Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction

Greta K Wood; Brendan F Sargent; Zain-Ul-Abideen Ahmad; Kukatharmini Tharmaratnam; Cordelia Dunai; Franklyn N Egbe; Naomi H Martin; Bethany Facer; Sophie L Pendered; Henry C Rogers; Christopher Hübel; Daniel J van Wamelen; Richard A I Bethlehem; Valentina Giunchiglia; Peter J Hellyer; William Trender; Gursharan Kalsi; Edward Needham; Ava Easton; Thomas A Jackson; Colm Cunningham; Rachel Upthegrove; Thomas A Pollak; Matthew Hotopf; Tom Solomon; Sarah L Pett; Pamela J Shaw; Nicholas Wood; Neil A Harrison; Karla L Miller; Peter Jezzard; Guy Williams; Eugene P Duff; Steven Williams; Fernando Zelaya; Stephen M Smith; Simon Keller; Matthew Broome; Nathalie Kingston; Masud Husain; Angela Vincent; John Bradley; Patrick Chinnery; David K Menon; John P Aggleton; Timothy R Nicholson; John-Paul Taylor; Anthony S David; Alan Carson; Ed Bullmore; Gerome Breen; Adam Hampshire; COVID-CNS Consortium; Benedict D Michael; Stella-Maria Paddick; E Charles Leek

doi:10.1038/s41591-024-03309-8

Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction

Nat Med. 2025 Jan;31(1):245-257. doi: 10.1038/s41591-024-03309-8. Epub 2024 Sep 23.

Authors

Greta K Wood^#^{1

2}, Brendan F Sargent^#^{1

3

4}, Zain-Ul-Abideen Ahmad⁵, Kukatharmini Tharmaratnam⁶, Cordelia Dunai^{1

7}, Franklyn N Egbe¹, Naomi H Martin⁵, Bethany Facer⁸, Sophie L Pendered¹, Henry C Rogers⁵, Christopher Hübel^{5

9

10}, Daniel J van Wamelen^{11

12

13}, Richard A I Bethlehem¹⁴, Valentina Giunchiglia¹⁵, Peter J Hellyer¹¹, William Trender¹⁵, Gursharan Kalsi⁵, Edward Needham¹⁶, Ava Easton^{1

17}, Thomas A Jackson¹⁸, Colm Cunningham¹⁹, Rachel Upthegrove²⁰, Thomas A Pollak^{21

22}, Matthew Hotopf²³, Tom Solomon^{1

7

24

25}, Sarah L Pett^{26

27

28}, Pamela J Shaw^{29

30}, Nicholas Wood^{31

32}, Neil A Harrison³³, Karla L Miller⁴, Peter Jezzard⁴, Guy Williams³⁴, Eugene P Duff³⁵, Steven Williams¹¹, Fernando Zelaya^{11

36}, Stephen M Smith⁴, Simon Keller⁸, Matthew Broome^{20

37}, Nathalie Kingston^{38

39}, Masud Husain^{40

41}, Angela Vincent⁴⁰, John Bradley³⁸, Patrick Chinnery^{16

42}, David K Menon⁴³, John P Aggleton⁴⁴, Timothy R Nicholson^{21

22

45}, John-Paul Taylor^{46

47}, Anthony S David⁴⁸, Alan Carson⁴⁹, Ed Bullmore^{34

50}, Gerome Breen^{5

36}, Adam Hampshire^{11

15}; COVID-CNS Consortium; Benedict D Michael^{51

52

53}, Stella-Maria Paddick^{46

54

55}, E Charles Leek^{56

57}

Collaborators

COVID-CNS Consortium:
Ali M Alam, Ammar Al-Chalabi, Christopher M Allen, Jay Amin, Cherie Armour, Mark R Baker, Suzanne Barrett, Neil Basu, Rahul Batra, Laura Benjamin, Alex Berry, Richard A I Bethlehem, Bethan Blackledge, Sarah A Boardman, John Bradley, David P Breen, Judith Breuer, Matthew Broome, Ed Bullmore, Matthew Butler, Hannah Castell, Jonathan Cavanagh, David Christmas, David M Christmas, Jonathan R I Coleman, Alaistair Coles, Ceryce Collie, Nadine Cossette, David Cousins, Alastair Darby, Nicholas Davies, Sylviane Defres, Katherine C Dodd, Alex Dregan, Eugene Duff, Mark A Ellul, Nikos Evangelou, Peter M Fernandes, Richard Francis, Ian Galea, Afagh Garjani, Lily George, Valentina Giunchiglia, Kiran Glen, Rebecca Gregory, Michael Griffiths, Victoria Grimbly, Alexander Grundmann, Savini Gunatilake, Shahd H M Hamid, Marc Hardwick, Jade D Harris, Ewan Harrison, Paul J Harrison, Monika Hartmann, Claire Hetherington, Orla Hilton, Julian Hiscox, Eva Maria Hodel, Angela E Holland, Yun Huang, Stella Hughes, Sarosh Irani, Thomas M Jenkins, Johan Kallberg Zvrskovec, Sandar Kyaw, Gabriella Lewis, James B Lilleker, Michael P Lunn, Claire L MacIver, Daniel Madarshahian, Parisa Mansoori, Naomi Martin, Gavin McDonnell, Emily McGlinchey, Stephen McKeever, Ryan McIlwaine, Andrew M McIntosh, Karla L Miller, Dina Monssen, Christopher M Morris, Ciaran Mulholland, Akshay Nair, Virginia Newcombe, Nathalie Nicholas, Timothy R Nicholson, Ronan O'Malley, Obioma Orazulume, Marlies Ostermann, Alish Palmos, Arvind Patel, Sharon Peacock, Sophie L Pendered, Thomas A Pollak, Angela Roberts, Silvia Rota, Rustam Al-Shahi Salman, Merna Samuel, Brendan F Sargent, Stephen J Sawcer, Adam W Seed, Scott Semple, Rajish S K Shil, Adam Sieradzki, Bhagteshwar Singh, Craig J Smith, Jacqueline Smith, Stephen M Smith, Leonie Taams, Arina Tamborska, Rhys H Thomas, Emma Thomson, William Trender, Zain-Ul-Abideen Ahmad, Jonathan Underwood, Tonny Veenith, Annalena Venneri, Daniel J van Wamelen, Guy Williams, Sui Hsien Wong, Michael S Zandi

Affiliations

¹ Department of Clinical Infection, Microbiology & Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
² Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
³ Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
⁴ Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
⁵ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁶ Department of Health Data Science, Institute of Population Health, University of Liverpool, Liverpool, UK.
⁷ NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
⁸ Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
⁹ National Centre for Register-based Research, Aarhus Business and Social Sciences, Aarhus University, Aarhus, Denmark.
¹⁰ Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹¹ Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹² Parkinson's Foundation Center of Excellence, King's College Hospital, London, UK.
¹³ Department of Neurology; Centre of Expertise for Parkinson & Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹⁴ Department of Psychology, University of Cambridge, Cambridge, UK.
¹⁵ Department of Brain Sciences, Imperial College London, London, UK.
¹⁶ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹⁷ Encephalitis International, Malton, UK.
¹⁸ Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
¹⁹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
²⁰ Institute for Mental Health, School of Psychology, University of Birmingham, Birmingham, UK.
²¹ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²² South London and Maudsley NHS Foundation Trust, London, UK.
²³ Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁴ The Pandemic Institute, University of Liverpool, Liverpool, UK.
²⁵ Department of Neurology, Walton Centre Foundation Trust, Liverpool, UK.
²⁶ MRC Clinical Trials Unit, UCL, London, UK.
²⁷ Institute of Clinical Trials and Methodology, UCL, London, UK.
²⁸ Institute for Global Health, UCL, London, UK.
²⁹ Division of Neuroscience, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.
³⁰ Sheffield Institute for Translational Neuroscience, NIHR Biomedical Research Centre, University of Sheffield, Sheffield, UK.
³¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, UCL, London, UK.
³² UCL Genetics Institute, Division of Biosciences, UCL, London, UK.
³³ Cardiff University Brain Research Imaging Centre, School of Medicine, Cardiff University, Cardiff, UK.
³⁴ Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
³⁵ UK Dementia Research Institute, Department of Brain Sciences, Imperial College London, London, UK.
³⁶ NIHR Maudsley Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust, London, UK.
³⁷ Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
³⁸ NIHR Bioresource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
³⁹ Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
⁴⁰ Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK.
⁴¹ Department of Experimental Psychology, University of Oxford, Oxford, UK.
⁴² MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
⁴³ Section of Perioperative, Acute, Critical Care and Emergency Medicine, Department of Medicine, University of Cambridge, Cambridge, UK.
⁴⁴ School of Psychology, Cardiff University, Cardiff, UK.
⁴⁵ Neuropsychiatry Research and Education Group, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁴⁶ Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
⁴⁷ Old Age Psychiatry, Tyne and Wear NHS Trust, Newcastle, UK.
⁴⁸ Department of Psychiatry, Institute of Mental Health, UCL, London, UK.
⁴⁹ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁵⁰ Department of Psychiatry, Institute of Behavioural and Clinical Neuroscience, University of Cambridge, Cambridge, UK.
⁵¹ Department of Clinical Infection, Microbiology & Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. benmic@liverpool.ac.uk.
⁵² NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. benmic@liverpool.ac.uk.
⁵³ Department of Neurology, Walton Centre Foundation Trust, Liverpool, UK. benmic@liverpool.ac.uk.
⁵⁴ Department of Old Age Psychiatry, Gateshead Health NHS Foundation Trust, Gateshead, UK.
⁵⁵ Millenium Institute for Care Research (MICARE), Santiago, Chile.
⁵⁶ Department of Psychology, Institute of Population Health, Institute of Life and Human Sciences, University of Liverpool, Liverpool, UK.
⁵⁷ School of Psychology, University of Southampton, Southampton, UK.

^# Contributed equally.

Abstract

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

MeSH terms

Adult
Aged
Biomarkers / blood
Brain Injuries* / blood
Brain Injuries* / diagnostic imaging
Brain Injuries* / pathology
COVID-19* / complications
COVID-19* / pathology
COVID-19* / psychology
Cognitive Dysfunction* / etiology
Cognitive Dysfunction* / pathology
Female
Gray Matter* / diagnostic imaging
Gray Matter* / pathology
Gyrus Cinguli / diagnostic imaging
Gyrus Cinguli / pathology
Hospitalization
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Neuroimaging
Prospective Studies
SARS-CoV-2

Substances

Biomarkers

Abstract

MeSH terms

Substances

Grants and funding