Changes in memory and cognition during the SARS-CoV-2 human challenge study.

Background

Patient-reported outcomes and cross-sectional evidence show an association between COVID-19 and persistent cognitive problems. The causal basis, longevity and domain specificity of this association is unclear due to population variability in baseline cognitive abilities, vulnerabilities, virus variants, vaccination status and treatment.

Methods

Thirty-four young, healthy, seronegative volunteers were inoculated with Wildtype SARS-CoV-2 under prospectively controlled conditions. Volunteers completed daily physiological measurements and computerised cognitive tasks during quarantine and follow-up at 30, 90, 180, 270, and 360 days. Linear modelling examined differences between 'infected' and 'inoculated but uninfected' individuals. The main cognitive endpoint was the baseline corrected global cognitive composite score across the battery of tasks administered to the volunteers. Exploratory cognitive endpoints included baseline corrected scores from individual tasks. The study was registered on ClinicalTrials.gov with the identifier NCT04865237 and took place between March 2021 and July 2022.

Findings

Eighteen volunteers developed infection by qPCR criteria of sustained viral load, one without symptoms and the remainder with mild illness. Infected volunteers showed statistically lower baseline-corrected global composite cognitive scores than uninfected volunteers, both acutely and during follow up (mean difference over all time points = -0.8631, 95% CI = -1.3613, -0.3766) with significant main effect of group in repeated measures ANOVA (F (1,34) = 7.58, p = 0.009). Sensitivity analysis replicated this cross-group difference after controlling for community upper respiratory tract infection, task-learning, remdesivir treatment, baseline reference and model structure. Memory and executive function tasks showed the largest between-group differences. No volunteers reported persistent subjective cognitive symptoms.

Interpretation

These results support larger cross sectional findings indicating that mild Wildtype SARS-CoV-2 infection can be followed by small changes in cognition and memory that persist for at least a year. The mechanistic basis and clinical implications of these small changes remain unclear.

Funding

This study was funded through the UK Vaccine Taskforce of the Department for Business, Energy and Industrial Strategy (BEIS) of Her Majesty's Government. WT was funded by the EPSRC through the CDT for Neurotechnology Imperial College London.

Informations de copyright

© 2024 The Authors.

Déclaration de conflit d'intérêts

AH is founder and director of Future Cognition Ltd and H2 Cognitive Designs, which develop custom cognitive assessment tasks and provide online assessment services respectively, primarily within the academic research sector. CC had funding to institution from the UK Vaccine Task Force and Wellcome Trust. DM had support for the present manuscript in the form of payments to the institution from the UKRI (UKRI, The COVID-19: Clinical Neuroscience Study (COVID-CNS) (Co-I) and UKRI. Convalescent plasma for COVID-19 patients (Co-I)), the Addenbrooke's Charitable Trust (COVID-19: understanding its long-term respiratory, cardiac and neuro-psychiatric sequelae and the determinants of adverse outcomes), the NIHR (NIHR Cambridge Biomedical Research Centre). They also received support unrelated to the current manuscript in the form of consultancy fees and research support from: Neurotrauma Sciences, Lantmannen AB, GlaxoSmithKline Ltd and PressuraNeuro Ltd. EN received a portion of their salary from Brain Research UK during the periods in question. PJH is Co-founder and director of H2 Cognitive Designs LTD, which markets online cognitive testing platforms for healthcare and research. In this role he receives Remuneration. RT received support for the present manuscript from UK Vaccine Taskforce of the Department of Business, Energy and Industrial Strategy of Her Majesty's Government (BEIS) and the Wellcome Trust (grant no. 224530/Z/21/Z). Also payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca. WT is employed by H2 Cognitive Designs LTD, which markets online cognitive testing platforms for healthcare and research. AJM is a holder of shares in hVIVO Ltd and an employee of hVivo Ltd. MK, GS, BK and APC have no declarations of interest.