Mouse model mimics multiple sclerosis in the clinico‐radiological paradox

Abstract

The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein-specific T-cell transfer in 26 female SJL/J mice, and applied high-field-strength magnetic resonance imaging (MRI) scans longitudinally, assessing blood-brain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP-C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast-enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico-radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

“…Although this may be the case for the spinal cord as a unit, it does not always hold true for the CNS because, as shown in mice with PLPinduced EAE, there is early (preclinical) blood-brain barrier breakdown, particularly in the cerebellum (29). Similar observations obtained with histochemical and MR imaging techniques have been reported (3,30,31). The regional differences in the sensitivity of brain areas to upregulation of inflammatory molecules earlier or more rapidly (after encephalitogenic T cells producing a variety of proinflammatory molecules have passed through these areas) influence the susceptibility of different brain regions to neuroinflammation.…”

Utilizing different methods for visualizing susceptibility from a single multi-gradient echo dataset

“…USPIO phantoms USPIO phantoms were manufactured by suspending different concentrations of VSOP-C184 [1] in 8% gelatin (Sigma-Aldrich Company Ltd. Gillingham, UK) in test-tubes. Concentrations varied from 0.02 to 2.60 mM and were prepared by serial two fold dilutions.…”

“…Objects that create such susceptibility gradients include ultra-small super-paramagnetic iron-oxide particles (USPIOs). These may be suspended free in solution, taken up by macrophages at the site of an immune response [1] or used for cell tracking [2]. Metallic objects such as the sources (or seeds) used in low dose rate prostate brachytherapy can also be visualized [3].…”

Clinical trials in multiple sclerosis: Current and future requirements – potential pitfalls

“…[12]. Since we have magnetic resonance imaging as an objective and quantifiable paraclinical outcome measurement of disease activity another important and controversial issue is still unresolved: The clinical/radiological paradox [1,15]. In other words: Just one strategically placed lesion (e.g.…”