Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

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.

Semi-Automatic Graphical Tool for Measuring Coronary Artery Spatially Weighted Calcium Score from Gated Cardiac Computed Tomography Images.

The current standard for measuring coronary artery calcification to determine the extent of atherosclerosis is by calculating the Agatston score from computed tomography (CT). However, the Agatston score disregards pixel values less than 130 Hounsfield Units (HU) and calcium regions less than 1 mm2. Due to this thresholding, the score is not sensitive to small, weakly attenuating regions of calcium deposition and may not detect nascent micro-calcification. A recently proposed metric called the spatially weighted calcium score (SWCS) also utilizes CT but does not include a threshold for HU and does not require elevated signals in contiguous pixels. Thus, the SWCS is sensitive to weakly attenuating, smaller calcium deposits and may improve the measurement of coronary heart disease risk. Currently, the SWCS is underutilized owing to the added computational complexity. To promote translation of the SWCS into clinical research and reliable, repeatable computation of the score, the aim of this study was to develop a semi-automatic graphical tool that calculates both the SWCS and the Agatston score. The program requires gated cardiac CT scans with a calcium hydroxyapatite phantom in the field of view. The phantom allows for deriving a weighting function, from which each pixel's weight is adjusted, allowing for the mitigation of signal variations and variability between scans. With all three anatomical views visible simultaneously, the user traces the course of the four main coronary arteries by placing points or regions of interest. Features such as scroll-to-zoom, double-click to delete, and brightness/contrast adjustment, along with written guidance at every step, make the program user-friendly and easy to use. Once tracing the arteries is complete, the program generates reports, which include the scores and snapshots of any visible calcium. The SWCS may reveal the presence of subclinical disease, which may be used for early intervention and lifestyle changes.

Pharyngeal Inflammation on Positron Emission Tomography/Magnetic Resonance Imaging Before and After Obstructive Sleep Apnea Treatment.

Rationale: There is upper airway inflammation in patients with obstructive sleep apnea (OSA), which reduces with continuous positive airway pressure (CPAP) therapy. Objectives: Validate the use of positron emission tomography (PET)/magnetic resonance imaging (MRI) to quantify metabolic activity within the pharyngeal mucosa of patients with OSA against nasal lavage proteomics and assess the impact of CPAP therapy. Methods: Adults with OSA underwent [18F]-Fluoro-2-deoxy-D-glucose PET/MRI of the neck before and 3 months after initiating CPAP. Nasal lavage samples were collected. Inflammatory protein expression from samples was analyzed using the Olink platform. Upper airway imaging segmentation was performed. Target-to-background ratio (TBRmax) was calculated from target pharyngeal maximum standard uptake values (SUV) and personalized background mean SUV. Most-diseased segment TBRmax was identified per participant at locations with the highest PET avidity. Correlation analysis was performed between baseline TBRmax and nasal lavage proteomics. TBRmax was compared before and after CPAP using linear mixed-effect models. Results: Among 38 participants, the baseline mean age was 46.3 years (standard deviation [SD], 12.5), 21% were female, the mean body mass index was 30.9 kg/m2 (SD, 4.6), and the mean respiratory disturbance index measured by peripheral arterial tonometry was 31 events/h (SD, 16.4). There was a significant positive correlation between pharyngeal mucosa most-diseased segment TBRmax and nasal lavage proteomic inflammation (r = 0.41 [P < 0.001, false discovery rate = 0.002]). Primary analysis revealed a reduction in the most-diseased segment TBRmax after a median of 2.91 months of CPAP therapy (-0.86 [standard error (SE) ± 0.30; P = 0.007]). Stratified analysis by smoking status revealed a significantly decreased most-diseased segment TBRmax after CPAP therapy among never-smokers but not among ever-smokers (-1.01 [SE ± 0.39; P = 0.015] vs. -0.64 [SE ± 0.49; P = 0.201]). Conclusions: CPAP therapy reduces metabolic activity measured by PET/MRI within the upper airway of adults with OSA. Furthermore, PET/MRI measures of upper airway metabolic activity correlate with a noninvasive marker of inflammation (i.e., nasal lavage inflammatory protein expression).

Scan-rescan measurement repeatability of 18F-FDG PET/MR imaging of vascular inflammation.

Non-invasive positron emission tomography (PET) of vascular inflammation and atherosclerotic plaque by identifying increased uptake of 18F-fluordeoxyglucose (18F-FDG) is a powerful tool for monitoring disease activity, progression, and its response to therapy. 18F-FDG PET/computed tomography (PET/CT) of the aorta and carotid arteries has become widely used to assess changes in inflammation in clinical trials. However, the recent advent of hybrid PET/magnetic resonance (PET/MR) scanners has advantages for vascular imaging due to the reduction in radiation exposure and improved soft tissue contrast of MR compared to CT. Important for research and clinical use is an understanding of the scan-rescan repeatability of the PET measurement. While this has been studied for PET/CT, no data is currently available for vascular PET/MR imaging. In this study, we determined the scan-rescan measurement repeatability of 18F-FDG PET/MR in the aorta and carotid arteries was less than 5%, comparable to similar findings for 18F-FDG PET/CT.

Novel non-invasive assessment of upper airway inflammation in obstructive sleep apnea using positron emission tomography/magnetic resonance imaging.

PURPOSE: To develop a novel non-invasive technique to quantify upper airway inflammation using positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with obstructive sleep apnea (OSA). METHODS: Patients with treatment naïve moderate-to-severe OSA underwent [18F]-fluoro-2-deoxy-D-glucose (FDG) PET/MRI. Three readers independently performed tracings of the pharyngeal soft tissue on MRI. Standardized uptake values (SUV) were generated from region of interest (ROI) tracings on corresponding PET images. Background SUV was measured from the sternocleidomastoid muscle. SUV and target-to-background (TBR) were compared across readers using intraclass correlation coefficient (ICC) analyses. SUV from individual image slices were compared between each reader using Bland-Altman plots and Pearson correlation coefficients. All tracings were repeated by one reader for assessment of intra-reader reliability. RESULTS: Five participants completed our imaging protocol and analysis. Median age, body mass index, and apnea-hypopnea index were 41 years (IQR 40.5-68.5), 32.7 kg/m2 (IQR 28.1-38.1), and 30.7 event per hour (IQR 19.5-48.1), respectively. The highest metabolic activity regions were consistently localized to palatine or lingual tonsil adjacent mucosa. Twenty-five ICC met criteria for excellent agreement. The remaining three were TBR measurements which met criteria for good agreement. Head-to-head comparisons revealed strong correlation between each reader. CONCLUSIONS: Our novel imaging technique demonstrated reliable quantification of upper airway FDG avidity. This technology has implications for future work exploring local airway inflammation in individuals with OSA and exposure to pollutants. It may also serve as an assessment tool for response to OSA therapies.

Review of radiographic findings in COVID-19.

The purpose of this study is to review the published literature for the range of radiographic findings present in patients suffering from coronavirus disease 2019 infection. This novel corona virus is currently the cause of a worldwide pandemic. Pulmonary symptoms and signs dominate the clinical picture and radiologists are called upon to evaluate chest radiographs (CXR) and computed tomography (CT) images to assess for infiltrates and to define their extent, distribution and progression. Multiple studies attempt to characterize the disease course by looking at the timing of imaging relative to the onset of symptoms. In general, plain CXR show bilateral disease with a tendency toward the lung periphery and have an appearance most consistent with viral pneumonia. Chest CT images are most notable for showing bilateral and peripheral ground glass and consolidated opacities and are marked by an absence of concomitant pulmonary nodules, cavitation, adenopathy and pleural effusions. Published literature mentioning organ systems aside from pulmonary manifestations are relatively less common, yet present and are addressed in this review. Similarly, publications focusing on imaging modalities aside from CXR and chest CT are sparse in this evolving crisis and are likewise addressed in this review. The role of imaging is examined as it is currently being debated in the medical community, which is not at all surprising considering the highly infectious nature of Severe Acute Respiratory Syndrome coronavirus 2.

A Preliminary 18F-FDG-PET/MRI Study Shows Increased Vascular Inflammation in Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Recent data suggest that patients with atopic dermatitis (AD) have increased systemic immune activation and cardiovascular risk. However, unlike psoriasis, evaluation of active vascular inflammation using state-of-the-art imaging is lacking in AD. OBJECTIVE: To assess aortic and carotid vascular inflammation using 18F-fluorodeoxyglucose-positron emission tomography/magnetic resonance imaging (18F-FDG-PET/MRI) imaging in moderate-to-severe AD versus healthy individuals. METHODS: A total of 27 patients with moderate-to-severe AD and 12 healthy controls were imaged using 18F-FDG-PET/MRI. Target-to-background ratio (TBR) values were calculated in multiple segments of the aorta and carotid vessels. RESULTS: Patients with AD had elevated aortic max TBR (fold change [FCH] = 1.45, P = .057) versus healthy controls and significantly elevated mean TBR (FCH = 1.20; P < .05) in the right carotid (RC) arteries versus controls. When examining greatest focal inflammation (most diseased segment [MDS] TBR), patients with AD had higher aortic inflammation (FCH = 1.28; P = .052). AD clinical severity significantly correlated with C-reactive protein (ρ = 0.60, P < .01) and with RC mean TBR levels (ρ = 0.60, P = .04). Stratifying patients into moderate-to-severe and very severe AD showed greater RC mean TBR in patients with very severe AD versus controls (FCH = 1.31; P = .02) and versus patients with moderate/severe AD (FCH = 1.23, P = .05). Aortic inflammation was also significantly greater in patients with very severe AD versus controls (max TBR: FCH = 1.6, P = .04; MDS TBR: FCH = 1.73, P = .03). CONCLUSIONS: This preliminary study is the first that establishes greater vascular (aorta and carotid) inflammation in moderate-to-severe AD versus healthy controls. Furthermore, very severe AD showed higher inflammation than both moderate/severe patients and healthy controls. Future studies with larger patient cohorts and evaluation before and after treatment are needed to determine the extent to which vascular inflammation in AD is modifiable.

Immune Checkpoint Inhibitor Therapy Aggravates T Cell-Driven Plaque Inflammation in Atherosclerosis.

BACKGROUND: Immunotherapy has revolutionized cancer treatment. However, immune checkpoint inhibitors (ICIs) that target PD-1 (programmed cell death protein-1) and/or CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) are commonly associated with acute immune-related adverse events. Accumulating evidence also suggests that ICIs aggravate existing inflammatory diseases. OBJECTIVES: As inflammation drives atherosclerotic cardiovascular disease, we studied the propensity of short-term ICI therapy to aggravate atherosclerosis. METHODS: We used 18F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) positron emission tomography-computed tomography to detect macrophage-driven vascular and systemic inflammation in pembrolizumab and nivolumab/ipilimumab-treated melanoma patients. In parallel, atherosclerotic Ldlr -/- mice were treated with CTLA-4 and PD-1 inhibition to study the proinflammatory consequences of immune checkpoint inhibition. RESULTS: ICI treatment did not affect 18F-FDG uptake in the large arteries, spleen, and bone marrow of melanoma patients, nor myeloid cell activation in blood and lymphoid organs in hyperlipidemic mice. In contrast, we found marked changes in the adaptive immune response (i.e., increased CD4+ effector T cell and CD8+ cytotoxic T cell numbers in lymphoid organs and the arterial wall of our hyperlipidemic mice). Although plaque size was unaffected, plaques had progressed toward a lymphoid-based inflammatory phenotype, characterized by a 2.7-fold increase of CD8+ T cells and a 3.9-fold increase in necrotic core size. Increased endothelial activation was observed with a 2.2-fold and 1.6-fold increase in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, respectively. CONCLUSIONS: This study demonstrates that combination therapy with anti-CTLA-4 and anti-PD-1 antibodies does not affect myeloid-driven vascular and systemic inflammation in melanoma patients and hyperlipidemic mice. However, short-term ICI therapy in mice induces T cell-mediated plaque inflammation and drives plaque progression.

Imaging plaque inflammation in asymptomatic cocaine addicted individuals with simultaneous positron emission tomography/magnetic resonance imaging.

BACKGROUND: Chronic cocaine use is associated with stroke, coronary artery disease and myocardial infarction, resulting in severe impairments or sudden mortality. In the absence of clear cardiovascular symptoms, individuals with cocaine use disorder (iCUD) seeking addiction treatment receive mostly psychotherapy and psychiatric pharmacotherapy, with no attention to vascular disease (i.e., atherosclerosis). Little is known about the pre-clinical signs of cardiovascular risk in iCUD and early signs of vascular disease are undetected in this underserved population. AIM: To assess inflammation, plaque burden and plaque composition in iCUD aiming to detect markers of atherosclerosis and vascular disease. METHODS: The bilateral carotid arteries were imaged with positron emission tomography/magnetic resonance imaging (PET/MRI) in iCUD asymptomatic for cardiovascular disease, healthy controls, and individuals with cardiovascular risk. PET with 18F-fluorodeoxyglucose (18F-FDG) evaluated vascular inflammation and 3-D dark-blood MRI assessed plaque burden including wall area and thickness. Drug use and severity of addiction were assessed with standardized instruments. RESULTS: The majority of iCUD and controls had carotid FDG-PET signal greater than 1.6 but lower than 3, indicating the presence of mild to moderate inflammation. However, the MRI measure of wall structure was thicker in iCUD as compared to the controls and cardiovascular risk group, indicating greater carotid plaque burden. iCUD had larger wall area as compared to the healthy controls but not as compared to the cardiovascular risk group, indicating structural wall similarities between the non-control study groups. In iCUD, wall area correlated with greater cocaine withdrawal and craving. CONCLUSION: These preliminary results show markers of carotid artery disease burden in cardiovascular disease-asymptomatic iCUD. Broader trials are warranted to develop protocols for early detection of cardiovascular risk and preventive intervention in iCUD.

Reproducibility of thrombus volume quantification in multicenter computed tomography pulmonary angiography studies.

AIM: To evaluate reproducibility of pulmonary embolism (PE) clot volume quantification using computed tomography pulmonary angiogram (CTPA) in a multicenter setting. METHODS: This study was performed using anonymized data in conformance with HIPAA and IRB Regulations (March 2015-November 2016). Anonymized CTPA data was acquired from 23 scanners from 18 imaging centers using each site's standard PE protocol. Two independent analysts measured PE volumes using a semi-automated region-growing algorithm on an FDA-approved image analysis platform. Total thrombus volume (TTV) was calculated per patient as the primary endpoint. Secondary endpoints were individual thrombus volume (ITV), Qanadli score and modified Qanadli score per patient. Inter- and intra-observer reproducibility were assessed using intra-class correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Analyst 1 found 72 emboli in the 23 patients with a mean number of emboli of 3.13 per patient with a range of 0-11 emboli per patient. The clot volumes ranged from 0.0041 - 47.34 cm3 (mean +/- SD, 5.93 +/- 10.15cm3). On the second read, analyst 1 found the same number and distribution of emboli with a range of volumes for read 2 from 0.0041 - 45.52 cm3 (mean +/- SD, 5.42 +/- 9.53cm3). Analyst 2 found 73 emboli in the 23 patients with a mean number of emboli of 3.17 per patient with a range of 0-11 emboli per patient. The clot volumes ranged from 0.00459-46.29 cm3 (mean +/- SD, 5.91 +/- 10.06 cm3). Inter- and intra-observer variability measurements indicated excellent reproducibility of the semi-automated method for quantifying PE volume burden. ICC for all endpoints was greater than 0.95 for inter- and intra-observer analysis. Bland-Altman analysis indicated no significant biases. CONCLUSION: Semi-automated region growing algorithm for quantifying PE is reproducible using data from multiple scanners and is a suitable method for image analysis in multicenter clinical trials.

Effect of varying computed tomography acquisition and reconstruction parameters on semi-automated clot volume quantification.

AIM: To examine effects of computed tomography (CT) image acquisition/reconstruction parameters on clot volume quantification in vitro for research method validation purposes. METHODS: This study was performed in conformance with HIPAA and IRB Regulations (March 2015-November 2016). A ten blood clot phantom was designed and scanned on a dual-energy CT scanner (SOMATOM Force, Siemens Healthcare GmBH, Erlangen, Germany) with varying pitch, iterative reconstruction, energy level and slice thickness. A range of clot and tube sizes were used in an attempt to replicate in vivo emboli found within central and segmental branches of the pulmonary arteries in patients with pulmonary emboli. Clot volume was the measured parameter and was analyzed by a single image analyst using a semi-automated region growing algorithm implemented in the FDA-approved Siemens syngo.via image analysis platform. Mixed model analysis was performed on the data. RESULTS: On the acquisition side, the continuous factor of energy showed no statistically significant effect on absolute clot volume quantification (P = 0.9898). On the other hand, when considering the fixed factor of pitch, there were statistically significant differences in clot volume quantification (P < 0.0001). On the reconstruction side, with the continuous factor of reconstruction slice thickness no statistically significant effect on absolute clot volume quantification was demonstrated (P = 0.4500). Also on the reconstruction side, with the fixed factor of using iterative reconstructions there was also no statistically significant effect on absolute clot volume quantification (P = 0.3011). In addition, there was excellent R2 correlation between the scale-measured mass of the clots both with respect to the CT measured volumes and with respect to volumes measure by the water displacement method. CONCLUSION: Aside from varying pitch, changing CT acquisition parameters and using iterative reconstructions had no significant impact on clot volume quantification with a semi-automated region growing algorithm.

Combined PET/DCE-MRI in a Rabbit Model of Atherosclerosis: Integrated Quantification of Plaque Inflammation, Permeability, and Burden During Treatment With a Leukotriene A4 Hydrolase Inhibitor.

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 18F-fluorodeoxyglucose (18F-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 18F-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 18F-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 18F-FDG PET in the group treated with a low dose of the LTA4H inhibitor BI691751.

Feasibility of imaging superficial palmar arch using micro-ultrasound, 7T and 3T magnetic resonance imaging.

AIM: To demonstrate feasibility of vessel wall imaging of the superficial palmar arch using high frequency micro-ultrasound, 7T and 3T magnetic resonance imaging (MRI). METHODS: Four subjects (ages 22-50 years) were scanned on a micro-ultrasound system with a 45-MHz transducer (Vevo 2100, VisualSonics). Subjects' hands were then imaged on a 3T clinical MR scanner (Siemens Biograph MMR) using an 8-channel special purpose phased array carotid coil. Lastly, subjects' hands were imaged on a 7T clinical MR scanner (Siemens Magnetom 7T Whole Body Scanner) using a custom built 8-channel transmit receive carotid coil. All three imaging modalities were subjectively analyzed for image quality and visualization of the vessel wall. RESULTS: Results of this very preliminary study indicated that vessel wall imaging of the superficial palmar arch was feasible with a whole body 7T and 3T MRI in comparison with micro-ultrasound. Subjective analysis of image quality (1-5 scale, 1: poorest, 5: best) from B mode, ultrasound, 3T SPACE MRI and 7T SPACE MRI indicated that the image quality obtained at 7T was superior to both 3T MRI and micro-ultrasound. The 3D SPACE sequence at both 7T and 3T MRI with isotropic voxels allowed for multi-planar reformatting of images and allowed for less operator dependent results as compared to high frequency micro-ultrasound imaging. Although quantitative analysis revealed that there was no significant difference between the three methods, the 7T Tesla trended to have better visibility of the vessel and its wall. CONCLUSION: Imaging of smaller arteries at the 7T is feasible for evaluating atherosclerosis burden and may be of clinical relevance in multiple diseases.