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. 2024 Jun;271(6):3203-3214.
doi: 10.1007/s00415-024-12240-4. Epub 2024 Mar 5.

The cognitive relevance of non-lesional damage to cortical networks in people with multiple sclerosis

Eva A Krijnen  1   2   3 , Tommy A A Broeders  4 , Samantha Noteboom  4 , Maureen van Dam  4 , Albulena Bajrami  4   5 , Piet M Bouman  4 , Frederik Barkhof  6   7 , Bernard M J Uitdehaag  8 , Eric C Klawiter  9 , Ismail Koubiyr  4 , Menno M Schoonheim  4
Affiliations

The cognitive relevance of non-lesional damage to cortical networks in people with multiple sclerosis

Eva A Krijnen et al. J Neurol. 2024 Jun.

Abstract

Background: Cognitive impairment, a common and debilitating symptom in people with multiple sclerosis (MS), is especially related to cortical damage. However, the impact of regional cortical damage remains poorly understood. Our aim was to evaluate structural (network) integrity in lesional and non-lesional cortex in people with MS, and its relationship with cognitive dysfunction.

Methods: In this cross-sectional study, 176 people with MS and 48 healthy controls underwent MRI, including double inversion recovery and diffusion-weighted scans, and neuropsychological assessment. Cortical integrity was assessed based on fractional anisotropy (FA) and mean diffusivity (MD) within 212 regions split into lesional or non-lesional cortex, and grouped into seven cortical networks. Integrity was compared between people with MS and controls, and across cognitive groups: cognitively-impaired (CI; ≥ two domains at Z ≤ - 2 below controls), mildly CI (≥ two at - 2 < Z ≤ - 1.5), or cognitively-preserved (CP).

Results: Cortical lesions were observed in 87.5% of people with MS, mainly in ventral attention network, followed by limbic and default mode networks. Compared to controls, in non-lesional cortex, MD was increased in people with MS, but mean FA did not differ. Within the same individual, MD and FA were increased in lesional compared to non-lesional cortex. CI-MS exhibited higher MD than CP-MS in non-lesional cortex of default mode, frontoparietal and sensorimotor networks, of which the default mode network could best explain cognitive performance.

Conclusion: Diffusion differences in lesional cortex were more severe than in non-lesional cortex. However, while most people with MS had cortical lesions, diffusion differences in CI-MS were more prominent in non-lesional cortex than lesional cortex, especially within default mode, frontoparietal and sensorimotor networks.

Keywords: Cognition; Cortical lesions; Diffusion; Multiple sclerosis; Networks.

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Conflict of interest statement

EAK, TAAB, and AB report no conflicts of interest; SN is supported by research grants from Atara Biotherapeutics, Merck and Biogen; MvD is supported by a research grant from BMS. PMB received research support from the Dutch MS Research Foundation; FB is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI, Prothena, is a consultant to Roche, Biogen, Merck, IXICO, Jansen, Combinostics, has research agreements with Novartis, Merck, Biogen, GE Healthcare, and Roche, and is co-founder & shareholder of Queen Square Analytics LTD; BMJU reports research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Immunic Therapeutics; ECK has received consulting fees from EMD Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1and TG Therapeutics, and received research funds from Abbvie, Biogen, and Genentech; IK received research grants from LabEx TRAIL and ARSEP and speakers’ honoraria from Celgene; MMS serves on the editorial board of Neurology and Frontiers in Neurology and Multiple Sclerosis Journal, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from EIP Pharma, Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck.

Figures

Fig. 1
Fig. 1
Cortical microstructural integrity measures in included participants. Mean diffusivity (MD) and fractional anisotropy (FA) in regions with non-lesional cortex in healthy controls (HC) and non-lesional and lesional cortex in people with multiple sclerosis (MS), divided into three cognitive subgroups: cognitively impaired (CI), mildly CI, cognitively preserved (CP) people with multiple sclerosis (MS). Inner lines denote quartiles (25–50–75%). Raw unadjusted p-values are shown. P-values surviving Bonferroni correction are marked with an asterisk (*)
Fig. 2
Fig. 2
Cortical microstructural integrity measures across functional networks in cognitive groups. Mean diffusivity (MD) Z-scores in regions with non-lesional and lesional cortex in cognitively preserved (CP) and cognitively impaired (CI) people with multiple sclerosis (MS) across functional networks. As no integrity alterations in cortical MD were detected in mildly CI-MS compared to either CP-MS or CI-MS, subsequent network analyses shown here focused on alterations in MD between CP-MS and CI-MS. Inner lines denote quartiles (25–50–75%). Raw unadjusted p-values are shown. P-values surviving Bonferroni correction are marked with an asterisk (*)
Fig. 3
Fig. 3
Visualization of the P-value distribution for the regional network differences in mean diffusivity Z-scores in people with multiple sclerosis versus healthy control. P-values were log-transformed to normalize the distribution and increase distinctiveness between networks
Fig. 4
Fig. 4
Association between mean diffusivity in the default mode network and average cognition in people with multiple sclerosis. Integrity (x-axis) and cognition (y-axis) measures shown in the figure are transformed to Z-scores based on data of the included healthy controls. Standardized Beta-coefficients (β) with 95% confidence interval (CI) are reported with corresponding p-value
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