The failure of multiple sclerosis lesions to resolve in the months after they form leads to smouldering demyelination and axon degeneration (chronic active/slowly expanding lesions). To define mechanisms underlying this disabling, progressive neurodegenerative state, and to foster development of new therapeutics, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation and compared with healthy control white matter. Overall design: Human single-nucleus RNA profiles collected from 5 progressive multiple sclerosis autopsy brains (sampling of the lesion core,the edge and the periplaque of chronic active vs inactive MS lesions) and 3 healthy controls autopsy brains via 10X Genomics protocol.