{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T11:32:04Z","timestamp":1770982324339,"version":"3.50.1"},"reference-count":174,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["335524"],"award-info":[{"award-number":["335524"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and\/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood\u2013brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.<\/jats:p>","DOI":"10.3390\/cells11213411","type":"journal-article","created":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T23:45:00Z","timestamp":1667087100000},"page":"3411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19"],"prefix":"10.3390","volume":"11","author":[{"given":"Helena T.","family":"Hogberg","sequence":"first","affiliation":[{"name":"National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27518, USA"},{"name":"Johns Hopkins University, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Lam","sequence":"additional","affiliation":[{"name":"Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA"},{"name":"Physicians Committee for Responsible Medicine, Washington, DC 20016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elan","family":"Ohayon","sequence":"additional","affiliation":[{"name":"Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA"},{"name":"Institute for Green & Open Sciences, Toronto, ON M6J 2J4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-6792","authenticated-orcid":false,"given":"Muhammad Ali","family":"Shahbaz","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-482X","authenticated-orcid":false,"given":"Laure-Alix","family":"Clerbaux","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Bal-Price","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2773-6408","authenticated-orcid":false,"given":"Sandra","family":"Coecke","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Concha","sequence":"additional","affiliation":[{"name":"Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"De Bernardi","sequence":"additional","affiliation":[{"name":"Division of Otorhinolaryngology, Department of Biotechnologies and Life Sciences, University of Insubria, Ospedale di Circolo e Fondazione Macchi, 21100 Varese, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eizleayne","family":"Edrosa","sequence":"additional","affiliation":[{"name":"Green Neuroscience Laboratory, Neurolinx Research Institute, San Diego, CA 92111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan J.","family":"Hargreaves","sequence":"additional","affiliation":[{"name":"School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-8589","authenticated-orcid":false,"given":"Katja M.","family":"Kanninen","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amalia","family":"Munoz","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 2440 Geel, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Pistollato","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surat","family":"Saravanan","sequence":"additional","affiliation":[{"name":"Centre for Predictive Human Model Systems Atal Incubation Centre-Centre for Cellular and Molecular Biology, Hyderabad 500039, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1667-5294","authenticated-orcid":false,"given":"Nat\u00e0lia","family":"Garcia-Reyero","sequence":"additional","affiliation":[{"name":"Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, MS 39180, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Wittwehr","sequence":"additional","affiliation":[{"name":"European Commission, Joint Research Centre (JRC), 21027 Ispra, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalini","family":"Sachana","sequence":"additional","affiliation":[{"name":"Environment Health and Safety Division, Environment Directorate, Organisation for Economic Cooperation and Development (OECD), 75016 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir. 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