Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence

Author:

Gelpi Ellen12ORCID,Klotz Sigrid12ORCID,Beyerle Miriam34ORCID,Wischnewski Sven56,Harter Verena7,Kirschner Harald7,Stolz Katharina8,Reisinger Christoph8ORCID,Lindeck-Pozza Elisabeth9,Zoufaly Alexander1011,Leoni Marlene12,Gorkiewicz Gregor12ORCID,Zacharias Martin12,Haberler Christine12ORCID,Hainfellner Johannes12,Woehrer Adelheid12ORCID,Hametner Simon12,Roetzer Thomas12ORCID,Voigtländer Till12,Ricken Gerda12ORCID,Endmayr Verena12,Haider Carmen12,Ludwig Judith12,Polt Andrea12,Wilk Gloria12,Schmid Susanne12,Erben Irene12,Nguyen Anita12,Lang Susanna13,Simonitsch-Klupp Ingrid13,Kornauth Christoph1314ORCID,Nackenhorst Maja13,Kläger Johannes13,Kain Renate13ORCID,Chott Andreas15,Wasicky Richard15,Krause Robert16,Weiss Günter17ORCID,Löffler-Rag Judith17,Berger Thomas1218,Moser Patrizia19,Soleiman Afshin19,Asslaber Martin12,Sedivy Roland7,Klupp Nikolaus8,Klimpfinger Martin713,Risser Daniele8,Budka Herbert12ORCID,Schirmer Lucas4520ORCID,Pröbstel Anne-Katrin34ORCID,Höftberger Romana12

Affiliation:

1. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria

2. Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria

3. Departments of Neurology, Biomedicine and Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland

4. Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Department of Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland

5. Department of Neurology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany

6. Mannheim Center for Translational Neuroscience and Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany

7. Department of Pathology, Klinik Favoriten, 1100 Vienna, Austria

8. Department of Forensic Medicine, Medical University of Vienna, 1090 Vienna, Austria

9. Department of Neurology, Klinik Favoriten, 1100 Vienna, Austria

10. Intensive Care Unit, Klinik Favoriten, 1100 Vienna, Austria

11. Faculty of Medicine, Sigmund Freud University, 1020 Vienna, Austria

12. D&F Institute of Pathology, Neuropathology, Medical University Graz, 8036 Graz, Austria

13. Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria

14. Münchner Leukämielabor, 81377 Munich, Germany

15. Institute of Pathology, Klinik Ottakring, 1160 Vienna, Austria

16. Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria

17. Department of Internal Medicine and Pulmonology, Medical University of Innsbruck, 6020 Innsbruck, Austria

18. Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria

19. Department of Neuropathology, Tirol Kliniken GmbH, 6020 Innsbruck, Austria

20. Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany

Abstract

Background: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. Methods: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. Results: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic–ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). Conclusions: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

Funder

Austrian Fonds of the Major of Vienna

Austrian Science Fund FWF, SYNABS

the German Academic Exchange Service

German Academic Scholarship Foundation

the Goldschmidt-Jacobson Foundation

National Multiple Sclerosis Society

Swiss National Science Foundation

the University of Basel

the Medical Faculty Mannheim of Heidelberg University

Hertie Foundation

European Research Council

German Research Foundation

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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