Atherosclerosis is responsible for the majority of disabilities and deaths in developed countries. Previous studies have shown that sudden clinical events correlate highly with plaque composition and the degree of plaque inflammation. These results stress the importance of developing non-invasive surrogate markers of plaque inflammation to detect asymptomatic high-risk plaques in clinical settings. Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) with combined computed tomography (CT) have shown promise in characterizing and quantifying metabolic activity (i.e., glyocolysis/ inflammation) in atherosclerosis, by targeting the presence of neovessels (DCE-MRI) and inflammatory cells such as macrophages (18F-FDG PET) in atherosclerotic plaques. However, several challenges need to be overcome prior to translating these imaging approaches to clinical practice. A significant obstacle to adapting conventional DCE-MRI approaches to atherosclerosis includes the necessity to image with high spatial resolution to capture plaque heterogeneity. This can be achieved with longer scan times, but conflicts with need for high temporal resolution required for kinetic modeling of the data.
In Aim 1, we will develop and validate a novel dual-imaging sequence for DCE-MRI of atherosclerosis where we acquire a high temporal resolution, but low spatial resolution, AIF image and a high spatial resolution/low temporal resolution vessel wall image to allow accurate quantification of contrast agent uptake within plaques. This approach will be compared to conventional approaches in both a rabbit model of atherosclerosis and in human subjects. The limited spatial resolution of conventional PET scanners has an impact on the accuracy of 18F- FDG PET quantification in atherosclerotic plaques because of the partial volume effect (PVE). A posteriori PVE correction methods using high-resolution anatomical images acquired with a different imaging modality can improve quantification, but are challenging since they require accurate co-registration. MR is an ideal choice for this second imaging modality as it produces high-resolution anatomical images without the use of ionizing radiation. A combined MR/PET scanner may therefore be better suited for developing novel PVE correction methodologies. As part of Aim 2, we will develop and validate the combined MR-PET(FDG) imaging approach to improve the quantification of atherosclerotic plaque metabolic activity. Attenuation correction based on MR will be compared with CT based attenuation correction. Approaches to improved PVE correction and optimal circulation time for plaque imaging will also be validated in both rabbits and humans. Finally, imaging parameters derived from the improved DCE-MRI and MR-PET(FDG) will be validated in patients undergoing carotid endarterecomy (CEA), with the primary endpoint of establishing the relationship with histological markers of plaque inflammation.Additionally, we will assess the relationship with serum biomarkers and, as an exploratory endpoint, with the gene expression of markers of plaque vulnerability.
If successful, the improved DCE-MRI and MR-PET methods will allow a more comprehensive and accurate quantification of inflammation in atherosclerotic plaques. By combining the excellent anatomical (MRI) with functional information (DCE-MRI and PET), these advancements may have a significant clinical impact for the non-invasive evaluation of atherosclerotic risk and for assessing the efficacy of therapeutic intervention. We hypothesize that an integrated evaluation of disease with different imaging techniques incorporating plaque physiology/metabolism to traditional anatomical/morphological imaging may improve patient risk stratification.
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