(Stroke. 1997;28:439-447.)
© 1997 American Heart Association, Inc.
Articles |
Neuroprotection With NBQX in Rat Focal Cerebral Ischemia
Effects on ADC Probability Distribution Functions and Diffusion-Perfusion Relationships
the Department of Radiology, the Center for Imaging and Pharmaceutical Research (E.H.L., A.R.P.), and the Nuclear Magnetic Resonance Center (J.B.M., B.R.R.), Massachusetts General Hospital, Harvard Medical School, Charlestown.
Correspondence to Eng H. Lo, PhD, Center for Imaging and Pharmaceutical Research, Harvard Medical School, MGH East Bldg 149, Charlestown, MA 02129. E-mail eng@cipr.mgh.harvard.edu.
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Abstract |
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Background and Purpose We have previously shown that treatment with glutamate receptor antagonists after focal ischemia can partially reverse acute lesions measured with diffusion-weighted MRI. The goal of this study was to examine the quantitative nature of these effects of neuroprotection.
Methods Rats were subjected to permanent occlusion of the middle cerebral artery under halothane anesthesia and treated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (30 mg/kg IP; two doses given immediately after ischemia and 1 hour after ischemia) or given injections of saline. Diffusion-weighted MRI scans were performed to map the changes in water diffusivity during the first 3 hours after ischemia. Apparent diffusion coefficients (ADCs) within the ischemic hemisphere were calculated, and ischemic changes were expressed as absolute reductions and as a percentage of contralateral mean values. Relative perfusion deficits in the ischemic hemisphere were assessed with dynamic MRI of transient changes in transverse relaxation rates (
R2*).
Results Analysis with ADC probability distribution functions showed that focal ischemia was present with gradients in ADC reductions emanating from the center to the periphery of the lesion. Ischemic evolution in control rats was manifested as a progressive shift of the probability distribution functions over time. NBQX treatment resulted in a reverse shift of these probability functions. By 3 hours after occlusion, probability distribution functions were significantly improved in treated rats (P<.05). Because of the temporal evolution of the probability distribution functions, ADC thresholds that correlated with histological outcomes of infarction changed over time. NBQX did not alter the cerebral perfusion index, measured as R2* peak values.
Conclusions The results indicate that ADC probability distribution functions can be used to quantitatively evaluate the effects of neuroprotective treatment on the gradients of injury in focal cerebral ischemia. The probability functions also allow for intrasubject comparisons and may therefore be useful for exploring therapeutic windows.
Key Words: cerebral ischemia, focal • diffusion • magnetic resonance imaging • neuroprotection • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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A large number of studies in experimental animal models have demonstrated that DWI is exquisitely sensitive to early changes in cerebral tissue within the acute phase of ischemia.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 DWI has also been shown to be useful in the early assessment of clinical stroke.17 18 19 20 DWI reveals early ischemic lesions as regions of increased signal intensity, ie, decreased water diffusivity. It has been proposed that these changes are likely to be due to acute cellular edema and the redistribution of water from extracellular to intracellular compartments.21 22 Early intervention with appropriate therapy can reduce the propagation of DWI-defined ischemic lesions over time.2 8 12 23 We have previously shown that treatment with a glutamate receptor antagonist can, in fact, partially reverse high-intensity DWI lesions after ischemia.9 The goal of this study was to examine the quantitative nature of these effects of neuroprotection.
Changes in water diffusivity measured by DWI can be quantified as ADCs.24 Acute ischemia results in large reductions in ADC, and therefore it would be expected that successful neuroprotection should be manifested as an amelioration of these ADC alterations. Recent studies have demonstrated that steep and variable ADC gradients are present in focal cerebral ischemia.4 25 This is not unexpected since spatial and temporal gradients in cerebral blood flow and metabolic deficits are the hallmark of focal ischemic insults.26 27 28 29 These gradients can complicate the analysis of ADC after neuroprotection because the choice of simple thresholds for defining what constitutes a lesion versus salvaged tissue may be difficult and somewhat arbitrary as the ischemic gradients evolve over time. Therefore, the aim of the present study was to use probability distribution functions to analyze the ADC gradients in a rat model of permanent focal ischemia. The use of these probability functions may enable us to better quantify the potentially variable ADC responses to neuroprotective therapy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Rat Focal Cerebral Ischemia Model
All procedures were conducted following an institutionally approved protocol in accordance with guidelines set by the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Male Sprague-Dawley rats (weight, 330 to 380 g) were subjected to focal ischemia with halothane anesthesia (1% to 2% in a 5:1 air/oxygen mixture) by face mask. A femoral artery was cannulated for monitoring mean arterial blood pressure and for sampling blood gases and pH. The subtemporal approach was used.9 10 30 Briefly, the zygomatic arch was partially removed, and a small craniectomy was made 1 mm anterior to the foramen ovale. The entire ascending trunk of the MCA from below the olfactory tract to the inferior cerebral vein was coagulated and cut. To increase ischemic severity and reproducibility, the ipsilateral common carotid artery was ligated with silk suture. After MCA occlusion, rats were randomly treated with NBQX (n=6) or given an injection of normal saline solution (n=9). NBQX was administered intraperitoneally as two doses of 30 mg/kg each. The first dose was given immediately after ischemia. The second dose was given 1 hour after ischemic onset.
MRI Scanning Procedures
Rats were scanned in a 2-T horizontal bore magnet (SISCO Systems). Animals were inserted into a cradle with a custom-designed MRI-compatible stereotaxic head holder (David Kopf). The head was positioned within a proton-tuned linear cosine radio frequency coil (40-mm diameter), and the coil was then centered in the magnet. Anesthesia was maintained with 0.5% to 1.5% halothane. Mean arterial blood pressure was continuously tracked with an MRI-compatible monitor (Micro-Med Inc). Arterial blood gases were sampled before, during, and after MRI scanning. T2-weighted conventional sagittal plane scout images were used to locate the rhinal fissure, and five contiguous axial slices were selected to include a volume that extended between a point approximately 2 mm posterior to the rhinal fissure and the edge of the cerebellum. Conventional diffusion-weighted spin-echo images on the same five slices were collected with two b values (256 and 1239 s/mm2; repetition time, 2000 ms; echo time, 50 ms; 128x64 matrix; resolution, 0.3x0.6x2-mm slice thickness; 4 averages; 8.5 minutes per scan). DWI scans were performed at 1, 2, and 3 hours after ischemia.
Additionally, perfusion-weighted MRI scans were performed immediately after the DWI scans at 1 and 3 hours after occlusion. A single slice was chosen centered at the optic chiasm and caudate putamen (see "Data Analysis"). The fast low-angle shot method (repetition time, 14 ms; echo time, 8 ms; flip angle, 25°; 64x64 matrix; resolution, 0.6x0.6x3-mm slice thickness; 1 image per second) was used to follow the first-pass transit of injected contrast agents. Gadodiamide (0.5 mmol/kg, Magnevist, Berlex Laboratories) was injected as a bolus into the tail vein.
Infarct Measurement With TTC Staining
Rats were allowed to survive 24 hours after ischemia. They were then killed with a lethal intravenous injection of sodium pentobarbital. Brains were removed and sectioned into 2-mm-thick axial slices. Sections were immersed into 2% TTC solution for at least 30 minutes and then fixed with formalin. Infarcted areas were visualized as regions lacking the typical brick-red staining of normal brain tissue. These areas were quantified with computer-assisted image analysis with the use of standard techniques that have been previously described.9 31 Total infarction volumes were calculated by integrating areas in all slices for comparison between control and NBQX-treated rats. For correlation with the MRI ADC data, only the single slice that encompassed the caudate putamen was used to match the DWI image slice. For these comparisons, infarction was expressed as percent area of ipsilateral hemisphere.
Data Analysis
An MR image slice positioned at approximately 4 mm posterior to the rhinal fissure was selected for quantitative analysis. The slice was centered at the optic chiasm and included the caudate putamen. This single slice was chosen because it represented the location of maximal ischemia for this rat model of focal ischemia.9 10 28 30 By using a single slice with maximal lesions, we sought to improve the signal-to-noise ratio of our probability distribution analysis (see below for details). Furthermore, other image slices with more heterogeneous structural components (eg, hippocampus, ventricles) would lead to more scatter in our estimates of what constituted "normal" ADC levels. All analyses were performed with a Macintosh-based image analysis system (DIPStation, Hayden Image Processing Group). ADC maps were generated by the standard equation: ADC=ln (So/S1)/(b1-bo). We have previously shown that ADCs calculated with two b values were no different from those fitted with four b values in our system.10
From the ADC maps, ROIs were drawn to outline the cortex and basal ganglia in ipsilateral and contralateral sides, and regional ADCs were calculated. On average, these ROIs encompassed 118 and 81 pixels for cortex and basal ganglia, respectively. Mean ADC levels were also obtained for all contralateral cerebral tissue excluding the ventricles. Note that since (1) ventricles have higher ADCs and (2) ADCs tend to be lower in basal ganglia than cortex, this approach will yield a proportion of pixels from the ipsilateral hemisphere with ADC values above the calculated contralateral means. In our system, these typically range from 10% to 20% of the ipsilateral area. ADC levels of each pixel within the ischemic hemisphere were expressed as both absolute reductions in ADC (ADC) and as a percentage of the contralateral levels (%ADC), and a histogram or probability density function was calculated for the entire ischemic hemisphere. The probability density function was then integrated to obtain cumulative histograms or probability distribution functions for both ADC and %ADC. Each point on the curve reveals the probability of encountering a pixel within the ischemic hemisphere with an ADC value that is reduced up to the defined ADC threshold or has an ADC value below the defined %ADC threshold. Probability distribution functions are ideally suited for analyzing parameters with steep gradients in their frequency distribution. It has been previously shown that probability distribution functions can be successfully applied to analyze the variable gradients in blood flow after focal cerebral ischemia.27 32
Probability distribution functions were integrated to obtain thresholded lesion areas within the ischemic hemisphere (expressed as percentage of ipsilateral hemispheric area). Lesion areas with increasing ADC thresholds were plotted as stacked graphs to display the growth of the ischemic areas over the 3-hour period of the DWI scans.
Perfusion-weighted MRI scans were analyzed as dynamic data sets of transient changes in transverse relaxation rates (R2*). The correlations between diffusion and perfusion were assessed by selecting ROIs that encompassed various regions within the ischemic hemisphere. The following ranges of ADC were used: <4x10-4 mm2/s; 4 to 5x10-4 mm2/s; 5 to 6x10-4 mm2/s; and >6x10-4 mm2/s. Peaks of the R2* versus time plots were expressed as ratios versus mean contralateral peak values and used as an index of the deficits in cerebral perfusion. Previous studies have shown that R2* peaks can be useful for assessing rat focal ischemia.1 14 33 34 It is important to remember, however, that this measure is only an indirect index of cerebral perfusion and will include both blood flow and blood volume influences.35
Repeated measures ANOVA was used to analyze the temporal evolution of damage. To account for multiple comparisons, Tukey's honestly significant difference was used to examine differences between control and NBQX-treated animals. Diffusion-perfusion relationships were assessed with the use of linear regressions. All data were expressed as mean±SEM.
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Results |
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Systemic Parameters
Systemic parameters fell within normal range for all experiments (Table 1
). Mean arterial blood pressure was significantly increased in all animals after MCA occlusion. This was probably due to a combination of the effects of cerebral ischemia as well as the lower halothane anesthesia levels required for maintenance during MRI scanning compared with surgical procedures. Within the postischemic period, blood pressure was significantly higher in NBQX-treated rats than in untreated controls. Other groups have also shown a similar elevation in blood pressure after NBQX treatment in rat focal ischemia models.36 There were no significant differences in all other systemic parameters between control and NBQX-treated rats.
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DWI Scans and Regional ADC
Focal ischemia was evident in all rats. Lesions were manifested as regions of increased signal intensity on the DWI scans with high b value. These were distributed within the MCA vascular territory and included the basal ganglia and the overlying cortex (Fig 1). During the first 3 hours after occlusion, the lesions appeared to grow and become more intense. High-intensity lesions appeared smaller in NBQX-treated rats than in untreated controls (Fig 1). Changes in lesion size observed on the high-intensity b value images were not quantified because to do so would require an arbitrary choice of ADC thresholds. Instead, the ADC changes in controls versus treated rats were assessed with probability distribution functions, as described below.
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ADC values in the contralateral hemisphere remained stable throughout the entire experiment (Table 2). For each individual rat, the coefficient of variation of contralateral ADC was no more than 4% to 5% over 3 hours of measurement. Regional ADCs in the ischemic basal ganglia and cortex of control rats were significantly reduced at all times (Table 2). When expressed as a percentage of contralateral means, ischemic regional ADCs in control rats slightly declined over time from 1 hour to 3 hours after ischemia: from 90% to 88% in cortex and from 81% to 77% in basal ganglia. In NBQX-treated rats, significant reduction in ADC was only present in the basal ganglia at 1 hour after occlusion. Thereafter, ADCs in this group improved over time. By 3 hours after ischemia, significant differences were found in all regional ADC values between control and treated rats (Table 2).
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ADC Probability Distribution Functions
ADC probability distribution functions were calculated as both absolute reductions versus contralateral mean levels (ADC) and as percentages of contralateral means (%ADC). The gradual slope of these functions demonstrated the presence of ADC gradients in focal ischemia. These ranged from severe reductions of up to 3x10-4 mm2/s (<50% of contralateral levels) in the center of the lesions to more moderate reductions of 0.5x10-4 mm2/s (
90% of contralateral levels) in the periphery of the lesions. In untreated rats, ischemic evolution was demonstrated as a shift of the probability distribution functions toward more severe ADC reductions. In the ADC functions, the shift was from left to right (Fig 2A), whereas in the %ADC functions, the shift was from right to left (Fig 2B). Although the precise temporal rates of these shifts were somewhat different in individual animals, all untreated controls showed the same directional shift in probability distribution functions as the lesions evolved. In NBQX-treated rats, ischemic evolution was arrested and partially reversed. This was manifested as a reverse shift in both the ADC and %ADC probability distribution functions (Fig 2C and 2D).
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One measure of the probability distribution function is the median. Therefore, the medians of ADC and %ADC probability distributions in all rats were calculated and averaged (Table 3). These data confirmed the overall shift in the probability distributions as the untreated controls deteriorated over time. Significant differences in the medians were found between control and NBQX-treated rats by 3 hours after ischemia.
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In untreated controls, areas with severe reductions in ADC progressively grew as the lesions evolved over time (Fig 3). By 3 hours after ischemia, regions with large ADC or low %ADC were increased compared with the 1-hour time point. NBQX treatment prevented the growth in lesion size and severity.
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R2* Peak Perfusion Index
First-pass transit of injected gadolinium boluses resulted in transient alterations in transverse relaxivity (R2*). In the ischemic hemisphere, reductions in cerebral perfusion were manifested as decreased ratios of R2* bolus transit peaks versus contralateral levels. There was a highly significant relationship (P<.001) between ADC values and R2* peak ratios, ranging from the most severe ischemia within the core of the lesion to more moderate ischemia toward the lesion periphery (Fig 4). This relationship was evident at both 1 hour and 3 hours after ischemic onset. There were no detectable differences in diffusion-perfusion relationships between NBQX-treated and control rats after ischemia (Fig 4).
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ADC Versus 24-Hour Infarct Correlations
Rats treated with NBQX had significantly (P<.05) smaller infarctions when assessed with TTC staining at 24 hours after occlusion. Total infarct volumes were 187±43 mm3 in untreated controls versus 89±26 mm3 in treated animals. Within the axial slice centered at the caudate putamen that was used for MRI analysis, infarct areas averaged 55±7% of the ipsilateral hemisphere in controls and 36±10% in treated animals.
Lesion areas determined by ADC analysis depended on the specific thresholds chosen. As expected, lesion areas would increase with increasing ADC thresholds. For ADC maps measured at 1 hour after ischemia in control rats, the closest correlations between ADC-defined lesions and the eventual TTC infarct areas were obtained with thresholds set either at reductions of 0.95x10-4 mm2/s or at an 85.5% level of contralateral mean values (Fig 5). As the ischemic damage continued to evolve over time, the thresholds needed to match the final TTC infarct became more stringent. By 3 hours, the matching levels were 1.1x10-4 mm2/s or 83.5% level of contralateral means (Fig 5). NBQX treatment both reduced the final infarct volumes as well as prevented the growth of the ADC-defined lesion over time. Therefore, ADC maps in NBQX-treated rats at 1 hour after ischemia showed that only regions with significantly more severe ADC reductions would evolve into final infarction, ie, reductions of at least 1.47x10-4 mm2/s or 76% of contralateral levels (Fig 5). By 3 hours after ischemia ADC gradients appeared to stabilize, and there were no longer any significant differences in the thresholds needed to predict the final TTC infarct in untreated controls versus NBQX-treated rats (Fig 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Although the sensitivity of DWI to early ischemic change has been exploited to describe noninvasive imaging correlates of neuroprotection, the quantitative aspects of these measurements have not been extensively examined. Previous studies have been primarily based on single-b-value DWI scans that defined lesions based on signal intensity elevations.1 2 8 11 12 23 While studies do exist that have looked at ADC values after therapy, these tended to involve measurements of averaged regional values.3 37 38 In this study we presented the use of probability distribution functions to capture the full range of ADC gradients after focal cerebral ischemia. We showed that ADC probability distribution functions were able to map the temporal evolution of ADC reductions as well document the significant improvements in ADC gradients after neuroprotection with the AMPA-type glutamate receptor antagonist NBQX. Since the gradients in ADC may be a manifestation of the transition from the ischemic core into penumbra, it is tempting to speculate that the shifts in ADC probability distribution functions may represent the effects of successful therapy on the evolution of the ischemic penumbra.
Regional ADC values for normal and ischemic rat brain measured in the present study were comparable with previous measurements from our laboratory10 and others.3 4 6 16 25 However, when the gradients in ADC changes after focal ischemia are analyzed, the potential contribution of partial volume effects must be considered. It has been previously estimated that partial volume effects in MRI of rat focal ischemia would translate into, at most, a 2-pixel shift between observed and actual boundaries.4 This is much smaller than the gradients in ADC measured in the present study, which range from 2 to 4 mm (ie, 6 to 12 pixels) from the lesion center to the periphery. Therefore, we believe that the ADC gradients quantified with the probability distribution functions represent actual pathophysiology. However, two important caveats remain. The first is related to the dynamic nature of these gradients. Others have demonstrated the existence of ADC transients after focal cerebral ischemia that may be related to the propagation of transient depolarizations.39 40 Since we were using relatively slow spin-echo DWI sequences, we were unable to detect these very rapid events in the present study. Second, the existence of gradients in the probability distribution functions per se cannot conclusively prove the existence of gradients in the spatial dimension since, in theory, a completely random spatial distribution may also result in a sloped probability distribution function. However, this is unlikely to be true for focal cerebral ischemia based on previous studies that examined the anatomic distribution of these ADC lesions.4 16 34
Other studies showed that DWI lesions during the acute phase were well correlated with the eventual histological outcomes of infarction.6 9 11 12 23 In human stroke patients, early DWI lesions were significantly related to clinical outcomes.20 In the present analysis, however, correlations between ADC-defined lesions and the 24-hour TTC infarct areas were dependent on the time of imaging. As the ischemic lesion evolved and grew over time, the ADC probability distribution functions demonstrated clear shifts toward more severe gradients in damage. In the early stage (1 hour after occlusion), the ADC thresholds required to predict infarction were higher than those at the later stage (3 hours after occlusion). More importantly, these thresholds were significantly altered by NBQX treatment. NBQX therapy resulted in smaller infarct sizes at 24 hours. Therefore, predictive thresholds of ADC reductions at 1 hour were lower in treated rats than in untreated controls. These data imply that absolute ADC thresholds cannot be used to reliably predict infarctions because (1) these thresholds change over time and (2) they are affected by treatment. Others have also shown that simple ADC thresholds may not always predict ischemic damage. In global cerebral ischemia, no differences were found for intraischemic ADC values in brain regions showing metabolic recovery after reperfusion versus those that did not.5 Furthermore, large ADC reductions were also present during spreading depression, when no tissue damage occurred,39 and during epileptic events, when blood flow actually increased.41
In this study differences in the ADC thresholds for the two treatment groups disappeared by 3 hours. These findings were consistent with previous studies showing the relative stability of DWI lesions by 3 to 4 hours after ischemia in rats.9 12 However, other groups have shown further increases in DWI lesion size from 4 to 24 hours after occlusion.2 These differences may be due to variations in the surgical model and thus ischemic severity between laboratories.
Ischemic alterations in ADC were expressed as either absolute reductions or a percentage of average contralateral levels. A comparison of the corresponding coefficients of variation from the data shown in Table 3
suggests that it might be better to calculate ischemic ADCs as percentages rather than absolute reductions. Normalizing for differences between individual experiments decreased the scatter in our results. However, this approach may be more complicated in clinical human stroke, in which contralateral changes may also occur due to cerebrovascular disease. Additionally, the human brain is more complex in anatomy and less isotropic in structure. Thus, the definition of "normal" levels may be more variable. Furthermore, in the subacute to chronic phase, ADC profiles demonstrate biphasic behavior.10 42 Recently, a statistically based cluster analysis has been used to address these issues.43 The initial results suggest that multiparameter analysis may improve the robustness of MRI methods for assessing and staging ischemic evolution.
The present results showed that NBQX therapy can significantly improve ADC gradients in permanent focal ischemia. Neuroprotection with NBQX has been well documented in a variety of experimental models of cerebral ischemia.44 Blockade of AMPA-type glutamate receptor ion channels would decrease neuronal swelling associated with abnormal sodium accumulations after ischemia.45 46 47 48 More recently, it has been shown that perturbations in RNA editing processes of specific glutamate receptor subtypes may render AMPA-type ion channels additionally permeable to toxic influxes of calcium.49 50 51 Therefore, NBQX efficacy under ischemic conditions may be due to prevention of both sodium and calcium currents. AMPA-type glutamate receptors exist on glial membranes.52 Since ADC measurements of acute cellular edema may represent the overall effects of sodium ion–related bulk swelling,53 the protective effects of NBQX on cerebral ADC observed in this study may also include an amelioration of glial swelling.
ADC reductions were significantly correlated with the degree of perfusion deficits assessed with R2* peak ratios. These data suggest that ADC values ranging from the lesion core into the lesion periphery paralleled the gradients in perfusion reductions. No differences in R2* peak ratios were seen between control and treated rats, suggesting that NBQX did not alter cerebral perfusion within the limitations of these indirect MR measurements. Furthermore, NBQX did not appear to change the gradient relationship between ADC and R2* peak ratios. It is important to note that the voxel sizes in the perfusion-sensitive images were much larger than the voxel sizes in the ADC maps, so that partial volume effects may have affected the correlations. Additionally, subtle but undetected changes in collaterals may be induced by the higher blood pressures in the NBQX-treated rats. However, other studies of NBQX in focal cerebral ischemia have also found no direct effects on cerebral blood flow.54 55 56
In conclusion, we have shown that ADC probability distribution functions can be used to quantitatively assess the gradients in damage and the effects of neuroprotection in a rat model of focal cerebral ischemia. The fact that the evolution of the probability distribution functions (and thus ADC gradients) is significantly affected by therapy implies that direct correlations of ADC thresholds versus histological outcomes may be variable after neuroprotection, depending on the temporal stage of the pathophysiology at the time of imaging. However, it is precisely this ability of probability distribution functions to map the spatial and temporal gradients in ADC response that will make it a useful approach for quantitatively assessing cerebral ischemia on a case-by-case basis.
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Selected Abbreviations and Acronyms |
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-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
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Acknowledgments |
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This study was funded in part by National Institute of Neurological Disorders and Stroke grant R29-NS32806 (Dr Lo), a Grant-in-Aid from the American Heart Association (Dr Lo), and National Heart, Lung, and Blood Institute grant R01-HL39810 (Dr Rosen). NBQX was kindly supplied as a gift by Dr Lars Nordholm from Novo Nordisk A/S. The authors thank Dr Elkan Halpern for assistance with the statistical analyses.
Received August 23, 1996; revision received October 18, 1996; accepted October 24, 1996.
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Editorial Comment
Effects on ADC Probability Distribution Functions and Diffusion-Perfusion Relationships
Department of Neurology and Mallinkrodt Institute of RadiologyWashington University School of MedicineSt Louis, Mo
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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DWI has been extensively applied to assess an early ischemic sign reflected by ischemia-induced alteration of water diffusion. DWI is a promising MR technique, especially if supplemented by perfusion-weighted MRI, for early detection of the ischemic brain tissue at risk of developing infarction. DWI assessment of water diffusivity can be quantitatively derived from ADCs. However, the heterogeneous distribution of ADC values within the ischemic zone makes it difficult to apply a simple ADC "threshold" to distinguish the ischemic area destined for infarction from that sustained reversible injury. The accompanying article by Lo and colleagues offers a more elaborate measure based on ADC probability distribution functions. This approach appears to be more sensitive in discerning spatial and temporal changes in water diffusivity after cerebral ischemia in a rat stroke model. The potential usefulness of this ADC measure to define therapeutic efficacy is illustrated by Lo et al in a study with a neuroprotective agent, NBQX.
Even distribution of variables between control and treatment groups is an essential task in both clinical and preclinical stroke trials. ADC probability distribution functions offer a potentially more sensitive indicator for early delineation of the brain region at risk of developing infarction. This method may aid in ensuring that before therapeutic intervention, the extent of ischemic injury is equal between the control and treatment groups. Such an approach is likely to reduce the sample sizes and lower the probability of generating spurious trial results.
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Selected Abbreviations and Acronyms |
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Values are mean±SEM.
*P<.05 between control and NBQX-treated groups.
P<.05 between 1- and 3-hour medians.
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