Rationale and Objectives
Ischemic penumbra (IP), the target of thrombolytic therapies, could be estimated by the mismatch region between magnetic resonance imaging (MRI) diffusion- and perfusion-defined abnormalities; however, the accuracy of this method has been challenged recently. In this study, we try to establish a method for calculating IP size based on computed tomography perfusion (CTP) and to observe the early evolution of IP in detail.
Materials and Methods
The middle cerebral artery occlusion (MCAO) model in monkey was used to compare the accuracy in estimating the IP between CTP and MRI methods. A receiver operating characteristic (ROC) curve was performed to calculate the IP threshold of the different CTP parameters, and then the best parameter was obtained. The dynamic evolutions of estimated size of IP by these two methods were compared.
Results
Among the three CTP parameters, relative cerebral blood flow (rCBF) had the highest sensitivity (83.3%) and specificity (98.5%) in estimating the IP. The optimal cutoff threshold of rCBF was 0.203. During the first 15 hours of the MCAO model, the estimated size of IP by the rCBF was larger than that of the MRI method; however, this relationship was reversed 15 hours later.
Conclusion
This study suggests that the rCBF method is more accurate in estimating the IP since previous studies have reported that the MRI method underestimated the exact IP in the early stage of ischemia and overestimated the exact IP in the later stages. Further experimental and clinical studies are needed to validate the conclusion.
In the field of ischemic stroke, ischemic penumbra (IP) is an important concept, proposed by Astrup in 1981 . It refers to the regions of brain tissue, usually peripheral in location, where blood flow is sufficiently reduced to cause hypoxia, severe enough to arrest physiological function, but not so complete as to cause irreversible failure of energy metabolism and cellular necrosis . IP is the target for thrombolytic therapy, which remains the only approved therapy for acute ischemic stroke. The existence time of the IP largely varied individually. So accurately estimating the size of IP is one of the important factors for deciding whether the thrombolytic therapy is needed or not, optimizing the therapeutic methods of ischemic stroke, monitoring the evolution of the disease, and assessing the outcome of the therapy.
Positron emission tomography (PET) can combine perfusion and metabolism information, and is regarded as the gold standard in estimating the IP with reduced cerebral blood flow (CBF) but preserved cerebral metabolic rate for oxygen and raised oxygen extraction fraction . However, PET is not suitable for assessing hyperacute and acute infarcts because it is expensive, radioactive, and not available in some clinical settings.
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Materials and methods
Animal Model
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CT and MRI Examination
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Data Analysis
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Statistical Analysis
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Visualization of IPs
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Results
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Differences in CTP Parameters between the Four Series of ROI
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Differences in CTP parameters between ROIs at different time points
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Table 1
ANOVA among the CTP Parameters of ROIs 1, 2, and 3 within Infarct Lesions in the Monkey MCAO Model ( P Value)
Time point (hours) rCBF rCBV rMTT PS 1&2 2&3 1&3 1&2 2&3 1&3 1&2 2&3 1&3 1&2 2&3 1&3 1 0.001 ∗ 0.003 ∗ 0.003 ∗ 0.063 0.076 0.008 ∗ 0.069 0.566 0.356 0.356 0.256 0.245 5 0.078 0.001 ∗ 0.005 ∗ 0.111 0.001 ∗ 0.001 ∗ 0.134 0.145 0.346 0.001 ∗ 0.058 0.001 ∗ 10 0.135 0.001 ∗ 0.0003 ∗ 0.456 0.005 ∗ 0.003 ∗ 0.342 0.466 0.234 0.134 0.005 ∗ 0.003 ∗ 15 0.222 0.005 ∗ 0.005 ∗ 0.365 0.005 ∗ 0.001 ∗ 0.125 0.263 0.464 0.235 0.567 0.450 20 0.141 0.002 ∗ 0.001 ∗ 0.654 0.564 0.396 0.268 0.295 0.235 0.432 0.452 0.267 24 0.071 0.321 0.235 0.098 0.287 0.345 0.256 0.007 ∗ 0.005 ∗ 0.535 0.244 0.457
ANOVA, analysis of variance; CTP, computed tomography perfusion; MCAO, middle cerebral artery occlusion; rCBF, relative cerebral blood flow; rCBV, relative cerebral volume; rMTT, relative mean transit time; PS, permeability surface; ROI, region of interest.
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Calculation of IP Thresholds
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Table 2
ROC Curve Analysis of the CTP Parameters
Parameter Area under the Curve ( x¯ x
¯ ± s )P Threshold Sensitivity Specificity rCBF 0.971 ± 0.015 <.001 0.203 83.3% 98.5% rCBV 0.924 ± 0.028 <.001 0.483 79.2% 86.4% rMTT 0.436 ± 0.066 .352 (—) (—) (—) PS 0.498 ± 0.079 .330 (—) (—) (—)
See Table 1 for abbreviations.
The diagnostic effect would be better if the area under curve was closer to 1.
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Changes of Sizes of Ischemic Regions on Different Parameter Maps at Different Time Points
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Table 3
The Ischemic Size Ratios of Imaging Parameters in Monkey MCAO Model ( x¯ x
¯ ± s )
Time point (hours) CBF CBV MTT PS PWI DWI 1 0.648 ± 0.203 0.414 ± 0.105 1.023 ± 0.237 1.121 ± 0.119 0.409 ± 0.039 0.831 ± 0.067 5 0.842 ± 0.153 0.491 ± 0.086 1.095 ± 0.218 1.019 ± 0.208 0.487 ± 0.096 0.918 ± 0.132 10 0.956 ± 0.160 0.722 ± 0.145 1.055 ± 0.223 1.238 ± 0.369 0.731 ± 0.175 0.930 ± 0.123 15 1.096 ± 0.249 0.773 ± 0.147 1.113 ± 0.138 1.209 ± 0.321 0.800 ± 0.179 0.963 ± 0.125 20 1.034 ± 0.198 0.774 ± 0.068 1.155 ± 0.141 1.110 ± 0.178 0.818 ± 0.129 1.016 ± 0.083 24 1.109 ± 0.057 0.830 ± 0.076 1.176 ± 0.080 0.998 ± 0.101 0.805 ± 0.123 0.993 ± 0.032
CBF, cerebral blood flow; CBV, cerebral volume; MTT, mean transit time; PS, permeability surface; PWI, perfusion-weighted imaging; DWI, diffusion-weighted imaging.
The ischemic size ratios of imaging parameters are standardized by the infarct size on T 2 -weighted imaging at 24 hours.
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Evolution of IP Size Estimated by CTP and MRI Methods
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Table 4
IP Size (the Ratio to Infarct Size) in Monkey MCAO Model Calculated by Two Methods
Time points (hours) Method No. 1 No. 2 No. 3 No. 4 No. 5x¯ x
¯ ± s 1 MRI 0.279 0.316 0.206 0.149 0.157 0.221 ± 0.074 CTP 0.286 0.372 0.298 0.257 0.224 0.287 ± 0.055 5 MRI 0.225 0.214 0.183 0.163 0.137 0.184 ± 0.036 CTP 0.267 0.298 0.277 0.24 0.201 0.257 ± 0.037 10 MRI 0.206 0.233 0.181 0.131 0.152 0.181 ± 0.041 CTP 0.253 0.284 0.257 0.231 0.21 0.247 ± 0.028 15 MRI 0.181 0.156 0.169 0.125 0.123 0.151 ± 0.026 CTP 0.216 0.201 0.203 0.175 0.175 0.194 ± 0.018 20 MRI 0.167 0.172 0.168 0.121 0.121 0.150 ± 0.026 CTP 0.147 0.154 0.113 0.098 0.093 0.121 ± 0.028 24 MRI 0.076 0.089 0.124 0.056 0.115 0.092 ± 0.028 CTP 0.051 0.076 0.107 0.068 0.087 0.078 ± 0.021
CTP, computerized tomography perfusion; IP, ischemic penumbra; MCAO, middle cerebral artery occlusion; MRI, magnetic resonance imaging.
MRI method represents perfusion-diffusion mismatch region.
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Discussion
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Acknowledgment
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