Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury, 2023, Taquet et al.

[SNT Gatchaman]

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

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.

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[SNT Gatchaman]

Hospitalised patients - many severe and requiring ventilation. Mean WHO score was 2.53 where 1 is supplemental oxygen, 2 is non-invasive ventilation and 3 is invasive ventilation / ECMO.

In this prospective cohort study of COVID-19 survivors, we found that markers of nervous system injury in plasma measured 6 months after hospital admission were not associated with post-acute neuropsychiatric features (cognitive deficits, depressive and anxiety symptoms) and not robustly associated with severity of the acute illness.

If post-acute neuropsychiatric consequences of COVID-19 are not explained by ongoing brain injury, then other mechanisms are needed to explain why new cases of neuropsychiatric sequelae (especially cognitive deficits) are being diagnosed up to 2 years after infection. A first possibility is that these sequelae are the product of acute immune or vascular events in the CNS, which lead to persistent symptoms. The ongoing diagnosis of new cases in the post-acute phase of the illness would then reflect delayed presentation of persistent symptoms that originated in the acute phase. A similar scenario has been observed in survivors of out-of-hospital cardiac arrest in whom evidence of acute brain injury predicted poor neurological outcomes 6 months later. This explanation would also be consistent with the observation that self-reported postacute neurological symptoms are associated with higher GFAP levels measured in the acute phase but not with those measured in the post-acute phase.

A second possibility is that post-acute neuropsychiatric sequelae are the results of ongoing neuropathological processes that are not captured by markers of nervous system injury, such as impaired hippocampal neurogenesis.

A third possibility is that some post-acute neuropsychiatric sequelae of COVID-19 are functional rather than structural in aetiology. Such functional neuropsychiatric sequelae can be precipitated by acute psychosocial stressors in the context of COVID-19.30 A wider range of investigations is needed in individual patients to make such a diagnosis, and if confirmed, targeted therapy should be offered to those individuals. These three possible explanations are not mutually exclusive, and different neuropsychiatric presentations might be underpinned by different mechanisms in different people. In particular, the different risk trajectories observed for anxiety and mood disorders on the one hand, and cognitive deficits on the other hand, suggest that different mechanisms might be at play.