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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., Competing Interests: 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., (© 2024 The Authors.)

Background: Autoimmune limbic encephalitis (ALE) is a neurological disease characterised by inflammation of the limbic regions of the brain, mediated by pathogenic autoantibodies. Because cognitive deficits persist following acute treatment of ALE, the accurate assessment of long-term cognitive outcomes is important for clinical assessments and trials. However, evaluating cognition is costly and an unmet need exists for validated digital methods., Methods: In this cross-sectional validation study, we investigated whether a remote digital platform could identify previously characterised cognitive impairments in patients with chronic ALE and whether digital metrics would correlate with standard neuropsychological assessment and hippocampal volume. Patients with ALE who had a chronic and stable presentation and received a clinical diagnosis of ALE were recruited for this study. The cognitive performance of 21 patients with ALE and 54 age-matched healthy controls - enrolled via the University of Oxford (UK) Cognitive Neurology Lab testing programme - was assessed with a battery of 12 cognitive tasks from the Cognitron online platform. The platform was optimised with National Institute for Health and Care Research (NIHR) support to be deliverable remotely to elderly and patient groups. The primary outcome measure was behavioural performance and corresponding neuroimaging and neuropsychological assessment metrics., Findings: Between February 15, 2021, and April 21, 2022, 21 patients with ALE (mean age 63.01 years, 14 males) and 54 healthy controls (mean age 65.56 years, 23 males) completed the digital cognitive assessment. Patients with ALE performed significantly worse in memory, visuospatial abilities, executive function, and language. No impairments in digit & spatial span, target detection (attention) and emotion discrimination were observed. The global score on the online cognitive tasks correlated significantly with the established Addenbrooke's Cognitive Examination III (ACE) pen-and-paper test. Deficits in visuospatial processing and language were identified in ALE compared to controls using remote digital testing but not using the ACE, highlighting higher sensitivity of computerised testing to residual cognitive impairment. Finally, the hippocampal volumes of patients with ALE and healthy controls correlated with online cognitive scores., Interpretation: These findings demonstrate that subtle cognitive deficits in patients with chronic ALE, who often show full recovery in measures of disability and dependence on daily activities, are detectable using a remote online platform, which also relates to hippocampal atrophy. Such methods may facilitate the characterisation of cognitive profiles in complex neurological diseases. Future longitudinal studies designed to assess the utility of such digital methods for further clinical characterisation are needed., Funding: The Wellcome Trust, Medical Research Council, National Institute for Health Research, Rhodes Scholarship, and the Berrow Foundation Scholarship., Competing Interests: AH and PJH are co-directors and owners of H2 Cognitive Designs Ltd. AH is the director and owner of Future Cognition Ltd, which supports online cognitive studies and develops custom cognitive assessment software respectively. SRI has received honoraria/research support from UCB, Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, ADC therapeutics, Brain, CSL Behring, and ONO Pharma and receives licensed royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’ and has filed two other patents entitled “Diagnostic method and therapy” (WO2019211633 and US-2021-0071249-A1; PCT application WO202189788A1) and “Biomarkers” (PCT/GB2022/050614 and WO202189788A1). MH is a shareholder of Neu Health. No other author declares competing interests., (© 2024 The Author(s).)

Background: Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery., Methods: 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control ( N  = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N  = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia., Findings: COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore ( p =​​0.0037) and G_RT ( p  = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance., Interpretation: Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed., Funding: This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care., Competing Interests: Dr. Hampshire reports grants from UK Dementia Research Institute, grants from NIHR Imperial Biomedical Research Centre, and grants from NIHR, outside the submitted work; and is Co-director and owner of H2 Cognitive Designs Ltd and director and owner of Future Cognition Ltd, which support online cognitive studies and develop custom cognitive assessment software, respectively. Ms. Chatfield has nothing to disclose. Ms. Manktelow has nothing to disclose. Dr. Jolly has nothing to disclose. Mr. Trender has nothing to disclose. Dr. Hellyer reports being Chief Executive of H2 Cognitive Designs LTD, which provides a platform for online cognitive tests for remote assessment and receives remuneration for role. Ms. Del Giovane has nothing to disclose. Dr. Newcombe reports grants from Academy of Medical Sciences / The Health Foundation Clinician Scientist Fellowship during the conduct of the study. Ms. Outrim has nothing to disclose. Mr. Warne has nothing to disclose. Mr. Bhatti has nothing to disclose. Ms. Pointon has nothing to declare. Ms. Elmer has nothing to disclose. Dr. Sithole has nothing to disclose. Dr. Bradley reports grants from Funding for NIHR BioResource (IS-BRC-1215-20014) during the conduct of the study. Dr. Kingston has nothing to disclose. Dr. Sawcer has nothing to disclose. Dr. Bullmore reports personal fees from GlaxoSmithKline, personal fees from Sosei Heptares, outside the submitted work; and is Honorary Treasurer and member of Council for the Academy of Medical Sciences. Dr. Rowe reports grants from Wellcome Trust, grants from NIHR, grants from Medical Research Council, during the conduct of the study. Dr. Menon reports grants from Lantmannen AB, grants from GlaxoSmithKline Ltd, personal fees from Calico LLC, personal fees from GlaxoSmithKline Ltd, personal fees from Lantmannen AB, other from Integra Neurosciences, outside the submitted work; and reports leadership and fiduciary roles for Queens’ College, Cambridge, Intensive Care National Audit and Research Centre, London, and European Brain Injury Consortium., (© 2022 Published by Elsevier Ltd.)

Background: There is growing concern about possible cognitive consequences of COVID-19, with reports of 'Long COVID' symptoms persisting into the chronic phase and case studies revealing neurological problems in severely affected patients. However, there is little information regarding the nature and broader prevalence of cognitive problems post-infection or across the full spread of disease severity., Methods: We sought to confirm whether there was an association between cross-sectional cognitive performance data from 81,337 participants who between January and December 2020 undertook a clinically validated web-optimized assessment as part of the Great British Intelligence Test, and questionnaire items capturing self-report of suspected and confirmed COVID-19 infection and respiratory symptoms., Findings: People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised ( N  = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection ( N  = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition., Interpretation: Interpretation. These results accord with reports of 'Long Covid' cognitive symptoms that persist into the early-chronic phase. They should act as a clarion call for further research with longitudinal and neuroimaging cohorts to plot recovery trajectories and identify the biological basis of cognitive deficits in SARS-COV-2 survivors., Funding: Funding. AH is supported by the UK Dementia Research Institute Care Research and Technology Centre and Biomedical Research Centre at Imperial College London. WT is supported by the EPSRC Centre for Doctoral Training in Neurotechnology. SRC is funded by a Wellcome Trust Clinical Fellowship 110,049/Z/15/Z. JMB is supported by Medical Research Council (MR/N013700/1). MAM, SCRW and PJH are, in part, supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London., Competing Interests: Dr. Hampshire reports grants from UK Dementia Research Institute, outside the submitted work and is Co-director and owner of H2CD Ltd, and owner and director of Future Cognition Ltd, which support online studies and develop custom cognitive assessment software respectively. Dr. Hellyer reports personal fees from H2CD Ltd, outside the submitted work. Dr. Chamberlain reports grants from Wellcome, personal fees from Elsevier, personal fees from Prometis (not current), outside the submitted work. Dr. Grant reports grants from Otsuka, grants from Biohaven, grants from Avanir, outside the submitted work. Dr. Patrick reports grants from H Lundbeck A/S, non-financial support from Astra Zeneca, non-financial support from Janssen, outside the submitted work. Dr. Mehta reports grants from H Lundbeck A/S, non-financial support from Astra Zeneca, non-financial support from Janssen, outside the submitted work. Dr. Williams has nothing to disclose. Dr. Mazibuko has nothing to disclose. Dr. Jolly has nothing to disclose. Mr. Trender has nothing to declare. Dr. Barnby has nothing to disclose., (© 2021 The Author(s).)