Cognitron task design and participant flow. Credit: Nature Communications (2025). DOI: 10.1038/s41467-025-62156-4

King's College London and Imperial College London, in collaboration with the UK MS Register, report a prevalent multiple sclerosis (MS) subtype marked by significant cognitive deficits with minimal motor impairment, a form of disability the authors state is currently unrecognized and untreated.

Cognitive problems in MS affect 40–70% of patients, can appear at any disease stage and across subtypes, and often affect work and quality of life more than physical impairment.

Standard neuropsychological assessments can be lengthy (several hours long) or narrowly focused. Cognition is not routinely measured in MS clinical trials where the focus tends to prioritize more obvious physical signs of the disease. Absence of reliable routine assessments excludes cognition from being part of phenotype definitions, making the impact, prevalence and severity of cognitive deficits unclear.

In the study, "Large-scale online assessment uncovers a distinct Multiple Sclerosis subtype with selective cognitive impairment, " published in Nature Communications, researchers optimized and deployed an automated online assessment to characterize MS-related cognitive deficits at population scale and to derive symptom-based phenotypes.

A total of 4, 526 UK MS Register members participated across three stages. Stage 1 invited 19, 188 registrants, with 3, 066 engaging. Stage 2 recorded 2, 696 engagements, including 1, 425 first-time participants for independent validation. Stage 3 enrolled 31 patients for in-person comparison with a standard neuropsychological assessment with trained examiners.

Stage 1 evaluated 22 online tasks on the Cognitron platform to gauge feasibility and MS discriminability, then selected a 12-task battery based on effect sizes, device sensitivity, and factor analysis spanning six latent domains. Accuracy was prioritized as the primary metric for most tasks due to weaker correlations with motor patient-reported outcomes.

Stage 2 administered the 12-task battery plus two object memory tasks and replicated discriminability in an independent cohort.

Stage 3 compared the online battery with a comprehensive in-person assessment and included the Nine-Hole Peg Test to index hand motor function.

Stage 1 and Stage 2 yielded high feasibility of use with over 70% finishing in a median single sitting of roughly 40 minutes.

Four symptom-based groups emerged when online thinking measures were combined with two motor questionnaires in Stage 2.

Stage 3 put the online battery side by side with an in-person clinic assessment of 31 people. Results from the two approaches matched closely for overall cognitive status. Of the 16 people the clinic tests labeled as cognitively impaired, the online battery identified 75%. Across all participants, the online battery classified 20 of 31 as impaired.

Authors conclude that a common MS subtype exists with minimal motor disability yet substantial cognitive problems, revealed only with detailed cognitive profiling and that a fully automated, large-scale online assessment is feasible for this selective cognitive subtype that standard motor-focused evaluations miss.

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More information: Annalaura Lerede et al, Large-scale online assessment uncovers a distinct Multiple Sclerosis subtype with selective cognitive impairment, Nature Communications (2025). DOI: 10.1038/s41467-025-62156-4  Journal information: Nature Communications

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