Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JL, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SM. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022 Apr;604(7907):697-707. Epub 2022 Mar 7 PubMed.

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  1. This study adds to our understanding that COVID-19 exposure is related to brain changes detected on MRI. By comparing subjects pre- and post-exposure in a longitudinal study design with controls, the authors effectively make the point that the brain is impacted by the disease. This contribution is important as it sets the stage for continued understanding of the biological mechanisms for the impact on brain, the vulnerability of select brain tissues, and the permanence of these suspected neurodegenerative changes.

    We expect this study will pave the way for many additional ones. For example, because this study was not designed to demonstrate the presence of a causal agent in brain tissue or CSF, the proximal cause of the nonspecific MRI brain changes remains unknown. Is this due to viral invasion or peripheral immunological signaling resulting in pathways that include CNS inflammatory, autoimmune, and hypoxic changes in the tissues and vessels?

    Second, the finding of MRI signals for the anatomy related to the olfactory system is important, but the specificity of this observation needs to be explored. Not all COVID-19 affected subjects show olfactory deficits (unexamined in the present study) and other diseases and exposures are known to affect this anatomy.

    Third, this two-point longitudinal study, while provocatively suggesting neural degeneration, begs extension to later time points to examine the permanence of the damage.

    View all comments by Anna Nordvig

  2. The paper is very interesting, since having such a large imaging biobank of 42,000 individuals is really a big data gold mine. Applying this strategy of gathering large biobanks is expensive and time-consuming, especially since at the time of collecting you don’t expect something like a pandemic to happen. In this case the data is well-suited to observing the effects of COVID-19 on the population.

    The change in brain volume detected was (as mentioned in the paper) modest, but still significantly more than the 0.2–0.3 percent of expected brain volume loss per year. Relating structural changes in the anatomy to functional changes (cognitive tests) can be difficult, and further evidence would be needed to draw the connection between the two. That regions of taste and smell appear affected supports a COVID connection, and anosmia/ageusia being a prevalent symptoms.

    It is surprising to see that so few of the patients were hospitalized, and that only one of the 401 patients was mechanically ventilated. It would be interesting to know how the brain is affected after critical illness with COVID-19. If such brain atrophy is already seen in mild cases, one could suspect even more atrophy in those more critically ill. The lack of data on non-COVID hospitalized patients is a limitation, as mentioned by the authors. This would have shed more light on how specific the findings are for COVID.

    It would be good to see the baseline data for the cognitive scores and brain volumes before COVID-19. This could have been informative as it would give an impression of the extent of mild cognitive impairment and early dementia in the cohort before some contracted COVID-19, and in this way could show the effect of pre-existent frailty on the risk of COVID-19-based brain atrophy.

    View all comments by Patrick Smeele

  3. The elderly are especially vulnerable to the coronavirus SARS-CoV-2, the cause of COVID-19, which is characterized in some patients by a post-infective syndrome termed long COVID (Vimercati et al., 2021; Søraas et al., 2021). Many symptoms of long COVID are likely central nervous system (CNS) based, driven by neuroinflammation, blood-brain-barrier dysfunction, and oxidative stress (Pinna et al., 2020). The sickest of COVID-19 patients show a decline in global intellectual performance greater than that of the average stroke patient (Hampshire et al., 2021). Over 50 percent of patients with long COVID who are not hospitalized rank their symptoms as moderate to severe seven months after recovery from COVID-19 (Davis et al., 2021). The most frequent symptoms are fatigue, post-exertional malaise, and cognitive dysfunction, including brain fog, poor attention, impaired executive function (difficulty thinking and problem solving), and short- and long-term memory loss.

    To determine the impact of SARS-CoV-2 infection in milder cases on brain pathology, Douaoud et al. assessed brain changes in 785 U.K. Biobank participants aged 51–81. Of these, 401 tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan. In controls, 384 days separated their scans. Significant longitudinal effects of infection with SARS-CoV-2 included a greater reduction in gray-matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus, greater changes in markers of tissue damage in regions functionally connected to the primary olfactory cortex, suggesting a degenerative spread of the disease via olfactory pathways, a greater reduction in global brain size, and a worsening of executive function (requiring more time to complete trail A and trail B of the Trail Making Test). These MRI and executive function effects remained after removal of data from 15 hospitalized cases.

    However, there were no memory impairments detected. The lack of memory impairments might be due to the fact that mild to moderate cases were included in this study and because there were subtle baseline differences; while no single cognitive score was different at baseline between controls and future cases, two cognitive principal components were different, suggesting slightly lower cognitive abilities for the future cases when compared with the controls. The lack of memory impairments might also be due to the fact that risk factors for long-term cognitive decline in long COVID, such as apolipoprotein E4 (Manzo et al., 2021; Miners et al., 2020), sex (males at greater risk for infection) (Gebhard et al., 2020), and pre-existing Type 2 diabetes (associated with excess adiposity) are all risk factors for AD as well and were not included in the analyses.

    As part of follow-up studies, gastrointestinal distress, the presence of anti-type I Interferon (IFN) antibodies (Su et al., 2022; Bastard, 2022), and vaccination against measles, mumps, and rubella (Ashford et al., 2021; Gold et al., 2020), all implicated in modulating the response to COVID-19 exposure, would be good to consider. This might reveal general patterns across neurological diseases. For example, increasing evidence supports a role for alterations in the gut microbiome and the gut-liver-brain axis in healthy aging (Wilmanski et al., 2021), Parkinson’s disease, and Alzheimer’s disease (Dodiya et al., 2019; Sampson et al., 2016; Kundu et al., 2022; Kundu et al., 2021). Such studies are timely and warranted to assess whether the brain pathology and cognitive injury seen following moderate COVID-19 are transient or persist long-term.

    References:

    Vimercati L, De Maria L, Quarato M, Caputi A, Gesualdo L, Migliore G, Cavone D, Sponselli S, Pipoli A, Inchingolo F, Scarano A, Lorusso F, Stefanizzi P, Tafuri S. Association between Long COVID and Overweight/Obesity. J Clin Med. 2021 Sep 14;10(18) PubMed.

    Søraas A, Kalleberg KT, Dahl JA, Søraas CL, Myklebust TÅ, Axelsen E, Lind A, Bævre-Jensen R, Jørgensen SB, Istre MS, Kjetland EF, Ursin G. Persisting symptoms three to eight months after non-hospitalized COVID-19, a prospective cohort study. PLoS One. 2021;16(8):e0256142. Epub 2021 Aug 26 PubMed.

    Pinna P, Grewal P, Hall JP, Tavarez T, Dafer RM, Garg R, Osteraas ND, Pellack DR, Asthana A, Fegan K, Patel V, Conners JJ, John S, Silva ID. Neurological manifestations and COVID-19: Experiences from a tertiary care center at the Frontline. J Neurol Sci. 2020 Aug 15;415:116969. Epub 2020 Jun 3 PubMed.

    Hampshire A, Trender W, Chamberlain SR, Jolly AE, Grant JE, Patrick F, Mazibuko N, Williams SC, Barnby JM, Hellyer P, Mehta MA. Cognitive deficits in people who have recovered from COVID-19. EClinica lMedicine, 2021 eClinical Medicine

    Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, Redfield S, Austin JP, Akrami A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021 Aug;38:101019. Epub 2021 Jul 15 PubMed.

    Manzo C, Serra-Mestres J, Isetta M, Castagna A. Could COVID-19 anosmia and olfactory dysfunction trigger an increased risk of future dementia in patients with ApoE4?. Med Hypotheses. 2021 Feb;147:110479. Epub 2021 Jan 5 PubMed.

    Miners S, Kehoe PG, Love S. Cognitive impact of COVID-19: looking beyond the short term. Alzheimers Res Ther. 2020 Dec 30;12(1):170. PubMed.

    Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ. 2020 May 25;11(1):29. PubMed.

    Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, Li S, Hong S, Zhang R, Xie J, Kornilov SA, Scherler K, Pavlovitch-Bedzyk AJ, Dong S, Lausted C, Lee I, Fallen S, Dai CL, Baloni P, Smith B, Duvvuri VR, Anderson KG, Li J, Yang F, Duncombe CJ, McCulloch DJ, Rostomily C, Troisch P, Zhou J, Mackay S, DeGottardi Q, May DH, Taniguchi R, Gittelman RM, Klinger M, Snyder TM, Roper R, Wojciechowska G, Murray K, Edmark R, Evans S, Jones L, Zhou Y, Rowen L, Liu R, Chour W, Algren HA, Berrington WR, Wallick JA, Cochran RA, Micikas ME, ISB-Swedish COVID-19 Biobanking Unit, Wrin T, Petropoulos CJ, Cole HR, Fischer TD, Wei W, Hoon DS, Price ND, Subramanian N, Hill JA, Hadlock J, Magis AT, Ribas A, Lanier LL, Boyd SD, Bluestone JA, Chu H, Hood L, Gottardo R, Greenberg PD, Davis MM, Goldman JD, Heath JR. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022 Mar 3;185(5):881-895.e20. Epub 2022 Jan 25 PubMed.

    Bastard P. Why do people die from COVID-19?. Science. 2022 Feb 25;375(6583):829-830. Epub 2022 Feb 24 PubMed.

    Ashford JW, Gold JE, Huenergardt MA, Katz RB, Strand SE, Bolanos J, Wheeler CJ, Perry G, Smith CJ, Steinman L, Chen MY, Wang JC, Ashford CB, Roth WT, Cheng JJ, Chao S, Jennings J, Sipple D, Yamamoto V, Kateb B, Earnest DL. MMR Vaccination: A Potential Strategy to Reduce Severity and Mortality of COVID-19 Illness. Am J Med. 2021 Feb;134(2):153-155. Epub 2020 Oct 23 PubMed.

    Gold JE, Baumgartl WH, Okyay RA, Licht WE, Fidel PL Jr, Noverr MC, Tilley LP, Hurley DJ, Rada B, Ashford JW. Analysis of Measles-Mumps-Rubella (MMR) Titers of Recovered COVID-19 Patients. mBio. 2020 Nov 20;11(6) PubMed.

    Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, Earls JC, Zimmer A, Glusman G, Robinson M, Yurkovich JT, Kado DM, Cauley JA, Zmuda J, Lane NE, Magis AT, Lovejoy JC, Hood L, Gibbons SM, Orwoll ES, Price ND. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021 Feb;3(2):274-286. Epub 2021 Feb 18 PubMed.

    Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J, Zhang X, Gottel N, Zhang X, Butovsky O, Gilbert JA, Sisodia SS. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019 Jul 1;216(7):1542-1560. Epub 2019 May 16 PubMed.

    Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. PubMed.

    Kundu P, Stagaman K, Kasschau K, Holden S, Shulzhenko N, Sharpton TJ, Raber J. Fecal Implants From App NL-G-F and App NL-G-F/E4 Donor Mice Sufficient to Induce Behavioral Phenotypes in Germ-Free Mice. Front Behav Neurosci. 2022;16:791128. Epub 2022 Feb 8 PubMed.

    Kundu P, Torres ER, Stagaman K, Kasschau K, Okhovat M, Holden S, Ward S, Nevonen KA, Davis BA, Saito T, Saido TC, Carbone L, Sharpton TJ, Raber J. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice. Sci Rep. 2021 Feb 25;11(1):4678. PubMed.

    View all comments by Jacob Raber

  4. On the back of the recent data strengthening the link between Epstein-Barr virus and multiple sclerosis, the authors present data linking mild COVID symptoms to reduced cognition and cortical thinning in regions associated with olfaction over a period of 140 days. Strikingly, visual inspection of the data suggests that older people showed greater loss of cognition and cortical thinning than younger people, independent of the severity of their COVID symptoms.

    Longer-term follow-up of these subjects will enable us to evaluate whether the COVID infection changes patients’ symptoms towards Alzheimer’s or Parkinson’s disease, perhaps within a few years. The enrollment of these cohorts within the U.K. Biobank also potentially enables the identification biomarkers and additional risk factors such as APOE status that could influence whether the cortical thinning and cognitive changes are temporary, permanent, or progressive. Perhaps the extent of hyposmia will be a telling measure.

    From the perspective of discovering and developing therapeutics, rodents rely heavily on their sense of smell and provide an excellent translational model for the interactions between inflammation and cell-type-specific vulnerability related to COVID infections and potentially dementia.

    View all comments by Oliver Cooper

  5. The detection of diffuse Aβ deposits in the cortices of 10 people under age 60 who died from severe COVID-19 (Rhodes et al., 2022) is intriguing. At first pass, however, I would guess this is the consequence of altered Aβ drainage or microglia uptake. There is an increasing body of evidence that microglia function involves the clearance of aggregation-prone peptides like Aβ. Since viral infections are known to modulate the physiological function of microglia, the detection of diffuse Aβ deposits might simply be the consequence of reduced Aβ clearance.

    In the case of long-term respiratory distress, various factors from treatment may further compromise the function of microglia, including anesthetics and benzodiazepines. The later may cause an overactivation of microglia in dendritic spine pruning, as we have shown recently, and may be the underlying cause of cognitive changes (Shi et al., 2022).

    Diffuse Aβ may not affect cognition and thus contribute to persistent cognitive impairment in COVID survivors, but I believe that its extracellular accumulation during long-term intensive care treatment may lead to the formation of fibrillary Aβ seeds and a higher risk of developing AD 25 years later.

    References:

    Harker Rhodes C, Priemer DS, Karlovich E, Perl DP, Goldman J. Β-Amyloid Deposits in Young COVID Patients. January 14, 2022 The Lancet Preprint

    View all comments by Jochen Herms

  6. In response to Charlotte Teunissen, Lisa Vermunt, and Patrick Smeele's comment that "It would be good to see the baseline data for the cognitive scores and brain volumes before COVID-19":

    We thank you for your comments. We have provided these baseline data. For imaging, it's in Supplementary Table 2; for non-imaging (including cognition), it's in Supplementary Table 4.

    View all comments by Gwenaelle Douaud

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  1. Mild COVID Infection Can Shrink Brain, Speed Cognitive Decline