Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions

• DOI: 10.1007/s00401-024-02742-w
• Publication Date: 2024-05-21T04:01:28Z
• Authors: Alyse de Boer; Aletta M. R. van ...; Nienke J. Mekkes; Nina L. Fransen; Ekaterina Dagkesa...; Eric Hoekstra; Jörg Hamann; Joost Smolders; Inge Huitinga; Inge R. Holtman
• Keywords: Identification; Neuropathology

Abstract Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative qualitative neuropathology data collected for 226 donors in Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified subsequently validated clinical, neuropathological, genetic data. Dimension 1 ranged from predominance remyelinated inactive lesions extensive pathological changes, higher proportions active mixed lesions, foamy microglia morphology. This pattern was positively correlated more severe disease, presence B T cells, neuroaxonal damage. Scoring high dimension 2 associated reactive sites, nodules. These had less specific cortical risk variants human leukocyte antigen region, latter indicating connection between disease onset this neuropathological dimension. Donors scoring 3 showed increased lesional pathology relatively ramified longer duration, subpial involvement adaptive immune system, axonal Taken together, three may represent (1) demyelination cell activity progression, (2) (re)activity possibly lesion initiation, (3) loss scar formation. Our findings highlight that thorough understanding interplay multiple characteristics crucial understand pathology, as well its association predictors outcomes. The scores can serve important starting point further disentanglement translation into observations interventions living cohorts MS.