Global functional connectivity reorganization reflects cognitive processing speed deficits and fatigue in multiple sclerosis

Background and purpose Cognitive impairment (CI) in multiple sclerosis (MS) is associated with bidirectional changes in resting‐state centrality measures. However, practicable functional magnetic resonance imaging (fMRI) biomarkers of CI are still lacking. The aim of this study was to assess the graph‐theory‐based degree rank order disruption index ( k D ) and its association with cognitive processing speed as a marker of CI in patients with MS (PwMS) in a secondary cross‐sectional fMRI analysis. Methods Differentiation between PwMS and healthy controls (HCs) using k D and its correlation with CI (Symbol Digit Modalities Test) was compared to established imaging biomarkers (regional degree, volumetry, diffusion‐weighted imaging, lesion mapping). Additional associations were assessed for fatigue (Fatigue Scale for Motor and Cognitive Functions), gait and global disability. Results Analysis in 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years) showed lower k D in PwMS than in HCs (median −0.30/−0.06, interquartile range 0.55/0.54; p = 0.009, Mann–Whitney U test), yielding acceptable yet non‐superior differentiation (area under curve 0.64). k D and degree in medial prefrontal cortex (MPFC) correlated with CI ( k D /MPFC Spearman's ρ = 0.32/−0.45, p = 0.019/0.001, n = 55). k D also explained fatigue ( ρ = −0.34, p = 0.010, n = 56) but neither gait nor disability. Conclusions k D is a potential biomarker of CI and fatigue warranting further validation.