Introduction 

   Hemodynamic status of chronic ischemic stroke patients can be assessed using a host of modalities that include positron emission tomography (PET), Xenon computed tomography (CT), single photon emission computed tomography (SPECT), transcranial doppler (TCD), perfusion CT and perfusion magnetic resonance image (MRI). Among these, PET is the method that can measure the oxygen extraction fraction (OEF) reflecting the vascular impairment and is the gold standard for quantitative measurements of cerebral blood flow (CBF) and cerebral blood volume (CBV).²⁾¹⁵⁾ However the need for cyclotron, time and spatial restrictions, and expensive equipment have prevented it from being a universally available imaging modality.¹³⁾ These restrictions of PET resulted in finding alternative methods for evaluating hemodynamic status, such as Xeon CT, SPECT with acetazolamide, perfusion CT or MRI, transcranial duplex sonography, and blood oxygen leveldependent (BOLD) functional MRI. The authors proposed that perfusion CT images are very useful and rapid diagnostic tools not only for evaluating acute ischemic stroke but assessing the hemodynamic status in chronic ischemic state. There are three maps, CBF, CBV, and time to peak (TTP). To find out which parameters are useful in evaluating hemodynamic status of patients who has chronic cerebrovascular steno-occlusive disease, we compared the parameters with SPECT findings. 

Materials and Methods 

   A retrospective investigation was performed on 47 patients diagnosed with unilateral ICA or MCA stenoocclusive disease. The mean age was 55.6 years (ranging between 37 and 77 years) among 25 males and 22 females. All patients conducted angiography and were found to have decreased collateral circulation. Afterwards, perfusion CT and SPECT were conducted, and their SPECT findings and CBV, CBF, TTP results from perfusion CT were compared. Among the 47 patients that underwent SPECT with acetazolamide testing, subjects that showed more than 10% right to left discrepancy of region of interest (ROI) value on the MCA territory were identified as decreased reserve capacity (Fig. 1), whereas subjects that showed little or no difference were placed at the normal reserve group. The SPECT with acetazolamide findings and the parameters of each perfusion CT were compared. 

Perfusion CT Protocol 

   Perfusion CT was performed by use of a SIEMENS somatome sensation 16 and syngo Neuro Perfusion CT software was used for generating perfusion maps. Patient was positioned such that it cuts through the basal ganglia at the level of the internal capsule. The slice was selected flatter than normal brain CT scan and the angulation was adjusted perpendicular to the occipital segment of the superior sagittal sinus. Contrast medium injection was done at a rate of 8ml/sec and total volume was 40ml. Because there is a strong linear relation between the concentration of contrast media and attenuation, passage of contrast bolus results in an increase in density of the areas being examined that is proportional to the amount of contrast material present in the blood vessel.¹⁾ A ROI was placed on an artery in the images to view the time-density curve. The time density curves were generated in arterial region of interest, a venous ROI, and in each pixel. Then the software analyzed data according to mathematical models. The maximum slope model approximated the CBF values (ml/100ml/min) from the slope of the time density curve and calculated CBV (ml/1000ml) as the area under the curve . The software then calculated TTP (sec). TTP is the time between the beginning of contrast administration and maximum enhancement in the ROI. On the basis of the integration of the time-density curves and deconvolution calculation the software generated pixel-based color-coded parameteric maps. Then ROI was placed in the brain parenchyma to yield quantitative data. We usually placed wedge shaped ROIs on the MCA territory of each hemisphere. 

SPECT Protocol 

   The SPECT scanner Millenium VG 4.0 (GE, USA) and image processor eNTEGRA ver. 2.5202 (GE) were used. The collimator used was a low-energy, high resolution, parallel hole collimator. Conditions for acquisition was matrix of 512 X 512. A slice thickness obtained was 5.89mm. Transaxial image was reconstructed into sagittal, coronal image by filtered backprojection method. Then ROI was placed in the brain. Typically six circular ROIs along the periphery of each hemisphere were placed and ROI value was checked at axial image. The entire protocol was considered of base and post diamox. Diamox study was checked after 20 minutes after acetazolamide intravenous injection. 

Statistical Analysis 

   All statistics were done using SPSS WIN 12.0K program. Data analysis was done by three methods. In the analysis using the correlation coefficient, SPECT results were not grouped into positive and negative groups, and were studied to find out how much they were relevant to CBV, CBF and TTP parameters, respectively. Positive SPECT results that showed more than 10% discrepancy of the ROI value on the MCA territory between normal cerebral hemisphere and the cerebral hemisphere with steno-occlusive disease were input as 1 and negative SPECT results that showed less than 10% discrepancy of the ROI value on the MCA territory between both cerebral hemispheres were input as 0. The data of CBV, CBF, and TTP parameters were put as the difference of the ROI values on the MCA territory between the normal cerebral hemisphere and the cerebral hemisphere with stenoocclusive disease. Statistics was done under p-value < 0.01. 
   Using logistic regression analysis, SPECT results were divided into positive and negative groups and were studied to find out their relevance to CBF, CBV, TTP parameters, respectively. It was performed under p-value <0.05. 
   Finally, receiver operating characteristic (ROC) curve analysis was used to expect the multiplying factor in the values of the TTP parameters between the normal cerebral hemisphere and the cerebral hemisphere with stenoocclusive disease that would be relevant with SPECT results. The multiplying factor between the values of TTP parameter of the normal cerebral hemisphere and the cerebral hemisphere with steno-occlusive disease was studied to find out the cut off value which means it has to be in order for it to be relevant with SPECT results. The attempt was done to seek that the most reliable highest sensitivity and the least false positive (1-sensitivity) between SPECT study and TTP parameter. In this analysis, SPECT study was considered as gold standard for evaluating the hemodynamic status in chronic ischemic stroke patient. It was performed under pvalue < 0.001. 

Results 

   In the correlation analysis of SPECT and CBF, there was no significant correlation, showing r=0.270 under p-value <0.05. No significant correlation was shown in the analysis of SPECT and CBV, exhibiting r=0.108 under p-value < 0.05. But SPECT and TTP analysis resulted in a significant static correlation, showing r=0.774 under p-value <01 (Table 1). 
   In the analysis of logistic regression between SPECT study and TTP parameter, the regression coefficient was β=4.753 and p=0.086 and showed a significant relevance to SPECT studies under p-value < 0.05, thus resulting in a difference in positive and negative groups (Table 2). The odds ratios was 4.5 but CBF, CBV did not show any difference (Fig. 2). 
   According to the ROC curve analysis, the cut off value of multiplying factor between the values of TTP parameter of the normal cerebral hemisphere and the cerebral hemisphere with steno-occlusive disease was 1.553797 (Table 3). A 1.553797 times difference in the values of the TTP parameters of the normal cerebral hemisphere and the cerebral hemisphere with steno-occlusive disease showed to make the results of the SPECT relevant. 

Discussion 

   Many modality was introduced due to assess hemodynamic status of ischemic stroke patients. PET is the gold standard for quantitave measurements of CBF and CBV. However, PET is limited by availability of isotope,cost and time. Xenon CT is a quantitative perfusion assessment tool, with validation studies which have shown that it is a reliable method of assessing cerebral perfusion.³⁾ However, it is no longer widely available; other disadvantages include long acquisition time (and resultant difficulty with motion artifact) and occasional reactions of nausea or dizziness. SPECT imaging, which utilizes the radionuclide 99mTc-HMPAO, has been extensively used. 
   T. Nariai⁹⁾ suggested that Xenon (Xe)-SPECT with acetazolamide could substitute PET, due to identical results between OEF PET and Xe-SPECT with acetazolamide challenge. Kuroda showed that there was significant increase of OEF in PET scans of patients with reduced blood flow.⁶⁾ Furthermore, Herold and Ogasawara also suggested that SPECT could prove as a valuable tool as a substitute for PET.⁴⁾¹⁰⁾ SPECT imaging is primarily a qualitative tool subject to reader variability. It is also limited by availability of isotope, cost and time limitation. Also there is always a risk for subsequent stroke due to acetazolamide. A less costly method of assessment is the use of TCD with either acetazolamide or breath-holding challenge to assess for reserve.⁶⁾¹²⁾ Perfusion CT, using standard spiral CT scanner and an intravenous bolus injection of iodinated contrast, has the advantage of wide availability and holds the potential to provide quantitative data.⁹⁾¹⁴⁾ As an addition, perfusion CT has the advantage of instant evaluation of hemodynamic status. 
   Data analysis revealed that TTP parameter had the significant relevance to SPECT study. In the correlation analysis of SPECT and perfusion CT parameters, SPECT study and TTP parameter analysis resulted in a significant static correlation. In the logistic regression analysis of SPECT study and perfusion CT parameters, TTP parameter showed significant relevance to SPECT study, namely the regression coefficient was =4.753 and p=0.086 and the odds ratios was 4.5 under p-value <0.05. It revealed that when subjects that showed more than 10% right to left discrepancy of region of interest (ROI) value on the MCA territory in SPECT study, the probability of TTP parameter relevance to SPECT study was 4.5times compared with the subject that showed less than 10% discrepancy of the ROI value on the MCA territory between both cerebral hemispheres. In the ROC curve analysis, when the difference of TTP parameters between normal cerebral hemisphere and cerebral hemisphere with steno-occlusive disease is greater than 1.55 times, we could expect that the cerebral hemisphere with steno-occlusive disease has decreased reserve capacity in SPECT study. The value of 1.55 times would be the cut off value because it represented the most reliable sensitivity and the least 1-specificity (false positive). Our study of the 47 patients shows that due to the many shortcomings, hemodynamic index of TTP may be a useful tool as substitute for SPECT study. 
   However perfusion CT also has its own downsides. Adverse reaction due to contrast media usage and renal dysfunction may occur. Discrepancies can also appear between different ROI measuring techniques or examining areas. For the patients with small lacunar or subcortical infarcts, perfusion CT could predict low accuracy, and falsenegative were encountered in small lesions or in inadequate coverage of data acquisition.⁸⁾ 
   The downside of this study is the relative scale of data obtained. Although a 95% Hemodynamic index TTP confidence interval was obtained amongst 47 patients, a more accurate analysis could have been provided with a larger scale of patients.

Conclusion 

   Perfusion CT is a very useful tool for the rapid and adequate diagnosis of almost all of the large territorial infarcts and some of non-territorial lacunar infarcts. It is an easy-to-perform and safe imaging technique to assess the hemodynamic status in ischemic stroke treatment. Among the three parameters of perfusion CT, TTP parameter is a very sensitive and reliable parameter that can be utilized to show the status of collateral circulation. The diagnostic value of perfusion CT is absolute in acute and chronic ischemic stroke. However the mandatory usage of iodinated contrast media still remains as a disadvantage. Despite all the downsides, perfusion CT proves to be a valuable tool in evaluating the hemodynamic status of chronic cerebrovascular occlusive disease, and serves as an alternative tool of determining vasodilatation capacity to CO2 challenge-especially SPECT. 

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