice thickness, field of view, and matrix as in the bolus-tracking images. In both groups, first-pass bolus tracking was performed after 40 and 100 minutes of MCA occlusion and after 10 and 80 minutes of reperfusion. DW images were obtained after 60 minutes of MCA occlusion (15 minutes after the start of treatment) and after 60 minutes of reperfusion.

The bolus-tracking images were processed as topographic maps of (1) the maximum change in signal intensity and (2) the time delay to the point of maximum signal-intensity change using pixel-to-pixel, nonparametric modeling of signal intensity versus time curves.14 40 These parameters will subsequently be referred to as (1) peak signal change and (2) time delay parameters, respectively. The relative parametric values were measured in regions of interest corresponding to the lateral caudoputamen and the upper frontoparietal cortex, these areas being regarded as representative for the ischemic core of severe ischemia and the surrounding perifocal penumbra in this ischemia model.38 39 41

The area of ischemic tissue damage was calculated from the DW images as the number of pixels with hyperintensity of 15% relative to the corresponding anatomic structures in the contralateral hemisphere and expressed as percent hemispheric lesion area. All three imaged slices were summed to provide an approximation of the total volume of ischemic tissue injury. The threshold value of 15% was found to be the lowest cutoff value that did not include pixels in the contralateral nonischemic hemisphere.

To compare the area showing DW hyperintensity with that depicted by histopathologic changes at the end of image acquisition, animals were transcardiac perfusion-fixed with 4% formalin immediately after death. The brains were removed, and 4-µm-thick paraffin sections corresponding to the level of the MR images were cut. The sections were stained with hematoxylin and eosin and were examined by a neuropathologist blinded to the results of the MR imaging. The sections were digitized, and areas of ischemic injury were calculated as percent hemispheric lesion area in three slices corresponding to the levels of DW imaging.

The various parameters were compared between the two groups using Student's t tests. In the case of a correlation analysis between two groups, the significance was assessed using ANOVA analysis of regression.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
There were no significant differences between the two groups in arterial PCO2, PO2, pH, base excess, body temperature, or systemic arterial pressure (data not shown).

Six consecutive images obtained at intervals of 0.6 second during the first passage of a 0.5-mmol/kg bolus of Sprodiamide injection in the brain of a rat with MCA occlusion are presented in Fig 1Down. As the bolus reaches the brain, the normally perfused tissue becomes darker, since the susceptibility effect of the contrast agent causes a reduction in signal intensity. The ischemic area, in the right hemisphere, is seen as a relatively brighter area due to a reduced and/or delayed supply of the contrast agent. The dynamic pattern of the bolus passage is better appreciated in Fig 2Down, which shows topographic maps of peak signal change and time delay during MCA occlusion (Fig 2ADown and 2BDown) and reperfusion (Fig 2CDown and 2DDown) of the rat in Fig 1Down.



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  		Figure 1. Six consecutive transaxial images of a rat head during the first passage of a 0.5-mmol/kg bolus of Sprodiamide injection (Dy-DTPA-BMA). The images are obtained at intervals of 0.6 second and depict the first passage of the bolus. The brain is the bright oval at the top of the images. In the left hemisphere (to the right in the images), the blood supply is uninterrupted, and the susceptibility effect of the contrast agent reduces signal intensity as the bolus reaches the brain. The ischemic area in the right hemisphere (to the left in the images) is seen as a relatively brighter spot, reflecting the reduced perfusion. The first-pass transit is rapid in the rat brain, and early washout is evident in the last image.



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  		Figure 2. Topographic maps calculated from the perfusion images obtained after 40 minutes of middle cerebral artery occlusion (MCAO) and after 80 minutes of reperfusion from the same rat as shown in Fig 1Up. Only the brain is shown, and the ischemic right hemisphere is to the left in the images. A, Parametric map of the peak signal change during MCAO (the smaller the change in signal intensity during passage of the bolus, the darker the pixel); B, parametric map of the time delay to peak signal change during MCAO (the longer the interval to maximal reduction in signal intensity, the brighter the pixel); C, peak signal change map obtained after 80 minutes of reperfusion; and D, time delay map obtained after 80 minutes of reperfusion.

In this animal model, the core and the penumbra of the ischemic lesion are typically expressed in the lateral caudoputamen and the upper frontoparietal cortex, respectively.38 39 41 Therefore, these two regions were selected for further analysis. In Fig 3Down, the relative (ie, compared with nonischemic hemisphere) parametric values in the lateral caudoputamen and upper frontoparietal cortex for the two perfusion parameters are displayed. During MCA occlusion and before the infusion of the drug, the relative peak signal change parameter was 0.58±0.11 (mean±SD) in the lateral caudoputamen and 0.75±0.15 in the upper frontoparietal cortex. Infusion of the drug produced no significant changes in these values during the second hour of ischemia. The second perfusion parameter, the time delay, was increased by a factor of 2.6 in both the ischemic lateral caudoputamen and the upper frontoparietal cortex before the infusion of the drug. After administration of the drug, the treated rats (Fig 3BDown) showed a significantly lower time delay parameter compared with the control group (P<.05, unpaired Student's t test) in both regions of interest. After reperfusion, both groups still showed a slightly increased time delay parameter in the former ischemic area; however, there were no statistically significant variations between the two groups. After reperfusion, the peak signal change parameter was normalized to the level of the contralateral side in both groups (Fig 3ADown).



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  		Figure 3. A, Graph shows relative variations (ie, with respect to the nonischemic hemisphere) in the peak signal change parameter in upper frontoparietal cortex (CX; dotted lines) and lateral caudoputamen (CP; solid lines) in the ischemic hemisphere during middle cerebral artery occlusion (MCAO) and reperfusion for the vehicle ({circ}) and treatment ({bullet}) groups. The infusion of U74389G was started after the first perfusion imaging series. B, Graph shows relative variations in the time delay parameter in the same two regions of interest. There is a reduction of the time delay in the treatment group in the first perfusion series after administration of the drug (*P<.05, Student's t test). Error bars represent SEM.

The DW images exhibited hyperintensity in the lateral caudoputamen; in some rats, parts of the lower frontoparietal cortex and subthalamic areas were also involved. Two rats in the control group and one rat in the treatment group also had increased hyperintensity in parts of the upper frontoparietal cortex in the ipsilateral hemisphere compared with the nonischemic hemisphere. In the TableDown, the results from calculations of the approximated volume of DW hyperintensity, based on all of the imaged slices, are shown. The first DW imaging was performed 15 minutes after the start of the infusion of U74389G, and already at that point there was a nonsignificant difference in hemispheric lesion area: 21±14% in the control group versus 14±10% in the treatment group. After 60 minutes of reperfusion, there had been a further reduction in the treatment group to 9±8% and no change in the control group (19±8%). The difference between the two groups at this point was statistically significant (P<.05, unpaired Student's t test).


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  		Table 1. Ischemic Injury Calculated From Diffusion-Weighted Images and Histological Sections

The ischemic injury was also assessed with histological examination. The areas with ischemic injury showed a reduced staining intensity and diffuse vacuolization of the neuropil and a widening of the pericellular and perivascular spaces. The changes were seen only in the ipsilateral hemisphere and were well demarcated from adjacent unaffected tissue. The neurons generally showed a dark and shrunken cytoplasm corresponding to so-called "dark neurons," but the survival time was too short for development of the characteristic ischemic nerve cell damage. In the treatment group, the approximated volume of ischemic injury was 25±10% in the control group and 10±8% in the group that received U74389G (P<.05, unpaired Student's t test). The areas of ischemic injury in histological sections and DW images (Fig 4Down) correlated well, with a correlation coefficient of 0.925 (P<.05, F test).



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  		Figure 4. Examples of diffusion-weighted images at 60 minutes of reperfusion (A and B) and histological sections from comparable slices (C and D) in the same rats at the end of the experiment.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
In the present study, we have demonstrated a reduction of the DW hyperintense lesion during early reperfusion after postocclusion administration of U74389G in a rat model of temporary MCA occlusion. Histological examination after 2 hours of reperfusion showed a reduction of approximately 60% in the mean area of ischemic injury, thus confirming this finding. This beneficial effect of U74389G in early reperfusion supports previous observations showing a neuroprotective effect of antioxidative treatment in transient focal ischemia.33 The tendency toward a reduced area of hyperintensity as soon as 15 minutes after the start of delivery of U74389G is not significant but may represent a beneficial effect of the drug also during MCA occlusion.34 Compared with the hyperintensity changes in the DW images, the ischemic injury in the histological sections affected a slightly larger area, with this difference being most pronounced in the control group. This may be explained by the time interval of 1 hour between the two examinations, allowing for further development of ischemic injury in the control group. Also, the DW image is calculated from a slice with a thickness of 2.5 mm in contrast to the 4-µm-thick histological sections. Each voxel in the MR image may contain a mixture of ischemic and nonischemic tissue, especially in perifocal areas. This partial volume effect may result in discrepancies between calculated areas from histological sections and DW images. In addition, the selected threshold value also influences the size of measured area in the DW images.

The DW hyperintense changes observed in this experiment were mainly restricted to the lateral caudoputamen but in some cases also extended to the adjacent lower frontoparietal cortex and subthalamic regions, the areas with the most severe ischemia in this model. Thus, the effect of the drug was seen mainly as a reduction in size of the ischemic core lesion. Some discrepancies have been reported concerning the sensitivity of DW imaging to early ischemic tissue damage in a "penumbra" of mild ischemia.3 5 42 43 44 We found hyperintense changes in the upper frontoparietal cortex in only two rats in the control group and one rat in the treatment group. Studies of focal ischemia in which calculation of the apparent diffusion constant of water have been performed have, however, showed perifocal areas with smaller reductions in the translational movement in water.43 45 We therefore cannot exclude the possibility that calculation of apparent diffusion constant values could have demonstrated an effect in the penumbral tissue. However, in our study histological evaluation after 120 minutes of reperfusion correlated with the area of DW hyperintensity and did not reveal any signs of ischemic tissue damage in the penumbra at this early stage. Another problem is that the development of ischemic injury was followed up only during early reperfusion in anesthetized rats, and we cannot exclude the possibility that the effect was temporary and that neurological damage could develop at a later stage, as shown by Kiyota et al46 for treatment with dimethylthiourea. We think that our study nevertheless demonstrates the usefulness of DW imaging for in vivo quantification of the direct effect of cerebroprotective therapy in experimental stroke.

It has been proposed that free radical injury mainly involves the microvasculature, and efforts have been made to study the effect of free radical scavengers on regional CBF28 33 35 with conflicting results. Calculation of regional CBF from the dynamic series of MR perfusion imaging with first passage of susceptibility contrast agents is controversial,12 13 especially in the case of ischemia.5 14 In our study, no attempt was made to calculate perfusion in exact terms. Instead, the two simple perfusion imaging parameters, peak signal change and time delay, which require neither sophisticated mathematical modeling nor assumptions about the form of the input function, were calculated. After administration of the drug, the time delay parameter was significantly reduced in the ischemic area. The pathophysiological relevance of this observation is difficult to evaluate, even more so as no changes were found for the peak change parameter. However, the results suggest a more rapid transport of contrast agent into the ischemic area. This may indicate an improved microcirculation or an increase in collateral flow to the ischemic area in the treatment group. During reperfusion, there were no differences between the groups in the calculated perfusion imaging parameters.

We conclude that DW imaging detected a beneficial effect of postocclusion treatment with the free radical scavenger U74389G and that the histological examination after 2 hours of reperfusion correlated well with these results. During MCA occlusion, there was a reduction of the time delay parameter in the treatment group that may indicate an improved microcirculation or increased collateral flow to the ischemic area. The potential for improving in vivo evaluation of cerebroprotective treatment of thromboembolic stroke by the combination of these two methods warrants clinical appraisal.


*    Acknowledgments
 
This study was supported in part by the Norwegian Council on Cardiovascular Diseases and Nycomed Imaging A/S. Dr Sebastiani was supported by a fellowship from Consiglio Nazionale delle Ricerche, Italy. The U74389G was a generous gift from the Upjohn Company.

Received December 9, 1994; revision received March 13, 1995; accepted April 24, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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