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Novel MR Tools Highlight Brain Barrier Alterations in a Mouse Model of Multiple Sclerosis

Hanke Vela, L;

Previous studies on multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) have highlighted the role of brain-barrier breakdown for the initiation and maintenance of neuroinflammation. Prior research generally confirms that visualization of barrier-disruption is of major interest for an early diagnostic of neuroinflammatory diseases. However, common contrast-agents like gadolinium-based contrast agents (GBCA) have important limitations as they dont accurately show all aspects of brain-barrier breakdown and recent reports point towards potential side effects of repeated gadolinium applications. In the last years, our group has applied novel magnetic resonance imaging (MRI) techniques to visualize more accurately neuroinflammation in vivo and to elucidate pathological pathways involved in disease development. In this study, we first used Europium-doped very small iron oxide particles (Eu-VSOP), a new kind of magnetic nanoparticles, to visualize alterations of the blood-cerebrospinal-fluid-barrier (BCSFB) at the site of the Choroid Plexus (CP) in a mouse model of MS. We performed MRI measurements in EAE mice at different phases of disease after injection of Eu-VSOP and analyzed histopathological correlates using fluorescent microscopy. Our results show the ability of Eu-VSOP to visualize BCSFB alterations and neuroinflammatory processes in vivo and to connect them to histopathological findings of a compromised barrier at the level of the CP. In the second part of the study, we performed MRE measurements in EAE mice to assess alterations of brain mechanical properties associated to blood-brain-barrier (BBB) breakdown. We previously demonstrated using MR-elastography (MRE) in both MS and EAE that inflammation led to a reduction of brain stiffness. Here, we demonstrated that highly active inflammatory areas are especially prone to softening, and that, in contrast to GBCA, MRE alterations correlate with clinical disability. We further demonstrate that perivascular areas, where BBB is disrupted, undergo a process of tissue remodeling, characterized by the presence of aggregates of the extracellular matrix protein fibronectin (Fn). Interestingly, Fn expression correlates with MRE changes. Therefore, this study contributes to better understanding the pathophysiological processes around brain barrier breakdown as a central step in the dynamic of lesion formation and to the development of novel MRI techniques as a diagnostic tool for MS.