Magnetization transfer ratio does not correlate to myelin content in the brain in the MOG-EAE mouse model

Sveinung Fjær,Lars Bø,Kjell-Morten Myhr,Øivind Torkildsen,Stig Wergeland

doi:10.1016/j.neuint.2015.02.006

Abstract

Magnetization transfer ratio (MTR) is a magnetic resonance imaging (MRI) method which may detect demyelination not detected by conventional MRI in the central nervous system of patients with multiple sclerosis (MS). A decrease in MTR value has previously been shown to correlate to myelin loss in the mouse cuprizone model for demyelination. In this study, we investigated the sensitivity of MTR for demyelination in the myelin oligodendrocyte (MOG) 1–125 induced experimental autoimmune encephalomyelitis (EAE) mouse model. A total of 24 female c57Bl/6 mice were randomized to a control group (N = 6) or EAE (N = 18). MTR images were obtained at a preclinical 7 Tesla Bruker MR-scanner before EAE induction (baseline), 17–19 days (midpoint) and 31–32 days (endpoint) after EAE induction. Mean MTR values were calculated in five regions of the brain and compared to weight, EAE severity score and myelin content assessed by immunostaining for proteolipid protein and luxol fast blue, lymphocyte and monocyte infiltration and iron deposition. Contrary to what was expected, MTR values in the EAE mice were higher than in the control mice at the midpoint and endpoint. No significant difference in myelin content was found according to histo- or immunohistochemistry. Changes in MTR values did not correlate to myelin content, iron content, lymphocyte or monocyte infiltration, weight or EAE severity scores. This suggest that MTR measures of brain tissue can give significant differences between control mice and EAE mice not caused by demyelination, inflammation or iron deposition, and may not be useful surrogate markers for demyelination in the MOG1-125 mouse model.

Highlights

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss
EAE mice had nonsignificantly higher than control mice
We have shown an unexpected increase in Magnetization transfer ratio (MTR) value in the brains of mice with myelin oligodendrocyte (MOG)-EAE as compared to controls that do not correlate to histopathological changes

Summary

Introduction

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss. MTR has been shown to decrease both in and in proximity of white matter MS lesions (Dousset et al, 1998; Filippi et al, 1995, 1998), and has detected gray matter changes in the MS brain, showing sensitivity to both demyelination and inflammation (Agosta et al, 2006; Vavasour et al, 2011). A 9.4 T post mortem study of formalin fixed MS brains showed a correlation between MTR and myelin content (Schmierer et al, 2010). MTR has been shown to correlate to both axonal density and myelin content from histopathological analyses of post-mortem tissue from brain- and spinal cord tissue of MS patients (Mottershead et al, 2003; Schmierer et al, 2004, 2007). Studies in an experimental model of toxic demyelination with little or no perivascular inflammation, the cuprizone (CPZ) model, have found correlation between myelin content and MTR value

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