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Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Open accessAbstract
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
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TL;DR
Mild respiratory SARS-CoV-2 infection in mice caused persistent white-matter-selective microglial reactivity, elevated CSF cytokines/chemokines including CCL11, impaired hippocampal neurogenesis, oligodendrocyte loss, and myelin loss. Similar white-matter microglial reactivity was seen in human post-COVID brain samples, and elevated plasma CCL11 was associated with cognitive symptoms in long COVID.
Key findings
- Mild respiratory COVID mice showed no weight loss or sickness behavior and no virus detected in brain, but had elevated serum and CSF cytokines/chemokines at 7 days and 7 weeks post-infection; CSF CCL11 was further increased at 7 weeks versus 7 days, while serum CCL11 normalized by 7 weeks.
- White-matter-selective microglial/macrophage reactivity (IBA1+CD68+) occurred in subcortical white matter and hippocampal white matter at 7 days and persisted to 7 weeks, without comparable reactivity in cortical gray matter; human COVID brain samples also showed elevated CD68+ microglial/macrophage reactivity in subcortical white matter (n = 9 COVID vs. 9 non-COVID controls).
- Hippocampal neurogenesis was decreased at 7 days and 7 weeks post-infection; mature oligodendrocytes were depleted by approximately one third at 7 days and remained depleted at 7 weeks, with a mild (~10%) decrease in oligodendrocyte precursor cells at 7 weeks and decreased myelinated axon density at 7 days and 7 weeks.
- In humans with long COVID, plasma CCL11 was elevated in those with cognitive symptoms (“brain fog”; n = 48) compared with those without cognitive symptoms (n = 15); systemic CCL11 administration in mice induced hippocampal microglial/macrophage reactivity and decreased hippocampal neurogenesis.
Methods
- Mouse models: 6- to 12-week-old female CD1 and BALB/c mice; mild respiratory SARS-CoV-2 via intratracheal AAV-hACE2 followed by intranasal SARS-CoV-2; comparison H1N1 influenza; systemic CCL11 administration (10 μg/kg intraperitoneally four times over 10 days); methotrexate chemotherapy model for myelin comparison.
- Human samples: postmortem brain cortex and subcortical white matter from 9 SARS-CoV-2-positive individuals (7 male, 2 female, age 24–73) and 9 non-COVID controls (9 male, age 43–84); plasma from long-COVID subjects with brain fog (n = 48, 16 male/32 female, mean age 46.1 ± 14.6 years) and without cognitive symptoms (n = 15, 4 male/11 female, mean age 46.7 ± 14.1 years).
- Analyses: immunohistochemistry and confocal quantification for microglia, neuroblasts, oligodendrocytes, OPCs, and neurons; electron microscopy for myelinated axon density and g-ratio; Luminex cytokine/chemokine assays; single-cell RNA sequencing of cortical and white matter microglia (5,983 microglial cells from mild COVID mice and 5,967 from control mice); statistics included t tests, ANOVA, multiple linear regression, and scRNA-seq differential expression/abundance testing.
Limitations
- Stated: the study used the original SARS-CoV-2 strain in adulthood without vaccination; effects of newer variants, breakthrough infection in vaccinated individuals, childhood, and old age remain to be determined.
- Stated: single-cell transcriptomics did not contain sufficient cells to draw conclusions about astrocytes or cell types other than microglia; microglial gene expression changes require spatial validation and functional testing; whether astrocyte-mediated neurotoxicity occurs after mild respiratory COVID remains unknown.
- Stated: mice were not behaviorally assessed for cognition, and the intermittent systemic CCL11 paradigm may not reflect higher or more consistent CCL11 levels; evident from the text: the human postmortem COVID cases died for reasons related to or possibly related to COVID and cannot be considered “mild,” and BSL-3 constraints limited further behavioral assessments.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At 7 days post-infection, elevated CSF cytokines and chemokines include IFN-γ, IL6, TNF-α, CXCL10, CCL7, CCL2, CCL11, GMCSF, and BAFF, among others (Figures 1F and 1H; Table S1).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“Notably, CSF levels of CCL11, a chemokine associated with cognitive impairment in aging (Villeda et al., 2011), were further increased at 7 weeks compared with 7 days post-infection (Figures 1J and 1K; Table S1).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No virus was detected in brain (Figure 1C), unlike in the case of a neuroinvasive model (Song et al., 2021) of SARS-CoV-2 infection (Figure S1 A).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“As expected, SARS-CoV-2 was present in the lungs of infected mice, and lung histopathology demonstrated minimal interstitial infiltrates without evidence of alveolar damage (Figures S1B and S1C).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“As expected, SARS-CoV-2 was present in the lungs of infected mice, and lung histopathology demonstrated minimal interstitial infiltrates without evidence of alveolar damage (Figures S1B and S1C).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“As hypothesized, we found increased microglial/macrophage reactivity in subcortical white matter, as assessed by IBA1 and CD68 co-positivity (Figure 2 ).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“Despite the lack of evident symptoms/signs of illness in this respiratory infection model, we found prominently elevated cytokine profiles in serum and in cerebrospinal fluid (CSF) at 7-day and 7-week time points following respiratory infection (Figures 1D–1G).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“In the same mice, serum CCL11 levels were elevated at 7 days post-infection and—in contrast to persistent elevation in CSF—normalized in serum by 7 weeks post-infection (Figures 1D, 1E, S6C, and S6D; Table S1).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“Systemic CCL11 induced microglial/macrophage reactivity specifically in hippocampal white matter (Figures 5F and 5G), and not in the cortex or subcortical white matter (Figures 5D and 5E).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID impairs hippocampal neurogenesis
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In the paper
“We also found transcriptional changes within the homeostatic microglia cluster in post-COVID mice compared with controls, with increased expression of genes commonly upregulated in inflammation and involved in antigen processing and presentation, like B2m, H2-D1, H2-K1, as well as the cell surface glycoprotein Cd300lf (Figures 3D, 3E, and S4C).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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- It may state two separate claims as one. 34
- Probably not a substantial claim. 51
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In the paper
“Of these, CXCL10, CCL7, CCL2, CCL11, and GMCSF remain elevated, and IL10 and CCL5 become elevated in CSF by 7 weeks post-infection (Figures 1G and 1I; Table S1).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“Mice exhibit no weight loss (Figure 1B) or observable sickness behavior; the challenges of working with a biosafety level-3 mouse model limited the feasibility of further behavioral assessments.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“This pattern of white-matter-specific microglial/macrophage reactivity was evident in two different mouse strains (CD1 and BALB/c) at 7 days post-infection (Figures 2A–2C) and persisted to 7 weeks post-infection (Figures 2D–2F).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“However, in contrast to most cases available for brain tissue examination, these individuals did not die during hospitalization and did not exhibit fulminant pulmonary disease (Figures S3B–S3E ; Table S2).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“We found a high degree of overlap between the upregulated and downregulated genes from both the chemokine and altered homeostatic gene signatures and the other microglial states, with both signatures in post-COVID microglia showing the greatest similarity to the WAM and DAM states (Figures 3F, 3G, and S4F).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
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In the paper
“These variables did not interact with one another, suggesting each was an independent predictor of CCL11 levels.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID impairs hippocampal neurogenesis
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In the paper
“Concordantly, we find here that even mild respiratory COVID can induce prominent elevation of multiple cytokines and chemokines together with lasting reactivity of white matter microglia in subcortical and hippocampal regions.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
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In the paper
“By 7 weeks after influenza infection, the only chemokine that remained elevated—and in fact increased from the 7 day time point—is CCL11 (Figures 7E–7G).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Comparison to H1N1 influenza mild respiratory infection
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In the paper
“Concordant with this pattern of microglial/macrophage reactivity, oligodendrocytes were decreased in the subcortical white matter at 7 days (Figure 7L) but recovered as microglial reactivity resolved by 7 weeks (Figure 7M).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Comparison to H1N1 influenza mild respiratory infection
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In the paper
“However, the oligodendroglial deficits observed in this study were more persistent following COVID than H1N1 influenza and were concordant with the lasting changes that follow methotrexate chemotherapy.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The methotrexate chemotherapy mouse model is comparable to COVID-related cognitive impairment.
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In the paper
“Examination of CSF cytokines at 7 days revealed elevation in several cytokines/chemokines similar to mice with mild respiratory COVID, including IFN-γ, CCL11, CCL2, and GMCSF, as well as distinct elevations in IL4 and CCL5 (Figure 7G).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Comparison to H1N1 influenza mild respiratory infection
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In the paper
“A small number of putative microglia or doublets clustered together with the erythrocyte and pericyte clusters, resulting in expression of some microglia markers like Tmem119 and P2ry12 in these clusters (Figure S5 G)–these few cells were excluded from downstream analysis as outliers.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
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In the paper
“The merged cluster was labeled Homeostatic due to its higher expression of typical microglia marker genes and lower expression of inflammation-related genes.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Note that while some non-microglial clusters appear to express the microglia-specific markers Tmem119 and P2ry12, this is driven by a small number of outlier microglia which clustered with these non-microglial cell types.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central.”
- Also stated in: § Introduction · hedged
“The syndrome of cognitive symptoms that COVID survivors frequently experience closely resembles the syndrome of cancer-therapy-related cognitive impairment (CRCI; Wefel et al., 2015), commonly known as “chemo fog.” Neuroinflammation is central to the pathophysiology of CRCI (for review, see Gibson and Monje [2021]), raising the possibility of shared pathophysiological mechanisms.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Abstract
What the sources say
- Not checked yetcites Wefel et al., 2015
- Not checked yetcites Gibson and Monje [2021]
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- Also stated in: § Introduction · hedged
None of the sources cited for this claim have been checked yet.
In the paper
“Colloquially known as “COVID fog,” this syndrome of COVID-associated cognitive impairment is characterized by impaired attention, concentration, speed of information processing, memory, and executive function (Becker et al., 2021; Nasserie et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Neuroinflammation is central to the pathophysiology of CRCI (for review, see Gibson and Monje [2021]), raising the possibility of shared pathophysiological mechanisms.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
- Not checked yetcites Gibson and Monje [2021]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Elevated circulating cytokine/chemokine levels, particularly CCL11, can also limit neurogenesis and contribute to cognitive impairment (Villeda et al., 2011).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
- Not checked yetcites Villeda et al., 2011 source
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None of the sources cited for this claim have been checked yet.
In the paper
“A distinct subpopulation of microglia that reside in white matter (Hammond et al., 2019) are selectively activated by systemic insults such as exposure to the chemotherapy drug methotrexate (Gibson et al., 2019).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Neurological symptoms are emerging as relatively common sequelae, with persistent cognitive impairment affecting approximately one in four COVID survivors (Nasserie et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
- Not checked yetcites Nasserie et al., 2021 source
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In the paper
“In addition to these direct effects of inflammatory mediators on cellular plasticity in the brain, microglia also induce neurotoxic astrocyte reactivity through cytokine signaling (Liddelow et al., 2017).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
- Not checked yetcites Liddelow et al., 2017 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“To test the effects of mild COVID, we used a mouse model of mild SARS-CoV-2 infection limited to the respiratory system that clears within 1 week (Israelow et al., 2020; Song et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
What the sources say
- Not checked yetcites Israelow et al., 2020 source
- Not checked yetcites Song et al., 2021
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In the paper
“This complex cellular dysregulation is thought to contribute importantly to cognitive impairment, and anti-inflammatory strategies correct this multicellular dysregulation and rescue cognition in disease states such as those occurring after exposure to neurotoxic cancer therapies (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003) and in aging (Villeda et al., 2011).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice exhibit no weight loss (Figure 1B) or observable sickness behavior; the challenges of working with a biosafety level-3 mouse model limited the feasibility of further behavioral assessments.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID causes prominent neuroinflammation
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“While severe COVID can cause multi-organ disease and numerous potential mechanisms affecting the nervous system (Lee et al., 2021; Nath and Smith, 2021; Remsik et al., 2021; Chen et al., 2021), even mild COVID could result in a detrimental neuroinflammatory response, including reactivity of these exquisitely sensitive white matter microglia.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
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In the paper
“Additionally, this sub-state of reactive astrocytes are poor supporters of synaptic connections—further adding to network dysfunction (Liddelow et al., 2017).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
- Not checked yetcites Liddelow et al., 2017 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Astrocytes can assume a range of reactive states (Hasel et al., 2021; Sadick et al., 2022) that can induce further pathophysiology, with certain states of reactive astrocytes inducing oligodendrocyte and neuronal cell death (Liddelow et al., 2017; Guttenplan et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Introduction
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such persistent loss of myelin in subcortical projections would be predicted to impair neural circuit function and axon health”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID impairs myelinating oligodendrocytes
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By comparison, H1N1 influenza elicited a partially overlapping but also distinct CSF cytokine/chemokine profile and more restricted pattern of persistent cellular changes.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The H1N1 influenza mouse model recapitulates mild respiratory influenza in humans.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“adding to the numerous deleterious neurobiological consequences of SARS-CoV-2 infection.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Mild respiratory COVID impairs myelinating oligodendrocytes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The H1N1 strain of influenza, which is not neuroinvasive in mouse models, causes acute elevation in CNS cytokines, hippocampal microglial reactivity, and impaired performance in cognitive behavioral tests (Hosseini et al., 2018; Jurgens et al., 2012).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Comparison to H1N1 influenza mild respiratory infection
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: The H1N1 strain of influenza is not neuroinvasive in mouse models.
None of the sources cited for this claim have been checked yet.
In the paper
“Other viral syndromes such as influenza can cause microglial reactivity, elevated CNS cytokine levels, and impair cognitive function, even in the absence of neuroinvasion (Hosseini et al., 2018; Jurgens et al., 2012).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Other respiratory viral infections such as influenza are associated with cognitive and other neurological sequelae.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The differences in neuroinflammatory profiles observed here in mouse models of SARS-CoV-2 and H1N1 influenza respiratory infection underscore this principle.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Various immune challenges induce diverse immunological responses that differentially involve particular subsets of immune cells and induce disease-specific cytokine and chemokine profiles systemically and in the CNS.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In comparison to SARS-CoV-2, mild respiratory infection with H1N1 influenza results in similar hippocampal pathology, but without the lasting effects on subcortical white matter integrity seen after respiratory COVID.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Comparison to H1N1 influenza mild respiratory infection
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The H1N1 influenza mouse model recapitulates mild respiratory influenza in humans.
In the paper
“People recovering from critical illness in general experience high rates of long-term cognitive impairment, and persistent cognitive impairment is an important component of post-intensive care syndrome (PICS; Pandharipande et al., 2013).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
- Not checked yetcites Pandharipande et al., 2013 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Systemic exposure of rats to low levels of bacterial liposaccharide (LPS)—sufficient to cause mild-moderate sickness behavior but not sepsis—similarly causes microglial reactivity and impairment in hippocampal neurogenesis (Monje et al., 2003).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
- Not checked yetcites Monje et al., 2003 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a finding that is consistent with the persistently elevated CSF CCL11 levels (Figure 7F), which we demonstrate above specifically increases reactivity of hippocampal microglia/macrophages (Figures 5F and 5G).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Results > Comparison to H1N1 influenza mild respiratory infection
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The particularly immunogenic nature of SARS-CoV-2 (Lucas et al., 2020) and the persistence of the neuroinflammatory changes observed here, together with the magnitude of the population infected during this pandemic, contribute to the emerging crisis of lasting cognitive impairment associated with COVID.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
- Not checked yetcites Lucas et al., 2020 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The magnitude of the population infected during the COVID-19 pandemic is large.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we studied the neurobiological consequences of respiratory system infection in adulthood with the original strain of SARS-CoV-2 in the absence of vaccination.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Elevated levels of CCL11 found in mice after respiratory infection with either SARS-CoV-2 or H1N1 influenza, and in humans with cognitive symptoms after COVID, can cause deficient hippocampal neurogenesis as shown here and previously (Villeda et al., 2011), and induces microglial reactivity specifically in the hippocampus.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
- Not checked yetcites Villeda et al., 2011 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
- Rests on an assumption: The human long-COVID blood samples are representative of cognitive symptoms after COVID.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with the clinical similarities in the “COVID fog” and “chemo fog” syndromes of cognitive impairment, the findings here illustrate numerous pathophysiological similarities including depletion of myelinating oligodendrocytes and myelin loss.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It is thus not surprising that the neurological sequelae of SARS-CoV-2 infection are proving to be both common and debilitating (Nasserie et al., 2021; Mazza et al., 2021; Qureshi et al., 2022; Becker et al., 2021; Tabacof et al., 2022).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the inflammation-induced multicellular dysregulation described here may be potentially reversible with therapeutic interventions as discussed below, these more severe possible complications of COVID such as stroke can cause irreversible damage to the brain.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In the context of severe COVID, astrocytes in the human cerebral cortex exhibit a transcriptional program consistent with neurotoxic reactivity (Yang et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
What the sources say
- Not checked yetcites Yang et al., 2021 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These include microvascular thrombi, neuron loss, cortical inflammation, and even direct brain infection in some cases (Lee et al., 2021; Remsik et al., 2021; Song et al., 2021; Yang et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This region/circuit-specific effect of CCL11 highlights the potential of varying cytokine/chemokine profiles to exert disease-specific effects on the nervous system and for different infections to therefore cause differing prevalence of certain cognitive or neuropsychiatric symptoms.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Systemic inflammation-induced neuroinflammation, consequent glial dysregulation and impairment of neural function is a principle that extends beyond COVID.
None of the sources cited for this claim have been checked yet.
In the paper
“Myelin modulates the speed of neural impulse conduction (Smith and Koles, 1970; Waxman, 1980), provides metabolic support to axons (Fünfschilling et al., 2012), and exhibits adaptive plasticity (Gibson et al., 2014);”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Emerging data indicate that the risk of cognitive impairment may be decreased in breakthrough infections of fully vaccinated individuals (Antonelli et al., 2022).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
What the sources say
- Not checked yetcites Antonelli et al., 2022 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“As occurs after cancer therapies and in other disease states, the microglial reactivity present after mild respiratory SARS-CoV-2 infection may also induce neurotoxic astrocyte reactivity (Liddelow et al., 2017; Gibson et al., 2019; Guttenplan et al., 2021), as well as aberrant microglial pruning of synapses (Hinkle et al., 2019; Hosseini et al., 2018; Vasek et al., 2016).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
In the paper
“While methotrexate directly stimulates reactivity of microglia (Gibson et al., 2019),”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion
What the sources say
- Not checked yetcites Gibson et al., 2019 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such insights from diseases such as CRCI may elucidate therapeutic strategies to restore healthy cognitive function following COVID.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All procedures used in this study complied with federal guidelines and the institutional policies of the Yale School of Medicine Animal Care and Use Committee.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Experimental method and subject details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For all quantifications, experimenters were blinded to sample identity and condition.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Human lung histology was assessed on standard clinical H&E images by board-certified pathologists.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Axons in the cingulum of the corpus callosum were analyzed for g-ratios calculated by dividing the shortest axonal diameter by the total diameter (diameter of axon/diameter of axon plus myelin sheath), as well as for myelinated axon density (total number of myelinated axons in each frame) by experimenters who were blinded to experimental conditions and genotypes.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Human blood samples from subjects with long-COVID were collected with informed consent as part of an IRB-approved protocol at Mount Sinai School of Medicine.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Experimental method and subject details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For the CCL11 study, 8-week-old CD1 male and female mice were purchased from Charles River and housed at Stanford University; all procedures complied with Institutional Animal Care and Use Committee protocol at Stanford.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Experimental method and subject details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Human brain tissue samples were prepared and analyzed as previously described (Lee et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
What the sources say
- Not checked yetcites Lee et al., 2021 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CD45 and CD11b analysis was used as a quality control prior to sorting.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In every experiment, “n” equals at least 3 mice per group; the exact “n” for each experiment is defined in the figure legends.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All cell counting was performed by experimenters blinded to experimental conditions”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this is driven by a small number of outlier microglia which clustered with these non-microglial cell types.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“these few cells were excluded from downstream analysis as outliers.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A blinded pulmonary pathologist reviewed the slides and identified immune cell infiltration and other related pathologies.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Patient plasma was collected with informed consent and IRB approval as previously described (Lucas et al., 2020).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
What the sources say
- Not checked yetcites Lucas et al., 2020 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Shapiro-Wilk test was used to determine normality for all datasets; all datasets were parametric.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A minimum of 300 axons were scored per group.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The oligodendrocyte loss observed here could be caused reactive astrocyte toxic lipids, which is known to cause oligodendrocyte cell death (Liddelow et al., 2017; Guttenplan et al., 2021).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, microglial depletion strategies can restore similar multicellular deficits and rescue impaired cognitive performance in mouse models of CRCI (Acharya et al., 2016; Gibson et al., 2019),”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > Discussion > Limitations of the study
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Perfusion buffer, dissection buffer and digestion buffer were freshly prepared as previously described (Marsh et al., 2022).”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
What the sources say
- Not checked yetcites Marsh et al., 2022 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All samples were measured at the time of the first thaw.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All blood samples were processed on the day of collection.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Method details
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“demonstrating the validity of the cell type labels.”
§ Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation > STAR★Methods > Quantification and statistical analysis
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
Circulating CCL11 levels in humans reflect CNS CCL11 levels or neuroinflammatory processes relevant to cognitive symptoms.
“To further explore the relevance of elevated CCL11 levels to cognitive sequelae of COVID infection in humans, we next examined circulating CCL11 cytokine levels in the plasma of people suffering from long COVID with and without cognitive symptoms.”
“We found elevated CCL11 levels in the plasma of people with long COVID exhibiting cognitive deficits, or “brain fog” (n = 48 subjects, 16 male/32 female, mean age 46.1 ± 14.6 years) compared with those with long COVID lacking cognitive symptoms (n = 15 subjects, 4 male/11 female, mean age 46.7 ± 14.1 years; Figure 5 A).”
The paper relies on this without support.
The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
“Mice were infected intratracheally with AAV-hACE2 as previously described (Song et al., 2021).”
The paper relies on this without support.
The H1N1 influenza mouse model recapitulates mild respiratory influenza in humans.
“We examined a mouse model of respiratory H1N1 influenza, which causes only minimal sickness behavior with mild (<10%) weight loss”
The paper relies on this without support.
The methotrexate chemotherapy mouse model is comparable to COVID-related cognitive impairment.
“Comparison to methotrexate chemotherapy-related cognitive impairment model”
The paper relies on this without support.
Various immune challenges induce diverse immunological responses that differentially involve particular subsets of immune cells and induce disease-specific cytokine and chemokine profiles systemically and in the CNS.
“Various immune challenges induce diverse immunological responses that differentially involve particular subsets of immune cells and induce disease-specific cytokine and chemokine profiles systemically and in the CNS.”
The paper relies on this without support.
Systemic inflammation-induced neuroinflammation, consequent glial dysregulation and impairment of neural function is a principle that extends beyond COVID.
“Systemic inflammation-induced neuroinflammation, consequent glial dysregulation and impairment of neural function is a principle that extends beyond COVID.”
The paper relies on this without support.
The magnitude of the population infected during the COVID-19 pandemic is large.
“together with the magnitude of the population infected during this pandemic, contribute to the emerging crisis of lasting cognitive impairment associated with COVID.”
The paper relies on this without support.
The H1N1 strain of influenza is not neuroinvasive in mouse models.
“The H1N1 strain of influenza, which is not neuroinvasive in mouse models, causes acute elevation in CNS cytokines”
The paper relies on this without support.
Other respiratory viral infections such as influenza are associated with cognitive and other neurological sequelae.
“Other respiratory viral infections such as influenza are also associated with cognitive and other neurological sequelae.”
The paper relies on this without support.
The human long-COVID blood samples are representative of cognitive symptoms after COVID.
“Human blood samples from subjects with long-COVID were collected with informed consent as part of an IRB-approved protocol at Mount Sinai School of Medicine.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“White-matter microglia reactivity has also been related to aging52 and diseases.53”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [53]
The cited source says what the claim attributes to it.
In the citing paper
“CCL11 efficiently crosses the blood brain barrier56, has been implicated in neuroinflammatory disorders and SARS-CoV-2 (COVID-19) cognitive impairment57,58, and impairs neurogenesis54,58,59.”
From Senescent-like microglia limit remyelination through the senescence associated secretory phenotype (2025) · cites this paper as [58]
The cited source says what the claim attributes to it.
In the citing paper
“evidence suggests microglia are the primary cell-type in the CNS responsive to CCL1158.”
From Senescent-like microglia limit remyelination through the senescence associated secretory phenotype (2025) · cites this paper as [58]
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.
Human CCL11 specimens called both plasma and serum
MinorThe human long-COVID comparison and sample-processing Methods identify the specimens as plasma, but the regression result calls the measured levels serum CCL11.
“This determined that two variables, patient sex and history of autoimmune disease, significantly accounted for variability in serum CCL11 levels.”
“We found elevated CCL11 levels in the plasma of people with long COVID exhibiting cognitive deficits, or “brain fog””
Different tests stated for GO-term enrichment
MinorThe Figure S4 legend says GO-term enrichment used an over-representation permutation test, while the statistical Methods say it used a hypergeometric test.
“For (D and E), significance of GO term enrichment was tested using over-representation permutation test.”
“Enrichment of gene ontology (GO) biological process terms in cluster differentially expressed genes was tested using a hypergeometric test in the clusterProfiler package (v4.0.5) (Wu et al., 2021) with the Benjamini and Hochberg procedure.”
Citations
Cites
Integrated analysis of multimodal single-cell data
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zagar, M., et al. (2020) · doi:10.1101/2020.10.12.335331 · Cited by 15,508
Self-citationclusterProfiler 4.0: A universal enrichment tool for interpreting omics data
(2021) · doi:10.1016/j.xinn.2021.100141 · Cited by 12,455
Fast, sensitive and accurate integration of single-cell data with Harmony
Korsunsky, I., Millard, N., Fan, J., Slowikowski, K., Zhang, F., Wei, K., Baglaenko, Y., Brenner, M., Loh, P.-R., & Raychaudhuri, S. (2019) · Nature Methods · doi:10.1038/s41592-019-0619-0 · Cited by 10,488
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
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Systems analysis of innate and adaptive immunity in Long COVID
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Neuroimmune pathophysiology of long COVID
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Metadata
- Authors
- Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M.-H., Wood, J., O’Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., Mancusi, R., Yalçın, B., Taylor, K. R., Acosta-Alvarez, L., Malacon, K., Keough, M. B., Ni, L., Woo, P. J., Contreras-Esquivel, D., Toland, A. M. S., Gehlhausen, J. R., Klein, J., Takahashi, T., Silva, J., Israelow, B., Lucas, C., Mao, T., Peña-Hernández, M. A., Tabachnikova, A., Homer, R. J., Tabacof, L., Tosto-Mancuso, J., Breyman, E., Kontorovich, A., McCarthy, D., Quezado, M., Vogel, H., Hefti, M. M., Perl, D. P., Liddelow, S., Folkerth, R., Putrino, D., Nath, A., Iwasaki, A., & Monje, M.
- Affiliations
- Stanford Medicine (US)
- Yale University (US)
- National Institute of Neurological Disorders and Stroke (US)
- Icahn School of Medicine at Mount Sinai (US)
- New York University (US)
- National Institutes of Health (US)
- University of Iowa (US)
- Uniformed Services University of the Health Sciences (US)
- NYU Langone Health (US)
- Office of Chief Medical Examiner (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Iwasaki, Akiko
- Monje, Michelle
- ORCID
- Fernández-Castañeda, Anthony
- Lu, Peiwen
- Geraghty, Anna C.
- Song, Eric
- Lee, Myoung-Hwa
- Wood, Jamie
- O’Dea, Michael R.
- Dutton, Selena
- Shamardani, Kiarash
- Nwangwu, Kamsi
- Mancusi, Rebecca
- Yalçın, Belgin
- Taylor, Kathryn R.
- Acosta-Alvarez, Lehi
- Malacon, Karen
- Keough, Michael B.
- Woo, Pamelyn J.
- Toland, Angus Martin Shaw
- Gehlhausen, Jeff R.
- Klein, Jon
- Takahashi, Takehiro
- Israelow, Benjamin
- Lucas, Carolina
- Mao, Tianyang
- Tabachnikova, Alexandra
- Homer, Robert J.
- Tabacof, Laura
- Tosto-Mancuso, Jenna
- Breyman, Erica
- Kontorovich, Amy
- Quezado, Martha
- Vogel, Hannes
- Hefti, Marco M.
- Perl, Daniel P.
- Liddelow, Shane
- Putrino, David
- Nath, Avindra
- Iwasaki, Akiko
- Monje, Michelle
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2022-07
- Volume
- 185
- Issue
- 14
- Pages
- 2452-2468.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC9189143
- OpenAlex
- W4282556362
- Semantic Scholar
- 18a52e1748a39fd8816c9a12e0186dc58f8c8edc
- Cited by
- 521
- References
- 69
- Citations by year
- 2026: 69 · 2025: 104 · 2024: 143 · 2023: 158 · 2022: 46
- FWCI
- 59.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- NIH
- Topics
- Health Sciences › Medicine › Clinical Neurology › Long-Term Effects of COVID-19
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- post-COVID neurological symptoms, COVID-19 pandemic, microglial activation, white matter, hippocampal neurogenesis, oligodendrocyte loss, demyelination, eotaxin, CSF cytokines, influenza, neuroinflammation
- MeSH terms
- COVID-19, SARS-CoV-2, Animals, Humans, Influenza, Human, Myelin Sheath, Neoplasms, Microglia, Mice
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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