Network analysis of intrathecally synthesized proteins to unravel mechanisms of disease course in multiple sclerosis

Multiple sclerosis (MS) is a heterogeneous disease, in both clinical presentation and neuro-immunopathology. Proteins secreted into the cerebrospinal fluid (CSF) can serve as molecular proxies of these pathologies in the central nervous system (CNS) but are biased by leakage of serum proteins into the CSF. Thus, a detailed analysis of intrathecal protein production, i.e., the fraction of CSF protein synthesized locally within the CNS, rather than derived from passive transfer across the blood-CSF barrier, can provide valuable insights into the heterogenous immunological and neurodegenerative processes at play. To understand the dynamic biological processes involved in MS disease course mechanisms, we used network analysis to untangle the intricacies of intrathecally produced protein-to-protein relationships in 60 patients diagnosed with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and primary progressive MS (PMS). These analyses revealed distinct immunological phenotypes linked to inflammation and neurodegeneration in the CNS in each disease course, providing novel insight into the disease course-specific pathophysiology of MS.