Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains

Abstract

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

Post-mortem Findings of Inflammatory Cells and the Association of 4-Hydroxynonenal with Systemic Vascular and Oxidative Stress in Lethal COVID-19

“…Our study revealed that the SOD2 might be another very important link between a malfunctioning immune system and oxidative stress, alongside 4-HNE. Namely, the immunohistochemical resemblance of the findings for 4-HNE and SOD2 in all the vital organs of our patients indicated a possible pathogenic interference between this crucial antioxidant enzyme specific for mitochondria (SOD2) and 4-HNE regulating mitochondrial RSO production, stability, and leakage [52]. Consequently, this could result in Fenton's reaction, ferroptosis, and the spread of lipid peroxidation, shown by the abundant immunostaining for both biomarkers.…”

“…Therefore, the lipid peroxidation trigger and 4-HNE mediated systemic vascular and oxidative stress could be associated with an uncontrolled (auto)immune stress response, which may lead to ARDS and MOF, as observed in our patients. The high importance of the malfunctioning immune system destroying vital organs, not only the lungs but even the brain, for severe/lethal SARC-CoV-2 infection is well known, even if the virus itself may not always be the [52][53][54], as is also the importance of uncontrolled oxidative stress [55,56]. Both of the supporting findings of our study suggest that lipid peroxidation, notably, 4-HNE, might be the link between these two vicious circles of lethal COVID-19.…”

Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC)

“…58–60 Additionally, there is evidence of multifocal inflammatory infiltrates consisting of lymphocytes as well as activated innate immune cells in autopsy tissue. 61 Further investigation of PASC will require in-depth exploration of what is occurring in the CNS compartment during both acute and recovery time periods.…”

2 Years into the Pandemic: What Did We Learn About the COVID-19 and Cerebellum?

“…There are major vascular changes in the cerebral cortex, while there is also substantial meningeal and perivascular inflammation of the cortical parenchyma with hypoxic cellular injury. The cerebellum and brainstem often show perivascular lymphocytic inflammation of CD8-positive T cells mixed with CD68-positive macrophages [11]. The inflammatory changes typically target disrupted vascular walls suggesting prominent role of microvascular injury in COVID-19-induced neurological comorbidity [11].…”

“…The cerebellum and brainstem often show perivascular lymphocytic inflammation of CD8-positive T cells mixed with CD68-positive macrophages [11]. The inflammatory changes typically target disrupted vascular walls suggesting prominent role of microvascular injury in COVID-19-induced neurological comorbidity [11]. The hypoxic changes are noticeable in COVID-19 patients with brainstem and cerebellar involvement [12].…”