Molecular MR imaging of atherosclerosis

\u3cp\u3eIn recent years, extensive research in atherosclerosis disease has elucidated many of the biological and molecular mechanisms and pathways involved in plaque development and progression. This has identified dozens of novel targets for diagnosis, therapy, and treatment evaluation. In vivo molecular imaging techniques, and in particular molecular magnetic resonance imaging (MRI), facilitate studies on the etiology of atherosclerosis and the evaluation of emerging therapies. In this chapter, we review contrast agents and (quantitative) MRI pulse sequences and strategies that have been developed for molecular MRI of atherosclerosis. We focus on targeted and nontargeted MRI contrast agents for specific imaging of inflammation (and especially macrophages), lipids, fibrous cap, thrombus, intra-plaque hemorrhage, apoptosis, and neovascularization. Contrast agents that are discussed include iron oxide-based agents (USPIO, MPIO), gadolinium- based materials (low molecular weight agents, micelles, liposomes, HDL-like particles) for 1 H MRI, as well as perfluorocarbon (PFC) emulsions for 19 F MRI. The most promising strategies for diagnosis (vulnerable, rupture-prone plaque detection), for determining therapeutic pathways, for monitoring of therapy, and for treatment personalization will be reviewed in more detail, discussing their value for preclinical research and clinical translation.\u3c/p\u3

Mouse myocardial first-pass perfusion MR imaging

A first-pass myocardial perfusion sequence for mouse cardiac MRI is presented. A segmented ECG-triggered acquisition combined with parallel imaging acceleration was used to capture the first pass of a Gd-DTPA bolus through the mouse heart with a temporal resolution of 300–400 msec. The method was applied in healthy mice (N = 5) and in mice with permanent occlusion of the left coronary artery (N = 6). Baseline semiquantitative perfusion values of healthy myocardium showed excellent reproducibility. Infarct regions revealed a significant decrease in the semiquantitative myocardial perfusion values (0.05 ± 0.02) compared to remote myocardium (0.20 ± 0.04). Myocardial areas of decreased perfusion correlated well to infarct areas identified on the delayed-enhancement scans. This protocol is a valuable addition to the mouse cardiac MRI toolbox for preclinical studies of ischemic heart disease. \u3cbr/\u3

Iron oxide nanoparticle-micelles (ION-micelles) for sensitive (molecular) magnetic particle imaging and magnetic resonance imaging

Background: Iron oxide nanoparticles (IONs) are a promising nanoplatform for contrast-enhanced MRI. Recently, magnetic particle imaging (MPI) was introduced as a new imaging modality, which is able to directly visualize magnetic particles and could serve as a more sensitive and quantitative alternative to MRI. However, MPI requires magnetic particles with specific magnetic properties for optimal use. Current commercially available iron oxide formulations perform suboptimal in MPI, which is triggering research into optimized synthesis strategies. Most synthesis procedures aim at size control of iron oxide nanoparticles rather than control over the magnetic properties. In this study, we report on the synthesis, characterization and application of a novel ION platform for sensitive MPI and MRI. Methods and Results: IONs were synthesized using a thermal-decomposition method and subsequently phase-transferred by encapsulation into lipidic micelles (ION-Micelles). Next, the material and magnetic properties of the ION-Micelles were analyzed. Most notably, vibrating sample magnetometry measurements showed that the effective magnetic core size of the IONs is 16 nm. In addition, magnetic particle spectrometry (MPS) measurements were performed. MPS is essentially zero-dimensional MPI and therefore allows to probe the potential of iron oxide formulations for MPI. ION-Micelles induced up to 200 times higher signal in MPS measurements than commercially available iron oxide formulations (Endorem, Resovist and Sinerem) and thus likely allow for significantly more sensitive MPI. In addition, the potential of the ION-Micelle platform for molecular MPI and MRI was showcased by MPS and MRI measurements of fibrin-binding peptide functionalized ION-Micelles (FibPep-ION-Micelles) bound to blood clots. Conclusions: The presented data underlines the potential of the ION-Micelle nanoplatform for sensitive (molecular) MPI and warrants further investigation of the FibPep-ION-Micelle platform for in vivo, non-invasive imaging of fibrin in preclinical disease models of thrombus-related pathologies and atherosclerosis

Quantitative T2 mapping of the mouse heart by segmented MLEV phase-cycled T2 preparation

Purpose A high-quality, reproducible, multi-slice T2-mapping protocol for the mouse heart is presented. Methods A T2-prepared sequence with composite 90 and 180 radiofrequency pulses in a segmented MLEV phase cycling scheme was developed. The T2-mapping protocol was optimized using simulations and evaluated with phantoms. Results Repeatability for determination of myocardial T2 values was assessed in vivo in n=5 healthy mice on 2 different days. The average baseline T2 of the left ventricular myocardium was 22.5±1.7 ms. The repeatability coefficient for R2=1/T2 for measurements at different days was ¿R2=6.3 s-1. Subsequently, T2 mapping was applied in comparison to late-gadolinium-enhancement (LGE) imaging, to assess 1-day-old ischemia/reperfusion (IR) myocardial injury in n=8 mice. T2 in the infarcts was significantly higher than in remote tissue, whereas remote tissue was not significantly different from baseline. Infarct sizes based on T2 versus LGE showed strong correlation. To assess the time-course of T2 changes in the infarcts, T2 mapping was performed at day 1, 3, and 7 after IR injury in a separate group of mice (n=16). T2 was highest at day 3, in agreement with the expected time course of edema formation and resolution after myocardial infarction. Conclusion T2 prepared imaging provides high quality reproducible T2 maps of healthy and diseased mouse myocardium. Magn Reson Med 72:409-417, 2014. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc

Relaxometric studies of gadolinium-functionalized perfluorocarbon nanoparticles for MR imaging

Fluorine MRI (19F MRI) is receiving an increasing attention as a viable alternative to proton-based MRI (1H MRI) for dedicated application in molecular imaging. The 19F nucleus has a high gyromagnetic ratio, a 100% natural abundance and is furthermore hardly present in human tissues allowing for hot spot MR imaging. The applicability of 19F MRI as a molecular and cellular imaging technique has been exploited, ranging from cell tracking to detection and imaging of tumors in preclinical studies. In addition to applications, developing new contrast materials with improved relaxation properties has also been a core research topic in the field, since the inherently low longitudinal relaxation rates of perfluorocarbon compounds result in relatively low imaging efficiency. Borrowed from 1H MRI, the incorporation of lanthanides, specifically Gd(III) complexes, as signal modulating ingredients in the nanoparticle formulation has emerged as a promising approach to improvement of the fluorine signal. Three different perfluorocarbon emulsions were investigated at five different magnetic field strengths. Perfluoro-15-crown-5-ether was used as the core material and Gd(III)DOTA-DSPE, Gd(III)DOTA-C6-DSPE and Gd(III)DTPA-BSA as the relaxation altering components. While Gd(III)DOTA-DSPE and Gd(III)DOTA-C6-DSPE were favorable constructs for 1H NMR, Gd(III)DTPA-BSA showed the strongest increase in 19FR1. These results show the potential of the use of paramagnetic lipids to increase 19FR1 at clinical field strengths (1.5-3T). At higher field strengths (6.3-14T), gadolinium does not lead to an increase in 19FR1 compared with emulsions without gadolinium, but leads to an significant increase in 19FR2. Our data therefore suggest that the most favorable situation for fluorine measurements is at high magnetic fields without the inclusion of gadolinium constructs. Copyright © 2014 John Wiley & Sons, Ltd