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Assessing atherosclerosis severity is essential for precise patient stratification. Specifically, there is a need to identify patients with residual inflammation because these patients remain at high risk of cardiovascular events despite optimal management of cardiovascular risk factors. Molecular imaging techniques, such as PET, can have an essential role in this context. PET imaging can indicate tissue-based disease status, detect early molecular changes and provide whole-body information. Advances in molecular biology and bioinformatics continue to help to decipher the complex pathogenesis of atherosclerosis and inform the development of imaging tracers. Concomitant advances in tracer synthesis methods and PET imaging technology provide future possibilities for atherosclerosis imaging. In this Review, we summarize the latest developments in PET imaging techniques and technologies for assessment of atherosclerotic cardiovascular disease and discuss the relationship between imaging readouts and transcriptomics-based plaque phenotyping., (© 2024. Springer Nature Limited.)

Background and Aims: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis., Methods: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala)., Results: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score., Conclusions: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Myocardial replacement fibrosis has been reported to occur in one-third of patients with mitral valve prolapse (MVP) and significant mitral regurgitation (MR). However, it remains unknown whether there are detectable changes in myocardial metabolism suggestive of inflammation or ischemia that accompany the development of fibrosis., Objectives: To characterize the burden and distribution of fluorine 18-labeled (18F) fluorodeoxyglucose (FDG) uptake and late gadolinium enhancement (LGE) in patients with degenerative MVP and ventricular ectopy., Design, Setting, and Participants: Prospective observational study of 20 patients with MVP and significant primary degenerative MR who were referred for mitral valve repair and underwent hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Ventricular arrhythmias were categorized as either complex (n = 12) or minor (n = 8). Coregistered hybrid 18F FDG-PET and MRI LGE images were assessed and categorized. Recruitment occurred in the new patient clinic of a mitral valve repair reference center. This study was conducted from January 11, 2018, to June 26, 2019., Exposures: Simultaneous cardiac 18F FDG-PET and MRI with LGE imaging on a hybrid PET/MRI system and ambulatory rhythm monitoring., Main Outcomes and Measures: Patients were categorized by the presence and pattern of FDG uptake and LGE, the severity of ventricular arrhythmias, and the indication for mitral valve surgery., Results: In the cohort of 20 patients, the median age was 59.5 years (interquartile range, 52.5-63.2 years). Focal, or focal-on-diffuse uptake, of 18F-FDG (PET positive) was detected in 17 of 20 patients (85%). The FDG uptake coexisted with areas of LGE (PET/MRI positive) in 14 patients (70%). Of the 5 asymptomatic patients with normal ventricular indices and absence of any surgical indications, all were PET/MRI positive., Conclusions and Relevance: In this pilot study, we demonstrate a novel association between degenerative MVP and FDG uptake, a surrogate for myocardial inflammation and/or ischemia. Such evidence of myocardial injury, even in asymptomatic patients, suggests an ongoing subclinical disease process. These findings warrant further investigation into whether imaging for myocardial inflammation, ischemia, and scar has a role in arrhythmic risk stratification and whether it provides incremental prognostic value in patients with chronic severe mitral regurgitation undergoing active surveillance.

Cardiovascular disease due to atherosclerosis is still the main cause of morbidity and mortality worldwide. This disease is a complex systemic disorder arising from a network of pathological processes within the arterial vessel wall, and, outside of the vasculature, in the hematopoietic system and organs involved in metabolism. Recent years have seen tremendous efforts in the development and validation of quantitative imaging technologies for the noninvasive evaluation of patients with atherosclerotic cardiovascular disease. Specifically, the advent of combined positron emission tomography and magnetic resonance imaging scanners has opened new exciting opportunities in cardiovascular imaging. In this review, we will describe how combined positron emission tomography/magnetic resonance imaging scanners can be leveraged to evaluate atherosclerotic cardiovascular disease at the whole-body level, with specific focus on preclinical animal models of disease, from mouse to nonhuman primates. We will broadly describe 3 major areas of application: (1) vascular imaging, for advanced atherosclerotic plaque phenotyping and evaluation of novel imaging tracers or therapeutic interventions; (2) assessment of the ischemic heart and brain; and (3) whole-body imaging of the hematopoietic system. Finally, we will provide insights on potential novel technical developments which may further increase the relevance of integrated positron emission tomography/magnetic resonance imaging in preclinical atherosclerosis studies.

The immune system's role in atherosclerosis has long been an important research topic and is increasingly investigated for therapeutic and diagnostic purposes. Therefore, noninvasive imaging of hematopoietic organs and immune cells will undoubtedly improve atherosclerosis phenotyping and serve as a monitoring method for immunotherapeutic treatments. Among the available imaging techniques, positron emission tomography's unique features make it an ideal tool to quantitatively image the immune response in the context of atherosclerosis and afford reliable readouts to guide medical interventions in cardiovascular disease. Here, we summarize the state of the art in the field of atherosclerosis positron emission tomography immunoimaging and provide an outlook on current and future applications.

Nanotherapy has recently emerged as an experimental treatment option for atherosclerosis. To fulfill its promise, robust noninvasive imaging approaches for subject selection and treatment evaluation are warranted. To that end, we present here a positron emission tomography (PET)-based method for quantification of liposomal nanoparticle uptake in the atherosclerotic vessel wall. We evaluated a modular procedure to label liposomal nanoparticles with the radioisotope zirconium-89 ( 89 Zr). Their biodistribution and vessel wall targeting in a rabbit atherosclerosis model was evaluated up to 15 days after intravenous injection by PET/computed tomography (CT) and PET/magnetic resonance imaging (PET/MRI). Vascular permeability was assessed in vivo using three-dimensional dynamic contrast-enhanced MRI (3D DCE-MRI) and ex vivo using near-infrared fluorescence (NIRF) imaging. The 89 Zr-radiolabeled liposomes displayed a biodistribution pattern typical of long-circulating nanoparticles. Importantly, they markedly accumulated in atherosclerotic lesions in the abdominal aorta, as evident on PET/MRI and confirmed by autoradiography, and this uptake moderately correlated with vascular permeability. The method presented herein facilitates the development of nanotherapy for atherosclerotic disease as it provides a tool to screen for nanoparticle targeting in individual subjects' plaques.

Objectives: This study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers., Background: Noninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated., Methods: We screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 ( 64 Cu), were extensively evaluated in Apoe -/- mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses., Results: The 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 ( 68 Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68 Ga-MMR-PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 ( 18 F)-labeled fluorodeoxyglucose ( 18 F-FDG) and 18 F-sodium fluoride ( 18 F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features., Conclusions: We have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiac positron emission tomography (PET) imaging suffers from image blurring due to the constant motion of the heart that can impact interpretation. Hybrid PET/magnetic resonance (MR) has the potential to use radiation-free MR imaging to correct for the effects of cardio-respiratory motion in the PET data, improving qualitative and quantitative PET imaging in the heart. The purpose of this study was (i) to implement a MR image-based motion-corrected PET/MR method and (ii) to perform a proof-of-concept study of quantitative myocardial PET data in patients. The proposed method takes reconstructions of respiratory and cardiac gated PET data and applies spatial transformations to a single reference frame before averaging to form a single motion-corrected PET (MC-PET) image. Motion vector fields (MVFs) describing the transformations were derived from affine or non-rigid registration of respiratory and cardiac gated MR data. Eight patients with suspected cardiac sarcoidosis underwent cardiac PET/MR imaging after injection of 5 MBq kg -1 of 18 F-fluorodeoxyglucose ( 18 F-FDG). Myocardial regions affected by motion were identified by expert readers within which target-to-background ratios (TBR) and contrast-to-noise ratios (CNR) were measured on non-MC-non-gated, MC-PET, and double respiratory and cardiac gated PET images. Paired t-tests were used to determine statistical differences in quantitative uptake-measures between the different types of PET images. MC-PET images showed less blurring compared to non-MC-non-gated PET and tracer activity qualitatively aligned better with the underlying myocardial anatomy when fused with MR. TBR and CNR were significantly greater for MC-PET (2.8  ±  0.9; 21  ±  22) compared to non-MC-non-gated PET (2.4  ±  0.9, p  =  0.0001; 15  ±  13, p  =  0.02), while TBR was lower and CNR greater compared to double-gated PET (3.2  ±  0.9, p  =  0.04; 6  ±  3, p  =  0.004). This study demonstrated in a patient cohort that motion-corrected (MC) cardiac PET/MR is feasible using a retrospective MR image-based method and that improvement in TBR and CNR are achievable. MC PET/MR holds promise for improving interpretation and quantification in cardiac PET imaging.

Objectives: The authors sought to develop combined positron emission tomography (PET) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to quantify plaque inflammation, permeability, and burden to evaluate the efficacy of a leukotriene A4 hydrolase (LTA4H) inhibitor in a rabbit model of atherosclerosis., Background: Multimodality PET/MRI allows combining the quantification of atherosclerotic plaque inflammation, neovascularization, permeability, and burden by combined 18 F-fluorodeoxyglucose ( 18 F-FDG) PET, DCE-MRI, and morphological MRI. The authors describe a novel, integrated PET-DCE/MRI protocol to noninvasively quantify these parameters in aortic plaques of a rabbit model of atherosclerosis. As proof-of-concept, the authors apply this protocol to assess the efficacy of the novel LTA4H inhibitor BI691751., Methods: New Zealand White male rabbits (N = 49) were imaged with integrated PET-DCE/MRI after atherosclerosis induction and 1 and 3 months after randomization into 3 groups: 1) placebo; 2) high-dose BI691751; and 3) low-dose BI691751. All animals were euthanized at the end of the study., Results: Among the several metrics that were quantified, only maximum standardized uptake value and target-to-background ratio by 18 F-FDG PET showed a modest, but significant, reduction in plaque inflammation in rabbits treated with low-dose BI691751 (p = 0.03), whereas no difference was detected in the high-fat diet and in the high-dose BI691751 groups. No differences in vessel wall area by MRI and area under the curve by DCE-MRI were detected in any of the groups. No differences in neovessel and macrophage density were found at the end of study among groups., Conclusions: The authors present a comprehensive, integrated 18 F-FDG PET and DCE-MRI imaging protocol to noninvasively quantify plaque inflammation, neovasculature, permeability, and burden in a rabbit model of atherosclerosis on a simultaneous PET/MRI scanner. A modest reduction was found in plaque inflammation by 18 F-FDG PET in the group treated with a low dose of the LTA4H inhibitor BI691751., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events., Objectives: The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions., Methods: An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 ( 89 Zr)-labeled LA25. In rabbits, 89 Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18 F-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence., Results: LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of 89 Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18 F-fluorodeoxyglucose PET, dynamic contrast-enhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining., Conclusions: 89 Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to explore the diagnostic usefulness of hybrid cardiac magnetic resonance (CMR) and positron emission tomography (PET) using 18 F-fluorodeoxyglucose (FDG) for active cardiac sarcoidosis., Background: Active cardiac sarcoidosis (aCS) is underdiagnosed and has a high mortality., Methods: Patients with clinical suspicion of aCS underwent hybrid CMR/PET with late gadolinium enhancement (LGE) and FDG to assess the pattern of injury and disease activity, respectively. Patients were categorized visually as magnetic resonance (MR)+PET+ (characteristic LGE aligning exactly with increased FDG uptake), MR+PET- (characteristic LGE but no increased FDG), MR-PET- (neither characteristic LGE nor increased FDG), and MR-PET+ (increased FDG uptake in absence of characteristic LGE) and further characterized as aCS+ (MR+PET+) or aCS- (MR+PET-, MR-PET-, MR-PET+). FDG uptake was quantified using maximum target-to-normal-myocardium ratio and the net uptake rate (K i ) from dynamic Patlak analysis. Receiver-operating characteristic methods were used to identify imaging biomarkers for aCS. FDG PET was assessed using computed tomography/PET in 19 control subjects with healthy myocardium., Results: A total of 25 patients (12 males; 54.9 ± 9.8 years of age) were recruited prospectively; 8 were MR+PET+, suggestive of aCS; 1 was MR+PET-, consistent with inactive cardiac sarcoidosis; and 8 were MR-PET-, with no imaging evidence of cardiac sarcoidosis. Eight patients were MR-PET+ (6 with global myocardial FDG uptake, 2 with focal-on-diffuse uptake); they demonstrated distinct K i values and hyperintense maximum standardized uptake value compared with MR+PET+ patients. Similar hyperintense patterns of global (n = 9) and focal-on-diffuse (n = 2) FDG uptake were also observed in control patients, suggesting physiological myocardial uptake. Maximum target-to-normal-myocardium ratio values were higher in the aCS+ group (p < 0.001), demonstrating an area under the curve of 0.98 on receiver-operating characteristic analysis for the detection of aCS, with an optimal maximum target-to-normal myocardium ratio threshold of 1.2 (Youden index: 0.94)., Conclusions: CMR/PET imaging holds major promise for the diagnosis of aCS, providing incremental information about both the pattern of injury and disease activity in a single scan. (In Vivo Molecular Imaging [MRI] of Atherothrombotic Lesions; NCT01418313)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiovascular imaging has largely focused on identifying structural, functional, and metabolic changes in the heart. The ability to reliably assess disease activity would have major potential clinical advantages, including the identification of early disease, differentiating active from stable conditions, and monitoring disease progression or response to therapy. Positron emission tomography (PET) imaging now allows such assessments of disease activity to be acquired in the heart, whereas magnetic resonance (MR) scanning provides detailed anatomic imaging and tissue characterization. Hybrid MR/PET scanners therefore combine the strengths of 2 already powerful imaging modalities. Simultaneous acquisition of the 2 scans also provides added benefits, including improved scanning efficiency, motion correction, and partial volume correction. Radiation exposure is lower than with hybrid PET/computed tomography scanning, which might be particularly beneficial in younger patients who may need repeated scans. The present review discusses the expanding clinical literature investigating MR/PET imaging, highlights its advantages and limitations, and explores future potential applications., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aims of this study were to describe the authors' initial experience with combined coronary artery positron emission tomographic (PET) and magnetic resonance (MR) imaging using 18 F-fluorodeoxyglucose ( 18 F-FDG) and 18 F-sodium fluoride ( 18 F-NaF) radiotracers, describe common problems and their solutions, and demonstrate the feasibility of coronary PET/MR imaging in appropriate patients., Background: Recently, PET imaging has been applied to the aortic valve and regions of atherosclerosis. 18 F-FDG PET imaging has become established for imaging inflammation in atherosclerosis in the aorta and carotid arteries. Moreover, 18 F-NaF has emerged as a novel tracer of active microcalcification in the aortic valve and coronary arteries. Coronary PET imaging remains challenging because of the small caliber of the vessels and their complex motion. Currently, most coronary imaging uses combined PET and computed tomographic imaging, but there is increasing enthusiasm for PET/MR imaging because of its reduced radiation, potential to correct for motion, and the complementary information available from cardiac MR in a single scan., Methods: Twenty-three patients with diagnosed or documented risk factors for coronary artery disease underwent either 18 F-FDG or 18 F-NaF PET/MR imaging. Standard breath-held MR-based attenuation correction was compared with a novel free-breathing approach. The impact on PET image artifacts and the interpretation of vascular uptake were evaluated semiquantitatively by expert readers. Moreover, PET reconstructions with more algorithm iterations were compared visually and by target-to-background ratio., Results: Image quality was significantly improved by novel free-breathing attenuation correction. Moreover, conspicuity of coronary uptake was improved by increasing the number of algorithm iterations from 3 to 6. Elevated radiotracer uptake could be localized to individual coronary lesions using both 18 F-FDG (n = 1, maximal target-to-background ratio = 1.61) and 18 F-NaF (n = 7, maximal target-to-background ratio = 1.55 ± 0.37), including in 1 culprit plaque post-myocardial infarction confirmed by myocardial late gadolinium enhancement., Conclusions: The authors provide the first demonstration of successful, low-radiation (7.2 mSv) PET/MR imaging of inflammation and microcalcification activity in the coronary arteries. However, this requires specialized approaches tailored to coronary imaging for both attenuation correction and PET reconstruction., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with 18 F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology., Competing Interests: R.W., N.K. and M.N. are inventors on a related patent application. The remaining authors declare no competing financial interests.

Unlabelled: (18)F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances (18)F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo., Methods: In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on (18)F-FDG uptake in normal versus inflamed arteries, using PET., Results: Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor-α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial (18)F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo (18)F-FDG uptake and macrophage staining (R = 0.75, P < 0.01)., Conclusion: GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-α) and increases (18)F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Positron emission tomography (PET) imaging of yttrium-90 in the liver post radioembolization has been shown useful for personalized dosimetry calculations and evaluation of extrahepatic deposition. The purpose of this study was to quantify the benefits of several MR-based data correction approaches offered by using a combined PET/MR system to improve Y-90 PET imaging. In particular, the feasibility of motion and partial volume corrections were investigated in a controlled phantom study., Methods: The ACR phantom was filled with an initial concentration of 8 GBq of Y-90 solution resulting in a contrast of 10:1 between the hot cylinders and the background. Y-90 PET motion correction through motion estimates from MR navigators was evaluated by using a custom-built motion stage that simulated realistic amplitudes of respiration-induced liver motion. Finally, the feasibility of an MR-based partial volume correction method was evaluated using a wavelet decomposition approach., Results: Motion resulted in a large (∼40%) loss of contrast recovery for the 8 mm cylinder in the phantom, but was corrected for after MR-based motion correction was applied. Partial volume correction improved contrast recovery by 13% for the 8 mm cylinder., Conclusions: MR-based data correction improves Y-90 PET imaging on simultaneous PET/MR systems. Assessment of these methods must be studied further in the clinical setting.

The application of nanoparticle drug formulations, such as nanoliposomal doxorubicin (Doxil), is increasingly integrated in clinical cancer care. Despite nanomedicine's remarkable potential and growth over the last three decades, its clinical benefits for cancer patients vary. Here we report a non-invasive quantitative positron emission tomography (PET) nanoreporter technology that is predictive of therapeutic outcome in individual subjects. In a breast cancer mouse model, we demonstrate that co-injecting Doxil and a Zirconium-89 nanoreporter ((89)Zr-NRep) allows precise doxorubicin (DOX) quantification. Importantly, (89)Zr-NRep uptake also correlates with other types of nanoparticles' tumour accumulation. (89)Zr-NRep PET imaging reveals remarkable accumulation heterogeneity independent of tumour size. We subsequently demonstrate that mice with >25 mg kg(-1) DOX accumulation in tumours had significantly better growth inhibition and enhanced survival. This non-invasive imaging tool may be developed into a robust inclusion criterion for patients amenable to nanotherapy.

With the introduction of clinical PET/magnetic resonance (MR) systems, novel attenuation correction methods are needed, as there are no direct MR methods to measure the attenuation of the objects in the field of view (FOV). A unique challenge for PET/MR attenuation correction is that coils for MR data acquisition are located in the FOV of the PET camera and could induce significant quantitative errors. In this review, current methods and techniques to correct for the attenuation of a variety of coils are summarized and evaluated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

By harnessing the versatility and soft tissue imaging capabilities of MR imaging alongside the unmatched sensitivity and biomolecular flexibility of PET, the potential to provide detailed multiparametric plaque characterization in the carotid arteries is clear. The ability to acquire simultaneous, and dynamic multimodal data is perhaps PET/MR's greatest strength that will be of major interest to researchers investigating carotid and coronary atherosclerosis alike. This review summarizes the current status of dedicated hybrid PET/MR imaging; to crystallize the rationale for and advantages of this technique with respect to carotid atherosclerosis; and to discuss current limitations, challenges, and future directions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Errors in quantification of carotid positron emission tomography (PET) in simultaneous PET/magnetic resonance (PET/MR) imaging when not incorporating bone in MR-based attenuation correction (MRAC) maps, and possible solutions, remain to be fully explored. In this study, we demonstrated techniques to improve carotid vascular PET/MR quantification by adding a bone tissue compartment to MRAC maps and deriving continuous Dixon-based MRAC (MRACCD) maps. We demonstrated the feasibility of applying ultrashort echo time-based bone segmentation and generation of continuous Dixon MRAC to improve PET quantification on five subjects. We examined four different MRAC maps: system standard PET/MR MRAC map (air, lung, fat, soft tissue) (MRACPET/MR), standard PET/MR MRAC map with bone (air, lung, fat, soft tissue, bone) (MRACPET/MRUTE), MRACCD map (no bone) and continuous Dixon-based MRAC map with bone (MRACCDUTE). The same PET emission data was then reconstructed with each respective MRAC map and a CTAC map (PETPET/MR, PETPET/MRUTE, PETCD, PECDUTE) to assess effects of the different attenuation maps on PET quantification in the carotid arteries and neighboring tissues. Quantitative comparison of MRAC attenuation values for each method compared to CTAC showed small differences in the carotid arteries with UTE-based segmentation of bone included and/or continuous Dixon MRAC; however, there was very good correlation for all methods in the voxel-by-voxel comparison. ROI-based analysis showed a similar trend in the carotid arteries with the lowest correlation to PETCTAC being PETPETMR and the highest correlation to PETCTAC being PETCDUTE. We have demonstrated the feasibility of applying UTE-based segmentation and continuous Dixon MRAC maps to improve carotid PET/MR vascular quantification.

Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention., Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis., Methods and Results: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta., Conclusions: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis., (© 2015 American Heart Association, Inc.)

Unlabelled: Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)-facilitated TAM PET imaging in a breast cancer model., Methods: Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide (89)Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. (89)Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate (89)Zr-PL-HDL and (89)Zr-AI-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of (89)Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry., Results: The phospholipid- and apoA-I-labeled rHDL were produced at 79% ± 13% (n = 6) and 94% ± 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 percentage injected dose per gram for apoA-I- and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and 39.5% of the total cellular DiO@Zr-PL-HDL and DiO@Zr-AI-HDL in tumors, respectively., Conclusion: We have developed (89)Zr-labeled TAM imaging agents based on the natural nanoparticle rHDL. In an orthotopic mouse model of breast cancer, we have demonstrated their specificity for macrophages, a result that was corroborated by flow cytometry. Quantitative macrophage PET imaging with our (89)Zr-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The purpose of the study was to evaluate the effect of attenuation of MR coils on quantitative carotid PET/MR exams. Additionally, an automated attenuation correction method for flexible carotid MR coils was developed and evaluated. The attenuation of the carotid coil was measured by imaging a uniform water phantom injected with 37 MBq of 18F-FDG in a combined PET/MR scanner for 24 min with and without the coil. In the same session, an ultra-short echo time (UTE) image of the coil on top of the phantom was acquired. Using a combination of rigid and non-rigid registration, a CT-based attenuation map was registered to the UTE image of the coil for attenuation and scatter correction. After phantom validation, the effect of the carotid coil attenuation and the attenuation correction method were evaluated in five subjects. Phantom studies indicated that the overall loss of PET counts due to the coil was 6.3% with local region-of-interest (ROI) errors reaching up to 18.8%. Our registration method to correct for attenuation from the coil decreased the global error and local error (ROI) to 0.8% and 3.8%, respectively. The proposed registration method accurately captured the location and shape of the coil with a maximum spatial error of 2.6 mm. Quantitative analysis in human studies correlated with the phantom findings, but was dependent on the size of the ROI used in the analysis. MR coils result in significant error in PET quantification and thus attenuation correction is needed. The proposed strategy provides an operator-free method for attenuation and scatter correction for a flexible MRI carotid surface coil for routine clinical use.

Objectives: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques., Methods: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR ≥ 1.6) at the baseline)., Results: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = -0.24 [95% CI: -0.46, -0.01], p = 0.04)., Conclusions: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an (89)Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms., Methods: (89)Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation. Pharmacokinetic and biodistribution studies, as well as PET/CT imaging of the radiolabeled nanoparticles, were performed on a mouse model of breast cancer. In addition, a dual PET/optical probe was prepared by incorporation of a near-infrared fluorophore and tested in vivo by PET and near-infrared fluorescence imaging., Results: The surface chelation approach proved to be superior in terms of radiochemical yield and stability, as well as in vivo performance. Accumulation of these liposomes in tumor peaked at 24 h after injection and was measured to be 13.7 ± 1.8 percentage injected dose per gram. The in vivo performance of this probe was not essentially perturbed by the incorporation of a near-infrared fluorophore., Conclusion: We have developed a highly modular and efficient strategy for the labeling of liposomal nanoparticles with (89)Zr. In xenograft and orthotopic mouse models of breast cancer, we demonstrated that the biodistribution of these nanoparticles can be visualized by PET imaging. In combination with a near-infrared dye, these liposomal nanoparticles can serve as bimodal PET/optical imaging agents. The liposomes target malignant growth, and their bimodal features may be useful for simultaneous PET and intraoperative imaging., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Understanding how leukocytes impact atherogenesis contributes critically to our concept of atherosclerosis development and the identification of potential therapeutic targets., Objectives: The study evaluates an in vivo imaging approach to visualize peripheral blood mononuclear cell (PBMC) accumulation in atherosclerotic lesions of cardiovascular (CV) patients using hybrid single-photon emission computed tomography/computed tomography (SPECT/CT)., Methods: At baseline, CV patients and healthy controls underwent (18)fluorodeoxyglucose positron emission tomography-computed tomography and magnetic resonance imaging to assess arterial wall inflammation and dimensions, respectively. For in vivo trafficking, autologous PBMCs were isolated, labeled with technetium-99m, and visualized 3, 4.5, and 6 h post-infusion with SPECT/CT., Results: Ten CV patients and 5 healthy controls were included. Patients had an increased arterial wall inflammation (target-to-background ratio [TBR] right carotid 2.00 ± 0.26 in patients vs. 1.51 ± 0.12 in controls; p = 0.022) and atherosclerotic burden (normalized wall index 0.52 ± 0.09 in patients vs. 0.33 ± 0.02 in controls; p = 0.026). Elevated PBMC accumulation in the arterial wall was observed in patients; for the right carotid, the arterial-wall-to-blood ratio (ABR) 4.5 h post-infusion was 2.13 ± 0.35 in patients versus 1.49 ± 0.40 in controls (p = 0.038). In patients, the ABR correlated with the TBR of the corresponding vessel (for the right carotid: r = 0.88; p < 0.001)., Conclusions: PBMC accumulation is markedly enhanced in patients with advanced atherosclerotic lesions and correlates with disease severity. This study provides a noninvasive imaging tool to validate the development and implementation of interventions targeting leukocytes in atherosclerosis., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: The objective of this study was to evaluate the performance of the built-in MR-based attenuation correction (MRAC) included in the combined whole-body Ingenuity TF PET/MR scanner and compare it to the performance of CT-based attenuation correction (CTAC) as the gold standard., Methods: Included in the study were 26 patients who underwent clinical whole-body FDG PET/CT imaging and subsequently PET/MR imaging (mean delay 100 min). Patients were separated into two groups: the alpha group (14 patients) without MR coils during PET/MR imaging and the beta group (12 patients) with MR coils present (neurovascular, spine, cardiac and torso coils). All images were coregistered to the same space (PET/MR). The two PET images from PET/MR reconstructed using MRAC and CTAC were compared by voxel-based and region-based methods (with ten regions of interest, ROIs). Lesions were also compared by an experienced clinician., Results: Body mass index and lung density showed significant differences between the alpha and beta groups. Right and left lung densities were also significantly different within each group. The percentage differences in uptake values using MRAC in relation to those using CTAC were greater in the beta group than in the alpha group (alpha group -0.2 ± 33.6%, R(2) = 0.98, p < 0.001; beta group 10.31 ± 69.86%, R(2) = 0.97, p < 0.001)., Conclusion: In comparison to CTAC, MRAC led to underestimation of the PET values by less than 10% on average, although some ROIs and lesions did differ by more (including the spine, lung and heart). The beta group (imaged with coils present) showed increased overall PET quantification as well as increased variability compared to the alpha group (imaged without coils). PET data reconstructed with MRAC and CTAC showed some differences, mostly in relation to air pockets, metallic implants and attenuation differences in large bone areas (such as the pelvis and spine) due to the segmentation limitation of the MRAC method.

Purpose: There is evidence that the link between obesity and cardiovascular disease might relate to inflammation in both fat tissue and the arterial wall. (18)F-FDG uptake on PET is a surrogate marker of vessel wall inflammation. The aim of the study was to measure FDG uptake in both regions using PET and identify links between adipose and arterial inflammation., Methods: Included in the study were 173 cardiovascular patients who were prospectively imaged with FDG PET/CT. Arterial FDG uptake was measured in the carotid arteries and ascending aorta. The same was done in fat tissue in the neck, the presternal region (both subcutaneous) and the pericardium. FDG uptake was quantified as average maximal target-to-background ratio (mean TBR max). Multivariate regression analyses were performed to identify significant associations between arterial and adipose tissue FDG uptake and clinical variables as given by the standardized correlation coefficient (β)., Results: FDG uptake values in all fat tissue regions were highly predictive of vascular FDG uptake in both the carotids (β 0.262, p < 0.0001, in the neck subcutaneous region) and aorta (β 0.22, p = 0.008, in the chest pericardial region; β 0.193, p = 0.019, in the chest subcutaneous region). Obesity was significantly associated with elevated FDG uptake in adipose tissue (β 0.470, p < 0.0001, in the neck subcutaneous region; β 0.619, p = 0.028, in the chest subcutaneous region; β 0.978, p = 0.035, in the chest pericardial region)., Conclusion: FDG uptake in diverse fat tissue regions was significantly associated with arterial FDG uptake, a reasonable surrogate of inflammation. Increasing body weight significantly predicted the level of fatty inflammation. FDG PET therefore provides imaging evidence of an inflammatory link between fat tissue and the vasculature in patients with cardiovascular disease.

Background: Hypoxia is an important microenvironmental factor influencing atherosclerosis progression by inducing foam-cell formation, metabolic adaptation of infiltrated macrophages, and plaque neovascularization. Therefore, imaging plaque hypoxia could serve as a marker of lesions at risk., Methods and Results: Advanced aortic atherosclerosis was induced in 18 rabbits by atherogenic diet and double balloon endothelial denudation. Animals underwent (18)F-fluoromisonidazole positron emission tomographic and (18)F-fluorodeoxyglucose positron emission tomographic imaging after 6 to 8 months (atherosclerosis induction) and 12 to 16 months (progression) of diet initiation. Four rabbits fed standard chow served as controls. Radiotracer uptake of the abdominal aorta was measured using standardized uptake values. After imaging, plaque hypoxia (pimonidazole), macrophages (RAM-11), neovessels (CD31), and hypoxia-inducible factor-1α were assessed by immunohistochemistry.(18)F-fluoromisonidazole uptake increased with time on diet (standardized uptake value mean, 0.10±0.01 in nonatherosclerotic animals versus 0.20±0.03 [P=0.002] at induction and 0.25±0.03 [P<0.001] at progression). Ex vivo positron emission tomographic imaging corroborated the (18)F-fluoromisonidazole uptake by the aorta of atherosclerotic rabbits. (18)F-fluorodeoxyglucose uptake also augmented in atherosclerotic animals, with an standardized uptake value mean of 0.43±0.02 at induction versus 0.35±0.02 in nonatherosclerotic animals (P=0.031) and no further increase at progression. By immunohistochemistry, hypoxia was mainly located in the macrophage-rich areas within the atheromatous core, whereas the macrophages close to the lumen were hypoxia-negative. Intraplaque neovessels were found predominantly in macrophage-rich hypoxic regions (pimonidazole(+)/hypoxia-inducible factor-1α(+)/RAM-11(+))., Conclusions: Plaque hypoxia increases with disease progression and is present in macrophage-rich areas associated with neovascularization. (18)F-fluoromisonidazole positron emission tomographic imaging emerges as a new tool for the detection of atherosclerotic lesions.

Baseline predictors of response to treatment of patients with coronary heart disease (CHD) with respect to vascular inflammation and atherosclerotic plaque burden are poorly understood. From post hoc analysis of the dal-PLAQUE study (NCT00655473), 18F-fluorodeoxyglucose-positron emission tomography (18-FDG-PET) imaging and carotid black blood magnetic resonance imaging (MRI) were used to track changes in these vascular parameters. Baseline demographics, imaging, and biomarkers were collected/measured in 130 patients with CHD or CHD risk-equivalents, and imaging follow-up at 6 months (PET) and 24 months (MRI) was performed. Using stepwise linear regression, predictors of change in carotid plaque inflammation by PET [target-to-background ratio (TBR), n = 92] and plaque burden by MRI [wall area (WA) and total vessel area (TVA), n = 89] were determined. Variables with p < 0.05 in multivariable models were considered independently significant. Interleukin-6, systolic blood pressure and standard deviation of wall thickness (WT) at baseline were independently positively associated with 18-FDG uptake (mean of maximum [MeanMax] TBR change over 6 months). Mean of mean TBR, phospholipase A2, apolipoprotein A-I, and high-sensitivity C-reactive protein at baseline were independently negatively associated with MeanMax TBR change over 6 months. Mean WT and plasminogen activator inhibitor-1 (PAI-1) activity at baseline, and age, were independently associated with change in WA over 24 months. For TVA changes; mean WA and PAI-1 activity at baseline, age, and female gender were independent predictors. These findings may help determine patients most suitable for clinical trials employing plaque inflammation or burden changes as endpoints.

Introduction: Attenuation correction for magnetic resonance (MR) coils is a new challenge that came about with the development of combined MR and positron emission tomography (PET) imaging. This task is difficult because such coils are not directly visible on either PET or MR acquisitions with current combined scanners and are therefore not easily localized in the field of view. This issue becomes more evident when trying to localize flexible MR coils (eg, cardiac or body matrix coil) that change position and shape from patient to patient and from one imaging session to another. In this study, we proposed a novel method to localize and correct for the attenuation and scatter of a flexible MR cardiac coil, using MR fiducial markers placed on the surface of the coil to allow for accurate registration of a template computed tomography (CT)-based attenuation map., Materials and Methods: To quantify the attenuation properties of the cardiac coil, a uniform cylindrical water phantom injected with 18F-fluorodeoxyglucose (18F-FDG) was imaged on a sequential MR/PET system with and without the flexible cardiac coil. After establishing the need to correct for the attenuation of the coil, we tested the feasibility of several methods to register a precomputed attenuation map to correct for the attenuation. To accomplish this, MR and CT visible markers were placed on the surface of the cardiac flexible coil. Using only the markers as a driver for registration, the CT image was registered to the reference image through a combination of rigid and deformable registration. The accuracy of several methods was compared for the deformable registration, including B-spline, thin-plate spline, elastic body spline, and volume spline. Finally, we validated our novel approach both in phantom and patient studies., Results: The findings from the phantom experiments indicated that the presence of the coil resulted in a 10% reduction in measured 18F-FDG activity when compared with the phantom-only scan. Local underestimation reached 22% in regions of interest close to the coil. Various registration methods were tested, and the volume spline was deemed to be the most accurate, as measured by the Dice similarity metric. The results of our phantom experiments showed that the bias in the 18F-FDG quantification introduced by the presence of the coil could be reduced by using our registration method. An overestimation of only 1.9% of the overall activity for the phantom scan with the coil attenuation map was measured when compared with the baseline phantom scan without coil. A local overestimation of less than 3% was observed in the ROI analysis when using the proposed method to correct for the attenuation of the flexible cardiac coil. Quantitative results from the patient study agreed well with the phantom findings., Conclusions: We presented and validated an accurate method to localize and register a CT-based attenuation map to correct for the attenuation and scatter of flexible MR coils. This method may be translated to clinical use to produce quantitatively accurate measurements with the use of flexible MR coils during MR/PET imaging.

Purpose: (18)F-FDG PET is increasingly used for imaging of vessel wall inflammation. However, limited data are available on the impact of methodological variables, i.e. prescan fasting glucose, FDG circulation time and injected FDG dose, and of different FDG uptake parameters, in vascular FDG PET imaging., Methods: Included in the study were 195 patients who underwent vascular FDG PET/CT of the aorta and the carotids. Arterial standardized uptake values (meanSUVmax), target-to-background ratios (meanTBRmax) and FDG blood-pool activity in the superior vena cava (SVC) and the jugular veins (JV) were quantified. Vascular FDG uptake values classified according to the tertiles of prescan fasting glucose levels, the FDG circulation time, and the injected FDG dose were compared using ANOVA. Multivariate regression analyses were performed to identify the potential impact of all variables described on the arterial and blood-pool FDG uptake., Results: Tertile analyses revealed FDG circulation times of about 2.5 h and prescan glucose levels of less than 7.0 mmol/l, showing a favorable relationship between arterial and blood-pool FDG uptake. FDG circulation times showed negative associations with aortic meanSUVmax values as well as SVC and JV FDG blood-pool activity, but positive correlations with aortic and carotid meanTBRmax values. Prescan glucose levels were negatively associated with aortic and carotid meanTBRmax and carotid meanSUVmax values, but were positively correlated with SVC blood-pool uptake. The injected FDG dose failed to show any significant association with vascular FDG uptake., Conclusion: FDG circulation times and prescan blood glucose levels significantly affect FDG uptake in the aortic and carotid walls and may bias the results of image interpretation in patients undergoing vascular FDG PET/CT. The injected FDG dose was less critical. Therefore, circulation times of about 2.5 h and prescan glucose levels less than 7.0 mmol/l should be preferred in this setting.

Unlabelled: Quantitative PET imaging relies on accurate attenuation correction. Recently, there has been growing interest in combining state-of-the-art PET systems with MR imaging in a sequential or fully integrated setup. As CT becomes unavailable for these systems, an alternative approach to the CT-based reconstruction of attenuation coefficients (μ values) at 511 keV must be found. Deriving μ values directly from MR images is difficult because MR signals are related to the proton density and relaxation properties of tissue. Therefore, most research groups focus on segmentation or atlas registration techniques. Although studies have shown that these methods provide viable solutions in particular applications, some major drawbacks limit their use in whole-body PET/MR. Previously, we used an annulus-shaped PET transmission source inside the field of view of a PET scanner to measure attenuation coefficients at 511 keV. In this work, we describe the use of this method in studies of patients with the sequential time-of-flight (TOF) PET/MR scanner installed at the Icahn School of Medicine at Mount Sinai, New York, NY., Methods: Five human PET/MR and CT datasets were acquired. The transmission-based attenuation correction method was compared with conventional CT-based attenuation correction and the 3-segment, MR-based attenuation correction available on the TOF PET/MR imaging scanner., Results: The transmission-based method overcame most problems related to the MR-based technique, such as truncation artifacts of the arms, segmentation artifacts in the lungs, and imaging of cortical bone. Additionally, the TOF capabilities of the PET detectors allowed the simultaneous acquisition of transmission and emission data. Compared with the MR-based approach, the transmission-based method provided average improvements in PET quantification of 6.4%, 2.4%, and 18.7% in volumes of interest inside the lung, soft tissue, and bone tissue, respectively., Conclusion: In conclusion, a transmission-based technique with an annulus-shaped transmission source will be more accurate than a conventional MR-based technique for measuring attenuation coefficients at 511 keV in future whole-body PET/MR studies.

Purpose: Inflammation and neovascularization in vulnerable atherosclerotic plaques are key features for severe clinical events. Dynamic contrast-enhanced (DCE) MRI and FDG PET are two noninvasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate, respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. We studied the relationship between DCE-MRI and (18)F-FDG PET data from the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD risk equivalent, as a substudy of the dal-PLAQUE trial (NCT00655473)., Methods: The dal-PLAQUE trial was a multicenter study that evaluated dalcetrapib, a cholesteryl ester transfer protein modulator. Subjects underwent anatomical MRI, DCE-MRI and (18)F-FDG PET. Only baseline imaging and biomarker data (before randomization) from dal-PLAQUE were used as part of this substudy. Our primary goal was to evaluate the relationship between DCE-MRI and (18)F-FDG PET data. As secondary endpoints, we evaluated the relationship between (a) PET data and whole-vessel anatomical MRI data, and (b) DCE-MRI and matching anatomical MRI data. All correlations were estimated using a mixed linear model., Results: We found a significant inverse relationship between several perfusion indices by DCE-MRI and (18)F-FDG uptake by PET. Regarding our secondary endpoints, there was a significant relationship between plaque burden measured by anatomical MRI with several perfusion indices by DCE-MRI and (18)F-FDG uptake by PET. No relationship was found between plaque composition by anatomical MRI and DCE-MRI or (18)F-FDG PET metrics., Conclusion: In this study we observed a significant, weak inverse relationship between inflammation measured as (18)F-FDG uptake by PET and plaque perfusion by DCE-MRI. Our findings suggest that there may be a complex relationship between plaque inflammation and microvascularization during the different stages of plaque development. (18)F-FDG PET and DCE-MRI may have complementary roles in future clinical practice in identifying subjects at high risk of cardiovascular events.

Objectives: This study sought to longitudinally investigate the relationship between a broad spectrum of serum inflammatory biomarkers and plaque inflammation assessed by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)., Background: Both plaque inflammation and serum biomarkers of inflammation are associated with atherothrombotic events; however, the relationship between them is unclear., Methods: We conducted a post hoc analysis of the dal-PLAQUE (A Randomized Placebo-Controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors), a randomized, placebo-controlled study of dalcetrapib, a cholesteryl ester transfer protein inhibitor, in 130 patients with coronary heart disease, or coronary heart disease risk equivalents on stable lipid-lowering therapy. Baseline and change after 3-month follow-up in inflammatory biomarker levels and baseline and change after 3-month follow-up in aorta and carotid (18)F-FDG PET/CT (mean maximum target-to-background ratio of the most diseased segment [TBRmds]) were analyzed., Results: Baseline myeloperoxidase positively correlated with baseline carotid TBRmds (rho = 0.25, p = 0.02). This correlation remained at the 3-month follow-up and was independent of traditional cardiovascular disease risk factors. Baseline lipoprotein-associated phospholipase A2 mass correlated with aorta TBRmds (rho = 0.21, p = 0.03). However, this correlation disappeared at the 3-month follow-up and was not independent of cardiovascular disease risk factors. There was no association between change from baseline in myeloperoxidase or lipoprotein-associated phospholipase A2 mass and change from baseline in aorta and carotid TBRmds. Baseline and change from baseline in high sensitivity C-reactive protein, interleukin 6, soluble P-selectin, soluble E-selectin, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and matrix-metalloproteinase 3 and 9 did not correlate with baseline or change from baseline in carotid or aorta TBRmds., Conclusions: Our data show that, in patients with coronary heart disease or at high risk of coronary heart disease on stable lipid-lowering therapy, circulating myeloperoxidase levels are associated with carotid plaque inflammation. (A Randomized, Placebo-controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors [dal-PLAQUE]; NCT00655473)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to compare the ability of (18)F-FDG PET and iron contrast-enhanced MRI with a novel USPIO (P904) to assess change in plaque inflammation induced by atorvastatin and dietary change in a rabbit model of atherosclerosis using a combined PET/MR scanner., Materials and Methods: Atherosclerotic rabbits underwent USPIO-enhanced MRI and (18)F-FDG PET in PET/MR hybrid system at baseline and were then randomly divided into a progression group (high cholesterol diet) and a regression group (chow diet and atorvastatin). Each group was scanned again 6 months after baseline imaging. R2* (i.e. 1/T2*) values were calculated pre/post P904 injection. (18)F-FDG PET data were analyzed by averaging the mean Standard Uptake Value (SUVmean) over the abdominal aorta. The in vivo imaging was then correlated with matched histological sections stained for macrophages., Results: (18)F-FDG PET showed strong FDG uptake in the abdominal aorta and P904 injection revealed an increase in R2* values in the aortic wall at baseline. At 6 months, SUVmean values measured in the regression group showed a significant decrease from baseline (p = 0.015). In comparison, progression group values remained constant (p = 0.681). R2* values showed a similar decreasing trend in the regression group suggesting less USPIO uptake in the aortic wall. Correlations between SUVmean or Change in R2* value and macrophages density (RAM-11 staining) were good (R(2) = 0.778 and 0.707 respectively)., Conclusion: This experimental study confirms the possibility to combine two functional imaging modalities to assess changes in the inflammation of atherosclerotic plaques. (18)F-FDG-PET seems to be more sensitive than USPIO P904 to detect early changes in plaque inflammation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The application of attenuation correction for combined magnetic resonance/positron emission tomography (MR/PET) systems is still a major challenge for accurate quantitative PET. Computed tomographic attenuation correction (CTAC) is the current clinical standard for PET/computed tomographic (CT) scans. Magnetic resonance, unlike CT, has no direct information about photon attenuation but, rather, proton densities. On combined MR/PET scanners, MR-based attenuation correction (MRAC) consists of assigning empirical attenuation coefficients to MR signal intensities. The objective of the current study was to evaluate the MRAC implemented on the combined MR/PET scanner versus the CTAC with the same PET data in an animal model., Materials and Methods: Acquisition was performed using a clinically approved sequential MR/PET scanner (Philips Ingenuity TF). Computed tomographic and MR/PET images of 20 New Zealand White rabbits were retrospectively analyzed. The animals were positioned on a customized animal bed to avoid movement between the CT and MR/PET scanners. Positron emission tomographic images from both methods (MRAC and CTAC) were generated. Voxel-by-voxel and region-of-interest (ROI) analyses were performed to determine differences in standardized uptake values (SUV). Regions of interest were drawn on the coregistered CT images for the aorta, liver, kidney, spine, and soft tissue (muscle) and superimposed on the PET images., Results: The voxel-by-voxel comparison of PET showed excellent correlation between MRAC and CTAC SUV values (R = 0.99; P < 0.0001). The mean of the difference of SUVs between all respective MRAC and CTAC voxels was -0.94% (absolute difference [AD] ± SD, -0.06 ± 0.30), confirming slight underestimation of MRAC. The ROI-based comparison similarly showed that MRAC SUV values were underestimated compared with CTAC SUV values. The mean difference between MRAC and CTAC for all ROIs was 10.8% (AD, -0.08 ± 0.06; R = 0.99; P < 0.0001) and -9.7% (AD, -0.15 ± 0.12; R = 0.99; P < 0.0001) for the SUV mean (SUV mean) and the SUV maximum (SUV max), respectively. The highest differences were found in the spine (SUV mean -26.1% [-0.11]) and areas close to large bones such as the back muscles (SUV mean, -16.8% [-0.04])., Conclusions: In this study, we have compared MRAC and CTAC methods for PET attenuation correction in an animal model. We have confirmed that the MRAC method implemented on a sequential MR/PET scanner underestimates PET values by less than 10% in most regions, except the areas containing or close to large bone structures such as the spine or the back muscles. Bone segmentation is therefore suggested to be included in the MR attenuation map to minimize the quantification error of MRAC methods compared with the clinical standard CTAC. Further clinical studies need to be carried out to validate the clinical use of MRAC.

The rate of acute complications of atherosclerosis (acute myocardial infarction, ischemic stroke) has continuously decreased over the last 20 years in Western countries. This is largely explained by improvements in the reduction and treatment of cardiovascular risk factors and by the increasing number of patients who benefit from preventive treatments such as antiplatelet, lipid-lowering, or antihypertensive drugs. This means also that, when testing new drugs aimed at either halting or even reversing the progression of atherosclerotic plaques, a large number of patients will need to be included in clinical trials to demonstrate an improvement in patient outcome with the drugs. Pharmaceutical companies are therefore looking for early surrogate markers that could be evaluated in a small number of patients to predict the beneficial effects of new drugs on atherosclerotic plaques before moving to costly clinical trials with a large number of patients. In this review, we will discuss the place of atherosclerotic plaque imaging with magnetic resonance imaging and positron emission tomography for the evaluation of new antiatherosclerotic drugs., (© 2012 Mount Sinai School of Medicine.)

With the recent development of integrated positron emission tomography-magnetic resonance imaging (PET-MRI) scanners, new possibilities for quantitative molecular imaging of cancer are realized. However, the practical advantages and potential clinical benefits of the ability to record PET and MRI data simultaneously must be balanced against the substantial costs and other requirements of such devices. In this review, we highlight several of the key areas where integrated PET-MRI measurements, obtained simultaneously, are anticipated to have a significant impact on clinical and/or research studies. These areas include the use of MR-based motion corrections and/or a priori anatomical information for improved reconstruction of PET data, improved arterial input function characterization for PET kinetic modeling, the use of dual-modality contrast agents, and patient comfort and practical convenience. For widespread acceptance, a compelling case could be made if the combination of quantitative MRI and specific PET biomarkers significantly improves our ability to assess tumor status and response to therapy, and some likely candidates are now emerging. We consider the relative advantages and disadvantages afforded by PET-MRI and summarize current opinions and evidence as to the likely value of PET-MRI in the management of cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

18F-FDG PET is a new noninvasive tool for inflammation functional imaging. Low spatial resolution is now compensated by coregistration with CT or MRI. New mechanistic insights have emerged from animal and histology to explain the obtained signals by hypoxia, macrophage infiltration, and differentiation. Mixed results have been found in biomarkers studies. Interesting data have come recently linking plaque anatomy and function in carotids and in aortic aneurysms as well as inflammation and events. In coronary arteries, plaque assessment is still hampered by myocardium uptake but developments are being made. 18-FDG PET has been able to monitor inflammation before and after several therapies in animals and humans but to date the lack of standardization and the absence of prospective event-driven studies prevent this promising technique to be used in clinical practice.

Unlabelled: Accurate γ-photon attenuation correction (AC) is essential for quantitative PET/MRI as there is no simple relation between MR image intensity and attenuation coefficients. Attenuation maps (μ-maps) can be derived by segmenting MR images and assigning attenuation coefficients to the compartments. Ultrashort-echo-time (UTE) sequences have been used to separate cortical bone and air, and the Dixon technique has enabled differentiation between soft and adipose tissues. Unfortunately, sequential application of these sequences is time-consuming and complicates image registration., Methods: A UTE triple-echo (UTILE) MRI sequence is proposed, combining UTE sampling for bone detection and gradient echoes for Dixon water-fat separation in a radial 3-dimensional acquisition (repetition time, 4.1 ms; echo times, 0.09/1.09/2.09 ms; field strength, 3 T). Air masks are derived mainly from the phase information of the first echo; cortical bone is segmented using a dual-echo technique. Soft-tissue and adipose-tissue decomposition is achieved using a 3-point Dixon-like decomposition. Predefined linear attenuation coefficients are assigned to classified voxels to generate MRI-based μ-maps. The results of 6 patients are obtained by comparing μ-maps, reciprocal sensitivity maps, reconstructed PET images, and brain region PET activities based on either CT AC, two 3-class MRI AC techniques, or the proposed 4-class UTILE AC., Results: Using the UTILE MRI sequence, an acquisition time of 214 s was achieved for the head-and-neck region with 1.75-mm isotropic resolution, compared with 164 s for a single-echo UTE scan. MRI-based reciprocal sensitivity maps show a high correlation with those derived from CT scans (R(2) = 0.9920). The same is true for PET activities (R(2) = 0.9958). An overall voxel classification accuracy (compared with CT) of 81.1% was reached. Bone segmentation is inaccurate in complex regions such as the paranasal sinuses, but brain region activities in 48 regions across 6 patients show a high correlation after MRI-based and CT-based correction (R(2) = 0.9956), with a regression line slope of 0.960. All overall correlations are higher and brain region PET activities more accurate in terms of mean and maximum deviations for the 4-class technique than for 3-class techniques., Conclusion: The UTILE MRI sequence enables the generation of MRI-based 4-class μ-maps without anatomic priors, yielding results more similar to CT-based results than can be obtained with 3-class segmentation only.

Objectives: The aim of this feasibility study was to evaluate [(18)F]-2-Fluoro-A85380 for in vivo imaging of arterial nicotinic acetylcholine receptors (nAChRs) in humans. Furthermore, potentially different vascular uptake patterns of this new tracer were evaluated in healthy volunteers and in patients with neurodegenerative disorders., Background: [(18)F]-2-Fluoro-A85380 was developed for in vivo positron emission tomography (PET) imaging of nAChR subunits in the human brain. These nAChRs are also found in arteries and seem to mediate the deleterious effects of nicotine as a part of tobacco smoke in the vasculature. It has been previously shown that uptake patterns of the radiotracer in the brain differs in patients with neurodegenerative disorders compared with healthy controls., Methods: [(18)F]-2-Fluoro-A85380 uptake was quantified in the ascending and descending aorta, the aortic arch, and the carotids in 5 healthy volunteers and in 6 patients with either Parkinson's disease or multiple system atrophy, respectively, as the maximum target-to-background ratio. The maximal standardized uptake value values, the single hottest segment, and the percent active segments of the [(18)F]-2-Fluoro-A85380 uptake in the arteries were also assessed., Results: [(18)F]-2-Fluoro-A85380 uptake was clearly visualized and maximum target-to-background ratio uptake values corrected for the background activity of the tracer showed specific tracer uptake in the arterial walls. Significantly higher uptake values were found in the descending aorta. Comparison between volunteers and patients revealed significant differences, with lower [(18)F]-2-Fluoro-A85380 uptake in the patient group when comparing single arterial territories but not when all arterial territories were pooled together., Conclusions: [(18)F]-2-Fluoro-A85380 can provide specific information on the nAChR distribution in human arteries. Vascular nAChR density seems to be lower in patients with Parkinson's disease or multiple system atrophy. Once confirmed in larger study populations and in the experimental setting, this approach might provide insights into the pathogenic role of nAChRs in the human vasculature., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)