Stratification of Heterogeneous Diffusion MRI Ischemic Lesion With Kurtosis Imaging
Evaluation of Mean Diffusion and Kurtosis MRI Mismatch in an Animal Model of Transient Focal Ischemia
Background and Purpose—Ischemic tissue damage is heterogeneous, resulting in complex patterns in the widely used diffusion-weighted MRI. Our study examined the spatiotemporal characteristics of diffusion kurtosis imaging in an animal model of transient middle cerebral artery occlusion.
Methods—Adult male Wistar rats (N=18) were subjected to 90 minutes middle cerebral artery occlusion. Multiparametric MR images were obtained during middle cerebral artery occlusion and 20 minutes after reperfusion with diffusion-weighted MRI obtained using 8 b-values from 250 to 3000 s/mm2 in 6 diffusion gradient directions. Diffusion and kurtosis lesions were outlined in shuffled images by 2 investigators independently. T2 MRI was obtained 24 hours after middle cerebral artery occlusion to evaluate stroke outcome.
Results—Mean diffusion lesion (23.5%±8.1%, percentage of the brain slice) was significantly larger than mean kurtosis lesion (13.2%±2.0%) during middle cerebral artery occlusion. Mean diffusion lesion decreased significantly after reperfusion (13.8%±4.3%), whereas mean kurtosis lesion showed little change (13.0%±2.5%) with their lesion size difference being insignificant.
Conclusions—We demonstrated that mean diffusion/mean kurtosis mismatch recovered reasonably well on reperfusion, whereas regions with concurrent mean diffusion and mean kurtosis deficits showed poor recovery. Diffusion kurtosis imaging may help stratify heterogeneous diffusion-weighted MRI lesions for enhanced characterization of ischemic tissue injury.
Diffusion-weighted imaging (DWI) detects severely damaged ischemic tissue that is likely to infarct and has been widely used in stroke imaging.1,2 However, tissue damage within DWI deficit is heterogeneous, which may partially recover with prompt treatment. There have been no well-established techniques capable of stratifying heterogeneously damaged DWI lesion.3,4 Diffusion kurtosis imaging is an emerging MRI technique that measures the degree of the non-Gaussian water diffusion and is sensitive to microscopic structural changes.5 Indeed, diffusion kurtosis imaging has been shown capable of detecting microstructural cerebral tissue changes in aging brains, acute stroke, and tumor.6–8 We postulated that diffusion kurtosis imaging could stratify heterogeneous DWI lesions, improving characterization of tissue injury. Our study examined the spatiotemporal characteristics of mean diffusion (MD) and kurtosis (MK) MRI using a transient filament middle cerebral artery occlusion (MCAO) rodent model.
Materials and Methods
Transient MCAO was induced in 18 adult male Wistar rats (Charles River Laboratory, Wilmington, MA), anesthetized under 1.5% to 2.0% isoflurane with heart rate and saturation of peripheral oxygen monitored online, following institution-approved guidelines. Animals were reperfused by withdrawing filament 95 minutes post-MCAO. One rat died during MRI and was excluded from analysis.
Magnetic Resonance Imaging
MR imaging was obtained using a Bruker 4.7-T small-bore scanner (5 slices, 2 mm/slice, field of view=25×25 mm2, matrix size=64×64). Multiparametric MR imaging was obtained during MCAO (20–90 minutes post-MCAO), after reperfusion (120–190 minutes post-MCAO). DWI was acquired with b-values of 250, 500, 750, 1000, 1500, 2000, 2500, and 3000 s/mm2 (repetition time/echo time [TE]=2500/40.5 ms, number of average=4, duration=8 minutes) along 6 diffusion directions. Cerebral blood flow was acquired with amplitude modulated arterial spin labeling MRI (repetition time/TE=6500/14.8 ms, number of average=32, duration=7 minutes). T1-weighted images were acquired using inversion-recovery MRI with 7 delays from 250 to 3000 ms (repetition time/TE=6500/14.8 ms, number of average=4, duration=3.5 minutes); T2-weigthed images were obtained with 2 TEs (repetition time/TE/TE=3250/30/100 ms, number of average=16, duration=1.8 minutes). We also obtained follow-up T2 MRI 24 hours post-MCAO.
Images were analyzed in Matlab (MathWorks, Natick, MA). DWI signal (S[b]) was fitted per pixel using S(b)=S(0)*exp(−b*Dapp+1/6B2*D2app*Kapp). MD and MK were obtained by averaging diffusion (Dapp) and kurtosis coefficients (Kapp) along 6 directions, respectively.5 Apparent diffusion coefficient (ADC) was derived from S(b)=S(0)*exp(−b*ADC) using b=250 and 1000 s/mm2, and cerebral blood flow was obtained from amplitude modulated arterial spin labeling MRI as described previously.9 MD and MK lesions were independently outlined from shuffled images by 2 investigators in the central slice (2 mm behind the bregma) and averaged. Lesions were mirrored to the contralateral brain as reference region of interest. Results were reported as mean±SD, and we used repeated measures analysis of variance with Tukey multiple comparison test.
Figure 1 shows that MD lesions were significantly larger than MK deficits during MCAO. After reperfusion, MD lesions decreased to approximately the size of MK lesions, which showed negligible change. Notably, MD and ADC maps showed very similar lesion, as expected. Stroke outcome was confirmed using follow-up T2 MRI and histology.
Figure 2 shows reperfusion-induced change in lesion size, calculated as the percentage of the brain. During MCAO, MD lesion (23.5%±8.1%) was larger than MK (13.2%±2.0%, P<0.01). MD lesion decreased significantly after reperfusion, and the difference between MD (13.8%±4.3%) and MK (13.0%±2.5%) lesion became insignificant. However, the follow-up T2 MRI showed infarction (28.1%±9.6%) significantly larger than acute MD and MK lesions (P<0.01), likely due to severe ischemia and reperfusion injury.
Figure 3 compares reperfusion-induced change in multiparametric MRI values. During MCAO, MD in ischemic lesion decreased significantly from the contralateral normal region (0.55±0.03 versus 0.78±0.02 μm2/ms, P<0.01), whereas MK was elevated (0.98±0.04 versus 0.69±0.03, P<0.01). Using the contralateral region of interest as reference, the percentage difference between nonischemic and ischemic tissues was −29.0%±3.6% and 42.6%±4.8% for MD and MK, respectively. After reperfusion, the ischemic lesion MD improved (0.60±0.04 μm2/ms, P<0.01) but was still significantly less than the reference (P<0.01). Moreover, ischemic tissue MK decreased significantly, yet it was still elevated from the contralateral normal tissue (0.93±0.06 versus 0.70±0.03, P<0.01). The percentage differences between nonischemic and ischemic tissues were −22.7%±5.3% and 33.9%±10.9% for MD and MK, respectively.
Our study found that the MD/MK mismatch recovered reasonably well on reperfusion, whereas areas with concurrent MD and MK deficits showed little recovery. In comparison, T1 and T2 MRI are not sensitive to ischemic tissue injury during acute stroke. Our results suggest that MD/MK mismatch may represent mildly damaged and potentially salvageable ischemic lesion, whereas areas with simultaneous MD and MK deficits likely indicate aggravated cellular damage.7 However, the mechanisms of diffusion and kurtosis deficits in acute stroke are complex. MD decreases in the MD/MK mismatch is likely due to cytotoxic edema.10,11 In contrast, MK is sensitive to intracellular tortuosity and viscosity changes subsequent to breakdown of cytoskeletal structures and swelling of mitochondria, likely indicating more severe tissue damage.5,7,12–14 Nevertheless, the filament stroke model used in our study is subject to severe ischemia and reperfusion injury, and the DWI renormalization was transient.15 Indeed, we found that cerebral blood flow decreased significantly in the ipsilateral hemisphere from the contralateral region of interest both during MCAO (0.88±0.27 versus 1.43±0.33 mL/g/min) and after reperfusion (1.15±0.23 versus 1.72±0.25 mL/g/min). Importantly, reperfusion induced significant cerebral blood flow increase in both hemispheres (P<0.01). Therefore, rodent embolic stroke models that more closely resemble human stroke may be more suitable to elucidate the mechanisms of stroke diffusion kurtosis imaging. Moreover, the study may be improved with remote reperfusion techniques to enable pixel-based analysis of MD and MK evolution. Furthermore, histology immediately after reperfusion may help characterize early tissue damage of MD and MK deficits, augmenting evaluation of stroke outcome currently assessed by follow-up MRI.
We showed that MD/MK lesion mismatch recovered reasonably well on reperfusion, whereas regions with concurrent MK and MD deficits responded poorly. Diffusion kurtosis imaging may augment DWI for improved characterization of ischemic tissue injury.
Sources of Funding
This study was partially supported by National Science Foundation of China-30900365, American Heart Association/Scientist Development Grant-0835384N, National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering-1K01EB009771, and National Institutes of Health/National Canter for Research Resources-P41RR14075.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.661926/-/DC1.
Christoph Kleinschnitz, MD, was the Guest Editor for this paper.
- Received April 27, 2012.
- Accepted May 25, 2012.
- © 2012 American Heart Association, Inc.
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