Hybrid FMT-MRI applied to in vivo atherosclerosis imaging
ABSTRACT
Combining Fluorescent Molecular Tomography (FMT) with anatomical imaging, e.g. MRI facilitates interpreting functional information. Furthermore, using a heterogeneous model for light propagation has been shown in simulations to be superior to homogeneous modeling to quantify fluorescence. Here, we present a combined FMT-MRI system and apply it to heart and aorta molecular imaging, a challenging area due to strong tissue heterogeneity and the presence of air-voids due to lungs. First investigating performance in a phantom and mouse corpse, the MRI-enabled heterogeneous models resulted in an improved quantification of fluorescence reconstructions. The system was then used in mice for in vivo atherosclerosis molecular imaging. Results show that, when using the heterogeneous model, reconstructions were in agreement with the ex vivo measurements. Therefore, the proposed system might serve as a powerful imaging tool for atherosclerosis in mice.
1. INTRODUCTION
One of the advantages of combining fluorescence molecular tomography (FMT) with anatomical imaging is anatomical guidance for an improved quantification of reconstructions [1–6]. While previous reports show that Born-normalization could cancel off some experimental factors, such as laser coupling loss, camera gain and exposing time, as well as reduce the effect of absorption heterogeneity in fluorescence reconstructions [7]; but limitations to suppress scattering variations were found [8]. Furthermore, it was demonstrated in simulations that homogeneous forward models might induce significant quantification errors in the reconstruction, which could be improved by propagating light in a heterogeneous model [9]. In this context, especially working with continuous wave (CW) mode, in which absorption and scattering cannot be separated [10], anatomical imaging is an essential addition in order to optimize forward modeling and achieve an accurate reconstruction.
Hybrid modality imaging combining FMT with MRI, X-ray CT, or ultrasound has been increasingly used in human breast, prostate and preclinical cancer models [11–14]. However, cardiovascular imaging in small animals has mostly been limited to ex vivo or in vitro imaging [15] due to the high absorption of light by the heart [16], the presence of air gaps due to lungs and the heterogeneous nature of light absorption properties of tissue in this region. Furthermore, the aorta, which is often a target in atherosclerosis imaging [17], has a relatively small size leading to challenges both for optical detection and structural delineation. Nevertheless noninvasive in vivo imaging plays an important role in preclinical atherosclerosis studies [17]. Therefore, combining the high sensitivity of FMT with the high spatial resolution of MRI, a hybrid FMT-MRI system is expected to improve in vivo atherosclerosis imaging in small animals.
The objectives of this study were threefold: (1) To develop a novel hybrid modality FMTMRI system to explore both functional information and anatomy simultaneously; (2) to evaluate the benefits of using a heterogeneous model of tissues for light propagation [9]; and (3) to provide a proof of concept for in vivo atherosclerosis imaging of mice. To achieve these objectives, we developed a fiber-based optical probe to acquire conduct FMT in parallel with MRI. By addressing source fibers sequentially with a Galvo mirror and detecting using a single snapshot of all the detection fibers with a sensitive electron multiplying charge coupled device (EMCCD) camera, our system enabled faster optical sampling than the existing FMTMRI systems [18–20]. The system was next characterized with a phantom and then with a mouse corpse containing a known fluorescent inclusion, thereby demonstrating quantification improvements when using heterogeneous modeling. Finally, the system was used to image matrix metalloproteinase (MMP) activity, an important target for atherosclerosis imaging [17, 21] in atherosclerotic (ATX) and control (Ctrl) mice [22].
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