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Cited by 98Long-Term Effects of COVID-19Infectious Encephalopathies and EncephalitisIntensive Care Unit Cognitive Disorders

Cognitive decline following acute viral infections: literature review and projections for post-COVID-19

Open access
Damiano, Rodolfo Furlan, Guedes, Bruno F., de Rocca, Cristiana Castanho, de Pádua Serafim, Antonio, Castro, Luiz Henrique Martins, Munhoz, Carolina Demarchi, Nitrini, Ricardo, Filho, Geraldo Busatto +3 more·2022·European Archives of Psychiatry and Clinical Neuroscience
DOI 10.1007/s00406-021-01286-4PMC PMC8231753
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Abstract

Recently, much attention has been drawn to the importance of the impact of infectious disease on human cognition. Several theories have been proposed, to explain the cognitive decline following an infection as well as to understand better the pathogenesis of human dementia, especially Alzheimer’s disease. This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review synthesizes evidence that several acute viral infections are followed by cognitive impairment, and projects similar short- and long-term cognitive sequelae for COVID-19. It argues that direct CNS invasion and indirect mechanisms such as neuroinflammation, hypercoagulability, and oxidative stress may drive these deficits.

Key findings

  • HSV-1 encephalitis causes enduring memory impairment: severe memory impairment in 40–58% of patients one year after encephalitis, and 80% show persistent mild cognitive deficits three years after the acute episode; cognitive impairment remains common even in acyclovir-treated patients.
  • VZV CNS infection is associated with neurological impairment in 20–60% at hospital discharge, 55% at one month, 51% at three months, and 71% at one year; Japanese encephalitis survivors show neurological sequelae in 45–64% at discharge, with one series reporting 75% significant functional limitations at discharge and 39% major limitations after 18 months.
  • West Nile neuroinvasive disease produces mild cognitive deficits in immediate and delayed memory and greater cortical thinning than controls; 80% of WNV encephalitis patients report persistent WNV-related symptoms one year after infection.
  • In COVID-19, preliminary studies report cognitive impairment two to four weeks after infection, mainly attentional deficits; cognitive impairment has been reported in 28–56% of patients with mild or asymptomatic COVID-19, and 26% of those with neuropsychiatric disorders due to COVID-19 had a dementia-like syndrome.

Methods

  • Narrative review following international guidelines for writing narrative reviews, conducted by a multi-specialist group including neurologists, geriatrists, psychiatrists, and neuropsychologists.
  • Two authors searched PubMed, SciELO, and EMBASE using cognition-, dementia-, virus-, and infection-related keywords, plus disease-specific terms such as HSV-1, varicella-zoster, West Nile virus, influenza, Japanese encephalitis, aseptic meningitis, and acute respiratory distress syndrome; references of selected articles were also searched.
  • Only articles in English, Spanish, Italian, and Portuguese were accepted; selected articles were discussed with all authors and included in the review.

Limitations

  • The paper states that its narrative nature creates a selection bias of articles.
  • The paper states that it chose only six acute viral infections or virus-related syndromes out of several possible ones, aiming to include both globally ubiquitous and regionally relevant viruses.
  • The paper states that COVID-19 is an ongoing and dynamic epidemic, making review challenging, and that projections about post-COVID-19 cognition were made because long-term studies on cognitive outcomes are largely lacking; evident from the text, the review also provides no quantitative synthesis or formal risk-of-bias assessment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00406-021-01286-4

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 180 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The occurrence of persistent cognitive deficits resulting from COVID-19 infection remains uncertain.

    “The occurrence of persistent cognitive deficits resulting from COVID-19 infection remains uncertain.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Evidence of SARS-CoV-2 impact on human cognition remains scarce.

    “Although several studies have reported neuropsychiatric symptoms associated with the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) [13, 125], evidence of SARS-CoV-2 impact on human cognition remains scarce.”
    Quote in the paperSubstantial claim
  • Premisecitation

    MRI changes in COVID-19 patients include acute necrotizing encephalopathy.

    “such as acute necrotizing encephalopathy [145]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B (2020) Covid-19–associated acute hemorrhagic necrotizing encephalopathy: imaging features. Radiology 296:E119–E120. https://doi.org/10.1148/radiol.2020201187 source

      Not checked in the free run.

  • Premisecitation

    COVID-19 may affect other major body organs, including renal, cardiovascular, and central nervous systems.

    “subsequent reports showed that COVID-19 may also affect other major body organs, including renal, cardiovascular, and central nervous systems (CNS) [16, 125, 128].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H, Wang H, Wang T, Guo W, Chen J, Ding C, Zhang X, Huang J, Han M, Li S, Luo X, Zhao J, Ning Q (2020) Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 368:m1091. https://doi.org/10.1136/bmj.m1091 source

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      Not checked in the free run.

    • cites [128] Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M, Anheim M, Meziani F (2020) Neurologic features in severe sars-cov-2 infection. N Engl J Med 382:2268–2270. https://doi.org/10.1056/NEJMc2008597 source

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  • Premisecitation

    Preliminary studies of convalescent COVID-19 patients using comprehensive neuropsychological assessment showed cognitive impairment two to four weeks after infection.

    “Preliminary studies of convalescent COVID-19 patients using comprehensive neuropsychological assessment showed cognitive impairment two to four weeks after infection.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [140] Zhou H, Lu S, Chen J, Wei N, Wang D, Lyu H, Shi C, Hu S (2020) The landscape of cognitive function in recovered covid-19 patients. J Psychiatr Res 129:98–102. https://doi.org/10.1016/j.jpsychires.2020.06.022 source

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  • Classified as probably not a substantial claim. 18
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    No articles have investigated cognitive decline or impairment following MERS or SARS-CoV-1.

    “To our knowledge, no articles have investigated cognitive decline/impairment following the middle east respiratory syndrome (MERS) or the severe acute respiratory syndrome-coronavirus-1 (SARS-CoV-1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals.

    “Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pathophysiology and cognitive sequelae of other acute viral infections can inform understanding of post-COVID-19 cognitive impairment.

  • May combine two claims.

    Premisecitation

    Cognitive impairment may be caused by viral infections associated with direct invasion of the central nervous system, or as an indirect effect of systemic infections not typically causing CNS infection.

    “Cognitive impairment may be caused by viral infections associated with direct invasion of the central nervous system [11, 24], or as an indirect effect of systemic infections not typically causing CNS infection (e.g. cytokine storm, neuro-inflammation, hypercoagulability) [11, 24].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Hosseini S, Wilk E, Michaelsen-Preusse K, Gerhauser I, Baumgärtner W, Geffers R, Schughart K, Korte M (2018) Long-term neuroinflammation induced by influenza a virus infection and the impact on hippocampal neuron morphology and function. J Neurosci 38:3060–3080. https://doi.org/10.1523/jneurosci.1740-17.2018 source

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    • cites [24] Sittinger H, Müller M, Schweizer I, Merkelbach S (2002) Mild cognitive impairment after viral meningitis in adults. J Neurol 249:554–560. https://doi.org/10.1007/s004150200064 source

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    Premisecitation

    Mechanisms underlying viral pathogenesis in these conditions may include a direct viral effect or indirect mechanisms, such as inflammation, epigenetic changes, and hypercoagulable changes, that may impact brain structure and function in healthy or cognitively impaired individuals.

    “Mechanisms underlying viral pathogenesis in these conditions may include a direct viral effect or indirect mechanisms, such as inflammation, epigenetic changes, and hypercoagulable changes, that may impact on brain structure and function in healthy or in cognitively impaired individuals [6, 11–15].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [6] Dobson CB, Wozniak MA, Itzhaki RF (2003) Do infectious agents play a role in dementia? Trends Microbiol 11:312–317. https://doi.org/10.1016/s0966-842x(03)00146-x source

      Not checked in the free run.

    • cites [11] Hosseini S, Wilk E, Michaelsen-Preusse K, Gerhauser I, Baumgärtner W, Geffers R, Schughart K, Korte M (2018) Long-term neuroinflammation induced by influenza a virus infection and the impact on hippocampal neuron morphology and function. J Neurosci 38:3060–3080. https://doi.org/10.1523/jneurosci.1740-17.2018 source

      Not checked in the free run.

    • cites [12] Aiello AE, Haan M, Blythe L, Moore K, Gonzalez JM, Jagust W (2006) The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc 54:1046–1054. https://doi.org/10.1111/j.1532-5415.2006.00796.x source

      Not checked in the free run.

    • cites [13] Aghagoli G, Gallo Marin B, Katchur NJ, Chaves-Sell F, Asaad WF, Murphy SA (2020) Neurological involvement in covid-19 and potential mechanisms: a review. Neurocrit Care. https://doi.org/10.1007/s12028-020-01049-4 source

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      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The brain abnormalities associated with COVID-19 are associated with encephalitis and may at least partially explain cognitive impairment in COVID-19.

    “These abnormalities are associated with encephalitis and may at least partially explain cognitive impairment in COVID-19.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MRI changes in COVID-19 patients include cortical signal intensity abnormalities and unilateral FLAIR or diffusion hyper-intensities in the medial temporal lobe.

    “cortical signal intensity abnormalities and unilateral FLAIR or diffusion hyper-intensities in medial the temporal lobe (MTL) [144, 146]”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims.

    Premisecitation

    Memory deficit severity correlates with the extent of medial temporal lobe involvement and is the most important late finding in HSV encephalitis.

    “Memory deficit severity correlates with the extent of medial temporal lobe involvement and is the most important late finding in HSV encephalitis [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Studies assessing prognosis using hard endpoints in the post-acyclovir era showed neurological impairment in 20-60% of VZV patients upon hospital discharge, 55% after one month, 51% after three months, and 71% after one year after the acute episode.

    “Studies assessing prognosis using hard endpoints in the post-acyclovir era showed neurological impairment in 20–60% of patients upon hospital discharge [62–64], 55% after one month, 51% after three months and 71% after one year [62, 65] after the acute episode.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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    Premisecitation

    Memory learning deficits have been presented in rats with JE.

    “as well as memory learning in rats [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Chauhan PS, Khanna VK, Kalita J, Misra UK (2017) Japanese encephalitis virus infection results in transient dysfunction of memory learning and cholinesterase inhibition. Mol Neurobiol 54:4705–4715. https://doi.org/10.1007/s12035-016-9963-6 source

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    Premisecitation

    Mortality rates in HSV-1 encephalitis have dropped below 20%.

    “Mortality rates have dropped below 20% [34, 57].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    According to the viral hypothesis of AD, the interaction between viral presence and AD may be non-specifically associated with up-regulation of inflammatory responses and oxidative stress.

    “According to the ‘viral hypothesis of AD’, this interaction may be non-specifically associated with up-regulation of inflammatory responses and oxidative stress, which are secondary, but relevant components of the amyloid cascade.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    • cites [12] Aiello AE, Haan M, Blythe L, Moore K, Gonzalez JM, Jagust W (2006) The influence of latent viral infection on rate of cognitive decline over 4 years. J Am Geriatr Soc 54:1046–1054. https://doi.org/10.1111/j.1532-5415.2006.00796.x source

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    Premisecitation

    Most WNE cases require rehabilitation.

    “Most cases require rehabilitation [85, 86].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Klee AL, Maidin B, Edwin B, Poshni I, Mostashari F, Fine A, Layton M, Nash D (2004) Long-term prognosis for clinical West Nile virus infection. Emerg Infect Dis 10:1405–1411. https://doi.org/10.3201/eid1008.030879 source

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    Premisecitation

    The advent of acyclovir in the late 1980s considerably modified the prognosis of HSV-1 encephalitis.

    “The advent of acyclovir, in the late 1980s, considerably modified the prognosis of HSV-1 encephalitis [54–56].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • May combine two claims.

    Interpretationcitation

    Although HSV-1 survivors may show improved cognition over time, cognitive impairment is an enduring long-term consequence of brain damage.

    “Although HSV-1 survivors may show improved cognition over time, cognitive impairment is an enduring long-term consequence of brain damage.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Coronavirus RNA has been found in brain tissue of deceased patients, raising the possibility of a direct brain injury mechanism.

    “The finding of coronavirus RNA in brain tissue of deceased patients raised the possibility of a direct brain injury mechanism [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, Braun F, Lu S, Pfefferle S, Schröder AS, Edler C, Gross O, Glatzel M, Wichmann D, Wiech T, Kluge S, Pueschel K, Aepfelbacher M, Huber TB (2020) Multiorgan and renal tropism of sars-cov-2. N Engl J Med 383:590–592. https://doi.org/10.1056/NEJMc2011400 source

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  • May combine two claims.

    Interpretationreasoning

    Post-COVID cognitive impairment may represent an important clinical feature of the disease and may impose an additional and long-lasting burden, especially psychiatric and cognitive issues, particularly among older adults.

    “Post-COVID cognitive impairment may represent an important clinical feature of the disease, and may impose an additional and long-lasting burden, especially psychiatric and cognitive issues, particularly among older adults.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pathophysiology and cognitive sequelae of other acute viral infections can inform understanding of post-COVID-19 cognitive impairment.

  • May combine two claims.

    Premisecitation

    Putative biological mechanisms underlying long-term cognitive impairment in ARDS patients include hypoxia, cytokine-mediated damage, cerebral autoregulation disruption, and blood-brain barrier damage-associated decrease in Amyloid-β clearance.

    “Putative biological mechanisms underlying long-term cognitive impairment in ARDS patients include hypoxia, cytokine-mediated damage, cerebral autoregulation disruption, and blood–brain barrier damage-associated decrease in Amyloid-β clearance [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Blood-brain barrier disruption is associated with encephalopathy, favoring the neuro-inflammation theory.

    “Several studies implied that blood–brain barrier disruption is associated with encephalopathy, favoring the neuro-inflammation theory [150, 151].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Alexopoulos H, Magira E, Bitzogli K, Kafasi N, Vlachoyiannopoulos P, Tzioufas A, Kotanidou A, Dalakas MC (2020) Anti-sars-cov-2 antibodies in the csf, blood–brain barrier dysfunction, and neurological outcome: studies in 8 stuporous and comatose patients. Neurol Neuroimmunol Neuroinflamm 7:893. https://doi.org/10.1212/nxi.0000000000000893 source

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    Premisecitation

    Patients with neuro-invasive WNV disease displayed mild cognitive deficits in immediate and delayed memory, and more significant cortical thinning than controls on magnetic resonance imaging.

    “Using comprehensive neuropsychological assessment tools, [88] showed that patients with neuro-invasive WNV disease displayed mild cognitive deficits in immediate and delayed memory, and more significant cortical thinning than controls on magnetic resonance imaging [88].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    SARS-CoV-2 has been found in neural and endothelial cells in frontal lobe tissues and in the cerebral spinal fluid of infected individuals.

    “This observation was corroborated by the finding of the virus in neural and endothelial cells in frontal lobe tissues [154], and in the cerebral spinal fluid of infected individuals [147, 155, 156].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [154] Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (sars-cov-2). J Med Virol 92:699–702. https://doi.org/10.1002/jmv.25915 source

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    • cites [147] Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H, Kondo K, Myose N, Nakao A, Takeda M, Haro H, Inoue O, Suzuki-Inoue K, Kubokawa K, Ogihara S, Sasaki T, Kinouchi H, Kojin H, Ito M, Onishi H, Shimizu T, Sasaki Y, Enomoto N, Ishihara H, Furuya S, Yamamoto T, Shimada S (2020) A first case of meningitis/encephalitis associated with sars-coronavirus-2. Int J Infect Dis 94:55–58. https://doi.org/10.1016/j.ijid.2020.03.062 source

      Not checked in the free run.

    • cites [155] Huang YH, Jiang D, Huang JT (2020) Sars-cov-2 detected in cerebrospinal fluid by pcr in a case of covid-19 encephalitis. Brain Behav Immun 87:149. https://doi.org/10.1016/j.bbi.2020.05.012 source

      Not checked in the free run.

    • cites [156] Khodamoradi Z, Hosseini SA, Gholampoor Saadi MH, Mehrabi Z, Sasani MR, Yaghoubi S (2020) Covid-19 meningitis without pulmonary involvement with positive cerebrospinal fluid pcr. Eur J Neurol 27:2668–2669. https://doi.org/10.1111/ene.14536 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The narrative review was conducted following international guidelines for writing narrative reviews.

    “We conducted a narrative review of literature following international guidelines for writing narrative reviews [20, 21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Ferrari R (2015) Writing narrative style literature reviews. Med Writ 24:230–235. https://doi.org/10.1179/2047480615Z.000000000329 source

      Not checked in the free run.

    • cites [21] Green BN, Johnson CD, Adams A (2006) Writing narrative literature reviews for peer-reviewed journals: secrets of the trade. J Chiropr Med 5:101–117. https://doi.org/10.1016/s0899-3467(07)60142-6 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One-year post-discharge, ARDS survivors show high rates of anxiety, depression, executive dysfunction and post-traumatic stress disorder.

    “Moreover, one-year post-discharge, ARDS survivors show high rates of anxiety, depression, executive dysfunction and post-traumatic stress disorder [121, 122].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [121] Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC (2012) The adult respiratory distress syndrome cognitive outcomes study: Long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 185:1307–1315. https://doi.org/10.1164/rccm.201111-2025OC source

      Not checked in the free run.

    • cites [122] Kapfhammer HP, Rothenhäusler HB, Krauseneck T, Stoll C, Schelling G (2004) Posttraumatic stress disorder and health-related quality of life in long-term survivors of acute respiratory distress syndrome. Am J Psychiatry 161:45–52. https://doi.org/10.1176/appi.ajp.161.1.45 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The virus reached the ganglion contralateral to the de-afferentation first, suggesting a less effective transport after vagus nerve injury.

    “The virus reached the ganglion contralateral to the de-afferentation first, suggesting a less effective transport after vagus nerve injury.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Matsuda K, Park CH, Sunden Y, Kimura T, Ochiai K, Kida H, Umemura T (2004) The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol 41:101–107. https://doi.org/10.1354/vp.41-2-101 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intranasal SARS-CoV-1 inoculation in K18-hACE2 mutant mice resulted in viral presence throughout the CNS, associated with local inflammatory mediators, respiratory dysfunction, and high mortality, with only mild lung infection.

    “Intranasal SARS-CoV-1 inoculation (80% homology to SARS-CoV-2) in K18-hACE2 mutant mice (with the human form of ACE-2) resulted in the viral presence throughout the CNS, and was associated with local inflammatory mediators, respiratory dysfunction, and high mortality, with only mild lung infection [171, 172].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [171] McCray PB, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, Meyerholz DK, Kirby P, Look DC, Perlman S (2007) Lethal infection of k18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 81:813–821. https://doi.org/10.1128/jvi.02012-06 source

      Not checked in the free run.

    • cites [172] Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace2. J Virol 82:7264–7275. https://doi.org/10.1128/jvi.00737-08 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individuals with the ApoE3 allele may be more susceptible to severe forms of COVID-19 disease.

    “Additionally, individuals with the ApoE3 allele may be more susceptible to severe forms of COVID-19 disease [183].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Kuo CL, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (2020) APOE e4 genotype predicts severe covid-19 in the uk biobank community cohort. J Gerontol A Biol Sci Med Sci 75:2231–2232. https://doi.org/10.1093/gerona/glaa131 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brain lesions in people who died by COVID-19 were non-specific and could not be directly attributed to SARS-CoV-2 lesions.

    “A recent article found SARS-CoV-2 virus in 53% of brain tissues of people who died by COVID-19, even though brain lesions were non-specific and could not be attributed to SARS-CoV-2 lesions directly [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, Fitzek A, Allweiss L, Dandri M, Dottermusch M, Heinemann A, Pfefferle S, Schwabenland M, Sumner Magruder D, Bonn S, Prinz M, Gerloff C, Püschel K, Krasemann S, Aepfelbacher M, Glatzel M (2020) Neuropathology of patients with covid-19 in germany: a post-mortem case series. Lancet Neurol 19:919–929. https://doi.org/10.1016/S1474-4422(20)30308-2 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The cytokine storm theory proposes that the SARS-CoV-2 inflammatory response in the CNS is mediated by massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III.

    “Finally, the cytokine storm theory proposes that SARS-CoV-2 inflammatory response in the CNS is mediated by the massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III [168, 169].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [168] Detje CN, Lienenklaus S, Chhatbar C, Spanier J, Prajeeth CK, Soldner C, Tovey MG, Schlüter D, Weiss S, Stangel M, Kalinke U (2015) Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon beta producers that protect from lethal encephalitis. J Virol 89:2731–2738. https://doi.org/10.1128/jvi.02044-14 source

      Not checked in the free run.

    • cites [169] Steardo L, Steardo L Jr, Zorec R, Verkhratsky A (2020) Neuroinfection may contribute to pathophysiology and clinical manifestations of covid-19. Acta Physiol (Oxf) 229:e13473. https://doi.org/10.1111/apha.13473 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Olfactory cells express ACE-2 and TMPRSS-2, which may represent the viral entry point to the CNS.

    “Olfactory cells express angiotensin-converting enzyme isoform 2 (ACE-2) and type II serine protease (TMPRSS-2), which may represent the viral entry point to the CNS [163].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu N-H, Nitsche A, Müller MA, Drosten C, Pöhlmann S (2020) Sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. Cell 181:271-280.e278. https://doi.org/10.1016/j.cell.2020.02.052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cognitive rehabilitation techniques have been shown to be effective and can be used through several different cognitive deficits and etiologies.

    “The spread of cognitive rehabilitation techniques is indispensable, as it has been showed to be effective and can be used through several different cognitive deficits and etiologies [186].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Cicerone KD, Dahlberg C, Malec JF, Langenbahn DM, Felicetti T, Kneipp S, Ellmo W, Kalmar K, Giacino JT, Harley JP, Laatsch L, Morse PA, Catanese J (2005) Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil 86:1681–1692. https://doi.org/10.1016/j.apmr.2005.03.024 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    SARS-CoV-2 infection might increase Alzheimer's disease risk through different mechanisms, which could be extrapolated to other cognitive diseases.

    “Abate et al. [18] reviewed the different mechanisms by which SARS-CoV-2 infection might increase Alzheimer’s disease (AD) risk, which could be extrapolated to other cognitive diseases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Abate G, Memo M, Uberti D (2020) Impact of covid-19 on Alzheimer’s disease risk: viewpoint for research action. Healthcare (Basel) 8:286. https://doi.org/10.3390/healthcare8030286 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once the virus enters the CNS, it affects neurons, microglia, oligodendrocytes, and especially astrocytes, undermining neuron viability.

    “Once the virus enters the CNS, it affects neurons, microglia, oligodendrocytes, and especially astrocytes, undermining neurons viability [17, 179, 180].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Crunfli F, Corasolla Carregari V, Veras FP, Vendramini PH, Valenca AGF, Antunes ASLM, Brandao-Teles C, Zuccoli GdS, Reis-de-Oliveira G, Silva-Costa LC, Saia-Cereda VM, Codo AC, Parise PL, Toledo-Teixeira DA, de Souza GF, Muraro SP, Melo BMS, Almeida GM, Firmino EMS, Ludwig RG, Palermo Ruiz G, Knittel TL, Davanzo GG, Gerhardt JA, Rodrigues PB, Forato J, Amorim MR, Brunetti Silva N, Martini MC, Benatti MN, Batah S, Siyuan L, Pereira Silva REM, João RB, Scardua Silva L, Nogueira MH, Karmann Aventurato I, Rabelo de Brito M, Machado Alvim MK, da Silva Junior JR, Damião LL, Castilho Stefano MEdP, Pe source

      Not checked in the free run.

    • cites [179] Tremblay M-E, Madore C, Bordeleau M, Tian L, Verkhratsky A (2020) Neuropathobiology of covid-19: the role for glia. Front Cell Neurosci 14:592214. https://doi.org/10.3389/fncel.2020.592214 source

      Not checked in the free run.

    • cites [180] Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A (2020) Neuroinvasion of sars-cov-2 in human and mouse brain. bioRxiv. https://doi.org/10.1101/2020.06.25.169946 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    COVID-19 could impact not only older individuals with cognitive impairment, but also healthy individuals more susceptible to it.

    “It could impact not only older individuals with cognitive impairment, but also healthy individuals more susceptible to it.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypercoagulable states may induce micro-vascular disease and induce vascular dementia and Alzheimer's disease.

    “Additionally, hypercoagulable states may induce micro-vascular disease and induce vascular dementia and AD [185].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Gupta A, Watkins A, Thomas P, Majer R, Habubi N, Morris G, Pansari K (2005) Coagulation and inflammatory markers in Alzheimer’s and vascular dementia. Int J Clin Pract 59:52–57. https://doi.org/10.1111/j.1742-1241.2004.00143.x source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent study pointed to the neural-mucosa interface in olfactory mucosa as a potential port of CNS entry for SARS-CoV-2.

    “A recent study pointed out to the neural–mucosa interface in olfactory mucosa as a potential port of CNS entry for SARS-CoV-2 [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, Laue M, Schneider J, Brünink S, Greuel S, Lehmann M, Hassan O, Aschman T, Schumann E, Chua RL, Conrad C, Eils R, Stenzel W, Windgassen M, Rößler L, Goebel H-H, Gelderblom HR, Martin H, Nitsche A, Schulz-Schaeffer WJ, Hakroush S, Winkler MS, Tampe B, Scheibe F, Körtvélyessy P, Reinhold D, Siegmund B, Kühl AA, Elezkurtaj S, Horst D, Oesterhelweg L, Tsokos M, Ingold-Heppner B, Stadelmann C, Drosten C, Corman VM, Radbruch H, Heppner FL (2021) Olfactory transmucosal sars-cov-2 invasion as a port of central nervous system entry in indiv source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In SARS-CoV-2, trans-nasal and trans-synaptic mechanisms might allow the virus to invade the olfactory bulb and brainstem, with both being possible initial sites for CNS invasion.

    “In SARS-CoV-2, trans-nasal and trans-synaptic mechanisms might allow the virus to invade the olfactory bulb and brainstem, with both being the possible initial site for CNS invasion [179].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Tremblay M-E, Madore C, Bordeleau M, Tian L, Verkhratsky A (2020) Neuropathobiology of covid-19: the role for glia. Front Cell Neurosci 14:592214. https://doi.org/10.3389/fncel.2020.592214 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Direct viral neuro-invasion and its association with ACE-2 expression in brain, especially in glial cells, could lead to oxidative stress and neuronal loss, due to microglia and astrocyte activation and increased nitric oxide production.

    “Direct viral neuro-invasion, as hypothesized above, and its association with ACE-2 expression in brain, especially in glial cells, could lead to oxidative stress and neuronal loss, due to both microglia and astrocyte activation, and increased nitric oxide (NO) production. [181, 182].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [181] Asiimwe N, Yeo SG, Kim MS, Jung J, Jeong NY (2016) Nitric oxide: exploring the contextual link with Alzheimer’s disease. Oxid Med Cell Longev. https://doi.org/10.1155/2016/7205747 source

      Not checked in the free run.

    • cites [182] Li Y, Fu L, Gonzales DM, Lavi E (2004) Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J Virol 78:3398–3406. https://doi.org/10.1128/jvi.78.7.3398-3406.2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    A wide body of evidence has shown that COVID-19 might lead to neuropsychiatric issues, especially cognitive impairments.

    “Recently, a wide body of evidence has shown that COVID-19 might lead to neuropsychiatric issues, especially cognitive impairments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The review chose only six out of several different acute viral infections and virus-related syndromes.

    “Second, we chose only six out of several different acute viral infections and virus-related syndromes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Many new articles are published daily, which makes reviewing this ever-changing field challenging.

    “Many new articles are published daily, which makes reviewing this ever-changing field challenging.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Due to the narrative nature of this review, there is a selection bias of articles.

    “First, due to the narrative nature of this review, there is a selection bias of articles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    This knowledge may help understand and predict possible long-term cognitive outcomes of COVID-19.

    “This knowledge may help us understand and predict possible long-term cognitive outcomes of COVID-19, helping both patients and health providers to cope better with this still unknown disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Some of these pathogens may cause long-term cognitive impairment, including parenchymal brain damage due to direct CNS infection or indirect mechanisms leading to disrupted brain function, such as hypercoagulable states and neuro-inflammation.

    “Some of these pathogens may cause long-term cognitive impairment, including parenchymal brain damage due to the direct CNS infection or to indirect mechanisms leading to disrupted brain function, such as hypercoagulable states and neuro-inflammation.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    The pathophysiology and cognitive sequelae of other acute viral infections can inform understanding of post-COVID-19 cognitive impairment.

    “Moreover, understanding about the pathophysiology of the cognitive impairment following other viral infections will help to better understand the emergence of neuro-cognitive symptoms among COVID-19 survivors.”

  • The paper relies on this without support.

    Long-term studies on cognitive outcomes of COVID-19 are largely lacking.

    “For instance, we made projections about post-COVID-19, because long-term studies on cognitive outcomes are largely lacking.”

  • The paper relies on this without support.

    The pathophysiological mechanisms by which COVID-19 leads to cognitive impairments are largely unknown.

    “However, lack is known about the pathophysiological mechanisms.”

  • The paper relies on this without support.

    Electron microscopy data confirmed the presence of the virus in neuronal vesicles.

    “Electron microscopy data confirmed the presence of the virus in neuronal vesicles.”

  • The paper relies on this without support.

    Lungs and intestines usually show significant signs of viral infection and inflammation, which may be associated with high ACE-2 levels in pneumocytes and enterocytes.

    “Lungs and intestines usually show significant signs of viral infection and inflammation, which may be associated with high ACE-2 levels in pneumocytes and enterocytes.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • APOE allele differs from the cited study

    Minor

    The text identifies ApoE3 as the allele associated with severe COVID-19, but the title of the cited study identifies APOE e4.

1 of 1

The citation lists haven’t been fetched yet

References 200 · Cited by 98

Research works printed but not linked: 2

  1. Cunningham EL, McGuinness B, Herron B, Passmore AP (2015) Dementia. Ulster Med J 84:79–87
  2. Sinclair W, Omar M (2021) Enterovirus. In: StatPearls Publishing, Treasure Island. https://www.ncbi.nlm.nih.gov/books/NBK562330/

Authors
Damiano, R. F., Guedes, B. F., de Rocca, C. C., de Pádua Serafim, A., Castro, L. H. M., Munhoz, C. D., Nitrini, R., Filho, G. B., Miguel, E. C., Lucchetti, G., & Forlenza, O.
Affiliations
  • Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
  • Universidade de São Paulo (BR)
  • Universidade Federal de Juiz de Fora (BR)
Corresponding author
Damiano, Rodolfo Furlan
ORCID
Venue
European Archives of Psychiatry and Clinical Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2021-06-25
Volume
272
Issue
1
Pages
139-154
ISSN
  • 0003-9373 (ISSN-L)
  • 0940-1334
  • 1433-8491
DOI
10.1007/s00406-021-01286-4
PMC
PMC8231753
OpenAlex
W3174568355
Semantic Scholar
3e33d743707b8be072f3a6023dad9d967d5c4b69
Cited by
98
References
200
Citations by year
2026: 7 · 2025: 17 · 2024: 29 · 2023: 29 · 2022: 13 · 2021: 3
FWCI
2.37
Type
journal article
Language
en
Open access
Licence
Locations
  • European Archives of Psychiatry and Clinical Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
  • Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Intensive Care Unit Cognitive Disorders
Keywords
cognitive decline, acute viral infection, COVID-19 pandemic, post-COVID cognitive impairment, long COVID, Alzheimer's disease, dementia pathogenesis, brain dysfunction, neuropsychiatric symptoms, asymptomatic infection
MeSH terms
COVID-19, SARS-CoV-2, Humans, Pandemics, Cognitive Dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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