Mapping of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease
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Abstract
The coronavirus SARS-CoV-2 (SCV2) causes acute respiratory distress, termed COVID-19 disease, with substantial morbidity and mortality. As SCV2 is related to previously-studied coronaviruses that have been shown to have the capability for brain invasion, it seems likely that SCV2 may be able to do so as well. To date, although there have been many clinical and autopsy-based reports that describe a broad range of SCV2-associated neurological conditions, it is unclear what fraction of these have been due to direct CNS invasion versus indirect effects caused by systemic reactions to critical illness. Still critically lacking is a comprehensive tissue-based survey of the CNS presence and specific neuropathology of SCV2 in humans. We conducted an extensive neuroanatomical survey of RT-PCR-detected SCV2 in 16 brain regions from 20 subjects who died of COVID-19 disease. Targeted areas were those with cranial nerve nuclei, including the olfactory bulb, medullary dorsal motor nucleus of the vagus nerve and the pontine trigeminal nerve nuclei, as well as areas possibly exposed to hematogenous entry, including the choroid plexus, leptomeninges, median eminence of the hypothalamus and area postrema of the medulla. Subjects ranged in age from 38 to 97 (mean 77) with 9 females and 11 males. Most subjects had typical age-related neuropathological findings. Two subjects had severe neuropathology, one with a large acute cerebral infarction and one with hemorrhagic encephalitis, that was unequivocally related to their COVID-19 disease while most of the 18 other subjects had non-specific histopathology including focal β-amyloid precursor protein white matter immunoreactivity and sparse perivascular mononuclear cell cuffing. Four subjects (20%) had SCV2 RNA in one or more brain regions including the olfactory bulb, amygdala, entorhinal area, temporal and frontal neocortex, dorsal medulla and leptomeninges. The subject with encephalitis was SCV2-positive in a histopathologically-affected area, the entorhinal cortex, while the subject with the large acute cerebral infarct was SCV2-negative in all brain regions. Like other human coronaviruses, SCV2 can inflict acute neuropathology in susceptible patients. Much remains to be understood, including what viral and host factors influence SCV2 brain invasion and whether it is cleared from the brain subsequent to the acute illness.
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SciScore for 10.1101/2021.02.15.21251511: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Subjects were enrolled in one of two separate Institutional Review Board (IRB) approved protocols reviewed by the Western IRB in Puyallup, Washington. Five of the ten COVID-19 disease subjects and the 4 non-COVID-19 disease control cases were volunteers who had donated their brains and/or bodies for research as part of the Arizona Study of Aging and Neurodegenerative Disorders 87 and Brain and Body Donation Program (AZSAND/BBDP; https://www.brainandbodydonationregistration.org/), a longitudinal clinicopathological study and biospecimen resource for normal aging and age-related diseases.
Consent: All of these subjects or their legal representatives signed …SciScore for 10.1101/2021.02.15.21251511: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Subjects were enrolled in one of two separate Institutional Review Board (IRB) approved protocols reviewed by the Western IRB in Puyallup, Washington. Five of the ten COVID-19 disease subjects and the 4 non-COVID-19 disease control cases were volunteers who had donated their brains and/or bodies for research as part of the Arizona Study of Aging and Neurodegenerative Disorders 87 and Brain and Body Donation Program (AZSAND/BBDP; https://www.brainandbodydonationregistration.org/), a longitudinal clinicopathological study and biospecimen resource for normal aging and age-related diseases.
Consent: All of these subjects or their legal representatives signed an IRB-approved informed consent form allowing both standardized research clinical assessments during life and several options for brain and/or bodily organ donation after death.Randomization not detected. Blinding To evaluate assay validity, RNA aliquots from each of 5 study subjects, with a total of 30 samples, including positive and negative samples of olfactory bulb, dorsal medulla and lung, were analyzed blinded to diagnosis and previous RT-PCR results using similar RT-PCR methods Stanford Health Care in Stanford, California, with complete agreement on positive vs negative results for all anatomical sites and subjects. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Banner Sun Health Research Institute Subjects: The Institute is located in Sun City, Arizona, a suburb of Phoenix. Phoenixsuggested: (Phoenix, RRID:SCR_003163)Subjects were enrolled in one of two separate Institutional Review Board (IRB) approved protocols reviewed by the Western IRB in Puyallup, Washington. Five of the ten COVID-19 disease subjects and the 4 non-COVID-19 disease control cases were volunteers who had donated their brains and/or bodies for research as part of the Arizona Study of Aging and Neurodegenerative Disorders 87 and Brain and Body Donation Program (AZSAND/BBDP; https://www.brainandbodydonationregistration.org/), a longitudinal clinicopathological study and biospecimen resource for normal aging and age-related diseases. Body Donation Programsuggested: (Brain and Body Donation Program, RRID:SCR_004822)s (BD Cat # 220531) from all BSHRI cases were assayed for SCV2 RNA using FDA EUA protocols https://www.fda.gov/media/136818/download at Clinical Laboratory Improvement Amendments (CLIA)-approved laboratories, either operated by Sonora Quest, a division of Quest Diagnostics, or by the Stanford Health Care in Stanford, California. Postmortem SCV2 RNA detection in blood serum, cerebrospinal fluid, lung and brain tissue: Frozen brain samples were dissected from 16 brain regions, including olfactory bulb, entorhinal area, CA1 region of the hippocampus, amygdala, temporal, frontal and primary visual neocortex, dorsal medulla in the region of the motor nucleus of the vagus nerve and area postrema, pontine tegmentum in the region of the trigeminal nuclei, substantia nigra, hypothalamus in the region of the median eminence, thalamus, putamen at the lentiform nucleus, cerebellar cortex, choroid plexus and leptomeninges. Questsuggested: (QUEST, RRID:SCR_005210)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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