In Vivo Molecular MRI of ICAM-1 Expression on Endothelium and Leukocytes from Subacute to Chronic Stages After Experimental Stroke

Abstract

Molecular MRI allows in vivo detection of vascular cell adhesion molecules expressed on inflamed endothelium, which enables detection of specific targets for anti-neuroinflammatory treatment. We explored to what extent MR contrast agent targeted to intercellular adhesion molecule-1 (ICAM-1) could detect endothelial- and leukocyte-associated ICAM-1 expression at different stages after experimental stroke. Furthermore, we assessed potential interfering effects of ICAM-1-targeted contrast agent on post-stroke lesion growth. Micron-sized particles of iron oxide (MPIO) functionalized with control IgG (IgG-MPIO) or anti-ICAM-1 antibody (αICAM-1-MPIO) were administrated at 1, 2, 3, 7, and 21 days after unilateral transient middle cerebral artery occlusion in mice, followed by in vivo MRI and postmortem immunohistochemistry. αICAM-1-MPIO induced significant contrast effects in the lesion core on post-stroke days 1, 2, and 3, and in the lesion borderzone and contralesional tissue on post-stroke day 2. αICAM-1-MPIO were confined to ICAM-1-positive vessels and occasionally co-localized with leukocytes. On post-stroke day 21, abundant leukocyte-associated αICAM-1-MPIO was immunohistochemically detected in the lesion core. However, MRI-based detection of αICAM-1-MPIO-labeled leukocytes was confounded by pre-contrast MRI hypointensities, presumably caused by phagocytosed blood remains. IgG-MPIO did not induce significant MRI contrast effects at 1 h after injection. Lesion development was not affected by injection of αICAM-1-MPIO or IgG-MPIO. αICAM-1-MPIO are suitable for in vivo MRI of ICAM-1 expression on vascular endothelium and leukocytes at different stages after stroke. Development of clinically applicable MPIO may offer unique opportunities for MRI-based diagnosis of neuroinflammation and identification of anti-inflammatory targets in acute stroke patients.