8 July 2021
Understanding the challenges of assessing cognitive function in patients recovering from COVID-19
While several initiatives have begun investigating the neuropsychological effects of COVID-19, the nature and causes of cognitive impairment found in COVID-19 survivors are not yet fully understood. In this article Operational Scientist, Iona Pickett, discusses the challenges faced by researchers assessing cognition in those recovering from COVID-19.
In a previous blog post, we discussed the emerging evidence that cognitive impairment may be a lasting consequence of COVID-19 infection. With mass vaccination efforts well underway, the long-term repercussions of the pandemic are becoming an increasingly important focus of research. While several databases, studies, and initiatives investigating the neuropsychological effects of COVID-19 have been launched in recent months [1-3], the nature and causes of cognitive impairment found in COVID-19 survivors are not yet fully understood. Evidence suggests that around a third of people recovering from COVID-19 experience cognitive impairments [4-6], including those with so-called “Long Covid”. Understanding the causes and nature of COVID-related cognitive impairment is an important step towards providing long-term care and support to COVID-19 survivors. This article discusses the scientific and practical challenges of assessing cognition in COVID-19 survivors during an ongoing pandemic.
Cognitive function following COVID-19
As more research explores the consequences of COVID-19, the nature of sustained cognitive impairment during and after recovery is becoming clearer [6-9]. Early estimates that neurological and/or cognitive impairments are present in approximately a third of COVID-19 survivors have been replicated [6,10,11], although inconsistency in study populations and definitions of cognitive or neurological impairment has resulted in some reports of cognitive deficits in up to 75-80% of COVID-19 survivors [12,13].
The cognitive domains suggested to be impaired following COVID-19 infection remain relatively broad, with deficits in attention, executive function, memory, and visuospatial processing being consistently identified [4, 13-18]. However, the precise profile and extent of cognitive impairment in COVID-19 survivors is not yet clear, in part due to inconsistency in cognitive domains assessed in each study.
How do we know what to assess?
Due to resource constraints and the time-sensitive nature of COVID-19 research, studies often aim to measure a range of cognitive, psychiatric, neurological, and biological outcomes [5, 15, 19], which can limit the ability to complete extensive and comprehensive cognitive assessments which would pinpoint the most affected cognitive domains. Researchers may focus on one or two cognitive domains or assessments, which can limit comparability between studies. This makes it difficult to build a full picture of the cognitive domains affected by COVID-19, and the relative severity of impairment in each domain.
In order to effectively assess cognition in COVID-19 survivors, researchers must balance the breadth of the cognitive battery with other factors, such as patient fatigue and resource constraints. While researchers could perform every available cognitive assessment in a single study, this would be expensive, time-consuming, and likely to induce boredom, fatigue, and frustration in participants. More importantly, this approach would also result in the collection of lots of unnecessary or irrelevant data.
A theory-driven approach to cognitive testing, conversely, would aim to target all domains which are expected or predicted to be impaired, without introducing redundancy or unnecessary additional testing. Designing a cognitive test battery for use in COVID-19 survivors is therefore particularly challenging as a) the expected domains of impairment are still unclear, and b) ongoing COVID-related fatigue may mean that the patient populations tire quicker than healthy adults, placing more emphasis on parsimony.
Other factors affecting cognition following COVID-19
Cognitive impairment isn’t the only long-term consequence of COVID-19. Many patients with COVID-19 related cognitive impairment also experience fatigue, as well as symptoms of depression and anxiety [15, 18]. Disentangling cognitive impairment caused by fatigue, depression, or anxiety from cognitive impairment directly caused by COVID-19 infection presents a further challenge for designing an informative test battery.
This is complicated even further by the heterogeneity of symptoms experienced by patients recovering from COVID-19. Research has shown that the incidence of negative cognitive and psychiatric outcomes differs between patients who have had mild COVID-19 , compared to those who have been hospitalised [4, 10, 12] received mechanical ventilation , or been admitted to ICU [5, 20]. The possibility that those with the most severe COVID-19 may also be cognitively impaired as a result of post-intensive care syndrome or post-viral fatigue syndrome , adds even more confounding factors into the mix.
To understand and account for the contribution of these factors to cognitive impairment in COVID-19 survivors, researchers may need to include some measures which assess fatigue, depression, and anxiety. Cognitive assessments should also be sensitive to, and ideally be able to discriminate between, smaller and larger degrees of impairment in order to capture differences in cognitive outcomes due to severity of COVID-19 infection.
Cognitive testing during a pandemic
Uncertainty in the profile of cognitive impairment in COVID-19 survivors is not the only challenge for researchers designing studies in this area. The unpredictable nature of the pandemic means that to guarantee meaningful data collection and effective resource use, study designs should be able to adapt to the ever-changing restrictions and lockdowns. Infection control procedures have limited the ability to conduct face-to-face in-clinic assessments, particularly in patient groups at elevated risk from COVID-19, such as those with dementia [8, 21]. Remote assessment methods, such as web-based testing, provide a valuable alternative to traditional data collection and can prevent the interruption of research due to increased COVID-19 restrictions.
Web-based assessments are a low-cost way to ensure research continuity and may also improve participation from typically under-represented groups , such as those unable to travel due to disability or socioeconomic factors. Although unsupervised, at-home assessments may increase concerns over performance validity, we have shown that web-based and lab-based delivery of several CANTAB tasks are broadly comparable across multiple performance indices, with the exception of reaction time measures . Therefore, web-based cognitive assessment may be a practical approach to cognitive testing during a pandemic.
Having said this, there are advantages to in-clinic assessment, including the ability to deliver and monitor pharmaceutical interventions or incorporate clinicians’ assessments or biomedical data into the study protocol. Thus, cognitive assessments which are validated for both in-clinic and web-based delivery provide researchers with flexibility which allows them to collect valuable data despite unpredictable changes in COVID-19 restrictions. CANTAB Connect Research offers both web-based and in-clinic task delivery and is capable of transferring in-clinic studies to web-based testing if restrictions come into force prior to the study start date which prevent in-person assessments.
When designing a study to assess cognition in COVID-19 survivors, researchers must make difficult choices about which assessments to include in their test battery. Typical trade-offs between breadth of assessment and efficient resource use are complicated by uncertainty in the profile of cognitive impairment. The contribution of other factors known to impact cognition, including fatigue, depression and ICU admission, must also be accounted for. Once these decisions have been made, researchers still have to contend with the unpredictable nature of the pandemic and must design studies which are robust to potential changes in restrictions to minimise research disruption.
- University of Glasgow. (2021, May 12). Major Long Covid Study Launched in Scotland. https://www.gla.ac.uk/news/headline_791487_en.html
- Collins, F. S. (2021, February 23). NIH launches new initiative to study “Long COVID”. https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-launches-new-initiative-study-long-covid
- McMakin, B. (2021, January 26). NIH launches database to track neurological symptoms associated with COVID-19. https://www.nih.gov/news-events/news-releases/nih-launches-database-track-neurological-symptoms-associated-covid-19
- Baker, H. A., Safavynia, S. A., & Evered, L. A. (2020). The 'third wave': impending cognitive and functional decline in COVID-19 survivors. British journal of anaesthesia., S0007-0912(20)30849-7. Advance online publication. https://doi.org/10.1016/j.bja.2020.09.045
- Helms, J., Kremer, S., Merdji, H., Schenck, M., Severac, F., Clere-Jehl, R., Studer, A., Radosavljevic, M., Kummerlen, C., Monnier, A., Boulay, C., Fafi-Kremer, S., Castelain, V., Ohana, M., Anheim, M., Schneider, F., Meziani, F. (2020). Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients. Crit Care., 24(1):491. doi: 10.1186/s13054-020-03200-1.
- Yates D. (2021.) A CNS gateway for SARS-CoV-2. Nat Rev Neurosci., 22(2):74-5. 3
- Vindegaard, N., & Benros, M. E. (2020). COVID-19 pandemic and mental health consequences: Systematic review of the current evidence. Brain, behavior, and immunity, 89, 531–542. https://doi.org/10.1016/j.bbi.2020.05.048
- de Erausquin, G. A., Snyder, H., Carrillo, M., Hosseini, A. A., Brugha, T. S., Seshadri, S., & CNS SARS-CoV-2 Consortium (2021). The chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning. Alzheimer's & dementia : the journal of the Alzheimer's Association, 17(6), 1056–1065. https://doi.org/10.1002/alz.12255
- Gulko, E., Oleksk, M. L., Gomes, W., Ali, S., Mehta, H., Overby, P., Al-Mufti, F., & Rozenshtein, A. (2020). MRI Brain Findings in 126 Patients with COVID-19: Initial Observations from a Descriptive Literature Review. AJNR. American journal of neuroradiology, 41(12), 2199–2203. https://doi.org/10.3174/ajnr.A6805
- Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Miao, X., Li, Y., & Hu, B. (2020). Neurologic Manifestations of Hospitalized Patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2020.1127
- Beaud V, Crottaz-Herbette S, Dunet V, et al Pattern of cognitive deficits in severe COVID-19 (2021). Journal of Neurology, Neurosurgery & Psychiatry, 92:567-568.
- Jaywant, A., Michael Vanderlind, W., Alexopoulos, G. S., Fridman, C. B., Perlis, R. H., & Gunning, F. M. (2020). Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19. In medRxiv. https://doi.org/10.1101/2020.10.28.20221887
- Woo, Marcel S.; Malsy, Jakob; Pöttgen, Jana; Seddiq Zai, Susan; Ufer, Friederike; Hadjilaou, Alexandros et al. (2020). Frequent neurocognitive deficits after recovery from mild COVID-19. Brain communications 2 (2), fcaa205. DOI: 10.1093/braincomms/fcaa205.
- Zubair A.S., McAlpine L.S., Gardin T., Farhadian S., Kuruvilla D.E., Spudich S. (2020). Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol., 77(8):1018–1027. doi:10.1001/jamaneurol.2020.2065
- Raman, B., Cassar, M., Tunnicliffe, E.M., Filippine, N., et al. (2020). Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge. medRxiv Preprint. doi: https://doi.org/10.1101/2020.10.15.20205054
- Ritchie, K., Chan, D., & Watermeyer, T. (2020). The cognitive consequences of the COVID-19 epidemic: collateral damage?. Brain Communications, 2,2, fcaa069, https://doi.org/10.1093/braincomms/fcaa069
- Pinna, P., Grewal, P., Hall, J.P., Tavarez, T., Dafer, R.M., Garg, R., Osteraas, N.D., Pellack, D.R., Asthana, A., Fegan, K., Patel, V., Conners, J.J., John, S., Silva, I.D.. (2020). Neurological manifestations and COVID-19: Experiences from a tertiary care center at the Frontline. J Neurol Sci., 415:116969. doi: 10.1016/j.jns.2020.116969. Epub 2020 Jun 3.
- Lu, Yiping; Li, Xuanxuan; Geng, Daoying; Mei, Nan; Wu, Pu-Yeh; Huang, Chu-Chung et al. (2020). Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study. EClinicalMedicine 25. DOI: 10.1016/j.eclinm.2020.100484
- Zhou, H., Lu, S., Chen, J., Wei, N., Wang, D., Lyu, H., Shi, C., & Hu, S. (2020). The landscape of cognitive function in recovered COVID-19 patients. Journal of psychiatric research, 129, 98–102.
- Hosey, M.M., Needham, D.M. (2020). Survivorship after COVID-19 ICU stay. Nat Rev Dis Primers 6, 60. https://doi.org/10.1038/s41572-020-0201-1
- Alonso-Lana, Silvia; Marquié, Marta; Ruiz, Agustín; Boada, Mercè (2020): Cognitive and Neuropsychiatric Manifestations of COVID-19 and Effects on Elderly Individuals With Dementia. In: Frontiers in aging neuroscience 12, S. 588872. DOI: 10.3389/fnagi.2020.588872.
- Backx, R., Skirrow, C., Dente, P., Barnett, J. H., & Cormack, F. K. (2020). Comparing Web-Based and Lab-Based Cognitive Assessment Using the Cambridge Neuropsychological Test Automated Battery: A Within-Subjects Counterbalanced Study. Journal of medical Internet research, 22(8), e16792. https://doi.org/10.2196/16792
Iona Pickett – Operational Scientist, Cambridge Cognition