Extended Data Fig. 1: Chronic active/slowly expanding rim lesions can be visualized with MRI in vivo.

a, Susceptibility-based axial MRI at three levels showing the chronic active MS lesions with paramagnetic rims (magnified view in the insets, arrows) of a 38-year-old man with progressive MS, who requires assistance to walk 100 meters without resting. Scale bar = 10 mm. b, MRI-pathology of a frontal periventricular chronic active/slowly expanding lesion in a man with progressive MS who died at age 59. On the serial in vivo T1-weighted coronal images (clinical MR images sensitive to both demyelination and axonal loss), the rim lesion clearly expanded over a period of 7 years. The lesion was classified as chronic active by histological analysis. Accumulation of iron-laden phagocytes (CD68 and Turnbull iron staining) was seen at the lesion edge. Smouldering demyelination can also be inferred by the co-presence of early (LFB+, blue) and late (PAS+, purple) myelin degradation products within phagocytes at the lesion edge. Most reactive GFAP+ astrocytes do not contain iron. Magnified views are shown in the insets. Scale bar = 20 μm (myelin PLP); 10 μm (LFB-PAS); 50 μm (CD68, Turnbull iron/CD68, Turnbull iron/GFAP). c, In vivo long-term evolution of PRLs: representative examples of persistent/stable, faded, and disappeared rims. d, Bar graph showing the evolution of PRLs in each MS case followed over time. All cases had >5 years of yearly MRI follow up, except for cases 2–4, where follow-up was between 3.5 and 5 years. e, Survival analysis showed that the median PRL survival time is about 7 years.