Spatiotemporal Evolution of Inflammatory Demyelinating Lesions in Cerebral White Matter
Lee, Nathanael J
Reich, Daniel S
Huang, Jeffrey K
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) affecting millions of patients worldwide. Despite its prevalence, the disease is imperfectly characterized and does not have a definitive cure. MS patients develop characteristic lesions in the CNS that have different pathological features depending on the stage of lesion development, providing an opportunity to investigate how such lesions develop. However, MS tissue is often not readily available for such pathological analyses.Experimental autoimmune encephalomyelitis (EAE) in the common marmoset (Callithrix jacchus) recapitulates many radiological and pathological features of MS lesions in the white matter that are not evident in rodent models, thus providing an opportunity to investigate how the lesions develop, as well as the different factors involved in lesion pathogenesis, evolution, and repair. Among different factors involved, the dissertation project focused on elucidating the role and involvement of two specific molecules: fibrinogen as an early, acute marker of the disease pathobiology; and iron as a late, chronic marker. Utilizing various magnetic resonance imaging sequences specifically developed for marmoset brain imaging, as well as histopathological staining protocols optimized for marmoset brain tissue, my work demonstrates that fibrinogen and iron both show different, specific spatiotemporal dynamics and involvement in the evolution of inflammatory demyelinating lesion pathobiology.The first project demonstrates that fibrinogen is a marker of an early, active stage of EAE lesion development, and corroborates the idea that fibrinogen may be pathogenic in inflammatory demyelinating lesion formation. The second study shows that intralesional iron is deposited in the subacute stage of lesion development, specifically in the perivascular region of chronic EAE lesions. The timing and the localization of the accumulation, and its relation to various markers of inflammation, injury, and disease progression, suggest that iron may not be pathogenic in EAE lesion development; rather, it may be needed for repair.
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