Progressive multiple sclerosis (MS) is driven by demyelination, neuroaxonal loss, and mitochondrial damage occurring behind a closed blood-brain barrier (BBB). 1,2 Patients with progressive MS typically fail to respond to available immunomodulatory drugs that reduce relapses in early disease. 2 This indicates a dire need to identify non-canonical therapeutic avenues to limit neurodegeneration and promote protection and repair. 3 Here, we have employed high-resolution multiomic profiling to characterise the biochemical and metabolic adaptations underpinning MS pathology, as these have been incompletely described but critically, may be amenable to BBB-permeable drug targeting. Using synchrotron radiation (SR)- and focal plane array (FPA)-based Fourier transform infrared microspectroscopy (μFTIR), we spatially mapped the biochemical features present in human progressive MS and control post-mortem brain and rare spinal cord tissue. By employing single-nuclear RNA sequencing (snRNA-seq), 10x Genomics Visium spatial transcriptomics and spatial proteomics to resolve their cellular context, we found that these biochemical features provide a uniquely and highly disease-specific barcode for distinct pathological niches within the tissue. Characterisation of the metabolic processes underpinning these niches revealed an associated re-organisation of the astrocytic landscape in the grey and white matter, with implications for the treatment of progressive MS.
