Molecular magnetic resonance imaging of brain-immune interactions

Abstract

Although the blood-brain barrier (BBB) was thought to protect the brain from the effects of the immune system, immune cells can nevertheless migrate from the blood to the brain, either as a cause or as a consequence of central nervous system (CNS) diseases, thus contributing to their evolution and outcome. Accordingly, as the interface between the CNS and the peripheral immune system, the BBB is critical during neuroinflammatory processes. In particular, endothelial cells are involved in the brain response to systemic or local inflammatory stimuli by regulating the cellular movement between the circulation and the brain parenchyma. While neuropathological conditions differ in etiology and in the way in which the inflammatory response is mounted and resolved, cellular mechanisms of neuroinflammation are probably similar. Accordingly, neuroinflammation is a hallmark and a decisive player of many CNS diseases. Thus, molecular magnetic resonance imaging (MRI) of inflammatory processes is a central theme of research in several neurological disorders focusing on a set of molecules expressed by endothelial cells, such as adhesion molecules (VCAM-1, ICAM-1, P-selectin, E-selectin, …), which emerge as therapeutic targets and biomarkers for neurological diseases. In this review, we will present the most recent advances in the field of preclinical molecular MRI. Moreover, we will discuss the possible translation of molecular MRI to the clinical setting with a particular emphasis on myeloperoxidase imaging, autologous cell tracking, and targeted iron oxide particles (USPIO, MPIO).

Keywords: Alzheimer; antibody; hemorrhage; inflammation; lymphocytes; microparticles; multiple sclerosis; stroke.

FIGURE 1

Main targets of molecular imaging. USPIO, ultrasmall particles of iron oxide; MPIO, microsized particles of iron oxide; MPO, myeloperoxidase; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1.

FIGURE 2

Schematic representation of the effects of different contrast agents on water magnetization in biological samples. TR, repetition time; TE, Echo Time.

FIGURE 3

Main characteristics of the most widely used contrastophores.

FIGURE 4

Schematic representation of the effect of different contrast agents on brain MRI of a rodent with inflammation in the right striatum. The inflammatory region with impaired BBB is represented in dark red, whereas the inflammatory region without BBB impairment is in light red. Time-dependent signal changes after contrast agent injection are represented vertically. In contrast to the signal changes induced by targeted MPIOs which are independent of the BBB status, the contrast enhancement induced by other contrast agents is not inflammation specific and strongly depends on the permeability of the BBB.

FIGURE 5

Example of ultrasensitive molecular MRI of brain inflammation using optimized MPIO-αVCAM-1. All the images presented were acquired 20 min after MPIO-αVCAM-1 injection as described by Montagne et al. (2012) and Gauberti et al. (2013). Experimental autoimmune encephalomyelitis was induced by Myelin oligodendrocyte glycoprotein (MOG) in C57BL6J mice. The T2*-weighted image presented is from a mouse with a clinical score of 3. Intrastriatal injection of TNF (1 μg) was performed 24 h before imaging. Intracerebral hemorrhage was induced by intrastriatal collagenase. Carotid artery stenosis was performed by ligation of the right common carotid artery. Ischemic stroke was induced by intra-arterial administration of thrombin.

FIGURE 6

Schematic representation of the inflammatory penumbra concept after ischemic stroke as revealed by MPIO-αVCAM-1 enhanced MRI. VCAM-1 overexpression is sustained and particularly significant in the peri-infarct area after ischemic stroke. From 24 h to 5 days post-stroke onset this inflammatory penumbra is recruited by the ischemic core. Interestingly, anti-inflammatory treatments block this secondary infarct expansion. In this context, the presence of an inflammatory penumbra 24 h after stroke onset revealed by molecular MRI of VCAM-1 may be used as a selection criteria for anti-inflammatory treatment in stroke patients.