Background: Multiple sclerosis (MS) is characterized by both acute and chronic intrathecal inflammation. A subset of MS lesions show paramagnetic rims on susceptibility-weighted MRI sequences, reflecting iron accumulation in microglia. These paramagnetic rim lesions (PRLs) have been proposed as a marker of compartmentalized smoldering disease. PRLs have been demonstrated at 7 T and, more recently, at 3 T. As susceptibility effects are weaker at lower field strength, it remains unclear if PRLs are visible at 1.5 T. Objective: To compare the visualization of PRLs using susceptibility-weighted imaging at 1.5-T and 3-T MRI in patients with MS. Methods: This retrospective study included 9 patients (5 women, 4 men; mean age, 46.8 years) with MS who underwent both 1.5-T and 3-T MRI using a comparable susceptibility-weighted sequence from the same manufacturer (GE SWAN). Lesions measuring >3 mm were annotated. Two reviewers independently assessed images at each field strength in separate sessions, classifying the annotated lesions based on susceptibility-weighted images as isointense, diffusely paramagnetic, or PRL. Discrepancies were discussed at consensus sessions including a third reviewer. Agreement was assessed using kappa coefficients. Results: Of 140 annotated lesions, based on the 3-T consensus readings, 115 (82%) were isointense, 16 (11%) were diffusely paramagnetic, and 9 (6%) were PRLs; based on the 1.5-T consensus readings, 115 (82%) were isointense, 14 (10%) were diffusely paramagnetic, and 11 (8%) were PRLs. Mean lesion diameter was 11.9 mm for PRLs, versus 6.4 mm for diffusely paramagnetic lesions (p=.006) and 7.8 mm for isointense lesions (p=.003). Interrater agreement for lesion classification as PRL was substantial at 1.5 T (kappa=0.65) and 3 T (kappa=0.70). Agreement for PRL was also substantial between the consensus readings at the two field strengths (kappa=0.79). Conclusion: We show comparable identification of PRLs at 1.5-T and 3-T MRI, with substantial interrater agreement at both field strengths and substantial consensus agreement between the field strengths. Clinical Impact: PRL may be an emerging marker of chronic neuroinflammation in MS. Their visibility at 1.5 T supports the translational potential of PRL identification to more widespread clinical settings, where 1.5-T scanners are prevalent.

Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans(1-3). Here, to define mechanisms underlying this disabling, progressive neurodegenerative state(4-6) and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using postmortem human MS tissue, a preclinical nonhuman primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system. Similar to other neurodegenerative diseases, microglial synaptic engulfment and profound synapse loss were observed. In mice, synapse loss occurred independently of local demyelination and neuronal degeneration but coincided with gliosis and increased complement component C3, but not C1q, at synapses. Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreased microglial engulfment of synapses and protected visual function. These results indicate that microglia eliminate synapses through the alternative complement cascade in demyelinating disease and identify a strategy to prevent synapse loss that may be broadly applicable to other neurodegenerative diseases. VIDEO ABSTRACT.