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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- Findingown data
At 7 days post-infection, CSF levels of IFN-γ, IL6, TNF-α, CXCL10, CCL7, CCL2, CCL11, GMCSF, and BAFF are elevated in mice with mild respiratory COVID.
“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).”
Quote in the paperSubstantial claim - Findingown data
CSF levels of CCL11 were further increased at 7 weeks compared with 7 days post-infection in mice with mild respiratory COVID.
“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).”
Quote in the paperSubstantial claim - Findingown data
No virus was detected in the brain of mice with mild respiratory SARS-CoV-2 infection.
“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).”
Quote in the paperSubstantial claim - Findingown data
Lung histopathology in the mild respiratory COVID mouse model demonstrated minimal interstitial infiltrates without evidence of alveolar damage.
“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).”
Quote in the paperSubstantial claim - Findingown data
SARS-CoV-2 was present in the lungs of infected mice in the mild respiratory COVID model.
“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).”
Quote in the paperSubstantial claim
- Findingown data
Mild respiratory COVID in mice causes increased microglial/macrophage reactivity in subcortical white matter, as assessed by IBA1 and CD68 co-positivity.
“As hypothesized, we found increased microglial/macrophage reactivity in subcortical white matter, as assessed by IBA1 and CD68 co-positivity (Figure 2 ).”
Quote in the paperSubstantial claim - Findingown data
Mild respiratory SARS-CoV-2 infection in mice causes prominently elevated cytokine profiles in serum and cerebrospinal fluid at 7 days and 7 weeks post-infection.
“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).”
Quote in the paperSubstantial claim - Findingown data
Serum CCL11 levels were elevated at 7 days post-infection and normalized by 7 weeks post-infection in mice with mild respiratory COVID.
“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).”
Quote in the paperNot a substantial claim - Findingown data
Systemic CCL11 administration in mice induces microglial/macrophage reactivity specifically in hippocampal white matter, and not in the cortex or subcortical white matter.
“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).”
Quote in the paperSubstantial claim - Findingown data
Post-COVID mice exhibit transcriptional changes within the homeostatic microglia cluster 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, and Cd300lf.
“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).”
Quote in the paperSubstantial claim - Findingown data
The depletion in mature oligodendrocytes persists until at least 7 weeks post-infection in mice with mild respiratory COVID.
“This depletion in mature oligodendrocytes persisted until at least 7 weeks post-infection (Figure 6E).”
Quote in the paperSubstantial claim - Findingown data
Microglial/macrophage reactivity was not observed in the cortical gray matter after mild respiratory COVID in mice.
“In contrast to the subcortical white matter, microglial/macrophage reactivity was not observed in the cortical gray matter (Figures 2G–2L).”
Quote in the paperNot a substantial claim - Findingown data
Overall numbers of microglia were largely unchanged in white matter after mild respiratory COVID in mice.
“While microglial/macrophage reactivity was evident in white matter by increased expression of the marker CD68, overall numbers of microglia were largely unchanged (Figure S2 ).”
Quote in the paperNot a substantial claim - Findingown data
Mild respiratory COVID in mice causes robustly increased microglial/macrophage reactivity in hippocampal white matter at 7 days post-infection that persists until at least 7 weeks post-infection.
“Examining the mouse hippocampus following mild respiratory COVID, we found robustly increased microglial/macrophage reactivity in hippocampal white matter at 7 days post-infection (Figures 4A and 4B) that persists until at least 7 weeks post-infection (Figures 4C and 4D).”
Quote in the paperSubstantial claim - Findingown data
The chemokine-enriched microglia subpopulation in post-COVID mice is characterized by expression of several chemokines and cytokines like Tnf, Il1a, and Il1b.
“a small but striking subpopulation of cells characterized by expression of several chemokines and cytokines like Tnf, Il1a, and Il1b (Figures 3C and S4B; Table 3), consistent with an inflammatory reactive response.”
Quote in the paperSubstantial claim - Findingown data
Lung examination of the human COVID cases revealed infection-associated lung injury ranging from none to moderate (diffuse alveolar damage), without evidence of necrotizing pneumonia.
“Lung examination of these cases revealed infection-associated lung injury that ranged from none to moderate (diffuse alveolar damage), without evidence of the necrotizing pneumonia that characterizes severe pulmonary COVID (Figures S3B–S3E; Table S2).”
Quote in the paperNot a substantial claim - Findingown data
Mild respiratory influenza in mice causes similar early patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 as mild respiratory SARS-CoV-2.
“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.”
Quote in the paperNot a substantial claim - Findingown data
Single-cell RNA sequencing of cortical and white matter microglia 7 days after mild respiratory SARS-CoV-2 infection in mice revealed five distinct microglial states.
“To characterize the state of microglia and other myeloid cells following mild respiratory COVID, we performed single-cell RNA sequencing of cortical and white matter microglia 7 days following mild respiratory SARS-CoV-2 infection (5,983 single microglial cells from mild COVID mice and 5,967 microglial cells from control mice; Figures 3 , S4 , and S5). This revealed five distinct microglial states”
Quote in the paperSubstantial claim - Findingown data
Overall numbers of microglia were unchanged after systemic CCL11 administration in mice.
“Overall numbers of microglia were unchanged (Figures S2K–S2M).”
Quote in the paperNot a substantial claim - Findingown data
Myelin loss persisted until at least 7 weeks following mild respiratory SARS-CoV-2 infection.
“This loss of myelin persisted until at least 7 weeks following mild respiratory SARS-CoV-2 infection”
Quote in the paperSubstantial claim - Findingown data
There is an inverse correlation between neurogenesis and reactive microglia/macrophages in the hippocampus after mild respiratory COVID in mice.
“Considering the number of newly generated hippocampal neurons as a function of the reactive microglial load, we found an inverse correlation between neurogenesis and reactive microglia/macrophages in the hippocampus (Figure S6A).”
Quote in the paperSubstantial claim - Findingown data
After mild respiratory influenza in mice, only elevated CCL11 and hippocampal pathology persist.
“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.”
Quote in the paperSubstantial claim - Findingown data
Patient sex and history of autoimmune disease significantly accounted for variability in serum CCL11 levels among people with long COVID and brain fog.
“To help discern the variability in CCL11 levels among COVID patients with brain fog, we performed a multiple linear regression. This determined that two variables, patient sex and history of autoimmune disease, significantly accounted for variability in serum CCL11 levels.”
Quote in the paperNot a substantial claim - Findingown data
Electron microscopy ultrastructural analyses revealed a frank loss of myelin after mild respiratory SARS-CoV-2 infection.
“Consistent with the loss of oligodendrocytes described above, electron microscopy ultrastructural analyses revealed a frank loss of myelin”
Quote in the paperSubstantial claim - Findingown data
The homeostatic microglia cluster in post-COVID mice exhibits downregulation of characteristic microglial genes such as Trem2 and Sall3, as well as Adrb1.
“The homeostatic microglia cluster in post-COVID mice exhibit downregulation of characteristic microglial genes such as Trem2 and Sall3, as well as Adrb1, a gene known to be downregulated in lipid-droplet-accumulating microglia (LDAM) in aging white matter (Marschallinger et al., 2020; Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
Patient's age, body mass index, and duration of time since symptom onset did not account for variability of CCL11 levels.
“Patient’s age, body mass index, and duration of time since symptom onset did not account for variability of CCL11 levels.”
Quote in the paperNot a substantial claim - Findingown data
Mild respiratory SARS-CoV-2 infection in mice and humans with COVID is associated with white-matter-selective microglial reactivity.
“Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans.”
Quote in the paperSubstantial claim - Findingown data
Post-COVID mice exhibited an increased abundance of the chemokine-enriched microglia compared with control mice.
“While each of these microglial states was detectable in both control mice and mice following mild respiratory SARS-CoV-2 infection, post-COVID mice exhibited an increased abundance of the chemokine-enriched microglia (Figure 3B)”
Quote in the paperSubstantial claim - Findingown data
People with long COVID exhibiting cognitive deficits ('brain fog') have elevated plasma CCL11 levels compared with those with long COVID lacking 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).”
Quote in the paperSubstantial claim- Rests on an assumption: Circulating CCL11 levels in humans reflect CNS CCL11 levels or neuroinflammatory processes relevant to cognitive symptoms.
- Findingown data
The decrease in myelinated axon density after mild respiratory COVID was not focal or plaque-like as occurs in inflammatory demyelinating disorders such as multiple sclerosis.
“The pattern of decreased myelinated axon density was not focal or plaque-like as occurs in inflammatory demyelinating disorders such as multiple sclerosis.”
Quote in the paperSubstantial claim - Findingown data
By 7 weeks following mild respiratory SARS-CoV-2 infection in mice, there is a mild decrease (∼10%) in the number of oligodendrocyte precursor cells.
“However, by 7 weeks following infection, a mild decrease (∼10%) in the number of oligodendrocyte precursor cells was evident (Figures 6B and 6C).”
Quote in the paperSubstantial claim - Findingown data
Mild respiratory COVID in mice causes myelin loss.
“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.”
Quote in the paperSubstantial claim - Findingown data
Systemic CCL11 administration in mice decreases hippocampal neurogenesis.
“As expected (Villeda et al., 2011), we also found decreased hippocampal neurogenesis following systemic CCL11 administration (Figures 5H and 5I).”
Quote in the paperSubstantial claim - Findingown data
Mild respiratory SARS-CoV-2 infection decreased myelinated axon density in subcortical white matter (cingulum of the corpus callosum) by 7 days post-infection.
“We found a decrease in myelinated axon density in subcortical white matter (cingulum of the corpus callosum) evident by 7 days post-infection (Figures 6G–6I).”
Quote in the paperSubstantial claim - Findingown data
Mild respiratory SARS-CoV-2 infection in mice maintains the oligodendrocyte precursor cell population marked by PDGFRα at 7 days post-infection.
“Examining oligodendroglial lineage cells in subcortical white matter (cingulum of the corpus callosum), we found maintenance of the oligodendrocyte precursor cell population marked by PDGFRα at 7 days after mild respiratory SARS-CoV-2 infection (Figure 6 A).”
Quote in the paperSubstantial claim - Findingown data
Mild respiratory COVID in mice causes a stark decrease in new neuron generation, as assessed by Doublecortin-positive cell quantification, at 7 days post-infection that persists until at least 7 weeks post-infection.
“Consistent with previous observations that reactive microglia/macrophages can inhibit hippocampal neurogenesis (Monje et al., 2003), a stark decrease in new neuron generation was evident, as assessed by Doublecortin-positive cell quantification, at 7 days post-infection (Figures 4E and 4F) and persisted until at least 7 weeks post-infection (Figures 4G and 4H).”
Quote in the paperSubstantial claim - Findingown data
Mature oligodendrocytes, assessed by ASPA and CC1 immunoreactivity, exhibit loss of approximately one third of oligodendrocytes by 7 days post-infection in mice with mild respiratory COVID.
“Mature oligodendrocytes, assessed by ASPA and CC1 immunoreactivity, exhibited a greater magnitude of depletion (Figures 6D–6F, S7A, and S7B), with loss of approximately one third of oligodendrocytes occurring by 7 days post-infection (Figure 6D).”
Quote in the paperSubstantial claim - Findingown data
People with long COVID and brain fog who had a history of autoimmune disease had higher CCL11 levels than those without.
“Subsequent comparisons revealed that those with a history of autoimmune disease had higher CCL11 levels than those patients who did not (Figure 5B)”
Quote in the paperNot a substantial claim - Findingown data
At 7 weeks after influenza infection, additional cytokines/chemokines were elevated that were not elevated at 7 days, including TNF-α, IL6, IL2, CXCL5, and IL18.
“However, a number of additional cytokines/chemokines were elevated at 7 weeks after influenza that were not elevated at 7 days, including TNF-α, IL6, IL2, CXCL5, and IL18, among others (Figures 7E–7G; Table S4).”
Quote in the paperNot a substantial claim - Findingown data
By 7 weeks after influenza infection, microglial reactivity had normalized in subcortical white matter.
“By 7 weeks, microglial reactivity had normalized in the subcortical white matter (Figure 7J).”
Quote in the paperSubstantial claim - Findingown data
Changes in myelin sheath thickness relative to axon diameter (g ratio) were not conclusively identified in remaining myelin sheaths after mild respiratory COVID, in contrast to methotrexate chemotherapy exposure.
“In contrast to methotrexate chemotherapy exposure (Geraghty et al., 2019; Gibson et al., 2019), changes in myelin sheath thickness relative to axon diameter (g ratio) were not conclusively identified in the remaining myelin sheaths after mild respiratory COVID (Figures S7C–S7F).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
Microglial/macrophage reactivity persisted at 7 weeks in hippocampal white matter after influenza infection.
“In contrast, microglial/macrophage reactivity persisted at 7 weeks in hippocampal white matter (Figure 7K)”
Quote in the paperSubstantial claim - Findingown data
The mouse model of respiratory H1N1 influenza causes only minimal sickness behavior with mild (<10%) weight loss and elevation in serum cytokines/chemokines.
“We examined a mouse model of respiratory H1N1 influenza, which causes only minimal sickness behavior with mild (<10%) weight loss (Figures 7A and 7B) and elevation in serum cytokines/chemokines (Figures 7C and 7D; Table S4).”
Quote in the paperSubstantial claim - Findingown data
Hippocampal neurogenesis was deficient at both 7-day and 7-week time points after influenza infection.
“Hippocampal neurogenesis was deficient at both 7-day and 7-week time points, consistent with the persistent hippocampal microglial/macrophage reactivity (Figures 7N and 7O).”
Quote in the paperNot a substantial claim - Findingown data
The decrease in myelinated cortical projection axons after mild respiratory COVID was not accounted for by changes in the number of cortical neurons.
“This observed decrease in myelinated cortical projection axons after mild respiratory COVID was not accounted for by changes in the number of cortical neurons (Figures S7G–S7I).”
Quote in the paperSubstantial claim - Findingown data
Overall numbers of microglia were unchanged after influenza infection.
“As above, overall numbers of microglia were unchanged (Figures S2N–S2S).”
Quote in the paperNot a substantial claim - Findingown data
Following respiratory influenza infection, white matter-selective microglial/macrophage reactivity occurred in subcortical and hippocampal white matter at 7 days post-infection.
“We found the same pattern of white matter-selective microglial/macrophage reactivity in the subcortical and hippocampal white matter (Figures 7H and 7I) at 7 days post-infection.”
Quote in the paperSubstantial claim - Findingown data
The magnitude of myelin loss after mild respiratory COVID was similar to the loss of myelinated axons seen 4 weeks and 6 months after methotrexate chemotherapy exposure.
“and was similar in magnitude to the loss of myelinated axons seen 4 weeks (Figures 6J, S7J, and S7K) and 6 months (Figures 6K, S7J, and S7K) after methotrexate chemotherapy exposure.”
Quote in the paperNot a substantial claim - Findingreasoning
Subcortical white matter microglial/macrophage reactivity and associated loss of oligodendrocytes and myelinated axons are similar in mouse models of SARS-CoV-2 respiratory infection and methotrexate chemotherapy-related cognitive impairment.
“Subcortical white matter microglial/macrophage reactivity and associated loss of oligodendrocytes and myelinated axons are similar in mouse models of SARS-CoV-2 respiratory infection and methotrexate chemotherapy-related cognitive impairment.”
Quote in the paperSubstantial claim- Rests on an assumption: The methotrexate chemotherapy mouse model is comparable to COVID-related cognitive impairment.
- Findingown data
The final microglia cluster does not express canonical markers of these other cell types.
“The final microglia cluster does not express canonical markers of these other cell types, indicating that the cluster is highly pure.”
Quote in the paperNot a substantial claim - Premisecitation
Local microglial cytokine secretion contributes to at least part of the dysregulation of cellular homeostasis and plasticity caused by reactive microglia.
“Local microglial cytokine secretion contributes to at least part of this dysregulation (Monje et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Monje et al., 2003 source
Not checked in the free run.
- Premisecitation
Even individuals with mild symptoms in the acute phase of COVID may experience lasting cognitive dysfunction.
“While more common in individuals who had experienced severe COVID requiring hospitalization, even those with mild symptoms in the acute phase may experience lasting cognitive dysfunction (Becker et al., 2021; Nasserie et al., 2021).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Reactive microglia and brain-infiltrating macrophages impair mechanisms of cellular homeostasis and plasticity such as the ongoing generation of myelin-forming oligodendrocytes, myelin plasticity, and new neuron generation in the hippocampus.
“Reactive microglia and brain-infiltrating macrophages impair mechanisms of cellular homeostasis and plasticity such as the ongoing generation of myelin-forming oligodendrocytes (Gibson et al., 2019), myelin plasticity (Geraghty et al., 2019), and new neuron generation in the hippocampus (Monje et al., 2002, 2003, 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Microglia become persistently reactive following exposure to certain chemotherapy drugs, after cranial radiation, or after systemic inflammatory challenge with low-dose lipopolysaccharide.
“Microglia, brain-resident macrophages, become persistently reactive following exposure to certain chemotherapy drugs, after cranial radiation, or after systemic inflammatory challenge with low-dose lipopolysaccharide (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2002, 2003, 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
This complex cellular dysregulation is thought to contribute importantly to cognitive impairment.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Isolated respiratory infection with SARS-CoV-2 can result in profound and prolonged changes in cytokines within the CNS.
“These results indicate that isolated respiratory infection with SARS-CoV-2 can result in profound and prolonged changes in cytokines within the CNS.”
Quote in the paperSubstantial claim - Interpretationown data
Even microglia without a 'full' reactive response have putative altered function after mild respiratory COVID in mice.
“Further investigation of these COVID-related transcriptional signatures using gene ontology highlighted upregulation of cytokine production, chemotaxis, and regulation of apoptosis (Figure S4D, chemokine sub-state), and upregulation of cytotoxicity, immune responses, and antigen processing and presentation (Figure S4E, homeostatic signature)—suggesting that even microglia without a “full” reactive”
Quote in the paperSubstantial claim - Interpretationreasoning
Cancer therapy and respiratory SARS-CoV-2 infection share similar neuropathophysiology.
“These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.”
Quote in the paperSubstantial claim - Study design and conductcitation
The human COVID cases examined cannot be considered 'mild' because each individual died for reasons that were or may have been related to COVID.
“As each of these individuals died for reasons that were or may have been related to COVID (Lee et al., 2021), these cases cannot be considered “mild.””
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lee et al., 2021 source
Not checked in the free run.
- Interpretationown data
The respiratory COVID-related transcriptional changes represent a distinct state of microglial/myeloid cell reactivity following mild respiratory COVID, not completely encompassed by previously described microglial states.
“However, the previously described microglial states in other disease contexts, neither individually nor in combination, completely encompass the respiratory COVID-related transcriptional changes, highlighting aspects of a distinct state of microglial/myeloid cell reactivity following mild respiratory COVID.”
Quote in the paperSubstantial claim - Interpretationown data
The similarity of these gene expression changes to white matter aging and injury is consistent with increased microglial reactivity in the subcortical white matter following SARS-CoV-2 infection.
“The similarity of these gene expression changes to white matter aging and injury is consistent with increased microglial reactivity in the subcortical white matter following SARS-CoV-2 infection.”
Quote in the paperSubstantial claim - Interpretationreasoning
This neuropathophysiology may contribute to cognitive impairment following even mild COVID.
“These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.”
Quote in the paperSubstantial claim- Rests on an assumption: Circulating CCL11 levels in humans reflect CNS CCL11 levels or neuroinflammatory processes relevant to cognitive symptoms.
- Premisecitation
SARS-CoV-2 infection induces a broad inflammatory response well beyond the typical type-1 immune response seen with other respiratory viral infections.
“SARS-CoV-2 infection induces a broad inflammatory response—well beyond the typical type-1 immune response seen with other respiratory viral infections (Lucas et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lucas et al., 2020 source
Not checked in the free run.
- Interpretationown data
Even mild respiratory infection with SARS-CoV-2 can result in persistent neuroinflammatory changes and consequent dysregulation of neural cell types important for healthy cognitive function.
“Taken together, the findings presented here illustrate that even mild respiratory infection with SARS-CoV-2 can result in persistent neuroinflammatory changes and consequent dysregulation of neural cell types important for healthy cognitive function.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
- Premisecitation
White-matter-selective/enriched microglial reactivity is associated with impaired hippocampal neurogenesis, dysregulation of the oligodendroglial lineage, and myelin loss in other disease contexts.
“Such neuroinflammatory changes—particularly white-matter-selective/enriched microglial reactivity—are associated with impaired hippocampal neurogenesis, dysregulation of the oligodendroglial lineage, and myelin loss in other disease contexts (Geraghty et al., 2019; Gibson et al., 2019; Guttenplan et al., 2021; Liddelow et al., 2017; Monje et al., 2003; Villeda et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The deficiency in hippocampal neurogenesis after influenza is consistent with persistent hippocampal microglial/macrophage reactivity.
“Hippocampal neurogenesis was deficient at both 7-day and 7-week time points, consistent with the persistent hippocampal microglial/macrophage reactivity (Figures 7N and 7O).”
Quote in the paperNot a substantial claim - Premisecitation
Even small changes in myelination can exert profound effects on neural circuit dynamics and consequently on cognitive function.
“even small changes in myelination can exert profound effects on neural circuit dynamics and consequently on cognitive function (Steadman et al., 2020; Noori et al., 2020; Pajevic et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
The finding that CCL11 effects are region/circuit-specific implies particular vulnerability of the hippocampus to the neuroinflammatory consequences of respiratory infection.
“but this finding implies particular vulnerability of the hippocampus to the neuroinflammatory consequences of respiratory infection, consistent with the recent reports of limbic system structural changes in COVID survivors (Douaud et al., 2022).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Douaud et al., 2022 source
Not checked in the free run.
- Premisecitation
More severe COVID can result in additional neuropathological consequences beyond those from mild respiratory infection.
“In addition to the neuropathophysiological changes resulting from even relatively mild acute respiratory infection and consequent neuroinflammation, more severe COVID can result in additional neuropathological consequences (Nath and Smith, 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nath and Smith, 2021
Not checked in the free run.
- Premisecitation
Preclinical studies in disease models sharing features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition.
“Preclinical studies in disease models that share numerous features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition (Ayoub et al., 2020; Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003; Villeda et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Study design and conductown data
Our single-cell transcriptomic studies did not contain sufficient numbers of cells to draw conclusions about the transcriptional state of astrocytes or cell types other than microglia.
“Our single-cell transcriptomic studies did not contain sufficient numbers of cells to draw conclusions about the transcriptional state of astrocytes or cell types other than microglia.”
Quote in the paperSubstantial claim - Interpretationown data
The final microglia cluster is highly pure.
“indicating that the cluster is highly pure.”
Quote in the paperNot a substantial claim
- May combine two claims. 34
- Classified as probably not a substantial claim. 51
May combine two claims.
Findingown dataIn mice with mild respiratory COVID, CSF levels of CXCL10, CCL7, CCL2, CCL11, and GMCSF remain elevated, and IL10 and CCL5 become elevated by 7 weeks post-infection.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMice with mild respiratory SARS-CoV-2 infection exhibit no weight loss or observable sickness behavior.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe white-matter-specific microglial/macrophage reactivity after mild respiratory COVID in mice was evident in two different mouse strains (CD1 and BALB/c) at 7 days post-infection and persisted to 7 weeks post-infection.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe human COVID cases examined did not die during hospitalization and did not exhibit fulminant pulmonary disease.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThere is a high degree of overlap between the upregulated and downregulated genes from both the chemokine and altered homeostatic gene signatures and other microglial states, with both signatures in post-COVID microglia showing the greatest similarity to the WAM and DAM states.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPatient sex and history of autoimmune disease did not interact with one another, suggesting each was an independent predictor of CCL11 levels.
“These variables did not interact with one another, suggesting each was an independent predictor of CCL11 levels.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEven 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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
May combine two claims.
Findingown dataBy 7 weeks after influenza infection, CCL11 was the only chemokine that remained elevated and had increased from the 7-day time point.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOligodendrocytes were decreased in subcortical white matter at 7 days after influenza infection but recovered as microglial reactivity resolved by 7 weeks.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe 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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: The methotrexate chemotherapy mouse model is comparable to COVID-related cognitive impairment.
May combine two claims.
Findingown dataAt 7 days after H1N1 influenza infection, CSF cytokines/chemokines were elevated similarly to mild respiratory COVID, including IFN-γ, CCL11, CCL2, and GMCSF, with distinct elevations in IL4 and CCL5.
“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).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataA 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.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe merged cluster has higher expression of typical microglia marker genes and lower expression of inflammation-related genes.
“The merged cluster was labeled Homeostatic due to its higher expression of typical microglia marker genes and lower expression of inflammation-related genes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSome non-microglial clusters appear to express the microglia-specific markers Tmem119 and P2ry12.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCOVID 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.
“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.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Wefel et al., 2015
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- cites Gibson and Monje [2021]
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- Also stated in: § Introduction · hedged
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCOVID-associated cognitive impairment ('COVID fog') is characterized by impaired attention, concentration, speed of information processing, memory, and executive function.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationNeuroinflammation is central to the pathophysiology of cancer-therapy-related cognitive impairment (CRCI).
“Neuroinflammation is central to the pathophysiology of CRCI (for review, see Gibson and Monje [2021]), raising the possibility of shared pathophysiological mechanisms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gibson and Monje [2021]
Not checked in the free run.
May combine two claims.
PremisecitationElevated circulating cytokine/chemokine levels, particularly CCL11, can limit neurogenesis and contribute to cognitive impairment.
“Elevated circulating cytokine/chemokine levels, particularly CCL11, can also limit neurogenesis and contribute to cognitive impairment (Villeda et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Villeda et al., 2011 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationA distinct subpopulation of microglia that reside in white matter are selectively activated by systemic insults such as exposure to the chemotherapy drug methotrexate.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPersistent cognitive impairment affects approximately one in four COVID survivors.
“Neurological symptoms are emerging as relatively common sequelae, with persistent cognitive impairment affecting approximately one in four COVID survivors (Nasserie et al., 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nasserie et al., 2021 source
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PremisecitationMicroglia induce neurotoxic astrocyte reactivity through cytokine signaling.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liddelow et al., 2017 source
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May combine two claims.
PremisecitationThe mouse model of mild SARS-CoV-2 infection used is limited to the respiratory system and clears within 1 week.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Israelow et al., 2020 source
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- cites Song et al., 2021
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PremisecitationAnti-inflammatory strategies correct multicellular dysregulation and rescue cognition in disease states such as those occurring after exposure to neurotoxic cancer therapies and in aging.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe challenges of working with a biosafety level-3 mouse model limited the feasibility of further behavioral assessments.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Premisenone givenEven mild COVID could result in a detrimental neuroinflammatory response, including reactivity of white matter microglia.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThis sub-state of reactive astrocytes are poor supporters of synaptic connections, adding to network dysfunction.
“Additionally, this sub-state of reactive astrocytes are poor supporters of synaptic connections—further adding to network dysfunction (Liddelow et al., 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liddelow et al., 2017 source
Not checked in the free run.
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PremisecitationCertain states of reactive astrocytes induce oligodendrocyte and neuronal cell death.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningPersistent loss of myelin in subcortical projections after mild respiratory COVID would be predicted to impair neural circuit function and axon health.
“Such persistent loss of myelin in subcortical projections would be predicted to impair neural circuit function and axon health”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataH1N1 influenza elicited a partially overlapping but distinct CSF cytokine/chemokine profile and a more restricted pattern of persistent cellular changes compared with SARS-CoV-2.
“By comparison, H1N1 influenza elicited a partially overlapping but also distinct CSF cytokine/chemokine profile and more restricted pattern of persistent cellular changes.”
Quote in the paperSubstantial claim- Rests on an assumption: The H1N1 influenza mouse model recapitulates mild respiratory influenza in humans.
Classified as probably not a substantial claim.
InterpretationreasoningThe persistent loss of myelin in subcortical projections adds to the numerous deleterious neurobiological consequences of SARS-CoV-2 infection.
“adding to the numerous deleterious neurobiological consequences of SARS-CoV-2 infection.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe H1N1 strain of influenza causes acute elevation in CNS cytokines, hippocampal microglial reactivity, and impaired performance in cognitive behavioral tests.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hosseini et al., 2018 source
Not checked in the free run.
- cites Jurgens et al., 2012 source
Not checked in the free run.
- Rests on an assumption: The H1N1 strain of influenza is not neuroinvasive in mouse models.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOther viral syndromes such as influenza can cause microglial reactivity, elevated CNS cytokine levels, and impair cognitive function, even in the absence of neuroinvasion.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hosseini et al., 2018 source
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- cites Jurgens et al., 2012 source
Not checked in the free run.
- Rests on an assumption: Other respiratory viral infections such as influenza are associated with cognitive and other neurological sequelae.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe differences in neuroinflammatory profiles observed here in mouse models of SARS-CoV-2 and H1N1 influenza respiratory infection underscore the principle that immune challenges induce diverse immunological responses.
“The differences in neuroinflammatory profiles observed here in mouse models of SARS-CoV-2 and H1N1 influenza respiratory infection underscore this principle.”
Quote in the paperNot a substantial claim- 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.
May combine two claims.
Interpretationown dataIn 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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: The H1N1 influenza mouse model recapitulates mild respiratory influenza in humans.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPeople 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).
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pandharipande et al., 2013 source
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PremisecitationSystemic exposure of rats to low levels of bacterial liposaccharide (LPS) sufficient to cause mild-moderate sickness behavior but not sepsis causes microglial reactivity and impairment in hippocampal neurogenesis.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Monje et al., 2003 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe persistence of hippocampal microglial/macrophage reactivity at 7 weeks after influenza is consistent with persistently elevated CSF CCL11 levels, which specifically increase reactivity of hippocampal microglia/macrophages.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe particularly immunogenic nature of SARS-CoV-2, the persistence of the neuroinflammatory changes observed here, and the magnitude of the population infected during this pandemic contribute to the emerging crisis of lasting cognitive impairment associated with COVID.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lucas et al., 2020 source
Not checked in the free run.
- Rests on an assumption: The magnitude of the population infected during the COVID-19 pandemic is large.
Classified as probably not a substantial claim.
Interpretationnone givenThe study examined neurobiological consequences of respiratory system infection in adulthood with the original strain of SARS-CoV-2 in the absence of vaccination.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataElevated 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 and induce microglial reactivity specifically in the hippocampus.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Villeda et al., 2011 source
Not checked in the free run.
- 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.
May combine two claims.
Interpretationown dataThe findings here illustrate numerous pathophysiological similarities between COVID fog and chemo fog, including depletion of myelinating oligodendrocytes and myelin loss.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe neurological sequelae of SARS-CoV-2 infection are proving to be both common and debilitating.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThe inflammation-induced multicellular dysregulation described here may be potentially reversible with therapeutic interventions, while severe complications such as stroke can cause irreversible brain damage.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn severe COVID, astrocytes in the human cerebral cortex exhibit a transcriptional program consistent with neurotoxic reactivity.
“In the context of severe COVID, astrocytes in the human cerebral cortex exhibit a transcriptional program consistent with neurotoxic reactivity (Yang et al., 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yang et al., 2021 source
Not checked in the free run.
May combine two claims.
PremisecitationThese additional neuropathological consequences of severe COVID include microvascular thrombi, neuron loss, cortical inflammation, and even direct brain infection in some cases.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThis 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 cause differing prevalence of certain cognitive or neuropsychiatric symptoms.
“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.”
Quote in the paperNot a substantial claim- Rests on an assumption: Systemic inflammation-induced neuroinflammation, consequent glial dysregulation and impairment of neural function is a principle that extends beyond COVID.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMyelin modulates the speed of neural impulse conduction, provides metabolic support to axons, and exhibits adaptive plasticity.
“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);”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEmerging data indicate that the risk of cognitive impairment may be decreased in breakthrough infections of fully vaccinated individuals.
“Emerging data indicate that the risk of cognitive impairment may be decreased in breakthrough infections of fully vaccinated individuals (Antonelli et al., 2022).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Antonelli et al., 2022 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe microglial reactivity present after mild respiratory SARS-CoV-2 infection may also induce neurotoxic astrocyte reactivity and aberrant microglial pruning of synapses.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Liddelow et al., 2017 source
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- cites Gibson et al., 2019 source
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- cites Guttenplan et al., 2021 source
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- Rests on an assumption: The mouse model of mild respiratory SARS-CoV-2 infection recapitulates key features of mild respiratory COVID in humans.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMethotrexate directly stimulates reactivity of microglia.
“While methotrexate directly stimulates reactivity of microglia (Gibson et al., 2019),”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gibson et al., 2019 source
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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningSuch insights from diseases such as CRCI may elucidate therapeutic strategies to restore healthy cognitive function following COVID.
“Such insights from diseases such as CRCI may elucidate therapeutic strategies to restore healthy cognitive function following COVID.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll procedures used in this study complied with federal guidelines and the institutional policies of the Yale School of Medicine Animal Care and Use Committee.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor all quantifications, experimenters were blinded to sample identity and condition.
“For all quantifications, experimenters were blinded to sample identity and condition.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenHuman lung histology was assessed on standard clinical H&E images by board-certified pathologists.
“Human lung histology was assessed on standard clinical H&E images by board-certified pathologists.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAxons in the cingulum of the corpus callosum were analyzed for g-ratios and myelinated axon density by experimenters blinded to experimental conditions and genotypes.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenHuman 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.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor the CCL11 study, all procedures complied with Institutional Animal Care and Use Committee protocol at Stanford.
“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.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductcitationHuman brain tissue samples were prepared and analyzed as previously described.
“Human brain tissue samples were prepared and analyzed as previously described (Lee et al., 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lee et al., 2021 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCD45 and CD11b analysis was used as a quality control prior to sorting.
“CD45 and CD11b analysis was used as a quality control prior to sorting.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn every experiment, n equals at least 3 mice per group.
“In every experiment, “n” equals at least 3 mice per group; the exact “n” for each experiment is defined in the figure legends.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAll cell counting was performed by experimenters blinded to experimental conditions.
“All cell counting was performed by experimenters blinded to experimental conditions”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe expression of microglia-specific markers in non-microglial clusters is driven by a small number of outlier microglia which clustered with these non-microglial cell types.
“this is driven by a small number of outlier microglia which clustered with these non-microglial cell types.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThese few cells were excluded from downstream analysis as outliers.
“these few cells were excluded from downstream analysis as outliers.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataA blinded pulmonary pathologist reviewed the slides and identified immune cell infiltration and other related pathologies.
“A blinded pulmonary pathologist reviewed the slides and identified immune cell infiltration and other related pathologies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationPatient plasma was collected with informed consent and IRB approval.
“Patient plasma was collected with informed consent and IRB approval as previously described (Lucas et al., 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lucas et al., 2020 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenShapiro-Wilk test was used to determine normality for all datasets; all datasets were parametric.
“Shapiro-Wilk test was used to determine normality for all datasets; all datasets were parametric.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA minimum of 300 axons were scored per group.
“A minimum of 300 axons were scored per group.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe oligodendrocyte loss observed here could be caused by reactive astrocyte toxic lipids, which are known to cause oligodendrocyte cell death.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMicroglial depletion strategies can restore similar multicellular deficits and rescue impaired cognitive performance in mouse models of CRCI.
“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),”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationPerfusion buffer, dissection buffer and digestion buffer were freshly prepared as previously described.
“Perfusion buffer, dissection buffer and digestion buffer were freshly prepared as previously described (Marsh et al., 2022).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Marsh et al., 2022 source
Not checked in the free run.
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Study design and conductnone givenAll samples were measured at the time of the first thaw.
“All samples were measured at the time of the first thaw.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll blood samples were processed on the day of collection.
“All blood samples were processed on the day of collection.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe cell type labels are valid.
“demonstrating the validity of the cell type labels.”
Quote in the paperSubstantial 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?
White-matter microglia reactivity has been related to aging and diseases.
“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]
CCL11 efficiently crosses the blood brain barrier, has been implicated in neuroinflammatory disorders and SARS-CoV-2 cognitive impairment, and impairs neurogenesis.
“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]
Microglia are the primary cell-type in the CNS responsive to CCL11.
“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.”
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Distinguishing features of long COVID identified through immune profiling
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Self-citationLong COVID science, research and policy
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Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model
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- 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 · 2020: 1
- 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 › 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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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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