Changes in memory and cognition during the SARS-CoV-2 human challenge study
William Trender, Peter J Hellyer, Ben Killingley, Mariya Kalinova, Alex J Mann, Andrew P Catchpole, David Menon, Edward Needham, Ryan Thwaites, Christopher Chiu, Gregory Scott, Adam Hampshire
eClinicalMedicine, doi:10.1016/j.eclinm.2024.102842
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.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi. org/10.1016/j.eclinm.2024.102842.
References
Amalakanti, Arepalli, Jillella, Cognitive assessment in asymptomatic COVID-19 subjects, VirusDisease
Bland, Barraclough, Trender, Profiles of objective and subjective cognitive function in Post-COVID Syndrome, COVID-19 recovered, and COVID-19 naïve individuals, Sci Rep
Brutto, Rumbea, Recalde, Mera, Cognitive sequelae of long COVID may not be permanent: a prospective study, Eur J Neurol
Brutto, Wu, Mera, Costa, Recalde et al., Cognitive decline among individuals with history of mild symptomatic SARS-CoV-2 infection: a longitudinal prospective study nested to a population cohort, Eur J Neurol
Burden, Long, Collaborators, Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021, JAMA
Cheetham, Penfold, Giunchiglia, The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study, eCli-nicalMedicine,
doi:10.1016/j.eclinm.2023.102086Douaud, Lee, Alfaro-Almagro, SARS-CoV-2 is associated with changes in brain structure in UK Biobank, Nature
Drefahl, Wallace, Mussino, A population-based cohort study of socio-demographic risk factors for COVID-19 deaths in Sweden, Nat Commun
Ellingjord-Dale, Brunvoll, Søraas, Prospective memory assessment before and after Covid-19, N Engl J Med
Ellul, Varatharaj, Nicholson, Defining causality in COVID-19 and neurological disorders, J Neurol Neurosurg Psychiatry
Evans, Mcauley, Harrison, Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study, Lancet Respir Med
França, Bitencourt, Maximilla, Barros, Monserrat, Hippocampal neurogenesis and pattern separation: a meta-analysis of behavioral data, Hippocampus
Frontera, Boutajangout, Masurkar, Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementia, Alzheimers Dement
Godoy-González, Ventura, Gomà, Objective and subjective cognition in survivors of COVID-19 one year after ICU discharge: the role of demographic, clinical, and emotional factors, Crit Care
Hampshire, Azor, Atchison, Cognition and memory after covid-19 in a large community sample, N Engl J Med
Hampshire, Chatfield, Mphil, Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort, eClinicalMedicine
Hampshire, Highfield, Parkin, Owen, Fractionating human intelligence, Neuron
Killingley, Mann, Kalinova, Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults, Nat Med
Lan, Filler, Mathew, Sociodemographic risk factors for coronavirus disease 2019 (COVID-19) infection among Massachusetts healthcare workers: a retrospective cohort study, Infect Control Hosp Epidemiol
Liu, Chen, Wang, One-year trajectory of cognitive changes in older survivors of COVID-19 in Wuhan, China: a longitudinal cohort study, JAMA Neurol
Miskowiak, Pedersen, Gunnarsson, Cognitive impairments among patients in a long-COVID clinic: prevalence, pattern and relation to illness severity, work function and quality of life, J Affect Disord
Needham, Ren, Digby, Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses, Brain
Pihlaja, Kauhanen, Ollila, Associations of subjective and objective cognitive functioning after COVID-19: a sixmonth follow-up of ICU, ward, and home-isolated patients, Brain Behav Immun Health
Rapeport, Smith, Gilbert, Catchpole, Mcshane et al., SARS-CoV-2 human challenge studiesestablishing the model during an evolving pandemic, N Engl J Med
Smith, Twenty-five years of research on the behavioural malaise associated with influenza and the common cold, Psychoneuroendocrinology
Soreq, Leech, Hampshire, Dynamic network coding of working-memory domains and working-memory processes, Nat Commun
Taquet, Skorniewska, Hampshire, Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization, Nat Med
Zhao, Shibata, Hellyer, Rapid vigilance and episodic memory decrements in COVID-19 survivors, Brain Commun
Zhou, Lu, Chen, The landscape of cognitive function in recovered COVID-19 patients, J Psychiatr Res
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'volume': '324',
'author': 'Miskowiak',
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'year': '2017',
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'author': 'Ellingjord-Dale',
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'DOI': '10.1186/s13054-023-04478-7',
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'after ICU discharge: the role of demographic, clinical, and emotional '
'factors',
'volume': '27',
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