Reza Forghani MD, PhD, Presenter: Stockholder, Real-Time Radiography, Inc

Gregory R. Wojtkiewicz MSC, Abstract Co-Author: Nothing to Disclose

Elizabeth R. Zhang BS, Abstract Co-Author: Nothing to Disclose

Elisenda Rodriguez PhD, Abstract Co-Author: Nothing to Disclose

Ben Bautz, Abstract Co-Author: Nothing to Disclose

Ralph Weissleder MD, PhD, Abstract Co-Author: Shareholder, VisEn Medical, Inc, Bedford, MA

John Chen MD, PhD, Abstract Co-Author: Nothing to Disclose

00030490-DMT et al, Abstract Co-Author: Nothing to Disclose

Active demyelinating plaques result from an immune-mediated inflammatory response and contain high levels of the oxidative enzyme myeloperoxidase (MPO), which is detectable by the MRI sensor bis-5-hydroxytryptamide-DTPA(Gd) (MPO-Gd). We hypothesized that inhibition of MPO activity would result in improved clinical scores with a concomitant decline in MPO-specific enhancement on molecular imaging in the murine experimental autoimmune encephalomyelitis (EAE) model for demyelinating disease.

We induced EAE in 40 SJL mice and divided them into control (n = 20; treated with saline) and treated groups (n=20; 4-aminobenzoic hydrazide (ABAH), a specific MPO inhibitor, 40 mg/kg IP bid). 20 mice (10 controls, 10 treated) were followed clinically at least until day 20, and 20 (10 controls, 10 treated) imaged at day 10, time of early onset of clinical symptoms. MRI for MPO activity was performed using a 4.7 T MRI scanner. T1w images were obtained before and after intravenous administration of MPO-Gd (0.3 mmol/kg). MPO activation was determined based on the activation ratio CNR60min/CNR6min ≥ 1.8.

The average maximal acute clinical score was 2.9±0.4 (on day 15) in the control group (± SEM; n=10) versus 1.3±0.4 (also on day 15) in the ABAH treated group (n=10) (P≤0.0086). In the imaging groups, the average clinical score on day 10 was 1.85±0.53 (controls; n=10) versus 0.05±0.05 (ABAH; n=10). There was a corresponding decrease in MPO-specific enhancement reflected in total lesion volume (41.8±9.1 mm3controls; 14.6±6.5 mm3 treated; p≤0.012) and lesion count (19.0±4.0 controls; 7.1±2.1 treated; p≤0.0089). There was positive correlation between MPO-specific lesion volume (r=0.49, p≤0.029) and lesion count (r=0.70, p<0.001) with clinical scores.

Our findings demonstrate a significant reduction in lesion volume and MPO activity in the brains of EAE mice following treatment with a specific MPO inhibitor, with a corresponding improvement in clinical score. In addition to therapeutic implications of these findings, our results provide the basis for application MPO-Gd molecular imaging for non-invasive investigation of demyelinating diseases in animal models and possibly humans.

In addition to providing a therapeutic target for demyelinating disease, MPO-Gd could be used for diagnosis and treatment follow-up of human demyelinating disease such as multiple sclerosis.

Forghani, R, Wojtkiewicz, G, Zhang, E, Rodriguez, E, Bautz, B, Weissleder, R, Chen, J, et al, 0, Reduced Myeloperoxidase (MPO) Activity and Lesion Load on Molecular Imaging Correlates with Improved Clinical Score in the Murine Experimental Allergic Encephalomyelitis (EAE) Model for Demyelinating Disease.  Radiological Society of North America 2009 Scientific Assembly and Annual Meeting, November 29 - December 4, 2009 ,Chicago IL. http://archive.rsna.org/2009/8006062.html