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

Abstract

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 (kD) 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 kD 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 kD 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). kD and degree in medial prefrontal cortex (MPFC) correlated with CI (kD/MPFC Spearman's ρ = 0.32/−0.45, p = 0.019/0.001, n = 55). kD also explained fatigue (ρ = −0.34, p = 0.010, n = 56) but neither gait nor disability. Conclusions: kD is a potential biomarker of CI and fatigue warranting further validation.