Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases

Abstract

Background This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. Methods Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. Results The mean age-at-death was 66.2 years (range: 26–97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. Conclusions Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

SARS-Cov-2 infection and neuropathological findings: a report of 18 cases and review of the literature

“…In addition to comorbidities such as diabetes, obesity, and hypertension, COVID-19-infected patients also usually receive invasive treatments such as extracorporeal membrane oxygenation (ECMO) and mechanical ventilation (MV), which can cause neuropathological changes such as haemorrhage [ 15 – 17 ]. This can lead to bias and misunderstanding in the interpretation of the neuropathological findings in postmortem brain tissue studies.…”

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

“…The decreased hippocampal T cell density in the Cav-1 KO mice with SARS-CoV-2 is predicted to yield decreased microgliosis and neuronal damage. Interestingly, extensive perivascular leukocyte cuffing reportedly occurs only in a subset of COVID-19 decedents, suggesting that individual risk factors contribute to CNS presentation of infection (Agrawal et al, 2022; Thakur et al ., 2021). Individual risk factors related to Cav-1 and other regulators of BBB adhesion and permeability may modify leukocytic infiltration and neurologic symptoms of SARS-CoV-2 infection (Adesse et al, 2022; Iadecola et al, 2020; Monje and Iwasaki, 2022; Teuwen et al, 2020; Vanderheiden and Klein, 2022; Vavougios et al, 2022).…”

Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms

“…It has been shown, using mouse studies, that the SARS-CoV-2 virus can persist in brain parenchyma for many months following an acute infection. In humans, significant brain swelling has been reported, even in young patients [110]. In particular, the hypothalamus and the cerebellum contained virus particles, along with the frontal cortex and areas associated with sensory input, such as the thalamus and the olfactory bulb.…”

“…In particular, the hypothalamus and the cerebellum contained virus particles, along with the frontal cortex and areas associated with sensory input, such as the thalamus and the olfactory bulb. In a study by Agrawal et al [110], they examined 20 donated brains from individuals with severe COVID-19 who died at the ages of 26-97. They described both acute and chronic alterations in brain health.…”