Integrative neuropathological and imaging study of multiple sclerosis: mechanisms of inflammation in intrathecal niches

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system characterized by persistent neuroinflammation, demyelination, and neurodegeneration. In MS, inflammation becomes compartmentalized within intrathecal niches, including the meninges, choroid plexus (CP), and perivascular spaces, sustaining chronic immune activation. Histopathological analysis of 40 MS cases identified subgroups defined by the presence or absence of tertiary lymphoid-like structures (TLS), which are associated with cortical demyelination and neuronal loss. Spatial transcriptomics revealed upregulation of genes involved in antigen presentation and immune response, with B cell signatures enriched in TLS+ cases and enhanced MHC class II activity in TLS- cases. TSPO emerged as a key marker of innate neuroinflammatory activation in microglia and macrophages, validated in vivo using TSPO-PET imaging. The CP acts as a critical immunological interface, showing infiltration by macrophages and lymphocytes, complement activation, and expression of inflammatory mediators. CSF cytokines partially reflected CP pathology, linking it to ongoing neuroinflammation in progressive disease. Quantitative MRI revealed enlarged CP volumes and microstructural changes, particularly in relapsing-remitting MS, correlating with periventricular, thalamic, and cortical damage. These findings reveal heterogeneous inflammatory phenotypes in MS and highlight meningeal inflammation, microglial activation, and CP immune dysregulation as key contributors to disease progression, providing a foundation for targeted therapeutic strategies.