MR Elastography-Based Assessment of Matrix Remodeling at Lesion Sites Associated With Clinical Severity in a Model of Multiple Sclerosis.

Shuangqing Wang,Bimala Malla,Susanne Mueller,Philipp Boehm-Sturm,Jing Guo,Kjara Pilch,Laura Hanke-Vela,Jason M Millward,Ingolf Sack,Carmen Infante-Duarte,Sonia Waiczies,Ana Gil-Infante

doi:10.3389/fneur.2019.01382

Abstract

Magnetic resonance imaging (MRI) with gadolinium based contrast agents (GBCA) is routinely used in the clinic to visualize lesions in multiple sclerosis (MS). Although GBCA reveal endothelial permeability, they fail to expose other aspects of lesion formation such as the magnitude of inflammation or tissue changes occurring at sites of blood-brain barrier (BBB) disruption. Moreover, evidence pointing to potential side effects of GBCA has been increasing. Thus, there is an urgent need to develop GBCA-independent imaging tools to monitor pathology in MS. Using MR-elastography (MRE), we previously demonstrated in both MS and the animal model experimental autoimmune encephalomyelitis (EAE) that inflammation was associated with a reduction of brain stiffness. Now, using the relapsing-remitting EAE model, we show that the cerebellum—a region with predominant inflammation in this model—is especially prone to loss of stiffness. We also demonstrate that, contrary to GBCA-MRI, reduction of brain stiffness correlates with clinical disability and is associated with enhanced expression of the extracellular matrix protein fibronectin (FN). Further, we show that FN is largely expressed by activated astrocytes at acute lesions, and reflects the magnitude of tissue remodeling at sites of BBB breakdown. Therefore, MRE could emerge as a safe tool suitable to monitor disease activity in MS.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that represents the most common cause of non-traumatic disability in young adults
MRE data were acquired in one 2 mm midsagittal slice and confirmed our previous MRE data in relapsing-remitting EAE acquired in coronal slices [15]
We investigated the capacity of MRE to detect acute inflammatory events in the mouse brain during relapsingremitting EAE

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that represents the most common cause of non-traumatic disability in young adults. MS is considered to be an autoimmune disease in which selfreactive immune cells gain access to the CNS leading to myelin destruction and neuronal damage and the subsequent formation of multifocal lesions [1]. These pathological hallmarks are characteristic for experimental autoimmune encephalomyelitis (EAE), which is the prototypical model for MS [2]. New lesions are visualized using gadolinium-based contrast agents (GBCA) on MRI. The more severe the inflammatory activity, the greater the burden of GBCA-enhancement on post-contrast T1-weighted scans [3]. There are emerging concerns that GBCA may deposit in the tissue after repeated applications [6]

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