Citation

Multiple sclerosis (MS) is a chronic neuroimmunological disease with growing incidence in which autoimmune-driven inflammation leads to damage to the central nervous system and demyelination. Although identification of demyelinating lesions by conventional magnetic resonance imaging (MRI) is paramount for diagnosis and prognosis of MS, the lack of consistent correlation with disease activity and progression motivates the search for complimentary imaging tools. Neuroinflammatory processes, anteceding demyelination and neurodegeneration, are known for exerting a significant effect on extracellular matrix (ECM) composition and can be imaged by MR elastography (MRE) and magnetic nanoparticle-based MRI. Hence, this thesis aimed at using these alternative imaging tools to investigate brain inflammation and the associated remodeling of its ECM. The studies compiled here examined the neuropathological processes behind alterations of the mechanical properties of the brain in association with accumulation of europium-doped very small superparamagnetic iron oxide particles (Eu-VSOP) and remodeling the ECM using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Additionally, characterization of alterations in glycosaminoglycans (GAGs) associated with disease development and progression was investigated. The results demonstrated that focal neuroinflammation resulted in microstructural changes affecting the mechanical properties of the brain tissue. Intense perivascular infiltration of inflammatory cell as well as inflammation at the periventricular space visualized by Eu-VSOPs are characterized by marked tissue softening compared with areas of disseminated inflammation. Furthermore, a quantitative mapping of brain stiffness revealed that MRE is able to detect region-specific alterations in tissue microstructure, revealing reduced cortical stiffness at peak EAE. These changes were associated with overexpression of laminin 4 and 5 as well as collagen type VI and downregulation of fibronectin. Finally, changes in GAG composition and metabolism indicate that early alterations in gene expression are followed by modifications in chondroitin sulfate (CS) and hyaluronic acid (HA) GAG fractions. Upregulation of genes associated with GAG degradation and HA synthesis persisted in inflammatory stages but was reduced in the remission phase. In agreement, quantification of CS and HA disaccharides by high performance liquid chromatography showed a reduction of CS-4S, the most abundant CS GAG fraction, and an increase in HA during peak EAE. Taken together, the presented results indicate that in vivo assessment of tissue microstructure using MRE may aid monitoring the pathological processes underlying disease development. Moreover, GAGs remodeling of within the ECM could be interesting targets for development of imaging probes or for interventional therapies able to hinder disease progression.