ABSTRACT
Aims: Activation of microglial cells represents the most common neu-ropathological change in fatal cases of COVID-19 with particular prominence in the brainstem. However, detailed assessments are lacking. Here, we assessed reactive microglia in COVID-19 tissue and tested for disease-specific activation patterns. Methods: We used an early-(Iba1) and a late-stage (CD68) immuno-histochemistry marker for microglial activation in human post-mortem brainstem and frontal lobe tissues in eight fatal COVID-19 cases, seven septic controls and six non-septic controls. We quantified the level of microglial activation employing a Qu-Path-based automated approach. Using a mixed three-way ANOVA, we tested for effects and interactions of brain region, microglial marker and group. Results: Reactive microglia were detected in all cases across brain regions and antibodies. However, COVID-19 brains exhibited significantly higher levels of microglial activation than septic and control brains, especially of late-stage microglia (CD68+). Irrespective of disease, microglia activation was significantly more pronounced and further progressed (CD68+) in brainstem tissues, particularly the medulla, than in the frontal lobe. Whilst survival time from admission marginally significantly correlated with the level of reactive microglia in COVID-19, no associations were found between neuroinflammation and either gender or age at death. Conclusions: Whilst the brainstem demonstrates a disease-independent high susceptibility to inflammation, microglial activation in COVID-19 (COVID-19 microglia encephalopathy) is specific and of importance for understanding the involvement of the CNS in this disease.
ABSTRACT
SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, are increasingly recognised. Through immunohistochemistry against the SARS-CoV-2 nucleocapsid protein (NP), we aimed to characterise the multisystem viral tropism of SARS-CoV-2. FFPE tissue was obtained from 16 PCR-confirmed post-mortem COVID cases. Of these cases, 10 were full-body, 5 were brain only and 1 was a brain biopsy. Brain regions studied included frontal cortex, medulla, cerebellum, pons and olfactory bulb. Neurological symptoms featured in the cohort included brainstem encephalitis, acute disseminated encephalomyelitis (ADEM) and brain infarction. Immunohistochemistry of digestive system tissues revealed presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE-2 expression, the entry receptor for SARS-CoV-2 and one of the earliest affected cells in Parkinson's disease (PD). Within the brain, staining was widespread in all sampled regions but limited to endothelial cells only (including in the olfactory bulb). Furthermore, in the full-body post-mortem cases, positivity in brain endothelia was restricted to cases exhibiting multiorgan tissue positivity (3/9 cases). The average time from symptom onset to time of death was shorter in positively versus negatively stained postmortem cases (mean = 10.3 days vs mean = 20.3 days, p = 0.0416) suggesting NP detection was confined to the infectious period. Together, our findings provide evidence for enteric nervous system but not brain neuroinvasion of SARS-CoV-2 as well as potential insights into long-term complications of COVID-19 and PD pathogenesis.
ABSTRACT
[Figure: see text].
ABSTRACT
There is increasing evidence that patients with Coronavirus disease 19 (COVID-19) present with neurological and psychiatric symptoms. Anosmia, hypogeusia, headache, nausea and altered consciousness are commonly described, although there are emerging clinical reports of more serious and specific conditions such as acute cerebrovascular accident, encephalitis and demyelinating disease. Whether these presentations are directly due to viral invasion of the central nervous system (CNS) or caused by indirect mechanisms has yet to be established. Neuropathological examination of brain tissue at autopsy will be essential to establish the neuro-invasive potential of the SARS-CoV-2 virus but, to date, there have been few detailed studies. The pathological changes in the brain probably represent a combination of direct cytopathic effects mediated by SARS-CoV-2 replication or indirect effects due to respiratory failure, injurious cytokine reaction, reduced immune response and cerebrovascular accidents induced by viral infection. Further large-scale molecular and cellular investigations are warranted to clarify the neuropathological correlates of the neurological and psychiatric features seen clinically in COVID-19. In this review, we summarize the current reports of neuropathological examination in COVID-19 patients, in addition to our own experience, and discuss their contribution to the understanding of CNS involvement in this disease.