Multiple sclerosis (MS) is the most common non-traumatic neurological disorder affecting young adults. Yet because both symptoms and conventional imaging findings of MS are nonspecific and do not always correspond to each other, prompt diagnosis of disease activity and treatment follow-up present significant challenges. In particular, the difficulty exists because conventional imaging using nonspecific contrast agents to report MS disease activity only reflects blood-brain barrier breakdown, not necessarily active inflammation. A radiologist could report that there is no evidence of active disease because there was no contrast-enhancing lesion on imaging, while the patient was having active symptoms. Conversely, another situation could also arise when the radiologist reports that there is active disease as evidenced by the existence of contrast-enhancing lesions, yet the patient was asymptomatic and only presented for routine follow-up. The first scenario reflects low sensitivity in detecting early disease in which blood-brain barrier breakdown is not sufficient to allow enough conventional contrast agents to leak across to be detectable. The second scenario is a problem in low detection specificity as blood-brain barrier breakdown can persist for weeks and months beyond the acute disease period. Myeloperoxidase (MPO) is an inflammatory enzyme that is abundantly made and released by active inflammatory cells. MPO activity and its products can be highly damaging to the brain, and MPO is found in active MS lesions. MPO activity is also highly associated with areas of inflammatory cell infiltration and demyelination in MS and animal models of MS.

We have recently shown that a novel magnetic resonance imaging agent called MPO-Gd and developed in our laboratory, is highly specific and sensitive to MPO activity in solution and animal experiments. We found that MPO-Gd is nontoxic, possesses high stability, and is well tolerated by animals even at high doses. MPO-Gd can detect and confirm MPO activity by imaging, and can identify significantly more and smaller lesions earlier compared to conventional MR contrast imaging in a mouse model of MS. Preliminary studies in our laboratory administering an MPO-specific inhibitor to block MPO activity also significantly ameliorated symptoms and reduced relapses. Therefore, we hypothesize that MPO is an important component in the development of demyelination of MS lesions, and metrics derived from MPO-Gd imaging will be highly useful to report on the status of inflammation and demyelination in MS.

In this study, we will use a mouse model of MS to evaluate MPO-Gd imaging systematically over the course of the disease to determine whether MPO-Gd can detect and confirm preclinical and subclinical disease activity even when the animals do not exhibit any symptoms. We will also evaluate different therapies including the current first line drugs and the MPO-specific inhibitor using MPO-Gd imaging. We will compare MPO-Gd imaging to conventional imaging to determine how much better MPO-Gd is at detecting early disease activity. Comparison studies will be performed to correlate and validate MPO-Gd imaging metrics to tissue specimen assays. We expect that the results of this study will establish MPOGd imaging as a superior method to detect early disease activity in MS as well as evaluating treatment effects of current and future therapies. These results will also set the stage for future translation of MPOGd imaging to human MS.