Clinical and MRI substrates of Symbol Digit Modalities Test impairment in multiple sclerosis patients with an adult- and late-onset

Background: Multiple sclerosis (MS) onset occurs at diverse ages. Age of onset impact on clinical, brain MRI, and cognitive profiles remains unclear. We investigated the substrates of Symbol Digit Modalities Test (SDMT) impairment in patients with late-onset MS (LOMS) (⩾45 years) compared to adult-onset MS (AOMS) (<45 years). Methods: 294 AOMS and 80 LOMS patients with disease duration of maximum 6 years from symptom onset and 519 healthy controls were retrospectively included from a multicenter MAGNIMS data set. We assessed between-group differences and correlates of SDMT impairment measuring lesion volume (LV), atrophy, global, intra- and inter-hemispheric structural connectivity and disconnection indices. Results: 38% LOMS were impaired on SDMT compared to 39% AOMS (p = 0.751). LOMS showed higher LV (FDR-p = 0.018), gray matter (GM) atrophy (FDR-p = 0.050), intra- and inter-hemispheric disconnection compared to AOMS (all FDR-p < 0.028). Furthermore, LOMS showed higher modularity (FDR-p = 0.018) and decreased density (FDR-p < 0.001). Substrates of SDMT impairment were intra-hemispheric disconnection, LV, clustering coefficient, mean strength and efficiency (AUC = 0.730) in AOMS and commissural ratio and GM atrophy (AUC = 0.760) in LOMS. Conclusions: Substrates contributing to SDMT impairment differ between these two distinct cohorts, being primarily driven by network dysfunction in AOMS and neurodegenerative processes in LOMS.