Neuropathology in COVID-19 autopsies is defined by microglial activation and lesions of the white matter with emphasis in cerebellar and brain stem areas

Abstract

IntroductionThis study aimed to investigate microglial and macrophage activation in 17 patients who died in the context of a COVID-19 infection in 2020 and 2021.MethodsThrough immunohistochemical analysis, the lysosomal marker CD68 was used to detect diffuse parenchymal microglial activity, pronounced perivascular macrophage activation and macrophage clusters. COVID-19 patients were compared to control patients and grouped regarding clinical aspects. Detection of viral proteins was attempted in different regions through multiple commercially available antibodies.ResultsMicroglial and macrophage activation was most pronounced in the white matter with emphasis in brain stem and cerebellar areas. Analysis of lesion patterns yielded no correlation between disease severity and neuropathological changes. Occurrence of macrophage clusters could not be associated with a severe course of disease or preconditions but represent a more advanced stage of microglial and macrophage activation. Severe neuropathological changes in COVID-19 were comparable to severe Influenza. Hypoxic damage was not a confounder to the described neuropathology. The macrophage/microglia reaction was less pronounced in post COVID-19 patients, but detectable i.e. in the brain stem. Commercially available antibodies for detection of SARS-CoV-2 virus material in immunohistochemistry yielded no specific signal over controls.ConclusionThe presented microglial and macrophage activation might be an explanation for the long COVID syndrome.

Neuropathological findings in COVID-19 vs. non-COVID-19 acute respiratory distress syndrome—A case-control study

“…A high frequency of acute brain injury (ABI) has also been described in non-COVID-19 patients with ARDS; the most common types of ABI reported are intracranial hemorrhage and hypoxicischemic brain injury (HIBI) (6). Neuroinflammatory changes recorded on brain pathology in COVID-19 are similar to neuropathological changes described in human and animal models of severe influenza (7,8). These findings suggest that severe respiratory disease may be independently linked with brain injury.…”

“…COVID-19 has been associated with neuro-inflammatory changes, and it was postulated that these findings were more pronounced in the brainstem and cerebellum ( 9 ). Microglial activation in the infratentorial region is commonly noted in COVID-19 patients ( 7 , 9 ). Infiltration of cytotoxic T-cells and microglial nodules is also more frequent in the brainstem and cerebellum ( 3 , 7 , 9 ).…”

“…Microglial activation in the infratentorial region is commonly noted in COVID-19 patients ( 7 , 9 ). Infiltration of cytotoxic T-cells and microglial nodules is also more frequent in the brainstem and cerebellum ( 3 , 7 , 9 ). It remains unclear if these inflammatory changes translate into ABI and if the regional tropism leads to a higher ABI in certain central nervous system locations in COVID-19 patients that is different from non-COVID-19 ARDS.…”

Microglia influence immune responses and restrict neurologic disease in response to central nervous system infection by a neurotropic murine coronavirus

“…In comparison with SARS-CoV-1 and MERS-CoV, neurologic symptoms which range in severity are more common following SARS-CoV-2 infection. Neuropathological findings associated with SARS-CoV-2 infection include lymphocyte inflammation, acute hypoxic-ischemic changes, astrogliosis, and spontaneous hemorrhage ( Pleasure et al, 2020 ; Lou et al, 2021 ; Maury et al, 2021 ; Schwabenland et al, 2021 ; Stein et al, 2023 ). In addition, microglial activation is also commonly detected in COVID-19 patients ( Pleasure et al, 2020 ; Lou et al, 2021 ; Maury et al, 2021 ; Schwabenland et al, 2021 ; Stein et al, 2023 ).…”

“…Neuropathological findings associated with SARS-CoV-2 infection include lymphocyte inflammation, acute hypoxic-ischemic changes, astrogliosis, and spontaneous hemorrhage ( Pleasure et al, 2020 ; Lou et al, 2021 ; Maury et al, 2021 ; Schwabenland et al, 2021 ; Stein et al, 2023 ). In addition, microglial activation is also commonly detected in COVID-19 patients ( Pleasure et al, 2020 ; Lou et al, 2021 ; Maury et al, 2021 ; Schwabenland et al, 2021 ; Stein et al, 2023 ). SARS-CoV-2 viral RNA and antigen have been detected within the CNS and cerebral spinal fluid of COVID-19 patients upon post-mortem analysis.…”