ASSESSMENT AND CHARACTERIZATION OF COVID-19 RELATED COGNITIVE DECLINE: RESULTS FROM A NATURAL EXPERIMENT

Abstract

Background: Cognitive impairment is the most common and disabling manifestation of post-acute sequelae of SARS-CoV-2. There is an urgent need for the application of more stringent methods for evaluating cognitive outcomes in research studies.

Objective: To determine whether cognitive decline emerges with the onset of COVID-19 and whether it is more pronounced in patients with Post-Acute Sequelae of SARS-CoV-2 or severe COVID-19.

Methods: This longitudinal cohort study compared the cognitive performance of 276 patients with COVID-19 to that of 217 controls across four neuroinflammation or vascular disease-sensitive domains of cognition using data collected both before and after the pandemic starting in 2015.

Results: The mean age of the COVID-19 group was 56.04±6.6 years, while that of the control group was 58.1±7.3 years. Longitudinal models indicated a significant decline in cognitive throughput ((β=-0.168, P=.001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. The effect sizes were large; the observed changes in throughput were equivalent to 10.6 years of normal aging and a 59.8% increase in the burden of mild cognitive impairment. Cognitive decline worsened with coronavirus disease 2019 severity and was concentrated in participants reporting post-acute sequelae of SARS-CoV-2.

Conclusion: COVID-19 was most likely associated with the observed cognitive decline, which was worse among patients with PASC or severe COVID-19. Monitoring patients with post-acute sequelae of SARS-CoV-2 for declines in the domains of processing speed and visual working memory and determining the long-term prognosis of this decline are therefore warranted.

Keywords: Coronavirus disease 2019 (COVID-19); Covid-19 related Cognitive Decline (CRCD); executive dysfunction; post-acute sequelae of SARS-CoV-2 (PASC); severe acute respiratory syndrome coronavirus 2 (SARS-COV-2).

Figure 1.

Sample Inclusion and Exclusion Criteria

Figure 2.

Trajectory plot showing expected throughput before and after the onset of COVID-19 symptoms (time 0). Expectations are stratified as SARS-CoV-2 infected (solid black line) and uninfected (black dashed line). 95% Confidence intervals are shown in translucent gray. The estimated model is Y_it = 5.85 − 0.014 * A_it − 0.146 * C_19t[−0.045 * NC₁₉ − 0.004 * NC₁₉ * t] + XB + γ_0i + γ_1it + ε_it, where XB contains an array of covariates, A_it denotes age of subject i at time t, C_19t is a time-varying indicator for the onset of COVID-19 symptoms, and NC₁₉ is a time-invariant indicator of belonging to a COVID-19 cohort: a measurement of selection bias that indicates the differences between individuals who ever developed symptomatic COVID-19 compared to those who were in the comparison group. For the unexposed group, the counterfactual symptom onset time (t=0 in the graph above) was calculated as the average date that those in the COVID-19 group were infected. Results enclosed in square brackets in the equation were not statistically significantly different from 0 but are reflected in the figure anyways. Results for all domains are shown in Table 6. Abbreviations: cs, centi-seconds.