Broad rim lesions are a novel pathological / morphologicaland imaging biomarker for rapid disease progression in Multiple Sclerosis (part 1)

Current Multiple Sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail due to insufficient understanding of its underlying mechanisms. This study analyzes a clinically well-characterized MS autopsy cohort comparing selected individuals with opposite disease trajectories of slow versus rapid progression by extensive unbiased histology and spatial transcriptomics. It unveils a novel lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of inflammation, enhanced antigen presentation and lymphocyte activation that is strongly linked to rapid progression. Validation through an independent TSPO-PET study confirms the association between lesions with a broad myeloid cell rim and disease progression. These findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting CNS intrinsic inflammation. Samples from broad rim lesions were investigated using spatial transcriptomics. For each sample 4 ROIs at the rim and 4 in the NAWM were selected and segmented into AOIs using CD68 as morphology marker.