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Background: Cortical lesion subtypes' occurrence and distribution across networks may shed light on cognitive impairment (CI) in multiple sclerosis (MS)., Methods: In 332 people with MS, lesions were classified as intracortical, leukocortical or juxtacortical based on artificially generated double inversion-recovery images., Results: CI-related leukocortical lesion count increases were greatest within sensorimotor and cognitive networks ( p < 0.001). Only intracortical lesion count could distinguish between cognitive groups ( p = 0.024). Effect sizes were two- to four-fold larger than differences between MS phenotypes., Conclusion: In CI-MS, leukocortical lesions predominate, whereas intracortical lesions distinguish cognitive groups. Lesions' grey matter (GM) involvement might be decisive for cognition in MS, surpassing overall disease burden., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: E.A.K. and R.K. report no disclosures relevant to the manuscript. S.N. is supported by research grants from Atara Biotherapeutics, Merck and Biogen. F.B. is part of the steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena, serves as a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics, has research agreements with Merck, Biogen, GE Healthcare and Roche and is co-founder and shareholder of Queen Square Analytics Ltd. B.M.J.U. reports research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics. E.C.K. has received consulting fees from EMD Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1 and TG Therapeutics and received research funds from Abbvie, Biogen and Genentech. M.D. Steenwijk is supported by research grants from Atara Biotherapeutics, Merck and Biogen. M.M. Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project no. 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. I.K. has received research grants from LabEx TRAIL (Translational Research and Advanced Imaging Laboratory) and ARSEP (Fondation pour l’Aide à la Recherche sur la Sclérose En Plaques) and speakers’ honoraria from Celgene.

Background: Digital monitoring of people with multiple sclerosis (PwMS) using smartphone-based monitoring tools is a promising method to assess disease activity and progression., Objective: To study cross-sectional and longitudinal associations between active and passive digital monitoring parameters and MRI volume measures in PwMS., Methods: In this prospective study, 92 PwMS were included. Clinical tests [Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk test (T25FW), 9-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT)] and structural MRI scans were performed at baseline (M0) and 12-month follow-up (M12). Active monitoring included the smartphone-based Symbol Digit Modalities Test (sSDMT) and 2 Minute Walk Test (s2MWT), while passive monitoring was based on smartphone keystroke dynamics (KD). Linear regression analyses were used to determine cross-sectional and longitudinal relations between digital and clinical outcomes and brain volumes, with age, disease duration and sex as covariates., Results: In PwMS, both sSDMT and SDMT were associated with thalamic volumes and lesion volumes. KD were related to brain, ventricular, thalamic and lesion volumes. No relations were found between s2MWT and MRI volumes. NHPT scores were associated with lesion volumes only, while EDSS and T25FW were not related to MRI. No longitudinal associations were found for any of the outcome measures between M0 and M12., Conclusion: Our results show clear cross-sectional correlations between digital biomarkers and brain volumes in PwMS, which were not all present for conventional clinical outcomes, supporting the potential added value of digital monitoring tools., (© 2024. The Author(s).)