SARS‐CoV‐2 and the brain: A review of the current knowledge on neuropathology in COVID‐19

Maiese, Aniello; Manetti, A; Bosetti, Chiara; Duca, Fabio Del; Russa, Raffaele La; Frati, Paola; Paolo, Marco Di; Turillazzi, Emanuela; Fineschi, Vittorio

doi:10.1111/bpa.13013

Cited by 88 publications

(85 citation statements)

References 117 publications

(157 reference statements)

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“…Here, we also performed whole-genome sequencing of this patient (findings of the main COVID-19-associated variants are shown in Additional file 1 : Supplementary Table 3), in addition to the APOE analysis. Microvascular brain injury has been reported to associate with COVID-19 [ 26 ], and autopsied COVID-19 patients have been reported to exhibit micro- and perivascular haemorrhages [ 27 , 28 ] (but see also [ 29 ]). However, we are not aware of any reports associating it with the APOE genotype status.…”

Section: Resultsmentioning

confidence: 99%

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

Kurki

Kantonen

Kaivola

et al. 2021

acta neuropathol commun

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Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.

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Section: Resultsmentioning

confidence: 99%

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

Kurki

Kantonen

Kaivola

et al. 2021

acta neuropathol commun

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“…Maiese et al [110] indicated that in patients with SARS-CoV-2 infection, the postmortem analyses demonstrated mainly hypoxic changes as the most frequently reported alteration of brain tissue, followed by ischemic and hemorrhagic lesions plus reactive astrogliosis and microgliosis. Since these findings are not specific to SARS-CoV-2 infection, the authors hypothesized a more likely association with systemic inflammation and coagulopathy caused by COVID-19.…”

Section: Precipitating Factorsmentioning

confidence: 99%

Delirium and Cognitive Impairment as Predisposing Factors of COVID-19 Infection in Neuropsychiatric Patients: A Narrative Review

et al. 2021

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SARS-CoV-2 neuroinvasive and neurotropic abilities may underlie delirium onset and neuropsychiatric outcomes. Only a limited number of studies have addressed the potential effect of SARS-CoV-2 infection on mental health so far. Most studies mainly reported the acute onset of mixed neuropsychiatric conditions in patients infected with SARS-CoV-2, characterized by agitated behavior, altered level of consciousness, and disorganized thinking, regardless of psychological or socioeconomic triggering factors. The present narrative review aims to analyze and discuss the mechanisms underlying the neuroinvasive/neurotropic properties of SARS-CoV-2 and the subsequent mental complications. Delirium appeared as a clinical manifestation of SARS-CoV-2 brain infection in some patients, without systemic or multiple organ failure symptoms. A small number of studies demonstrated that neuropsychiatric symptoms associated with COVID-19, initially presenting as a confused state, may subsequently evolve in a way that is consistent with the patients’ neuropsychiatric history. A literature analysis on this topic prevalently showed case reports and case series of patients presenting delirium or delirium-like symptoms as the main outburst of COVID-19, plus a cognitive impairment, from mild to severe, which pre-existed or was demonstrated during the acute phase or after infection. Dementia appeared as one of the most frequent predisposing factors to SARS-CoV-2 infection complicated with delirium. Instead, contrasting data emerged on the potential link between COVID-19 and delirium in patients with cognitive impairment and without a neuropsychiatric history. Therefore, clinicians should contemplate the possibility that COVID-19 appears as delirium followed by a psychiatric exacerbation, even without other systemic symptoms. In addition, cognitive impairment might act as a predisposing factor for COVID-19 in patients with delirium.

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“…However, expression of the hACE2 transgene in these mice is nonphysiological with both a high number of hACE2 transgene insertions as well as ectopic expression on cells that do not normally express ACE2. This is best exemplified by SARS-CoV-2 infection in the brains of K18-hACE2 Tg mice, which does not reflect the central nervous system (CNS) involvement seen in humans or other animals such as hamsters or nonhuman primates ( 5 – 8 ). Because expression of hACE2 in K18-hACE2 Tg mice is independent of the transcriptional regulation that normally governs ACE2 levels, some aspects of infection or transmission likely are not modeled in a physiologically relevant manner.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Causes Lung Infection without Severe Disease in Human ACE2 Knock-In Mice

Winkler

Chen

Alam

et al. 2022

J Virol

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The development of mouse models for COVID-19 has enabled testing of vaccines and therapeutics and defining aspects of SARS-CoV-2 pathogenesis. SARS-CoV-2 disease is severe in K18 transgenic mice (K18-hACE2-Tg) expressing human ACE2 (hACE2), the SARS-CoV-2 receptor, under an ectopic cytokeratin promoter, with high levels of infection measured in the lung and brain. Here, we evaluated SARS-CoV-2 infection in hACE2 KI mice that express hACE2 under an endogenous promoter in place of murine ACE2 (mACE2). Intranasal inoculation of hACE2 KI mice with SARS-CoV-2 WA1/2020 resulted in substantial viral replication within the upper and lower respiratory tracts with limited spread to extra-pulmonary organs. However, SARS-CoV-2-infected hACE2 KI mice did not lose weight and developed limited pathology. Moreover, no significant differences in viral burden were observed in hACE2 KI mice infected with B.1.1.7 or B.1.351 variants compared to WA1/2020 strain. Because the entry mechanisms of SARS-CoV-2 in mice remains uncertain, we evaluated the impact of the naturally-occurring, mouse-adapting N501Y mutation by comparing infection of hACE2 KI, K18-hACE2-Tg, ACE2-deficient, and wild-type C57BL/6 mice. The N501Y mutation minimally affected SARS-CoV-2 infection in hACE2 KI mice but was required for viral replication in wild-type C57BL/6 mice in a mACE2-dependent manner and augmented pathogenesis in the K18-hACE2 Tg mice. Thus, the N501Y mutation likely enhances interactions with mACE2 or hACE2 in vivo . Overall, our study highlights the hACE2 KI mice as a model of mild SARS-CoV-2 infection and disease and clarifies the requirement of the N501Y mutation in mice. IMPORTANCE Mouse models of SARS-CoV-2 pathogenesis have facilitated the rapid evaluation of countermeasures. While the first generation of models developed pneumonia and severe disease after SARS-CoV-2 infection, they relied on ectopic expression of supraphysiological levels of human ACE2 (hACE2). This has raised issues with their relevance to humans as the hACE2 receptor shows a more restricted expression pattern in the respiratory tract. Here we evaluated SARS-CoV-2 infection and disease with viruses containing or lacking a key mouse-adapting mutation in the spike gene in hACE2 KI mice, which express hACE2 under an endogenous promoter in place of murine ACE2. While infection of hACE2 KI mice with multiple strains of SARS-CoV-2 including variants of concern resulted in viral replication within the upper and lower respiratory tracts, the animals did not sustain severe lung injury. Thus, hACE2 KI mice serve as a model of mild infection with both ancestral and emerging SARS-CoV-2 variant strains.

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SARS‐CoV‐2 and the brain: A review of the current knowledge on neuropathology in COVID‐19

Cited by 88 publications

References 117 publications

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

Delirium and Cognitive Impairment as Predisposing Factors of COVID-19 Infection in Neuropsychiatric Patients: A Narrative Review

SARS-CoV-2 Causes Lung Infection without Severe Disease in Human ACE2 Knock-In Mice

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