Cognition and Memory after Covid-19 in a Large Community Sample

Abstract

Background: Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear.

Methods: We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting ≥12 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating ("brain fog").

Results: Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported.

Conclusions: Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.).

Figure 1. Association of Global Cognitive Scores with Infection Date.

Shown are the mean global cognitive scores according to the date of infection (i.e., the number of days since January 1, 2020) among the 58,108 participants who had a single infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The red line shows results before time-varying covariates that are proxies and likely mediators of coronavirus disease 2019 (Covid-19) severity, including illness duration, hospitalization, period when the original virus or variant of SARS-CoV-2 was predominant, and vaccination status, were factored out; the gray line shows results after these covariates were factored out. Results in the no–Covid-19 group (participants who had not had SARS-CoV-2 infection or had unconfirmed infection) are shown on the right side of the graph. Values are point estimates for the linear regression as reported on a standard deviation (SD) scale. Error bars indicate the 95% confidence interval.

Figure 2. Association of Global Cognitive Scores with SARS-CoV-2 Variant Period, Illness Duration, and Hospitalization.

Panel A shows the probability distributions of global cognitive scores within discrete ranges for the period of SARS-CoV-2 infection (left), illness duration (middle), and hospitalization (right). As compared with the no–Covid-19 group, there was a shift in distributions to the left, with a higher frequency of moderate impairment (defined as a score below −2 SD) and a lower frequency of superior performance (defined as a score >2 SD). The predominant strain in the United Kingdom at the time of infection was used to assign the period of infection: original virus, before December 1, 2020; the B.1.1.7 (alpha) variant, from December 1, 2020, to April 30, 2021; the B.1.617.2 (delta) variant, from May 1, 2021, to December 15, 2021; and the B.1.1.529 (omicron) variant, from December 16, 2021, onward. Distributions were adjusted for age, other demographic characteristics, and preexisting conditions but not for other covariates. ED denotes emergency department, and ICU intensive care unit. Panel B shows the results of stepwise multiple regression on the global cognitive scores with adjustment for age, other demographic characteristics, and specific preexisting conditions (as separate factors); all selected covariates were included simultaneously in the model and are therefore additive. The reference category in the model is indicated for each covariate. Values are point estimates for the linear regression as reported on a standard deviation scale. 𝙸 bars indicate the 95% confidence interval.

Figure 3. Performance of Specific Tasks According to SARS-CoV-2 Variant Period, Illness Duration, and Hospitalization.

Shown are associations from the multiple regression analyses of the summary scores of the eight individual tasks according to SARS-CoV-2 variant period (left), illness duration (middle), and hospitalization (right). On each task, higher scores, indicated by higher standard deviations, indicate better performance. The reference category in the multiple linear regression model is indicated for each covariate. Error bars indicate the 95% confidence interval. Values are point estimates for the linear regression as reported on a standard deviation scale. The term 2D denotes two-dimensional.

Figure 4. Associations of Subjective and Objectively Measured Cognitive Deficits.

Shown are associations of specific cognitive-task performance measures among participants who had poor memory or brain fog in the previous 2 weeks as compared with those who did not. Results are shown for three participant groups: the group with unresolved persistent symptoms (lasting ≥12 weeks), the combined group with resolved symptoms, and the no–Covid-19 group. The direction of the scoring for the individual analyses is shown in the figure. Decrements in performance were greater in the group with unresolved persistent symptoms, with a similar pattern (but smaller decrements) in the group with resolved symptoms. The largest decrements in performance were observed in the memory tasks (immediate and delayed memory and spatial working memory), reasoning tasks (verbal analogical reasoning), and executive tasks (spatial planning) in the group with unresolved persistent symptoms. Definitions of each task are provided in the Supplemental Methods: Cognitive Task Designs section in the Supplementary Appendix. SD indicates the standard-deviation difference in the mean cognitive performance, and error bars indicate the 95% confidence interval.