18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study

Alex T Vesey, William S A Jenkins, Agnese Irkle, Alastair Moss, Greg Sng, Rachael O Forsythe, Tim Clark, Gemma Roberts, Alison Fletcher, Christophe Lucatelli, James H F Rudd, Anthony P Davenport, Nicholas L Mills, Rustam Al-Shahi Salman, Martin Dennis, William N Whiteley, Edwin J R van Beek, Marc R Dweck, David E Newby, Alex T Vesey, William S A Jenkins, Agnese Irkle, Alastair Moss, Greg Sng, Rachael O Forsythe, Tim Clark, Gemma Roberts, Alison Fletcher, Christophe Lucatelli, James H F Rudd, Anthony P Davenport, Nicholas L Mills, Rustam Al-Shahi Salman, Martin Dennis, William N Whiteley, Edwin J R van Beek, Marc R Dweck, David E Newby

Abstract

Background: Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque.

Methods and results: We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype.

Conclusions: 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.

Keywords: carotid stenosis; fluorides; inflammation; nuclear medicine; phenotype; stroke.

© 2017 The Authors.

Figures

Figure 1.
Figure 1.
18F-Fluoride and 18F-fluorodeoxyglucose (FDG) positron emission tomography of carotid arteries. Example of 18F-fluoride (A, B, C) and 18F-FDG (D, E, F) positron emission tomography (PET)/computed tomography (CT) of 1 patient before surgery for symptomatic carotid stenosis. A, 18F-Fluoride PET axial slice. B, Registered CT angiogram axial slice. C, Fused PET/CT image. White arrow, Ruptured plaque showing 18F-fluoride uptake. D–F, Same slice but with 18F-FDG. Culprit shows uptake, but the contralateral side is obscured by uptake in the right longus colli (green star). An oblique computed tomography carotid angiogram reformat of the culprit (G). The operative specimen (H).
Figure 2.
Figure 2.
18F-Fluoride micro positron emission tomography (PET)/computed tomography (CT), autoradiography, and alizarin red staining. Two examples of ex vivo 18F-fluoride micro PET/CT are shown (A–D, F). A, Coronal micro CT slice; B, corresponding micro PET; C, fused image; D, the plaque. Green arrow, Adherent thrombus over plaque rupture. Red arrow, Associated area of 18F-fluoride uptake (microcalcification). Black arrows, Areas of macrocalcification showing comparatively little uptake (A, C, F). These examples show that 18F-fluoride provides information of the presence of microcalcification and does not simply highlight all calcification. E, An example of micro CT slice registered to an alizarin red-stained section and the corresponding autoradiogram from a specimen that had been incubated whole in 18F-fluoride. It can be seen that the tracer is unable to penetrate the deeper layers of macrocalcification (black arrow), but is able to highlight microcalcification beyond the resolution of even micro CT (red arrow), thus explaining the findings in the micro PET/CT images.
Figure 3.
Figure 3.
Dynamic positron emission tomography (PET) acquisition and examples of 18F-fluoride uptake. A, Correlation between statically derived standardized uptake value (SUV)mean and dynamically measured Ki (dotted line is 95% confidence interval). Photograph shows a dynamic PET study in process. B, C, 18F-Fluoride uptake into areas of cerebral infarction. D–F, From 1 patient. D, Axial image from computed tomography carotid angiogram; E, Fused axial 18F-fluoride PET/computed tomography (CT; white arrow, culprit plaque); F, Oblique reconstruction. G–I, Similar reconstructions from a different patient. J, Obliquely reformatted PET/CT image from a patient who developed a fatal stroke (ipsilateral to the lesion marked by a white arrow) 2 weeks after this scan. The contralateral side, which had shown minimal uptake, had been deemed the culprit based on duplex assessment.
Figure 4.
Figure 4.
18F-Fluoride and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography uptake. Dynamic PET acquisition and examples of 18F-fluoride uptake. Uptake in clinically adjudicated culprit vs contralateral and vs controls. Tukey box and whisker plots. A, B, 18F-Fluoride uptake into culprit (red) and contralateral (blue) plaque using the standardized uptake value (SUV)mean and target to background ratio (TBR)mean measurements, respectively. C, D, Each demonstrate comparison in 18F-fluoride uptake between carotid endarterectomy (CEA) patients (red) and controls (blue); uptake is reported by SUVmean in C and TBRmean in D. E–H, The same comparisons but using 18F-FDG.

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