Unfolding Neurological and Neuropsychiatric
Complications due to Covid-19

Neurological Manifestations of LongCOVID

Neurological deficits and psychiatric complications are recognised in patients with COVID-19. Symptoms are diverse and difficult to predict, and little is known about which cell types in the brain are directly or indirectly affected by SARS-CoV-2 infection. The long-term complications of COVID-19 (LongCOVID or Post-COVID syndrome, we refer here to Post-COVID) are not restricted to severe COVID-19 cases but have been demonstrated in over half of all patients at six months following primary infection. Several large retrospective cohorts have reported an increase specifically for neurological and neuropsychiatric complications at six months following COVID-19 with incidences as high as 33-49%. While neurological symptoms during Post-COVID are incredibly broad, including ischemic stroke and even involvement of the peripheral nervous system, NEUROCOV will focus on the involvement of the immune system and direct loss of neuronal function as the cellular and molecular basis of cognitive decline and/or neurodegeneration as major neurological and neuropsychiatric complications (referred to here as NeuroCOVID).

Despite this focus on NeuroCOVID, the neurological and neuropsychiatric complications following COVID-19 encompass a broad clinical phenotype. It includes symptoms such as fatigue, brain fog, cognitive dysfunction, delerium, encephalopathy, anosmia, parkinsonism, disturbed sleep patterns, psychotic, mood and anxiety disorders. These symptoms significantly affect the quality of life of many patients who have suffered from COVID-19 and whether these symptoms are transient or part of a permanent neurological and neuropsychiatric dysfunction remains unknown.

Much of the research to date on COVID-19 has been aimed at understanding the acute pulmonary disease and the immune dysfunction that occurs. Research on NeuroCOVID has for the most part focused on the characterisation of clinical cohorts to better understand the diversity of neurological and neuropsychiatric symptoms and their prevelance as complications of COVID-19. Several studies that have profiled NeuroCOVID patient samples (plasma, cerebrospinal fluid) have provided more insight into NeuroCOVID immune signatures by identifying potential drivers of neuroinflammation following COVID-19 and resolving risk factors for Post-COVID, while MRI imaging studies have found significant longitudinal effects following COVID-19 with patients showing a greater reduction in grey matter thickness in specific regions (the orbitofrontal cortex and parahippocampal gyrus) and a greater reduction in global brain size. Animal models have been used to gain a better understanding of the neuroinflammation that may occur following SARS-CoV-2 infection and spread into the central nervous system, while human autopsy reports have helped translate these findings to humans.

By leveraging human pluripotent stem cell technology, experimental models have shown differential susceptibility to infection for specific cells in the human brain (e.g., endothelial cells of the choroid plexus and midbrain dopaminergic neurons).