Multiple Sclerosis: Myeloperoxidase Immunoradiology Improves Detection of Acute and Chronic Disease in Experimental Model

Abstract

.q RSNA, 2014 Purpose:To test if MPO-Gd, a gadolinium-based magnetic resonance (MR) imaging probe that is sensitive and specific for the proinflammatory and oxidative enzyme myeloperoxidase (MPO), which is secreted by certain inflammatory cells, is more sensitive than diethylenetriaminepentaacetic acid (DTPA)-Gd in revealing early subclinical and chronic disease activity in the brain in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Materials and Methods:The protocol for animal experiments was approved by the institutional animal care committee. A total of 61 female SJL mice were induced with EAE. Mice underwent MPOGd-or DTPA-Gd-enhanced MR imaging on days 6, 8, and 10 after induction, before clinical disease develops, and during chronic disease at remission and the first relapse.Brains were harvested at these time points for flow cytometric evaluation of immune cell subtypes and immunohistochemistry. Statistical analysis was performed, and P , .05 was considered to indicate a significant difference. Results:MPO-Gd helps detect earlier (5.2 vs 2.3 days before symptom onset, P = .004) and more (3.1 vs 0.3, P = .008) subclinical inflammatory lesions compared with DTPAGd, including in cases in which there was no evidence of overt blood-brain barrier (BBB) breakdown detected with DTPA-Gd enhancement. The number of MPO-Gd-enhancing lesions correlated with early infiltration of MPOsecreting monocytes and neutrophils into the brain (r = 0.91). MPO-Gd also helped detect more lesions during subclinical disease at remission (5.5 vs 1.3, P = .006) and at the first relapse (9.0 vs 2.7, P = .03) than DTPA-Gd, which also correlated well with the presence and accumulation of MPO-secreting inflammatory cells in the brain (r = 0.93). Conclusion:MPO-Gd specifically reveals lesions with inflammatory monocytes and neutrophils, which actively secrete MPO. These results demonstrate the feasibility of detection of subclinical inflammatory disease activity in vivo, which is different from overt BBB breakdown.q RSNA, 2014

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis

“…The cerebrum and cerebellum were homogenized separately. Brain leukocytes were isolated and used for flow cytometry as previously described (24). Additional details are given in SI Materials and Methods.…”

Spinal Cord Inflammation: Molecular Imaging after Thoracic Aortic Ischemia Reperfusion Injury

“…On the other hand, MPO imaging has molecular specificity for a key enzyme expressed during active inflammation, as well as increased sensitivity due to signal amplification. Thus, MPO imaging can reveal ongoing inflammation at an earlier time point than conventional agents such as DTPA-Gd (30). Indeed, we found that both imaging sensors, bis-5-HT-DTPA-Gd (MPO-Gd, for MR imaging) and 111 In-bis-5-HT-DT-PA (for SPECT/CT), revealed increased MPO activity after TAR.…”

“…Spinal cord tissues were harvested from separate groups of sham-procedure mice and mice at 6 and 24 hours after TAR and were processed for flow cytometry (30). The cell numbers of different cell populations were Plymouth Meeting, Pa), followed by detection of MPO activity with 10-Acetyl-3,7-dihydroxyphenoxazine (ADHP; AAT Bioquest, Sunnyvale, Calif) (29).…”

Gelsolin decreases actin toxicity and inflammation in murine multiple sclerosis

“…Clinical severity (Figure 2a) was reduced in the rhp-GSN group (closed squares) compared to the vehicle-treated group (open circles). We also administered rhp-GSN on days 8 and 10, when there is developing neuroinflammation and early symptom onset(Pulli et al, 2015), and found that this delayed treatment also resulted in improvement in the clinical course, demonstrating that gelsolin’s beneficial effects were not from interfering with EAE induction. Interestingly, the delayed treatment resulted in a faster and more complete resolution of the clinical symptoms (Figure 2a, open squares), likely due to higher bioavailability compared to the earlier administration.…”