By Ellen Feldman, MD
Altru Health System, Grand Forks, ND
SYNOPSIS: A large observational study finds objective evidence of lingering cognitive deficits associated with past COVID-19 infection, particularly in patients infected early in the pandemic, those hospitalized, or those with prolonged illness duration.
SOURCE: Hampshire A, Azor A, Atchison C, et al. Cognition and memory after COVID-19 in a large community sample. N Eng J Med 2024;390:806-818.
Is there objective evidence of persistent cognitive deficits after COVID-19 infection? While many reports highlight “brain fog” during and after COVID-19, objective data defining this phenomenon have been limited.1,2
This large-scale observational study conducted in England attempted to fill the gap in understanding the cognitive impact of COVID-19 by inviting 800,000 adults from a larger, randomly selected community sample to participate in online cognitive assessments.
The initial study, the Real-Time Assessment of Community Transmission (REACT), tracked participants from May 2020 until March 31, 2022, and included individuals with documented COVID infections as well as those who never tested positive, providing a comprehensive comparison of cognitive functioning across these groups.3
Of the original 800,000 subgroup, 112,964 individuals completed online tests measuring various cognitive domains, such as immediate and delayed memory, working memory, executive functioning (e.g., planning), reasoning, and spatial manipulation. A global cognitive score was calculated based on the cumulative score.
The participants were then categorized into six groups reflecting the duration and severity of their COVID-19 infection, ranging from no infection (category 1) to asymptomatic (category 2) to continued symptoms at time of assessment (category 6). Global cognitive score distribution for each of these categories was plotted, allowing mean scoring and standard deviation (SD) to be calculated.
Key Findings
Note that no baseline cognitive scores were available. All results are based on shifts in the mean global cognitive score for each category:
- Cognitive deficits: Cognitive deficits, especially in areas of memory, executive functioning and reasoning, persisted for more than a year in many individuals post-COVID-19 and were most pronounced in those with more severe illness and/or in those who were hospitalized. The severity of cognitive impairment correlated with the duration and severity of the illness.
For example, individuals reporting disease lasting longer than 12 weeks had greater cognitive deficits than those who had never been infected (SD, -0.42). This difference correlated with an approximate loss of 6 intelligence quotient (IQ) points. On the other hand, people with shorter durations of illness (four to 12 weeks) showed smaller cognitive deficits of -0.23 to -0.24 SD, equivalent to a loss of 3 IQ points. - Intensive care unit (ICU) admission: Hospitalization and, particularly, ICU admission were correlated with more pronounced cognitive deficits (-0.63 SD), equivalent to a loss of about 9 IQ points.
- Vaccination: Vaccinated individuals showed less significant cognitive deficits compared to unvaccinated peers. This finding suggests that vaccination may play a role in preserving cognitive functioning as well mitigating the severity of the illness.
- Variants: When comparing individuals who had contracted COVID-19 during the pandemic, those infected earlier (presumably with the initial virus or Alpha variant) showed greater cognitive impairment than those infected during later waves of the pandemic (P < 0.001). This suggests the variant of the virus might influence the extent of cognitive deficits experienced by an individual.
Commentary
This study provides robust evidence of the long-term cognitive effects of COVID-19, with results pointing toward persistent deficits in memory and executive functioning. Executive functioning includes areas such as planning, attention, and self-control, and it is a key factor in the performance of daily activities. Deficits in these areas likely are clinically meaningful. These findings underscore the need for increased awareness and resources to support and strengthen the cognitive health of COVID-19 survivors. Most importantly, ongoing research is needed to fully understand the long-term trajectory of the impairments and to develop effective interventions.
The large-scale, community-based design of the study enhances the generalizability of the findings. However, potential bias exists based on self-selection. For example, individuals who chose to complete the cognitive panels might differ from the general population in ways that could affect the results. Also, individuals with the most severe cognitive impairments may have been unable to complete the tests because of their cognitive limitations.
In parallel, and strengthening confidence in these results, a similar study from Norway published in correspondence in The New England Journal of Medicine reported on participants in the Norwegian COVID-19 Cohort Study who completed an objective test of memory. Worse memory problems were found in individuals who had tested positive for COVID-19 compared to those who had never tested positive, with more pronounced deficits in women.4 This aligns with the findings of Hampshire et al, adding to the growing evidence of the neuropsychiatric effects of COVID-19.
There are several limitations to this study. The group acknowledges some, such as the self-report nature of the COVID-19 illness severity and lack of objective evidence of the viral strain. Additionally, it is challenging to differentiate the neurobiological effects of an illness from the psychosocial ones. Financial and emotional stressors also can lead to problems with cognitive functioning. Finally, the observational nature of this investigation points to an association, but it does not extend to evidence of causation.
Even with the limitations, the results of the study have clear clinical implications for providers managing post-COVID-19 care. Remembering that cognitive deficits can be a long-term consequence of COVID-19, especially in those who had severe cases and those with prolonged symptoms, can alter the focus of an exam. Medical providers may want to consider incorporating cognitive assessments into follow-up care for COVID-19 survivors. Early identification and intervention may be a key step in mitigating the effects of these deficits on the daily life and overall well-being of patients.
References
- Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 30 March 2023. Published March 30, 2023. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/30march2023
- Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: Major findings, mechanisms, and recommendations. Nat Rev Microbiol 2023;21:133-146.
- Imperial. Real-Time Assessment of Community Transmission (REACT) study. https://www.imperial.ac.uk/medicine/research-and-impact/groups/react-study/
- Ellingjord-Dale M, Brunvoll SH, Søraas A. Prospective memory assessment before and after COVID-19. N Engl J Med 2024;390:863-865.
A large observational study finds objective evidence of lingering cognitive deficits associated with past COVID-19 infection, particularly in patients infected early in the pandemic, those hospitalized, or those with prolonged illness duration.
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