Multiple sclerosis synaptic connectome: Insights from fluid biomarkers

Multiple sclerosis is a chronic immune-mediated and degenerative disease of the central nervous system. Increasing evidence highlights the role of brain network disconnection in the pathogenesis of clinical progression and irreversible disability accumulation in people with multiple sclerosis. Several pathologic changes contribute to multiple sclerosis-related disconnection, ranging from focal areas of demyelination and axonal transection to atrophy of both cortical and subcortical gray matter structures. In the last years, increasing evidence also suggests a prominent role of synaptic dysfunction in determining brain connectome changes in multiple sclerosis, but objective measures of such alterations are still lacking. In this scenario, the evolving landscape of fluid biomarkers might help to provide the first data on synaptic integrity in multiple sclerosis, as already investigated in primary neurodegenerative diseases, where research has led to the identification of synaptic proteins measurable in cerebrospinal fluid and blood. This review explores the relevance of synaptic dysfunction and loss in multiple sclerosis, as mirrored by synaptic proteins that may serve as fluid biomarker, with specific attention given to presynaptic markers (such as SNAP-25, VAMP-2, and β-synuclein), postsynaptic proteins (such as neurogranin and NPTX2), and astrocyte-derived proteins. The encouraging findings obtained to date, as well as ongoing methodological challenges, will be discussed, together with a proposal for future directions of research in the field, with regard to the need of defining the temporal dynamics of these markers and their relationship with neuroinflammatory and neurodegenerative processes.