Potential of Integrated [18F] Fluorodeoxyglucose Positron-Emission Tomography/CT in Identifying Vulnerable Carotid Plaques

It is known that risk of cerebrovascular accident is not only associated with degree of carotid artery stenosis but probably more importantly with type of plaque: vulnerable vs stable. Myriad studies have looked at this issue with high-resolution MR imaging but the present one used FDG-PET and CT. Fifty patients with transient ischemic attack/stroke who had ipsilateral stenosis and plaque along with contralateral asymptomatic plaque were imaged. High uptake was seen in ipsilateral plaques when compared with contralateral asymptomatic ones but these differences were not significant. CT also showed larger lipid-rich necrotic cores and thicker arterial walls in symptomatic plaques, but again these differences were not significant. Thus, it remains to be determined if the combination of FDG-PET/CT is valuable. BACKGROUND AND PURPOSE: There is a need for improved risk stratification of patients with TIA/stroke and carotid atherosclerosis. The purpose of this study was to prospectively investigate the potential of integrated 18F-FDG PET/MDCT in identifying vulnerable carotid plaques. MATERIALS AND METHODS: Fifty patients with TIA/stroke with an ipsilateral carotid plaque causing <70% stenosis and a plaque on the contralateral asymptomatic side underwent integrated 18F-FDG PET/MDCT within 36.1 ± 20.0 days (range, 9–95 days) of the last symptoms. Carotid plaque 18F-FDG uptake was measured as both the mean and maximum blood-normalized SUV, known as the TBR. Using MDCT, we assessed volumes of vessel wall and individual plaque components. RESULTS: Mean TBR was only significantly larger in the ipsilateral plaques of patients who were imaged within 38 days (1.24 ± 0.04 [SE] versus 1.17 ± 0.05, P = .014). This also accounted for maximum TBR (1.53 ± 0.06 versus 1.42 ± 0.06, P = .015). MDCT-assessed vessel wall and LRNC volumes were larger in ipsilateral plaques of all patients (982.3 ± 121.3 versus 811.3 ± 106.6 mm3, P = .016; 164.7 ± 26.1 versus 134.3 ± 35.2 mm3, P = .026, respectively). CONCLUSIONS: In the present study, 18F-FDG PET only detected significant differences between ipsilateral and contralateral asymptomatic plaques in patients with TIA/stroke who were imaged within 38 days, whereas MDCT detected larger vessel wall and LRNC volumes, regardless of time after symptoms. In view of the substantial overlap in measurements of both sides, it remains to be determined whether the differences we found will be clinically meaningful.

L arge clinical trials demonstrated that patients with highgrade carotid artery stenosis due to atherosclerosis may benefit from CEA. 1 However, for patients with symptomatic 70%-99% stenosis, 6.3 patients needed to undergo surgery to prevent 1 ipsilateral stroke in 5 years, whereas for patients with asymptomatic 60%-99% stenosis, this number was as high as 17. 1 These numbers show that there is a considerable difference in stroke risk between both groups and that many patients are undergoing surgery unnecessarily. Histopathologic studies suggest that so-called vulnerable plaques, character-ized by attenuated inflammation and large LRNC size, are more prone to rupture. 2 Plaque rupture can lead to thrombus formation and subsequent stroke. Difference in stroke risk can be explained by differences in plaque characteristics: Plaques ipsilateral to the symptomatic side may be more vulnerable than asymptomatic plaques.
It has been shown that 18 F-FDG PET and MDCT are able to noninvasively assess plaque inflammation and composition, respectively. 3,4 Integrated PET/MDCT scanners are now widely available and may be used to differentiate vulnerable from nonvulnerable carotid plaques, which may lead to a better risk stratification of patients. To assess the potential of integrated 18 F-FDG PET/MDCT in identifying vulnerable plaques, we prospectively investigated whether these combined imaging modalities can detect differences between carotid plaques ipsilateral to the symptomatic (infarct) side and contralateral to asymptomatic plaques. We performed this study in patients with TIA/stroke with lowgrade (Ͻ70%) stenosis, because if 18 F-FDG PET and/or MDCT can detect differences between ipsilateral and contralateral plaques, it is this group of patients who are expected to benefit most from improved personalized risk stratification.

Patients
Fifty consecutive patients (34 men; mean age, 67.8 Ϯ 8.9 years) who were diagnosed by a neurologist as having recent TIA or nondisabling ischemic stroke in the carotid artery territory and ipsilateral carotid plaque causing Ͻ70% stenosis at duplex sonography 5 underwent integrated 18 F-FDG PET/MDCT of both carotid arteries. Forty-five patients were on statin therapy. The mean time interval between the date of last symptoms and imaging was 36.1 Ϯ 20.0 days (range, 9 -95 days). The mean blood glucose level, measured before each 18 F-FDG PET/MDCT study was 102 Ϯ 14 mg/dL. Exclusion criteria were the following: atrial fibrillation, history of clinical cerebral ischemia at the contralateral side, no visible plaque or occlusion at the contralateral side at duplex ultrasonography, 5 glomerular filtration rate Ͻ 60 mL/ min/1.73 m 2 , and blood glucose level Ͼ 150 mg/dL. This study was approved by the institutional review board of our hospital, and all patients gave written informed consent.

Image Review
One investigator with 2 years of experience in plaque analysis (R.M.K.) evaluated 18 F-FDG PET/MDCT images, blinded to all clinical information. Stenosis grade was assessed on the MDCT images by using the NASCET method. 6 Plaque was identified as the presence of calcification and/or thickening of the vessel wall on the MDCT images. Regions of interest were manually drawn, encompassing the plaque (Fig 1), and were placed to avoid plaque borders to reduce partial volume effects. Regions of interest were drawn on all sections around the carotid bifurcation where plaque was identified for both arteries, and each one was transferred onto the corresponding coregistered PET images (Fig 1). Dedicated fusion software (Syntegra, Philips Healthcare) was used to analyze the PET images. Mean and  A polymeasure plug-in for the software package ImageJ (Wayne Rasband; National Institutes of Mental Health, Bethesda, Maryland) was used to semiautomatically quantify volumes of the vessel wall, LRNC (including hemorrhage), fibrous tissue, and calcifications, as described before. 4,7 MDCT segmentation thresholds were LRNC Ͻ 60 HU; fibrous tissue ϭ 60 -130 HU; and calcification Ͼ 130 HU. Previously, it was shown that overall interobserver agreement for the assessment of carotid plaque components by MDCT was moderate, with ICCs ranging from 0.76 to 0.97 and CVs ranging from 13% to 47%. 7

Statistical Analysis
Statistical analyses were performed by using the Statistical Package for the Social Sciences, Version 11.5 (SPSS, Chicago, Illinois). Because the degree of plaque macrophage content and/or activity may be time-dependent, 2,8 we assessed correlations between the time after symptoms and TBRs by Pearson rank correlation tests. Very weak, weak, moderate, strong, and very strong correlations were defined as Pearson s of 0 -0.19, 0.20 -0.39, 0.40 -0.59, 0.60 -0.79, and 0.80 -1.00, respectively. 9 Wilcoxon signed rank tests were used to compare 18 F-FDG PET and MDCT findings between ipsilateral and contralateral carotid plaques. Because of the time dependency of plaque macrophage content and/or activity, we also performed a sensitivity analysis to assess whether patients who were imaged sooner after symptoms had significantly larger TBRs in the ipsilateral plaques. When a certain plaque parameter was found to be significantly higher at 1 side, we assessed whether this difference was not related to stenosis grade. This was done by performing linear regression analysis for ipsilateral and contralateral plaques with overlapping stenosis grade, by using ipsilateral/contralateral plaque status and stenosis grade as independent variables. Logarithmic transformation was performed to normalize distribution of data. Correlations between TBRs of ipsilateral and contralateral asymptomatic plaques were assessed by Pearson rank correlation tests. All levels of statistical significance were set at .05.

Results
Correlations between the time after symptoms and TBRs are shown in Table 1. There were moderate negative correlations between time after symptoms and mean and maximum TBRs at the ipsilateral side. Comparisons and correlations of 18 F-FDG PET and MDCT findings between ipsilateral and contralateral asymptomatic plaques are shown in Table 2. Plaques ipsilateral to the symptomatic side caused a significantly higher degree of stenosis. For all patients, there was no significant difference between mean and maximum 18 F-FDG TBRs of ipsilateral and contralateral asymptomatic plaques. When we limited the analysis to patients who were imaged within 38 days after symptoms, the mean TBR was significantly larger in ipsilateral plaques (1.24 versus 1.17, P ϭ .014). This also accounted for maximum TBR (1.53 versus 1.42, P ϭ .015).

Discussion
Integrated PET/MDCT scanners are now widely available and can provide information on plaque inflammation and composition in a single examination. This technique may be used to differentiate vulnerable from nonvulnerable carotid plaques, which may lead to a better risk stratification of patients with TIA/stroke with carotid atherosclerosis. This study compared 18 F-FDG PET and MDCT findings between plaques ipsilateral to the side of symptoms and contralateral asymptomatic plaques causing Ͻ70% stenosis. Overall 5-year risk of (recurrent) ipsilateral stroke for the former is approximately 20%, 10 while for the latter, it is approximately 2%. 11 In the present study, 18 F-FDG PET only detected significant differences in patients who were imaged within 38 days. However, in this subgroup of patients, there was still substantial overlap in 18 F-FDG uptake measurements.
In light of the error in TBR measurement (CV of 10.8%-12.1%), our findings suggest that selection of vulnerable versus nonvulnerable plaques on the basis of a TBR threshold may have a low sensitivity and/or specificity. In addition, we found strong positive correlations between 18 F-FDG uptake in ipsilateral and contralateral asymptomatic plaques, which support the concept that atherosclerosis is a systemic inflammatory disease and may also explain why differences between both sides are small. MDCT detected larger vessel wall and LRNC volume in ipsilateral plaques, regardless of the time after symptoms. However, there was also substantial overlap between both sides. Moreover, interobserver variability of semiautomatic assessment of vessel wall and LRNC volume by MDCT, as previously reported by de Weert et al, 6 is still considerable (CV of 23%-34% and 42%-58%, respectively), which may limit its clinical usefulness.
To date, only a few studies have compared 18 F-FDG uptake between ipsilateral and contralateral asymptomatic plaques in relatively small sample sizes. 12,13 Using a stand-alone PET scanner, Rudd et al 12 performed a study in 8 patients with TIA with an ipsilateral carotid stenosis of at least 70%. The median time between symptoms and 18 F-FDG PET imaging was 3.5 months. 12 Their analysis was limited to 6 of the 8 included patients, showing 34% higher 18 F-FDG uptake on the symptomatic side. 12 However, this series of patients 12 may be too small to make any assumptions. Moreover, statins attenuate plaque inflammation on 18 F-FDG PET, 13 whereas the study of Rudd et al 12 was performed in an era when statin therapy was not as intensive or prevalent as it is at present. Font et al 14 studied 15 patients with Ͼ70% stenosis, of whom 10 were defined as being symptomatic. In these 10 symptomatic patients who underwent an 18 F-FDG PET scanning between 7 and 114 days (median, 33 days) after symptoms, there was no significant difference in 18 F-FDG uptake between ipsilateral and contralateral asymptomatic plaques (1.19 versus 1.15, P ϭ .185). However, due to the relatively limited sample size, 14 no analysis with regard to timing of 18 F-FDG PET could be performed.
In the present study, in which all patients were defined as symptomatic according to NASCET and European Carotid Surgery Trial criteria, 6,15 we did find a negative correlation between TBRs of ipsilateral plaques and the time after symptoms. This finding is in accordance with the results of a large histopathologic study 8 showing that symptomatic carotid lesions remodel into more stable plaques with time after stroke. Sensitivity analysis indicated that 18 F-FDG PET only detected significant differences if performed within 38 days after symptoms. Future independent studies should confirm our findings.
We found that MDCT identified significantly larger vessel wall and LRNC volume in ipsilateral plaques. Wintermark et al, 16 who performed an MDCT study in 40 patients with stroke, also found larger vessel wall volume in ipsilateral plaques (1404.1 versus 1281.9 mm 3 , P ϭ .020). They also found larger LRNC volumes, though this finding was not significant (24.9 versus 16.4 mm 3 , P ϭ .196). In accordance, an MR imaging study by Saam et al 17 demonstrated that plaques at the symptomatic side had larger mean LRNC areas (8.1 versus 6.3 mm 2 , P ϭ .2). A disadvantage of MDCT is that LRNC can only be adequately quantified in mildly calcified plaques. 4 Other disadvantages of MDCT are that it cannot reliably distinguish intraplaque hemorrhage from LRNC, and fibrous cap status cannot be assessed. These parameters, which are also potential markers of plaque vulnerability, can be assessed by MR imaging. 17 Whether MDCT or MR imaging may be more helpful in identifying vulnerable plaques can only be determined by prospective longitudinal studies.
Our study has several limitations. First, 90% of the included patients were on statin therapy, which may have attenuated plaque inflammation on 18 F-FDG PET. 13 However, the fact that most of the included patients with TIA/stroke used statins reflects current clinical practice. Second, the time between 18 F-FDG injection and PET imaging was 1 hour. By increasing this interval, higher lesion-to-background contrast could have been achieved. 12 However, this was not possible due to too much patient discomfort. Third, 18 F-FDG PET measurements may have been affected by partial volume errors. Future studies may use methods to reduce these errors. 18 Fourth, we used a manual outlining method for 18 F-FDG PET measurements, whereas a semiautomated method was used for MDCT measurements. The development and use of fully automated software may enhance reproducibility. Last, our study had a cross-sectional design. The true value of integrated 18 F-FDG PET/MDCT in identifying vulnerable plaques can only be determined by performing a large prospective clinical trial.

Conclusions
In the present study, 18 F-FDG PET only detected significant differences between ipsilateral and contralateral asymptomatic plaques in patients with TIA/stroke who were imaged within 38 days, whereas MDCT detected larger vessel wall and LRNC volume regardless of time after symptoms. However, there was substantial overlap in measurements of both sides. Whether integrated 18 F-FDG PET/MDCT is clinically meaningful can only be assessed by a large prospective clinical trial.