Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
Authors: Michael Benedict D. , Dunai Cordelia , Needham Edward J. , Tharmaratnam Kukatharmini , Williams Robyn , Huang Yun , Boardman Sarah A. , Clark Jordan J. , Sharma Parul , Subramaniam Krishanthi , Wood Greta K. , Collie Ceryce , Digby Richard , Ren Alexander , Norton Emma , Leibowitz Maya , Ebrahimi Soraya , Fower Andrew , Fox Hannah , Tato Esteban , Ellul Mark A. , Sunderland Geraint , Held Marie , Hetherington Claire , Egbe Franklyn N. , Palmos Alish , Stirrups Kathy , Grundmann Alexander , Chiollaz Anne-Cecile , Sanchez Jean-Charles , Stewart James P. , Griffiths Michael , Solomon Tom , Breen Gerome , Coles Alasdair J. , Kingston Nathalie , Bradley John R. , Chinnery Patrick F. , Cavanagh Jonathan , Irani Sarosh R. , Vincent Angela , Baillie J. Kenneth , Openshaw Peter J. , Semple Malcolm G. ,   ISARIC4C Investigators, Baillie J. Kenneth , Openshaw Peter J. , Semple Malcolm G. , Alex Beatrice , Andrikopoulos Petros , Bach Benjamin , Barclay Wendy S. , Bogaert Debby , Chand Meera , Chechi Kanta , Cooke Graham S. , da Silva Ana , de Silva Thushan , Docherty Annemarie B. , dos Santos Gonçalo , Dumas Marc-Emmanuel , Dunning Jake , Fletcher Tom , Green Christoper A. , Greenhalf William , Griffin Julian L. , Gupta Rishi K. , Harrison Ewen M. , Wai Antonia Y. , Holden Karl , Horby Peter W. , Ijaz Samreen , Khoo Saye , Klenerman Paul , Law Andrew , Lewis Matthew R. , Liggi Sonia , Lim Wei S. , Maslen Lynn , Mentzer Alexander J. , Merson Laura , Meynert Alison M. , Moore Shona C. , Noursadeghi Mahdad , Olanipekun Michael , Osagie Anthonia , Palmarini Massimo , Palmieri Carlo , Paxton William A. , Pollakis Georgios , Price Nicholas , Rambaut Andrew , Robertson David L. , Russell Clark D. , Sancho-Shimizu Vanessa , Sands Caroline J. , Scott Janet T. , Sigfrid Louise , Solomon Tom , Sriskandan Shiranee , Stuart David , Summers Charlotte , Swann Olivia V. , Takats Zoltan , Takis Panteleimon , Tedder Richard S. , Thompson A. A. R. , Thomson Emma C. , Thwaites Ryan S. , Turtle Lance C. , Zambon Maria , Drake Thomas M. , Fairfield Cameron J. , Knight Stephen R. , Mclean Kenneth A. , Murphy Derek , Norman Lisa , Pius Riinu , Shaw Catherine A. , Connor Marie , Dalton Jo , Gamble Carrol , Girvan Michelle , Halpin Sophie , Harrison Janet , Jackson Clare , Lee James , Marsh Laura , Plotkin Daniel , Roberts Stephanie , Saviciute Egle , Clohisey Sara , Hendry Ross , Knight Susan , Lahnsteiner Eva , Leeming Gary , Norris Lucy , Scott-Brown James , Tait Sarah , Wham Murray , Clark Richard , Coutts Audrey , Donnelly Lorna , Fawkes Angie , Gilchrist Tammy , Hafezi Katarzyna , MacGillivray Louise , Maclean Alan , McCafferty Sarah , Morrice Kirstie , Murphy Lee , Wrobel Nicola , Carson Gail , Adeniji Kayode , Agranoff Daniel , Agwuh Ken , Ail Dhiraj , Aldera Erin L. , Alegria Ana , Allen Sam , Angus Brian , Ashish Abdul , Atkinson Dougal , Bari Shahedal , Barlow Gavin , Barnass Stella , Barrett Nicholas , Bassford Christopher , Basude Sneha , Baxter David , Beadsworth Michael , Bernatoniene Jolanta , Berridge John , Berry Colin , Best Nicola , Bothma Pieter , Brittain-Long Robin , Bulteel Naomi , Burden Tom , Burtenshaw Andrew , Caruth Vikki , Chadwick David , Chambler Duncan , Chee Nigel , Child Jenny , Chukkambotla Srikanth , Clark Tom , Collini Paul , Cosgrove Catherine , Cupitt Jason , Cutino-Moguel Maria-Teresa , Dark Paul , Dawson Chris , Dervisevic Samir , Donnison Phil , Douthwaite Sam , Drummond Andrew , DuRand Ingrid , Dushianthan Ahilanadan , Dyer Tristan , Evans Cariad , Eziefula Chi , Fegan Chrisopher , Finn Adam , Fullerton Duncan , Garg Sanjeev , Garg Atul , Gkrania-Klotsas Effrossyni , Godden Jo , Goldsmith Arthur , Graham Clive , Grammatikopoulos Tassos , Hardy Elaine , Hartshorn Stuart , Harvey Daniel , Havalda Peter , Hawcutt Daniel B. , Hobrok Maria , Hodgson Luke , Hormis Anil , Howard Joanne , Jacobs Michael , Jain Susan , Jennings Paul , Kaliappan Agilan , Kasipandian Vidya , Kegg Stephen , Kelsey Michael , Kendall Jason , Kerrison Caroline , Kerslake Ian , Koch Oliver , Koduri Gouri , Koshy George , Laha Shondipon , Laird Steven , Larkin Susan , Leiner Tamas , Lillie Patrick , Limb James , Linnett Vanessa , Little Jeff , Lyttle Mark , MacMahon Michael , MacNaughton Emily , Mankregod Ravish , Masson Huw , Matovu Elijah , McCullough Katherine , McEwen Ruth , Meda Manjula , Mills Gary , Minton Jane , Mohandas Kavya , Mok Quen , Moon James , Moore Elinoor , Morgan Patrick , Morris Craig , Mortimore Katherine , Moses Samuel , Mpenge Mbiye , Mulla Rohinton , Murphy Michael , Nagarajan Thapas , Nagel Megan , Nelson Mark , Norris Lillian , O’Shea Matthew K. , Ostermann Marlies , Otahal Igor , Pais Mark , Panchatsharam Selva , Papakonstantinou Danai , Papineni Padmasayee , Paraiso Hassan , Patel Brij , Pattison Natalie , Pepperell Justin , Peters Mark , Phull Mandeep , Pintus Stefania , Planche Tim , Post Frank , Price David , Prout Rachel , Rae Nikolas , Reschreiter Henrik , Reynolds Tim , Richardson Neil , Roberts Mark , Roberts Devender , Rose Alistair , Rousseau Guy , Ruge Bobby , Ryan Brendan , Saluja Taranprit , Schmid Matthias L. , Shah Aarti , Shankar-Hari Manu , Shanmuga Prad , Sharma Anil , Shawcross Anna , Pooni Jagtur S. , Sizer Jeremy , Smith Richard , Snelson Catherine , Spittle Nick , Staines Nikki , Stambach Tom , Stewart Richard , Subudhi Pradeep , Szakmany Tamas , Tatham Kate , Thomas Jo , Thompson Chris , Thompson Robert , Tridente Ascanio , Tupper-Carey Darell , Twagira Mary , Vallotton Nick , Vancheeswaran Rama , Vincent Rachel , Vincent-Smith Lisa , Visuvanathan Shico , Vuylsteke Alan , Waddy Sam , Wake Rachel , Walden Andrew , Welters Ingeborg , Whitehouse Tony , Whittaker Paul , Whittington Ashley , Wijesinghe Meme , Williams Martin , Wilson Lawrence , Winchester Stephen , Wiselka Martin , Wolverson Adam , Wootton Daniel G. , Workman Andrew , Yates Bryan , Young Peter , McDonald Sarah E. , Shaw Victoria , Ahmed Katie A. , Armstrong Jane A. , Ashworth Milton , Asiimwe Innocent G. , Bakshi Siddharth , Barlow Samantha L. , Booth Laura , Brennan Benjamin , Bullock Katie , Carlucci Nicola , Cass Emily , Catterall Benjamin W. , Clark Jordan J. , Clarke Emily A. , Cole Sarah , Cooper Louise , Cox Helen , Davis Christopher , Dincarslan Oslem , Carracedo Alejandra D. , Dunn Chris , Dyer Philip , Elliott Angela , Evans Anthony , Finch Lorna , Fisher Lewis W. , Flaherty Lisa , Foster Terry , Garcia-Dorival Isabel , Gunning Philip , Hartley Catherine , Holmes Anthony , Jensen Rebecca L. , Jones Christopher B. , Jones Trevor R. , Khandaker Shadia , King Katharine , Kiy Robyn T. , Koukorava Chrysa , Lake Annette , Lant Suzannah , Latawiec Diane , Lavelle-Langham Lara , Lefteri Daniella , Lett Lauren , Livoti Lucia A. , Mancini Maria , Massey Hannah , Maziere Nicole , McDonald Sarah , McEvoy Laurence , McLauchlan John , Metelmann Soeren , Miah Nahida S. , Middleton Joanna , Mitchell Joyce , Murphy Ellen G. , Penrice-Randal Rebekah , Pilgrim Jack , Prince Tessa , Reynolds Will , Ridley P. M. , Sales Debby , Shaw Victoria E. , Shears Rebecca K. , Small Benjamin , Subramaniam Krishanthi S. , Szemiel Agnieska , Taggart Aislynn , Tanianis-Hughes Jolanta , Thomas Jordan , Trochu Erwan , Tonder Libby v. , Wilcock Eve , Zhang J. E. , Keating Seán , Donegan Cara , Spencer Rebecca G. , Donohue Chloe , Griffiths Fiona , Hardwick Hayley , Oosthuyzen Wilna ,   COVID-CNS Consortium, Hampshire Adam , Sieradzki Adam , Seed Adam W. , Garjani Afagh , Nair Akshay , Coles Alaisdair , Carson Alan , Darby Alastair , Berry Alex , Dregan Alex , Grundmann Alexander , Palmos Alish , Al-Chalabi Ammar , McIntosh Andrew M. , Holland Angela E. , Roberts Angela , Vincent Angela , Venneri Annalena , David Anthony S. , Tamborska Arina , Patel Arvind , Easton Ava , Michael Benedict D. , Blackledge Bethan , Facer Bethany , Singh Bhagteshwar , Sargent Brendan , Collie Ceryce , Leek Charles , Armour Cherie , Morris Christopher M. , Allen Christopher M. , Mulholland Ciaran , MacIver Claire L. , Dunai Cordelia , Smith Craig J. , van Daniel J. , Madarshahian Daniel , Christmas David , Cousins David , Menon David K. , Christmas David M. , Breen David P. , Monssen Dina , Bullmore Edward , Needham Edward , McGlinchey Emily , Thomson Emma , Duff Eugene , Hodel Eva M. , Harrison Ewan , Zelaya Fernando , Lewis Gabriella , McDonnell Gavin , Breen Gerome , Wood Greta K. , Williams Guy B. , Hannah C. , Rogers Henry C. , Galea Ian , Smith Jacqueline , Harris Jade D. , Lilleker James B. , Amin Jay , Aggleton John P. , Bradley John R. , Taylor John-Paul , Cavanagh Jonathan , Coleman Jonathan R. , Underwood Jonathan , Breuer Judith , Hiscox Julian , Miller Karla , Dodd Katherine C. , Glen Kiran , Benjamin Laura , Taams Leonie , George Lily , Hardwick Marc , Baker Mark R. , Husain Masud , Butler Matthew , Hotopf Matthew , Broome Matthew R. , Samuel Merna , Griffiths Michael , Lunn Michael P. , Zandi Michael S. , Hartmann Monika , Cossette Nadine , Martin Naomi , Nicholas Nathalie , Harrison Neil A. , Basu Neil , Harrison Neil , Davies Nicholas , Wood Nicholas , Evangelou Nikos , Orazulume Obioma , Shaw Pamela J. , Mansoori Parisa , Harrison Paul J. , Jezzard Peter , Fernandes Peter M. , Upthegrove Rachel , Batra Rahul , Gregory Rebecca , Thomas Rhys H. , Bethlehem Richard , Francis Richard , O’Malley Ronan , Salman Rustam A. , McIlwaine Ryan , Kyaw Sandar , Irani Sarosh , Gunatilake Savini , Semple Scott , Hamid Shahd H. , Peacock Sharon , Rota Silvia , Keller Simon , Pendered Sophie , Barrett Suzanne , Hughes Stella , Paddick Stella-Maria , Sawcer Stephen J. , Smith Stephen , Williams Steven , Wong Sui H. , Defres Sylviane , Jackson Thomas , Jenkins Thomas M. , Pollak Thomas , Nicholson Timothy , Veenith Tonny , Grimbly Victoria , Newcombe Virginia , Taams Leonie S. , Menon David K. 
Published: December 2023

AbstractTo understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.