Global Rearrangement of Degree Centrality Reflects Cognitive Impairment and Fatigue in Multiple Sclerosis

Background and Objectives: The aim of this secondary data analysis was to determine whether multiple sclerosis (MS) is associated with changes in global degree rank order disruption index (kD), a graph theory-based functional connectivity measure representing shift in overall distribution of nodal degree centrality. Additionally, we tested the relationship between kD and MS symptoms (cognitive and motor impairment, fatigue, and global disability). Methods: Global kD was computed in a pre-existing cross-sectional fMRI dataset and compared between patients with MS (PwMS) and healthy controls (HCs). Group differentiation was tested against other known biomarkers in MS (regional degree centrality, structural MRI with volumetry, diffusion-weighted imaging, lesion mapping) using receiver operating characteristic and logistic regression analysis. Associations between kD and cognitive processing speed (Symbol Digit Modalities Test), fatigue (Fatigue Scale for Motor and Cognitive Functions), gait (Timed Up and Go Test), and disability (Expanded Disability Status Scale [EDSS]) were evaluated using Spearman correlation coefficient and ordinal regression adjusted for structural imaging, age, sex, and disease duration. Results: Analysis included 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years). Global kD was lower in PwMS (median −0.30, inter-quartile range [IQR] 0.55) than in HCs (median −0.06, IQR 0.54; p = 0.009, Mann-Whitney U test). kD yielded acceptable differentiation between groups (area under curve 0.64), but did not improve such differentiation on top of structural imaging. Both kD and regional degree in medial prefrontal cortex (MPFC) were correlated with cognitive decline (kD: Spearman's ρ = 0.32, p = 0.019; MPFC: ρ = −0.45, p = 0.001, n = 55), while kD was also correlated with fatigue (ρ = −0.34, p = 0.010, n = 56), but not with EDSS (ρ = −0.06, p = 0.674, n = 56) or gait (ρ = −0.18, p = 0.211, n = 52). kD significantly explained cognitive impairment (χ2 = 4.49, p = 0.034) and fatigue (χ2 = 7.18, p = 0.007). Discussion: Our data provide evidence that kD is a potential biomarker of cognitive decline and fatigue. Further cross-validations are required to assess its generalizability. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement P. Hok was awarded a Gerhard-Domagk fellowship by University Medicine Greifswald for undertaking this study. K. Řasova was supported by Charles University, programme Cooperatio (Neuroscience) and 260648/SVV/2024. J. Hlinka was supported by the ERDF-Project Brain dynamics, No. CZ.02.01.01/00/22_008/0004643. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of the Faculty Hospital Kralovske Vinohrady gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data not provided in the article because of space limitations may be shared (anonymized) at the request of any qualified investigator for purposes of replicating procedures and results, upon signing a data sharing agreement. Part of the dataset (imaging data for 60 PwMS with the respective global disability and motor scales) is publicly available in an on-line repository at https://osf.io/p2kj7/. The custom Matlab script for kD calculation is available at https://github.com/pavelhok/calculate_kd/tree/MS-project.