Exploring the origin of gray matter damage in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune, demyelinating and degenerative disease that affects the central nervous system (CNS) in young adults (1). The course of MS is highly varied and unpredictable. In general, the disease is identified by episodes of reversible neurological deficits that are followed by progressive neurological deterioration over time (2). During disease progression, the immune system become malfunctional. Immune cells are recruited from the bloodstream to the CNS, where they initiate relapses. Leukocyte trafficking across the blood-brain barrier (BBB) is an essential step in the initiation of relapses. Leukocyte infiltration further triggers a disruption of the myelin sheath eventually leading to neuronal loss (3). MS has long been considered to primarily affect the white matter (WM). However, it has become increasingly clear that gray matter (GM) pathology is an important aspect of the disease. GM is responsible for the decrease of brain volume and is involved in the progression of the disease (1). GM pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological, and imaging studies have provided new insight in this field and form the basis of the most recent hypothesis on the pathogenesis of GM damage. Overall, this thesis aims to provide a comprehensive overview of the interplay between neuronal damage and inflammatory response throughout the course of MS via the analysis of both WM and GM pathology.