Investigating the impact of different dichotomous definitions for cognitive impairment on functional connectivity in secondary progressive MS

Background: Altered brain network function is associated with cognitive impairment in multiple sclerosis (MS), but recent studies highlight a lack of consensus in the field. These differences may relate to the stage of MS, or different definitions for cognitive impairment. Objective: We investigated cognitive impairment and functional connectivity (FC) specifically in SPMS (secondary progressive MS) using resting-state functional MRI (rs-fMRI) and assessed the alterations in FC using two commonly used dichotomous criteria for cognitive impairment. Methods: 65 SPMS subjects from a British cohort underwent rs-fMRI at 3T, with independent component analysis of resting state networks. Cognitive impairment, assessed by neuropsychometry, was defined using a z-score of ≤ -1.96SD on ≥ 2 domains (-1.96SD group) or z-score of ≤ -1.5SD on ≥ 2 domains (-1.5SD group). Results: Cognitive impairment was, as expected, more prevalent in the -1.5SD (47 %) than -1.96SD criteria (30 %) group, despite similar demographics in both; mean age of 55 ± 7.1 years, disease duration 22 ± 9.6 years, median EDSS of 6.0 [range 4.0–6.5]. Adopting the -1.96SD criteria substantially increased the number of altered brain regions, with a 2.8 fold increase in regions showing decreased FC; including the ventral attentional and sensorimotor networks, and 1.5 fold increase in regions showing increased FC; including the precuneus and auditory networks. Conclusions: The criteria chosen for cognitive impairment significantly impacts patterns of global FC change and may miss key network alterations, which could impact the efficacy of future therapeutic interventions highlighting the need for a consensus in the field. Agreed cut-offs for designating cognitive impairment could facilitate clinical management including monitoring disease activity, progression, and treatment efficacy.