Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model

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

Fear in Tg2576 mice is a common observation made in this genotype.

“Fear in Tg2576 mice is a common observation made in this genotype (Dineley et al., 2002).”

• cites Dineley et al., 2002 sourceDisputed

  The Results (page unavailable) report that APP mice showed no anomalous anxiety-related behavior in the open-field test, contrary to the claim that fear is a common characteristic of this genotype. The paper’s fear-conditioning results concern learned responses to a cue and foot shock, not a general observation that these mice are fearful. (LLM, conf=0.84)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

New World alphaviruses such as Venezuelan equine encephalitis, eastern equine encephalitis, and western equine encephalitis viruses result in up to 90% of survivors exhibiting encephalitis and neurological sequelae.

“New-world alphaviruses, such as Venezuelan equine encephalitis (VEE), eastern equine encephalitis (EEE), and western equine encephalitis (WEE) viruses, are spread within the Americas and result in up to 90% of survivors exhibiting encephalitis and neurological sequelae (Mulder et al., 1951; Rivas et al., 1997; Ronca et al., 2016)”

• cites Mulder et al., 1951 sourceNot checked — no full text of the source
• cites Rivas et al., 1997 sourceNot checked — no full text of the source
• cites Ronca et al., 2016 sourceSupported

May combine two claims.

VEEV infects neurons and glial cells in the CNS, promoting neurodegeneration and potentially leading to permanent neurological sequelae during its lymphotropic and neurotropic phases.

“It infects neurons and glial cells in the CNS, promoting neurodegeneration and potentially leading to permanent neurological sequelae during its lymphotropic and neurotropic phases (Bocan et al., 2019; Gleiser et al., 1962; Schoneboom et al., 2000).”

• cites Bocan et al., 2019 sourcePartly supported

  The Introduction (page not provided) describes lymphotropic and neurotropic phases of VEEV infection in mice. The Discussion (page not provided) identifies neurons as primary target cells and reports neuronal death, but describes microglial activation rather than infection of glial cells. It does not establish permanent neurological sequelae. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Gleiser et al., 1962 sourceNot checked — no full text of the source
• cites Schoneboom et al., 2000 sourceNot checked — no full text of the source

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

Sporadic (idiopathic) Alzheimer's disease is slowly progressive and is the most common cause of dementia in those aged 65 and older, making up more than 90% of disease cases.

“Sporadic (idiopathic) AD is slowly progressive and the most common cause of dementia in those aged 65 and older making more than 90% of the disease cases (Geschwind et al., 2007).”

• cites Geschwind et al., 2007 sourcePartly supported

  The Introduction says that most slowly progressive dementias are due to Alzheimer's disease, and its discussion of chronic degenerative dementias says AD is rarely rapid. It does not specify sporadic or idiopathic AD, establish the claim for people aged 65 and older, or give a figure exceeding 90% of cases. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

WEEV infection in a rodent model produces phospho-serine129 alpha-synuclein positive, proteinase K-resistant protein aggregates, indicating neurological sequelae and neuronal injury consistent with a Parkinson's neurodegenerative phenotype.

“Interestingly, phospho-serine129 α-synuclein positive, proteinase K-resistant protein aggregates are also present, indicating neurological sequelae and neuronal injury consistent with Parkinson's neurodegenerative phenotype (Bantle et al., 2019).”

• cites Bantle et al., 2019 sourceSupported

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

Neuropsychiatric symptoms, alongside behavioral disorders, deficits in locomotor activity, and changes in reflex and sensory function, precede cognitive deficits in AD.

“Moreover, neuropsychiatric symptoms, alongside behavioral disorders, deficits in locomotor activity, and changes in reflex and sensory function, precede cognitive deficits in AD (Albers et al., 2015; Buchman and Bennett, 2011; Cortes et al., 2018).”

• cites Albers et al., 2015 sourcePartly supported

  The Introduction says that changes in smell, hearing, and walking speed may precede cognitive impairment by 5–15 years. The Discussion likewise says some sensory and motor deficits may precede cognitive symptoms, but cautions that others appear concurrently and not all patients show such early changes. These passages do not establish that neuropsychiatric symptoms, behavioral disorders, or reflex changes precede cognitive deficits. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Buchman and Bennett, 2011 sourcePartly supported

  The Motor performances section (page unavailable) says motor decline in cognitively intact people can precede cognitive impairment by several years. The Odor identification section links impaired smell identification with later MCI and cognitive decline. Our copy does not establish that neuropsychiatric symptoms, behavioral disorders, or reflex changes precede cognitive deficits; its reference to “noncognitive behaviors” does not specify those conditions. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Cortes et al., 2018 sourceNot checked — no full text of the source

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

In AD and CNS infections, pro- and anti-inflammatory signaling is primarily initiated by CNS resident immune cells, the astrocytes, and microglia.

“In AD and CNS infections, pro- and anti-inflammatory signaling is primarily initiated by CNS resident immune cells, the astrocytes, and microglia (Di Benedetto et al., 2022; Russo and McGavern, 2015).”

• cites Di Benedetto et al., 2022 sourceSupported
• cites Russo and McGavern, 2015 sourcePartly supported

  The sections on pathogen recognition and regulation of neuroinflammation describe microglial inflammatory responses to CNS infection and say that microglia and astrocytes can secrete anti-inflammatory cytokines. The paper does not establish that these cells primarily initiate both kinds of signaling. Its only discussion of Alzheimer’s disease, in “Immune clean-up of the injured CNS,” concerns microglial uptake of β-amyloid, not initiation of inflammatory signaling in AD. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Abnormalities in hippocampal pathology have been linked to AD and other neurodegenerative disorders.

“Notably, abnormalities in hippocampal pathology have been linked to AD and other neurodegenerative disorders (Tombaugh et al., 2002).”

• cites Tombaugh et al., 2002 sourceCould not verify

  The Discussion describes hippocampal synaptic changes and learning in aged rats, but does not link hippocampal pathology to Alzheimer’s disease or other neurodegenerative disorders. Searches for Alzheimer’s disease and neurodegenerative disorders found only a reference title mentioning Alzheimer’s disease, not a statement of the claimed link. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

May combine two claims.

Exposure to VEEV TC-83 in a model predisposed to develop AD exacerbates the decline in cognition, heightening fear, anxiety, and caution; similar outcomes are observed in patients developing AD.

“These measurements indicate that exposure to VEEV TC-83 in a model predisposed to develop AD exacerbates the decline in cognition, heightening fear, anxiety, and caution; similar outcomes are observed in patients developing AD (Zhou et al., 2022; Zielinski et al., 1993).”

• cites Zhou et al., 2022 sourceCould not verify

  The experimental-design section describes studies in C57BL/6J mice, and the passages retrieved for VEEV TC-83 and Alzheimer’s disease do not address viral exposure, AD-related cognitive decline, or patients developing AD. The section ‘Action caution is not because of increased anxiety’ instead examines caution in an avoidance task and concludes that mice can be cautious without being anxious; it does not test the effects claimed here. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites Zielinski et al., 1993Not checked — no full text of the source

• AssumptionRests on an assumption: Tg2576 mice are a valid preclinical model of Alzheimer's disease.

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

A cascade of events following cytokine alterations may result in hyperexcitability of the neuronal network, which is important in the pathophysiology of Alzheimer's disease.

“This cascade of events may result in hyperexcitability of the neuronal network, which is important in the pathophysiology of AD (Clarkson et al., 2017; Targa Dias Anastacio, Matosin and Ooi, 2022).”

• cites Clarkson et al., 2017 sourcePartly supported

  The Results and Discussion (page numbers unavailable) support the proposed link between inflammatory cytokines, disrupted GABAergic signaling, and neuronal network hyperexcitability in murine cortical cultures. They do not establish that this mechanism is important in Alzheimer’s disease pathophysiology; Alzheimer’s disease appears in reference titles, not in the paper’s stated findings on hyperexcitability. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Targa Dias Anastacio, Matosin and Ooi, 2022 sourceSupported

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

Neuroinflammation is a common hallmark for both AD and CNS infections.

“Neuroinflammation is a common hallmark for both AD and CNS infections (Cle et al., 2020).”

• cites Cle et al., 2020 sourcePartly supported

  The clinical-perspective section describes neuroinflammation in arboviral CNS infections, and the Conclusions call it a key mechanism in various neuronal disorders. The paper mentions Alzheimer’s disease and cites work on microglia-mediated synapse loss in AD, but it does not establish neuroinflammation as a hallmark of AD specifically. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

VEEV infection induces neuropathology, including meningoencephalitis, gliosis, and multifocal neuropil vacuolation, localized to multiple regions including the hippocampus.

“It induces neuropathology, including meningoencephalitis, gliosis, and multifocal neuropil vacuolation, which is localized to multiple regions, including the hippocampus (Charles et al., 2001; Kundin et al., 1966; Schoneboom et al., 2000; A. Taylor et al., 2015).”

• cites Charles et al., 2001 sourcePartly supported

  The CNS histopathology section reports leptomeningitis and inflammatory infiltration in VEE-infected immunocompetent mice, but spongiosis with microglial and astrocytic proliferation in SCID mice. The CNS pathogenesis section also reports neuropil vacuolation in SCID mice. The paper says spongiosis was widely distributed throughout the CNS, but the passages do not specifically locate lesions in the hippocampus; the sentence also combines findings from mice with different immune status. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Kundin et al., 1966 sourceNot checked — no full text of the source
• cites Schoneboom et al., 2000 sourceNot checked — no full text of the source

May combine two claims.

Abnormalities in neuropsychiatric states were common among the VEEV TC-83 inoculated WT and Tg2576 mice and were exaggerated responses to the normal, indicating anxiety-like behavior, irritability, or dementia, which are associated with the sequelae of alphaviruses and with AD.

“Abnormalities in neuropsychiatric states were common among the VEEV TC-83 inoculated WT and Tg2576 mice and were exaggerated responses to the normal, indicating anxiety-like behavior, irritability, or dementia, which are associated with the sequelae of alphaviruses (Reisberg et al., 1987) and with AD (Cerejeira et al., 2012).”

• cites Reisberg et al., 1987Not checked — no full text of the source
• cites Cerejeira et al., 2012 sourceSupported

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

Environmental risk factors are suspected but unproven in exacerbating Alzheimer's disease.

“Notwithstanding the role of aging in AD, environmental risk factors are suspected but unproven in exacerbating the disease (Sochocka et al., 2017).”

• cites Sochocka et al., 2017 sourceSupported

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

Among the enduring neurological consequences experienced by VEEV survivors, symptoms such as paralysis, sensory impairments, headaches, fatigue, depression, seizures, neuropsychological alterations, and changes in mental status have been most frequently reported.

“Among the enduring neurological consequences experienced by VEEV survivors, symptoms such as paralysis, sensory impairments, headaches, fatigue, depression, seizures, neuropsychological alterations, and changes in mental status have been most frequently reported (Bowen et al., 1976; Carrera et al., 2013; Rivas et al., 1997).”

• cites Bowen et al., 1976Not checked — no full text of the source
• cites Carrera et al., 2013 sourcePartly supported

  The Results (Initial Human Cases of Viral Encephalitis; page unavailable) report seizures, hemiparesis and psychomotor retardation as sequelae at discharge, but identify the patients with reported sequelae as having EEE, including one dual EEE–VEE infection. The paper does not establish these as enduring or frequently reported consequences among VEEV survivors, or report the other listed symptoms as such. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Rivas et al., 1997 sourceNot checked — no full text of the source

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

Neuroinflammation is linked to neurodegeneration and neuronal loss, which are features associated with amyloid plaque formation.

“Neuroinflammation is also linked to neurodegeneration and neuronal loss, which are features that coincidently are associated with amyloid plaque formation (DeTure and Dickson, 2019; Kinney et al., 2018; Sung et al., 2020).”

• cites DeTure and Dickson, 2019 sourceSupported
• cites Kinney et al., 2018 sourceSupported
• cites Sung et al., 2020 sourceSupported

Classified as probably not a substantial claim.

Active avoidance tests are particularly valuable for evaluating hippocampal-dependent cognitive functions.

“Active avoidance tests are particularly valuable for evaluating hippocampal-dependent cognitive functions (Anagnostaras et al., 2010; Chaudry et al., 2022; Kajs et al., 2022).”

• cites Anagnostaras et al., 2010 sourcePartly supported

  The Introduction (page unavailable in our copy) describes contextual fear conditioning as hippocampus-dependent and Pavlovian fear conditioning as a useful memory assay. It does not establish that active avoidance tests are particularly valuable for evaluating hippocampal-dependent cognitive functions; that is a different test paradigm. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Chaudry et al., 2022 sourceSupported
• cites Kajs et al., 2022 sourceCould not verify

  The Introduction and Discussion describe active avoidance as a way to study avoidance behavior and its encoding in dorsomedial prefrontal circuits. The Materials and methods section describes the active avoidance test used, but neither it nor the retrieved passages addresses whether such tests are particularly valuable for evaluating hippocampal-dependent cognitive functions (searched: hippocampus, hippocampal-dependent learning and memory). (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

This infection can lead to the activation of microglial cells, which mediate neuron communication through the production of proinflammatory factors such as cytokines including IL-1β, IL-10, TNF-α, and IFN-γ ultimately facilitating the migration of immune cells across the blood-brain barrier.

“This infection can lead to the activation of microglial cells, which mediate neuron communication through the production of proinflammatory factors such as cytokines including IL-1β, IL-10, TNF-α, and IFN-γ ultimately facilitating the migration of immune cells across the blood-brain barrier (BBB) (Ramesh et al., 2013).”

• cites Ramesh et al., 2013 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

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

Previous studies demonstrate that in animal models of neurodegenerative disorders, such as AD, cognitive function and learning and memory are significantly impaired.

“Previous studies demonstrate that in animal models of neurodegenerative disorders, such as AD, cognitive function and learning and memory are significantly impaired (Anagnostaras et al., 2010; Chaudry et al., 2022; Kajs et al., 2022; Webster et al., 2014) and that VEEV infections can have an adverse effect on learning memory (Dave and Klein, 2023; Ronca et al., 2016).”

• cites Anagnostaras et al., 2010 sourceCould not verify

  The Introduction (page unavailable) describes fear conditioning as a memory assay and mentions Alzheimer's disease as a potential target for cognitive-function research. It does not report significant cognitive or learning-and-memory impairment in animal models of Alzheimer's or other neurodegenerative disorders; searches for those models and impairments found no supporting passage. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Chaudry et al., 2022 sourceSupported
• cites Kajs et al., 2022 sourceCould not verify

  The Materials and methods (Animals; page unavailable) describe wild-type mice, and the Results examine active avoidance learning, not neurodegenerative-disease models. Searches for Alzheimer’s disease, neurodegeneration, and impaired cognition or memory found no passage addressing the attributed claim. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

IL-1β, IL-10, TNF-α, and IFN-γ are implicated in neurodegenerative processes.

“which are implicated in neurodegenerative processes (Keck et al., 2018; Keck et al., 2018b; Sharma and Knollmann-Ritschel, 2019).”

• cites Keck et al., 2018Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Keck et al., 2018bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sharma and Knollmann-Ritschel, 2019 sourcePartly supported

  Section 6 (page unavailable) links IL-1β and TNF-α to inflammation in VEEV-infected brains and reports greater neuronal death with a more inflammatory VEEV strain. It does not implicate IL-10 or IFN-γ in neurodegenerative processes; Section 2 instead describes interferon as protective against VEEV infection. The evidence is also specific to VEEV-associated brain inflammation, rather than neurodegenerative processes generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

In preclinical Alzheimer's disease, mouse models that contain a mutation in amyloid precursor protein (APP) have been widely used as models of AD, and APP plays an essential role in cognitive function.

“In preclinical AD, mouse models that contain a mutation in amyloid precursor protein (APP) have been widely used as models of AD, which play an essential role in cognitive function (Webster et al., 2014).”

• cites Webster et al., 2014 sourcePartly supported

  The section on temporal progression of cognitive deficits (page not provided) describes APP-mutation mice as commonly used AD models. The APP/PS1 section reports cognitive deficits in one such model, but the paper does not establish that APP itself plays an essential role in cognitive function. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Exposure to common viral pathogens increases the risk of developing Alzheimer's and other neurodegenerative diseases.

“A recent report utilizing information from national biobanks suggests that exposure to common viral pathogens increases the risk of developing Alzheimer's and other neurodegenerative diseases (Blackhurst and Funk, 2023).”

• cites Blackhurst and Funk, 2023 sourceSupported

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

The prefrontal cortex is involved in processing anxiety, which can interfere with goal-directed behavior and cognitive performance.

“The prefrontal cortex is involved in processing anxiety, which can interfere with goal-directed behavior and cognitive performance (Park and Moghaddam, 2017).”

• cites Park and Moghaddam, 2017 sourceSupported

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

The hippocampus is important in learning and memory and in Alzheimer's disease neuropathogenesis.

“Given the importance of the hippocampus in learning and memory and AD neuropathogenesis (Tombaugh et al., 2002)”

• cites Tombaugh et al., 2002 sourcePartly supported

  The paper’s opening discussion states that spatial learning in rodents is strongly hippocampus-dependent and that the hippocampus plays a key role in spatial memory formation. It does not address the hippocampus’s role in Alzheimer’s disease neuropathogenesis; Alzheimer’s disease appears only in the title of a work listed in the References. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Cellular and molecular mechanisms resulting from injury or infections that underlie the development of proinflammatory cytokines and chemokines in the CNS are canonically triggered and modulated by astrocytes and microglia.

“Cellular and molecular mechanisms resulting from injury or infections, underlying the development of proinflammatory cytokines and chemokines in the CNS, are canonically triggered and modulated by astrocytes and microglia (Hanisch, 2002; Murphy et al., 1997)”

• cites Hanisch, 2002 sourceSupported
• cites Murphy et al., 1997 sourceNot checked — no full text of the source

May combine two claims.

The neurological abnormalities detected in greater than half of WT mice inoculated with VEEV TC-83 were related to their neuropsychiatric state; however, those irregularities recovered at 6 mpi.

“The neurological abnormalities detected in greater than half of WT mice inoculated with VEEV TC-83 were related to their neuropsychiatric state; however, those irregularities recovered at 6 mpi.”

May combine two claims.

For the most part, all abnormal reactions were absent in saline Tg2576 mice except for fear responses, which developed in greater than 50% of the Tg2576 saline mice.

“We expected to detect similar responses in saline Tg2576 mice, in the absence of VEEV TC-83, since they develop age-associated deficits, and at this point in the study the mice were 9 months of age, but for the most part, all abnormal reactions were absent except for fear responses, which developed in greater than 50% of the Tg2576 saline mice.”

• AssumptionRests on an assumption: Tg2576 mice develop age-associated deficits.

May combine two claims.

In saline inoculated WT mice, no detectable levels of IL-1β were measured; IL-1β levels were detected in saline-inoculated Tg2576 mice; and an increase in IL-1β levels was quantified in WT inoculated mice.

“In saline inoculated WT mice, no detectable levels of IL-1β were measured; however, IL-1β levels were detected in saline-inoculated Tg2576 mice and an increase in IL-1β levels were quantified in WT inoculated mice (Fig. 4A).”

May combine two claims.

In Tg2576 mice inoculated with VEEV TC-83, weight loss trended downward over eight days post-inoculation, but weights of all mice recovered at 30 dpi regardless of VEEV TC-83 exposure.

“A downward trend in weight loss was measured in Tg2576 mice inoculated with VEEV TC-83 over the course of eight days post-inoculation (dpi); however, the weights of all mice recovered at 30 dpi, regardless of VEEV TC-83 exposure (Fig. 1A).”

May combine two claims.

Exposure to VEEV TC-83 triggered the development of abnormal responses, despite genotype, at 1 month post-inoculation, and these responses recovered in WT mice at 6 months post-inoculation.

“Taken together, exposure to VEEV TC-83 triggered the development of abnormal responses, despite genotype, at 1 mpi that recovered in WT mice at 6 mpi (*p < 0.05, ***p < 0.01, Fig. 2A and B).”

May combine two claims.

Significantly higher levels of IBA1 were observed in the DG and CA1 of WT VEEV TC-83 inoculated mice compared to WT saline, with an increasing trend in CA3.

“Specifically, we observed significantly higher levels of IBA1 in DG and CA1 of WT VEEV TC-83 inoculated mice compared to WT saline (*p < 0.05, Fig. 5A1-A2, B1–B2, D, E) and an increasing trend in the WT mice inoculated with VEEV TC-83 compared to WT counterparts in the CA3 (Fig. 5C1-C2, F).”

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

No differences in temperature were detected between the groups, including between WT and Tg2576 VEEV TC-83 inoculated mice.

“No differences in temperature were detected between the groups (Fig. 1C).”

• Also stated in: § VEEV TC-83 inoculation differentially impacts disease severity in WT and Tg2576 mice · plain

  “No significant changes in temperature were quantified between WT VEEV TC-83 inoculated, and Tg2576 VEEV TC-83 inoculated mice (Fig. 1D).”

May combine two claims.

Inflammation was present in every VEEV TC-83 inoculated brain but none in saline inoculated ones.

“Results of the evaluation (summarized in Supplemental Table 2) show inflammation in every VEEV TC-83 inoculated brain but none in saline inoculated ones.”

May combine two claims.

No Aβ plaques were found, most likely due to the young age of mice; Aβ immunoreactivity was mostly localized intracellularly in the soma of pyramidal neurons in the CA1/CA3 regions, as well as in the hilus and granule cell layer of the DG.

“Intriguingly, we did not find any Aβ plaques, most likely due to the young age of mice, but rather Aβ immunoreactivity was mostly localized intracellularly in the soma of pyramidal neurons in the CA1/CA3 regions, as well as in the hilus and granule cell layer of the DG.”

May combine two claims.

Following VEEV TC-83 inoculation, WT and Tg2576 mice developed Aβ deposition, glial cell activation, neuroinflammation, and neuropathological characteristics coinciding with AD neuropathology compared to saline controls.

“Compared to their saline controls, we measured the development of Aβ deposition, glial cell activation, neuroinflammation, and neuropathological characteristics coinciding with AD neuropathology following inoculation with VEEV TC-83 in WT and Tg2576 mice.”

May combine two claims.

There were no statistical differences in Aβ levels between WT saline and Tg2576 saline within DG or CA3 regions, but there was a significant increase in Aβ within the CA1 region and overall hippocampus.

“The images and the quantitative analyses revealed no statistical differences among the WT saline (n = 5) or Tg2576 saline (n = 5) within DG (Fig. 7A1-A2 & D) or CA3 (Fig. 7C1-C2 & F) regions, but there was a significant increase in Aβ within the CA1 region (**p < 0.01, Fig. 7B1-B2 & E) and overall hippocampus (**p < 0.01, Fig. 7G).”

May combine two claims.

There were no differences between days of testing in latency to escape shock; VEEV TC-83 inoculation significantly impacted latency to escape shock; and there was a significant interaction between VEEV TC-83 inoculation and days tested.

“In parallel, we found no differences between days of testing (ns, F[1.898, 53.15] = 2.105) in latency to escape shock; however, VEEV TC-83 inoculation significantly impacted the latency to escape shock (***p < 0.001, F[3,29] = 26.74) and a significant interaction was found between VEEV TC-83 inoculation and the days tested (*p < 0.05, F[6, 56] = 2.538) (Fig. 3D).”

May combine two claims.

The results exhibited a trend in the reduction of Aβ1-42/1-40 ratios in WT VEEV TC-83 vs WT saline; Tg2576 saline vs WT saline; and in Tg2576 VEEV TC-83 vs Tg2576 saline.

“The results exhibited a trend in the reduction of Aβ1-42/1–40 ratios in WT VEEV TC-83 vs WT saline; Tg2576 saline vs. WT saline; and in Tg2576 VEEV TC-83 vs Tg2576 saline (Fig. 7J).”

May combine two claims.

There was a significant effect of days of testing and VEEV TC-83 inoculation on latency to avoid shock, but no significant interaction between days of testing and VEEV TC-83 inoculation.

“Using a mixed effects analysis, we found a significant effect between the days of testing (*p < 0.05, F[1.856, 57.55] = 4.627), and VEEV TC-83 inoculation (***p < 0.001, F[3, 62] = 39.76) on latency to avoid shock, but no significant interaction between days of testing and VEEV TC-83 inoculation (ns, F[6, 62] = 0.9341; Fig. 3C).”

May combine two claims.

More than half of Tg2576 mice inoculated with VEEV TC-83 developed neurological abnormalities that, unlike their WT counterparts, continued to stay elevated at 6 mpi.

“In parallel, we observed more than half of Tg2576 mice inoculated with VEEV TC-83 developed neurological abnormalities, that unlike their WT counterparts, continued to stay elevated at 6 mpi.”

May combine two claims.

Tg2576 mice inoculated with TC-83 show more severe cognitive deficits and brain pathology than their mock controls.

“We found more severe cognitive deficits and brain pathology in Tg2576 mice inoculated with TC-83 than in their mock controls.”

May combine two claims.

The levels of Aβ did not significantly increase following inoculation with VEEV TC-83 in either WT or Tg2576 mice in any specific brain region, though VEEV TC-83 inoculated mice showed an increasing trend of Aβ in all areas considered and in the overall hippocampus.

“The levels of Aβ did not significantly increase following inoculation with VEEV TC-83, in either WT or Tg2576 mice in any specific brain region (Fig. 7) even though VEEV TC-83 inoculated mice showed an increasing trend of Aβ in all the areas considered (DG, CA1, CA3) (Fig. 7A–F) and in the overall hippocampus (Fig. 7G).”

May combine two claims.

At 6 months post-inoculation, Tg2576 inoculated mice continued to have 50% or greater abnormal responses in seven categories but recovered in respiratory rate and gait.

“At 6 mpi, Tg2576 inoculated mice continued to have 50% or greater abnormal responses in seven categories but recovered in respiratory rate and gait (Table 3).”

May combine two claims.

VEEV TC-83 inoculated Tg2576 mice display an increased neuroinflammatory phenotype compared to their inoculated controls, including increased perivascular cuffing and GFAP and Iba1 staining.

“Although saline inoculated Tg2576 mice developed neuroinflammatory characteristics, VEEV TC-83 inoculated Tg2576 mice displayed an increased neuroinflammatory phenotype compared to their inoculated controls, including increased perivascular cuffing and GFAP and Iba1 staining.”

May combine two claims.

In VEEV TC-83 inoculated Tg2576 mice compared to VEEV TC-83 inoculated WT mice, activated microglia but not astrocytes are significantly increased.

“found activated microglia, but not astrocytes, to be significantly increased in VEEV TC-83 inoculated Tg2576 mice compared to VEEV TC-83 inoculated WT mice.”

May combine two claims.

VEEV infection causes gliosis and neuroinflammation, indicating indirect mechanisms of neuronal degeneration, like neurotoxic mechanisms related to Alzheimer's disease.

“VEEV infection causes gliosis and neuroinflammation, indicating indirect mechanisms of neuronal degeneration, like neurotoxic mechanisms related to AD (Schoneboom et al., 2000).”

• cites Schoneboom et al., 2000 sourceNot checked — no full text of the source

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

The observations of weight loss and recovery in Tg2576 mice coincide with post-alphavirus infection in humans, where symptoms begin to fade and the illness resolves.

“These preliminary observations coincide with post-alphavirus infection in humans, where symptoms begin to fade, and the illness resolves (Baxter and Heise, 2020).”

• cites Baxter and Heise, 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

TC-83, an attenuated VEEV strain, induces neurological sequelae in a mouse model for VEEV neurological sequelae and allows researchers to work at lower biocontainment level to study virus-induced behavioral changes and CNS inflammation.

“TC-83, an attenuated VEEV strain, induces neurological sequelae in a mouse model for VEEV neurological sequelae and allows researchers to work at lower biocontainment level to study virus-induced behavioral changes as well as CNS inflammation (K. Taylor, Kolokoltsova, Ronca, Estes and Paessler, 2017b).”

• cites K. Taylor, Kolokoltsova, Ronca, Estes and Paessler, 2017bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

VEEV TC-83 can replicate and produce detectable titers in the brains of multiple mouse strains causing non-lethal disease at low doses.

“Although VEEV TC-83, an attenuated strain of VEEV derived from the highly pathogenic Trinidad Donkey (TrD) strain, this virus can replicate and produce detectable titers in the brains of multiple mouse strains causing not lethal disease at low doses (Ludwig et al., 2001).”

• cites Ludwig et al., 2001 sourceNot checked — no full text of the source

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

The sample size for sex was not enough to stratify data based on sex, so sex was collapsed for all analyses.

“The sample size for sex were not enough to stratify data based on sex, thus sex was collapsed for all analysis.”

May combine two claims.

This represents a robust hallmark of Alzheimer's disease, establishing a significant association between Tg2576 mice and VEEV TC-83 infection.

“This represents a robust hallmark of Alzheimer's disease, establishing a significant association between Tg2576 mice and VEEV TC-83 infection.”

May combine two claims.

VEEV TC-83 exposure in WT mice triggers the development of neuropathological outcomes related to AD, and in a model genetically susceptible to developing AD, exposure to an encephalitic alphavirus exacerbates AD phenotypes.

“Taken together, not only did we find that VEEV TC-83 exposure in WT mice trigger the development of neuropathological outcomes related to AD, but that in a model genetically susceptible to developing AD, exposure to an encephalitic alphavirus exacerbates AD phenotypes.”

• AssumptionRests on an assumption: Tg2576 mice are a valid preclinical model of Alzheimer's disease.

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

GAPDH was used as an internal control for real-time PCR.

“The housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Mm99999915_g1), was used as an internal control.”

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

Previous studies found that the VEEV TC-83 strain of VEEV induces robust inflammation during the early stages of disease progression in the brain of hamsters.

“Previous studies found that the VEEV TC-83 strain of VEEV induces robust inflammation during the early stages of disease progression in the brain of hamsters (Jahrling et al., 1976).”

• cites Jahrling et al., 1976 sourceNot checked — no full text of the source

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

The study's animal procedures complied with the U.S. Department of Agriculture Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, and IACUC-approved protocols.

“UTMB complies with the U.S. Department of Agriculture Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, and Institutional Animal Care and Use Committee (IACUC)-approved protocols.”

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

A modified SHIRPA screen was used to analyze the general health of each animal pre- and post-infection, as previously described.

“A modified SHIRPA screen was used to analyze the general health of each animal pre- and post-infection (Rogers et al., 1997).”

• Also stated in: § General health assessment · plain

  “The assays were slightly modified but mostly performed as previously described (Lalonde et al., 2021; Rogers et al., 2001; Zhang et al., 2016).”

• cites Rogers et al., 1997 sourceNot checked — no full text of the source
• cites Lalonde et al., 2021 sourceNot checked — no full text of the source
• cites Rogers et al., 2001 sourceNot checked — no full text of the source

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

Normal distribution was tested using the Shapiro-Wilk test.

“Normal distribution was tested using the Shapiro-Wilk test.”

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

Encephalitic viral infections, such as alphaviral infection, may exacerbate the onset and neuropathology of Alzheimer's disease.

“Given that encephalitic viral infections can have profoundly detrimental neurological consequences long after acute infection has resolved, it is logical that encephalitic viral infections, such as alphaviral infection, may exacerbate the onset and neuropathology of AD.”

• AssumptionRests on an assumption: Increased and chronic production of pro-inflammatory cytokines in the CNS results in neurological sequelae and possible development of permanent neuronal damage and death.
• AssumptionRests on an assumption: In sporadic Alzheimer's disease, genetic and environmental risk factors contribute to impaired amyloid beta clearance and abnormal amyloid beta accumulation in the brain, triggering the pathophysiology of early Alzheimer's disease, including synaptic dysfunction, synaptic loss, and progressive memory deficits.
• AssumptionRests on an assumption: Whether encephalitic viral infections provide a causative link in initiating the development of Alzheimer's disease remains unknown.

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

Alterations in cytokine expression can increase the permeability of the blood-brain barrier and activate several signaling pathways in different brain cells.

“These alterations in cytokine expression can increase the permeability of the BBB and play a crucial role in activating several signaling pathways located in different brain cells (Carrano et al., 2012).”

• cites Carrano et al., 2012 sourceNot checked — no full text of the source

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

There is an inverse relationship between plasma Aβ1-42/1-40 and cortical Aβ burden in Alzheimer's disease patients.

“These findings align with the inverse relationship between plasma Aβ1-42/1–40 and cortical Aβ burden observed in AD patients (Rembach et al., 2014).”

• cites Rembach et al., 2014 sourceNot checked — no full text of the source

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

Glia, microglia, and astrocyte activations are associated with cerebral amyloid deposits necessary for phagocytic activity induction.

“Glia, microglia, and astrocyte activations are associated with cerebral amyloid deposits necessary for phagocytic activity induction (D'Andrea et al., 2004).”

• cites D'Andrea et al., 2004 sourceNot checked — no full text of the source

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

Disrupting neurogenesis and neural progenitor cell homeostasis in the hippocampus causes learning and memory impairments, developing into an early onset Alzheimer's disease.

“A recent study in transgenic animal models of AD has shown that disrupting neurogenesis and neural progenitor cell homeostasis in the hippocampus causes learning and memory impairments, developing into an early onset AD (Haughey et al., 2002).”

• cites Haughey et al., 2002 sourceNot checked — no full text of the source

May combine two claims.

Delayed response latencies reflect caution and indicate significant loss of spatial ability and memory dysfunction.

“reflecting caution and indicating significant loss of spatial ability and memory dysfunction.”