Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38–97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT-PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT- PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.

Objective Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk. Methods We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors. Results The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-4, and soluble Il-2 receptors. Conclusions Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk.

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