Developing magnetic resonance and optical imaging techniques for measuring macromolecule uptake by the artery wall

Abstract

Elevated arterial macromolecule uptake is an early event in the atherosclerotic process that could be critical to predicting its evolution. In vivo imaging may identify arterial uptake and provide an early biomarker of the atherosclerotic disease. Current approaches, based on confocal microscopy are too invasive for investigational studies in humans. An MRI-based technique using an albumin-binding contrast agent, gadofosveset trisodium, is a more feasible strategy. However, at the clinical dose, only 75% of the contrast agent is bound to albumin which adversely affects measurements. Effects of unbound gadofosveset can be removed by applying a previously developed mathematical model, the Proton Relaxation Enhancement algorithm. The algorithm, which requires quantitative parametric mapping of the vessel, was validated in phantoms of arterial permeability, where the MR signal was successfully de-composed into concentration maps of bound and unbound gadofosveset. It was subsequently applied to the brachiocephalic artery of rats with healthy and injured endothelium. In order to validate the results, an alternative method was also developed using 3D confocal microscopy imaging of rhodamine-albumin uptake by the intact healthy vessel. Since the confocal method displayed high sensitivity and spatial resolution, uptake was compared spatially with MRI. For both modalities, albumin uptake occurred approximately along the inner curvature of the vessel, but correlations were not statistically significant. Arterial wall voxels may have been affected by partial volume artefacts brought about by the low spatial resolution. Despite this shortcoming, the study showed that MRI exhibited elevated uptake in injured animals compared to their healthy counterparts. In conclusion, the Proton Relaxation Enhancement algorithm applied to imaging the uptake of albumin- binding contrast agents is promising, particularly to assess injured endothelium. The adoption of novel multi-parametric quantitative MR sequences with high spatial and temporal resolution is also desirable. The methods developed herein may be instrumental in our advancement in understanding atherogenesis.