Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

Abstract

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury.

Keywords: biomarkers; long COVID; neural injury.

Graphical Abstract

Figure 1

Associations between markers of nervous system injury and post-acute neuropsychiatric features measured at 6 and 12 months. Each bar represents the number of SDs by which the neuropsychiatric scale varies when the level of the nervous system injury marker varies by 1 SD. The error bars indicate 95% CIs. Uncorrected P-values are reported next to each bar, and Bonferroni-corrected P-values meeting statistical significance thresholds are flagged as follows: *<0.05, **<0.01 and ***<0.001. See Supplementary Figs 2 and 3 for the same results based on different statistical models.

Figure 2

Associations between markers of nervous system injury and markers of severity of the acute COVID-19 illness. Each bar represents the number of SDs by which the levels of nervous system injury marker vary when the marker of severity is present versus absent (for dichotomous variables, i.e. the presence of thrombosis, ICU admission and confusion) or when the marker of severity varies by 1 SD (for non-dichotomous variables, i.e. WHO class, NEWS score and the duration of admission). The error bars indicate 95% CIs. Uncorrected P-values are reported next to each bar, and Bonferroni-corrected P-values meeting statistical significance thresholds are flagged as follows: *<0.05, **<0.01 and ***<0.001. WHO severity refers to the World Health Organization classification of COVID-19 severity (in terms of oxygen requirement). Very severe impairment, severe impairment and moderate impairment with cognitive impairment refer to predefined clusters of post-COVID impairment. See Supplementary Figs 4 and 5 for the same results based on different statistical models.