Interaction of gadolinium-based MR contrast agents with choline: implications for MR spectroscopy (MRS) of the breast.

It has been shown that magnetic resonance spectroscopy (MRS) can improve the specificity of the MR examination by the spectroscopic detection of choline (Cho). Commonly, the lesion is first visualized on postcontrast studies, and the MRS voxel is prescribed accordingly. The implicit assumption made in this approach is that the presence of gadolinium-based contrast agents will have a negligible effect on the MR spectra obtained from the lesion. In this work, we examined this assumption by determining the effects of six gadolinium-based contrast agents: Magnevist, Multihance, Omniscan, Optimark, Pro- Hance, and Dotarem, on the Cho peak in phantoms and in a rat model for breast cancer. We found that only the three negative- ly-charged chelates: Magnevist, MultiHance, and Dotarem, broadened the Cho peak in phantoms and reduced the area of the Cho peak in vivo by an average of about 40%. The use of negatively-charged chelates may lead to an underestimation of the levels of Cho present in human breast cancers, since most studies use MRS postcontrast administration. Therefore, we recommend the use of the neutral chelates in MRI/MRS studies of the breast. Magn Reson Med 61:1286 -1292, 2009. © 2009 the lesion. The only report that has addressed this issue explicitly in breast MRS is the study of Joe et al. (14), which showed that there were changes in both the line- width (increase of 15-21%) and area (decrease of 11-18%) of the Cho peak, in the same subjects, pre- and postinjec- tion of Omniscan (gadodiamide). There have been several reports addressing the effects of gadolinium-containing contrast agents on MR spectra both in vitro (15,16) and in vivo (17-22). All of the in vivo studies involved determin- ing the effects of gadolinium diethylenetriamine penta acetate (Gd-DTPA; Magnevist) or gadolinium-tetraazacy- clododecane tetra acetate (Gd-DOTA; Dotarem) on the pro- ton MRS of brain tumors. Although the in vitro studies reported significant alterations in the spectral properties of Cho in phantoms, in the presence of Gd-DTPA, the in vivo studies reported smaller changes (10 -15%) in the Cho peak postcontrast administration. This smaller change was attributed to the fact that in the brain the Cho is predom- inantly intracellular and thus cannot come into direct contact with the contrast agent. There are currently five gadolinium-based contrast agents approved for human use in the United States. These are: Magnevist, Multihance, Omniscan, Optimark, and ProHance (see Fig. 1 for the chemical names). The struc- tures of these five agents and a sixth agent, Dotarem, which was part of the studies of brain MRS reported by Sijens et al. (19 -21), are shown in Fig. 1. Note that three of these agents are neutral at physiological pH, i.e., they have no overall charge (Omniscan, Optimark, and ProHance), while the other three agents (Magnevist, Multihance, and Dotarem) are negatively charged. It has been suggested that the charge of the agent is important since Cho is a posi- tively-charged molecule at neutral pH and in solution Cho can form a weak complex with negatively-charged gado- linium chelates (22,23). The situation in vivo may be com- plicated by the fact that Cho must come into direct contact with the contrast agent in order to form a complex. The formation of this complex can lead to shortening of the relaxation times of the methyl protons of Cho through the electron-nuclear dipole interaction. The overall goal of this work was to determine the ef- fects of the six gadolinium-containing contrast agents, shown in Fig. 1, on the proton MRS resonance of Cho, both in phantoms and in an animal model for breast cancer. We discuss the implications of these findings with respect to clinical MRS studies of breast lesions.