CoChat
Sign Up
Cited by 128Traumatic Brain Injury and Neurovascular DisturbancesNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury Research

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

Open access
Kokiko-Cochran, Olga N., Godbout, Jonathan P.·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.00672PMC PMC5900037
Open this paper in CoChat — free accountOpen PDF

Abstract

The post-injury inflammatory response is a key mediator in long-term recovery from traumatic brain injury (TBI). Moreover, the immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges. For example, recent evidence shows that the presence of beta-amyloid and phosphorylated tau protein, two hallmark features of AD that increase during normal aging, substantially alter the macrophage response to TBI. Additional data demonstrate that post-injury microglia are "primed" and become hyper-reactive following a subsequent acute immune challenge thereby worsening recovery. These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology. Therefore, the purpose of this review is to summarize experimental studies examining the relationship between TBI and development of AD-like pathology with an emphasis on the acute and chronic microglial and macrophage response following injury. Furthermore, studies will be highlighted that examine the degree to which beta-amyloid and tau accumulation as well as pre- and post-injury immune stressors influence outcome after TBI. Collectively, the studies described in this review suggest that the brain's immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery will be altered.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that post-traumatic brain injury (TBI) neuroinflammation, mediated by microglia and macrophages, is a malleable continuum shaped by pre-existing Alzheimer’s disease (AD)-like pathology and by pre- or post-injury immune challenges. It synthesizes experimental and clinical evidence that beta-amyloid and tau accumulation alter the macrophage response to TBI, and that transient microglial/macrophage modulation may influence recovery and AD-like pathology.

Key findings

  • TBI induces a conserved microglial/macrophage response; chronic microglial and astrocytic reactivity persists in subcortical regions months to years post-injury, with human evidence of increased OX-6/CD68 mRNA at 1 year and PK-[11C](R)PK11195 binding between 11 months and 17 years post-injury.
  • Pre-injury peripheral immune challenge can be protective: a single i.p. LPS dose (0.1 mg/kg) 5 days before controlled cortical impact reduced CD68, increased IL-6, decreased contusion volume, and improved behavioral recovery; LPS (1.0 mg/kg for 4 days) reduced neuronal death and lesion volume after lateral cryogenic brain injury.
  • Post-injury immune challenge worsens recovery: LPS at 30 days post-injury after midline fluid percussion injury exaggerated MHC-II, IL-1β, and TNFα expression and depressive-like behavior; LPS 5 days post-injury after impact acceleration was associated with depressive-like behavior and cognitive impairments 3 months post-injury.
  • Aβ and tau modify the macrophage response: TBI in APP/PS1 mice delayed peak cytokine elevations by 7 days; R1.40 AD-model mice showed a muted acute macrophage response and significant tissue loss between 3 and 120 days post-injury; hTau TBI mice showed enhanced acute macrophage response and, at 120 days post-injury, increased tau pathology and persistent macrophage response correlating with memory-task deficits. CSF1R inhibition after a chronic hippocampal lesion improved behavioral recovery and increased dendritic spines.

Methods

  • Narrative review summarizing experimental and clinical studies on TBI, neuroinflammation, and AD-like pathology, with emphasis on acute and chronic microglial and macrophage responses.
  • Discusses animal TBI models including controlled cortical impact, fluid percussion injury, weight drop, penetrating ballistic-brain injury, closed head injury, cryogenic injury, and a chronic hippocampal lesion model, as well as transgenic AD/tau models.
  • Draws on human epidemiological, neuropathological, imaging, and cerebrospinal fluid studies; no systematic review, meta-analysis, or primary data collection is reported.

Limitations

  • The paper states that global TBI reporting and categorization are not standardized; experimental models each reflect a specific TBI type and do not fully recapitulate human TBI; more than 30 phase-III clinical trials have failed to improve secondary injury outcomes; some experimental studies fail to show TBI induces or worsens AD-related pathology; transgenic AD models express mutant APP/tau at nonphysiological levels and clinical co-occurrence of TBI and APP mutation is rare; no universal repetitive TBI model exists; inter-injury macrophage changes are not defined; and the distinct roles of microglia versus monocytes remain unclear.
  • The paper also states that the role of soluble Aβ oligomers and tau oligomers in post-injury pathology is understudied, and that cell-specific inflammatory profiles are not routinely performed in transgenic mice before TBI.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy, formal quality appraisal, or quantitative synthesis, and its conclusions rely on heterogeneous animal models, injury severities, and outcome measures.

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

Integrity signals

Registry

Crossref · 10.3389/fimmu.2018.00672

Cites

248 of 248 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

90 of 184 cited sources checked · 39 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Several lines of evidence point to a relationship between single-incident TBI and AD.

    “Several lines of evidence point to a relationship between single-incident TBI and AD (10, 11).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Johnson, 2010, Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease?, Nat Rev Neurosci source
    • cites [11] Johnson, 2013, Inflammation and white matter degeneration persist for years after a single traumatic brain injury, Brain source
  • Premisecitation

    Accumulation of APP and extracellular deposition of the 40- to 42-amino acid Aβ peptide in senile plaques has been identified in human brain tissue soon after severe TBI.

    “Third, accumulation of APP and extracellular deposition of the 40- to 42-amino acid Aβ peptide in senile plaques has been identified in human brain tissue soon after severe TBI (29, 30).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [29] Roberts, 1994, Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease, J Neurol Neurosurg Psychiatry source

      The Abstract reports Aβ deposits after severe head injury and increased APP immunoreactivity near those deposits. The βAPP immunoreactivity section distinguishes the early diffuse deposits from classical or senile plaques, which it says were restricted to the oldest cases. Our copy does not establish that the deposited peptide was specifically 40–42 amino acids long. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [30] DeKosky, 2007, Association of increased cortical soluble Aβ42 levels with diffuse plaques after severe brain injury in humans, Arch Neurol source
  • Premisecitation

    Many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI.

    “Second, many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI (16, 21–28).”
    Quote in the paperSubstantial claim7 of 9 sources checked
    • cites [16] Webster, 2015, Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment, J Neurosci source

      The Results section reports increased Aβ deposition after closed head injury in APP/PS1 mice and states that TBI can increase APP levels in mice. The Introduction reports changes in amyloid or tau pathology across animal studies, but the paper does not establish increased production of APP, Aβ, and tau or specifically show accumulation of pathological tau. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [21] Tran, 2011, Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-β accumulation and independently accelerates the development of tau abnormalities, J Neurosci source

      The Results (page unavailable) show increased APP- and Aβ-stained axonal accumulations after TBI in 3xTg-AD mice, along with increased tau phosphorylation. This study therefore supports the sentence as one animal-study example, but it does not establish increased production of APP, Aβ, or tau after TBI. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [22] Shishido, 2016, Traumatic brain injury accelerates amyloid-β deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer’s disease, Neurosci Lett source
    • cites [23] Washington, 2014, Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer’s disease mouse model, J Neurotrauma source

      The Results (page not available in our copy) report increased APP processing and Aβ production after TBI in mice, and the Discussion reports increased soluble and insoluble Aβ. The paper does not report increased production or accumulation of APP itself, or a finding about pathological tau; the tau mention found is in a reference title. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] Tajiri, 2013, Traumatic brain injury precipitates cognitive impairment and extracellular Aβ aggregation in Alzheimer’s disease transgenic mice, PLoS One source

      The Results report increased extracellular Aβ deposits after TBI in mice, and the Discussion reports another mouse study finding Aβ accumulation and increased phospho-tau immunoreactivity. The paper does not report increased production or accumulation of APP; its Discussion only proposes increased cleavage of APP to Aβ. It also does not establish the claim across “many” animal studies. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [25] Tran, 2011, Distinct temporal and anatomical distributions of amyloid-β and tau abnormalities following controlled cortical impact in transgenic mice, PLoS One source

      The Discussion reports post-injury APP accumulation in injured axons and this study’s Aβ accumulation and tau abnormalities in transgenic mice (pages not provided). It does not establish increased APP production after TBI, and its findings are limited to particular transgenic models rather than animal studies generally. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [26] Itoh, 2009, Expression of amyloid precursor protein after rat traumatic brain injury, Neurol Res source
    • cites [27] Hartman, 2002, Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer’s disease, J Neurosci source

      The Discussion reports that TBI accelerated Aβ deposition in the study’s PDAPP mice expressing APOE4 and describes Aβ findings from other animal studies. It does not report increased production or accumulation of APP or pathological tau after TBI; nor does it establish increased Aβ production. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [28] Smith, 1998, Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein, Am J Pathol source

      The Aβ Tissue Levels section reports an acute rise in Aβ after injury in PDAPP mice, and the introductory passage reports APP accumulation after trauma in experimental animals. The paper does not report pathological tau in injured animals; it mentions neurofibrillary tangles in human boxers. The Histopathological Analysis section also finds no increase in Aβ plaque deposition after injury, so the claim's accumulation language does not hold for plaques in this study. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Numerous population-based studies demonstrate that head injury during adulthood increases the risk of AD later in life.

    “First, numerous population-based studies demonstrate that head injury during adulthood increases the risk of AD later in life (12–19)”
    Quote in the paperSubstantial claim5 of 8 sources checked
    • cites [12] Guo, 2000, Head injury and the risk of AD in the MIRAGE study, Neurology source
    • cites [13] Schofield, 1997, Alzheimer’s disease after remote head injury: an incidence study, J Neurol Neurosurg Psychiatry source

      The Results (page not supplied) report an increased risk of incident Alzheimer’s disease for participants who reported head injury with loss of consciousness to a physician. But the Discussion (page not supplied) describes the association cautiously, and notes that two earlier cohort studies failed to find it. This paper therefore supports an association in its cohort, not the stronger claim that numerous population-based studies demonstrate an increased risk specifically from injury during adulthood. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] Plassman, 2000, Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias, Neurology source
    • cites [15] LoBue, 2017, Traumatic brain injury history is associated with earlier age of onset of Alzheimer disease, Clin Neuropsychol source

      The introductory passage indexed under Abstract > Conclusions reports increased later AD risk following TBI in several case-control, meta-analytic, and chart-review studies. It also says not all studies support the association. The source therefore supports an association, but not the stronger claim that numerous population-based studies demonstrate increased risk after head injury during adulthood. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [16] Webster, 2015, Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment, J Neurosci source

      The Introduction (page not provided) says head injury is associated with increased risk of later-life dementia, including AD, and the Discussion cites epidemiological studies linking prior head injury to cognitive impairment and dementia. The paper does not specify injury during adulthood or establish that numerous population-based studies demonstrate a causal increase in AD risk. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [17] Gilbert, 2014, The association of traumatic brain injury with rate of progression of cognitive and functional impairment in a population-based cohort of Alzheimer’s disease: the cache county dementia progression study, Int Psychogeriatr source

      The Introduction reports that prior studies associate traumatic brain injury with higher AD risk, including a study of veterans and evidence about the age at injury. The References identify one cited study as population-based, but our copy does not establish that numerous studies reporting this association were population-based. This paper’s own population-based cohort examines progression after AD onset, not the risk of developing AD. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
    • cites [18] Li, 2016, Traumatic brain injury and age at onset of cognitive impairment in older adults, J Neurol source

      The Discussion says previous studies found traumatic brain injury to be a risk factor for AD or non-AD dementia, supporting the broad association. The Introduction and References include population-based studies of dementia risk, but our copy does not establish that numerous population-based studies specifically demonstrated increased later-life AD risk following injury during adulthood. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [19] Yang, 2015, Accumulation of amyloid in cognitive impairment after mild traumatic brain injury, J Neurol Sci source
  • Premisecitation

    Given the distinct genetic and transcriptomic profile of microglia and macrophages identified via high throughput sequencing technology, the two cell types likely maintain different roles in the injured CNS.

    “Given the distinct genetic and transcriptomic profile of microglia and macrophages identified via high throughput sequencing technology (69–71), the two cell types likely maintain different roles in the injured central nervous system (CNS) (72–74).”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [69] Gosselin, 2014, Environment drives selection and function of enhancers controlling tissue-specific macrophage identities, Cell source
    • cites [70] Butovsky, 2014, Identification of a unique TGF-β-dependent molecular and functional signature in microglia, Nat Neurosci source

      The indexed passages are labeled as corrections to other articles, including “Corrigendum: Immune surveillance in the central nervous system” (Abstract; page unavailable). Searches for microglia, their transcriptomic differences from macrophages, and roles in the injured CNS found no passage addressing the claim. The available copy therefore cannot verify it. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [71] Lavin, 2014, Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment, Cell source
    • cites [72] Yamasaki, 2014, Differential roles of microglia and monocytes in the inflamed central nervous system, J Exp Med source
    • cites [73] Greenhalgh, 2014, Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death, J Neurosci source
    • cites [74] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat Neurosci source
  • May combine two claims. 65
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Premisecitation

    CCI TBI induced a surge of plaque pathology in PDAPP mice soon after injury at 6 months of age, but a substantial reduction in cortical and hippocampal plaque load was detected chronically.

    “Although CCI TBI induced a surge of plaque pathology in PDAPP mice soon after injury at 6 months of age, a substantial reduction in cortical and hippocampal plaque load was detected chronically (28, 40).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [28] Smith, 1998, Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein, Am J Pathol source

      The Brain Injury section says the PDAPP mice were injured at 4 months of age, not 6 months. The Histopathological Analysis section reports no discernible difference in plaque number or distribution between injured and sham mice two months later, contradicting both the claimed surge in plaques and the claimed chronic reduction. The reported acute surge was in Aβ peptide levels, not plaque pathology (Aβ Tissue Levels section); page numbers are unavailable in our copy. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [40] Nakagawa, 1999, Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Abeta deposition during aging, J Comp Neurol source

  • May combine two claims.

    Premisecitation

    CCX872 and RS504393, two selective CCR2 antagonists, reduce post-injury macrophage recruitment and improve functional recovery after CCI and weight drop TBI.

    “Separate groups have shown that CCX872 and RS504393, two selective CCR2 antagonists, reduce post-injury macrophage recruitment and improve functional recovery after CCI and weight drop TBI (76, 77).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [76] Morganti, 2015, CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury, J Neurosci source
    • cites [77] Liu, 2013, Chemokine CCL2 induces apoptosis in cortex following traumatic brain injury, J Mol Neurosci source

  • May combine two claims.

    Premisecitation

    Clinical studies indicate that Aβ accumulates within hours after severe TBI and is spread throughout the cerebral cortex compared to age-matched controls.

    “Clinical studies indicate that Aβ accumulates within hours after severe TBI and is spread throughout the cerebral cortex compared to age-matched controls (29, 31).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [29] Roberts, 1994, Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease, J Neurol Neurosurg Psychiatry source

      The βAP immunoreactivity results report deposits in 30% of severe-head-injury cases, including some who survived less than 24 hours, and higher positivity than in age-matched controls. They do not show that deposits were spread throughout the cerebral cortex: a positive case could have deposits in just one cortical area, and the pattern varied between cases. The copy does not establish that the patients who survived only four hours had deposits. Page numbers were not supplied for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [31] Ikonomovic, 2004, Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury, Exp Neurol source

  • May combine two claims.

    Premisecitation

    A primed microglia profile includes increased basal expression of inflammatory markers and mediators, decreased activation threshold to express and release pro-inflammatory molecules, and exaggerated inflammatory response to immune challenge.

    “A primed microglia profile includes (1) increased basal expression of inflammatory markers and mediators, (2) decreased activation threshold to express and release pro-inflammatory molecules, and (3) exaggerated inflammatory response to immune challenge (93).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [93] Norden, 2015, Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease, Neuropharmacology source

  • May combine two claims.

    Premisecitation

    Accumulating evidence shows that microglia and monocytes play distinct roles in AD pathogenesis, thus implicating both the central and peripheral immune response in long-term outcome.

    “Finally, accumulating evidence shows that microglia and monocytes play distinct roles in AD pathogenesis (116–119), thus implicating both the central and peripheral immune response in long-term outcome.”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [116] Bhaskar, 2010, Regulation of tau pathology by the microglial fractalkine receptor, Neuron source

      The Introduction and Discussion (pages unavailable) link microglial signaling to AD-related pathology. The Results also show that peripheral LPS administration increases tau phosphorylation in mice. Our copy does not establish distinct roles for microglia and monocytes in AD, or show how both affect long-term outcome. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [117] Lee, 2010, CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models, Am J Pathol source

      The Discussion reports enhanced amyloid-beta phagocytosis by microglia in the AD mouse models. The Microglial Proliferation/Migration section mentions migration of peripheral monocytes or macrophages only as a possibility; it does not establish a distinct role for them alongside microglia. The paper therefore supports a microglial role in amyloid pathology, but not the attributed distinction between the two cell populations. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [118] Lee, 2014, Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway, J Neurosci source

      The Introduction (page unavailable) says accumulating evidence implicates microglia-mediated neuroinflammation in AD pathogenesis, and the Discussion reports effects of altered microglial activity in APPPS1 mice. The paper does not establish distinct roles for microglia and monocytes or connect peripheral immune responses to long-term outcome; its mention of monocyte chemotactic protein 1 is not a comparison of the two cell types. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [119] Martin, 2017, Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer’s disease models: effects of aging and amyloid pathology, Aging Cell source

  • May combine two claims.

    Premisecitation

    After a single CCI TBI, Cx3cr1−/− mice have improved motor recovery and decreased neuronal loss through 15 days post-injury.

    “After a single CCI TBI, Cx3cr1−/− mice have improved motor recovery and decreased neuronal loss through 15 days post-injury (DPI).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [80] Febinger, 2015, Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury, J Neuroinflammation source

      The Results sections on neuromotor function and neuronal survival report better motor scores in injured CX3CR1−/− mice than injured wild-type mice at 24 hours, and less neuronal loss at day 15. The motor-score difference between injured groups was not significant at days 7 or 15, so improved motor recovery relative to wild-type mice throughout that period is not established. Page numbers are not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Many biological pathways are disrupted by experimental TBI resulting in progressive neurodegeneration including atrophy, neuronal loss, and axonal degeneration which are often associated with neuroinflammation including macrophage reactivity.

    “Many biological pathways are disrupted by experimental TBI resulting in progressive neurodegeneration including atrophy, neuronal loss, and axonal degeneration which are often associated with neuroinflammation including macrophage reactivity (82–85).”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [82] Carbonell, 1998, Adaptation of the fluid percussion injury model to the mouse, J Neurotrauma source
    • cites [83] Carbonell, 1999, Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse, Acta Neuropathol source
    • cites [84] Smith, 1997, Progressive atrophy and neuron death for one year following brain trauma in the rat, J Neurotrauma source
    • cites [85] Pierce, 1998, Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats, Neuroscience source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Each animal model reflects a specific type of TBI and does not fully recapitulate primary and secondary damage evident in human TBI, resulting in restricted translation.

    “This strategy presents additional challenges as each animal model reflects a specific type of TBI and does not fully recapitulate primary and secondary damage evident in human TBI (45) resulting in restricted translation (46).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [45] Saatman, 2008, Classification of traumatic brain injury for targeted therapies, J Neurotrauma source
    • cites [46] Margulies, 2009, Combination therapies for traumatic brain injury: prospective considerations, J Neurotrauma source

  • May combine two claims.

    Premisecitation

    Myeloid cells are instrumental in maintaining CNS homeostasis; however, aging significantly alters their properties.

    “For example, myeloid cells are instrumental in maintaining CNS homeostasis; however, aging significantly alters their properties (88).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [88] Harry, 2013, Microglia during development and aging, Pharmacol Ther source

  • May combine two claims.

    Premisecitation

    Individuals with genetic predisposition to developing AD (ApoE4 risk alleles) display altered outcome after TBI, making the distinction between environmental and genetic risk factors for post-injury recovery unclear.

    “Also, several clinical studies report that individuals with genetic predisposition to developing AD (ApoE4 risk alleles) display altered outcome after TBI making the distinction between environmental and genetic risk factors for post-injury recovery unclear (33, 34).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [33] Li, 2015, The association between apolipoprotein E and functional outcome after traumatic brain injury, Medicine (Baltimore) source
    • cites [34] Padgett, 2016, Exploring the effect of the apolipoprotein E (APOE) gene on executive function, working memory, and processing speed during the early recovery period following traumatic brain injury, J Clin Exp Neuropsychol source

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    The cause of microglial priming is unclear and likely results from multiple factors, including loss of inhibitory ligand-receptor communication with aging neurons, interactions with age-related misfolded proteins such as Aβ, age-related exposure to increasing transforming growth factor-β, age-related alterations in production of IL-4 and CCL11 in the choroid plexus, and unique microenvironmental 3

    “The cause of microglial priming is unclear and likely results from multiple factors, including but not limited to (1) a loss of inhibitory ligand–receptor communication with aging neurons (94), (2) interactions with age-related misfolded proteins such as Aβ which promote pro-inflammatory cytokine production (95), (3) age-related exposure to increasing transforming growth factor-β which could”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [94] Perry, 2014, Microglial priming in neurodegenerative disease, Nat Rev Neurol source
    • cites [95] Flanary, 2007, Evidence that aging and amyloid promote microglial cell senescence, Rejuvenation Res source
    • cites [96] Cohen, 2014, Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner, EMBO J source

      The Results section on the M1-to-M2 phenotype switch reports that prolonged TGFβ1 exposure impaired microglia’s ability to adopt an anti-inflammatory phenotype. The Discussion links this effect to chronic exposure in the adult CNS, but our copy does not show that TGFβ exposure increases with age or establish it as a cause of age-related microglial priming. Page numbers were not available in the indexed passages. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Interruption of CCR2 signaling through the use of Ccr2RFP/RFP mice reduces post-injury monocytic infiltration and axonal pathology but enhances cortical and hippocampal MAPT mislocalization and hyperphosphorylation soon after lateral fluid percussion TBI.

    “Interruption of CCR2 signaling through the use of Ccr2RFP/RFP mice reduces post-injury monocytic infiltration and axonal pathology but enhances cortical and hippocampal MAPT mislocalization and hyperphosphorylation soon after lateral fluid percussion TBI suggesting that monocyte sub-populations may differentially influence outcome (78).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [78] Gyoneva, 2015, Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury, J Neuroinflammation source

  • May combine two claims.

    Premisecitation

    Secondary damage includes excitotoxicity, oxidative stress, and widespread neuroinflammation.

    “Secondary damage includes excitotoxicity (64), oxidative stress (65), and widespread neuroinflammation (63).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [64] Dorsett, 2017, Glutamate neurotransmission in rodent models of traumatic brain injury, J Neurotrauma source
    • cites [65] Hall, 2010, Antioxidant therapies for traumatic brain injury, Neurotherapeutics source
    • cites [63] Simon, 2017, The far-reaching scope of neuroinflammation after traumatic brain injury, Nat Rev Neurol source

  • May combine two claims.

    Premisecitation

    While both brain-injured AD and wild-type mice had increased expression of inflammatory cytokines IL-1β, IL-6, and TNFα, peak elevations were delayed by 7 days in the AD mice but persisted in conjunction with astrocyte activation.

    “While both brain-injured AD and wild-type mice had increased expression of inflammatory cytokines IL-1β, IL-6, and TNFα, peak elevations were delayed by 7 days in the AD mice but persisted in conjunction with astrocyte activation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Webster, 2015, Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment, J Neurosci source

      The cytokine-response Results section reports that IL-1β, IL-6, and TNFα gene expression peaked at 7 days after injury in APP/PS1 mice, later than in wild-type mice. But cytokine protein levels followed similar time courses in both groups, and the chronic-time-point Results report no injury-related increase in those cytokines at day 32. Persistent activation is supported for astrocytes, not for sustained elevation of all three cytokines. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Post-injury microglial depletion followed by microglial repopulation improves behavioral recovery, attenuates the lesion-induced neuroinflammatory response, and increases dendritic spin densities despite extensive neuronal loss in the hippocampus.

    “Recent studies using the same injury model confirmed that post-injury microglial depletion followed by microglial repopulation improves behavioral recovery, attenuates the lesion-induced neuroinflammatory response, and increases dendritic spin densities despite extensive neuronal loss in the hippocampus (240).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [240] Rice, 2017, Microglial repopulation resolves inflammation and promotes brain recovery after injury, Glia source

      The Results sections report behavioral recovery and reduced inflammatory markers after microglial repopulation despite extensive hippocampal neuronal loss. However, the dendritic-spine Results report no significant difference in spine density between lesioned mice with and without repopulation; the reported increase was relative to uninjured controls. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A recent highly repetitive mouse model of TBI including 30 injuries has been characterized.

    “A recent highly repetitive mouse model of TBI including 30 injuries has also been characterized (59).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [59] Winston, 2016, Dendritic spine loss and chronic white matter inflammation in a mouse model of highly repetitive head trauma, Am J Pathol source

  • May combine two claims.

    Premisecitation

    The co-occurrence of TBI and APP mutation in the clinical setting is rare, thereby restricting the results of many of these studies.

    “The co-occurrence of TBI and APP mutation in the clinical setting is rare (29) thereby restricting the results of many of these studies.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Roberts, 1994, Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease, J Neurol Neurosurg Psychiatry source

      In the discussion (page not available in our copy), the paper describes two pedigrees in which a person with an APP gene mutation had a history of significant head injury. It does not establish that this co-occurrence is rare in clinical settings or say that its rarity restricts the results of other studies. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Tau oligomers are neurotoxic and contribute to tau spreading throughout the brain.

    “supporting the notion that tau oligomers are neurotoxic and contribute to tau spreading throughout the brain (180).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [180] Gerson, 2016, Tau oligomers derived from traumatic brain injury cause cognitive impairment and accelerate onset of pathology in htau mice, J Neurotrauma source

  • May combine two claims.

    Premisecitation

    Treatment with MW151, a small-molecule inhibitor targeting pro-inflammatory cytokines in glia, attenuated the persistent increase in pro-inflammatory cytokine expression and improved cognitive recovery in APP/PS1 mice.

    “Treatment with MW151, a small-molecule inhibitor targeting pro-inflammatory cytokines in glia, attenuated the persistent increase in pro-inflammatory cytokine expression and improved cognitive recovery in APP/PS1 mice.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Webster, 2015, Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment, J Neurosci source

  • May combine two claims.

    Premisecitation

    CCI TBI increased soluble and insoluble cortical Aβ40 and Aβ42 within 24 h after injury in the 3xTg mouse model of AD, but both soluble and insoluble Aβ returned to sham levels by 7 DPI.

    “While CCI TBI increased soluble and insoluble cortical Aβ40 and Aβ42 within 24 h after injury, both soluble and insoluble Aβ returned to sham levels by 7 DPI (23).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Washington, 2014, Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer’s disease mouse model, J Neurotrauma source

  • May combine two claims.

    Premisecitation

    CSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines.

    “Similarly, CSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines (239).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [239] Rice, 2015, Elimination of microglia improves functional outcomes following extensive neuronal loss in the hippocampus, J Neurosci source

      The Abstract reports that CSF1R inhibition after a 25-day hippocampal lesion improved behavioral recovery and reduced elevated pro-inflammatory molecules. The Results (‘Microglia regulate dendritic spine densities in the intact brain’) report increased spine density with microglial elimination alone, but no further increase in overall spine numbers when elimination was combined with the lesion. The claim incorrectly presents the spine increase as an outcome of post-lesion treatment. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Single TBI induces acute tau phosphorylation but not aggregation.

    “Together, these studies demonstrate that single TBI induces acute tau phosphorylation but not aggregation.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [31] Ikonomovic, 2004, Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury, Exp Neurol source
    • cites [165] Uryu, 2002, Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis, J Neurosci source

      The Histology and Discussion passages address single mild TBI in terms of tissue pathology, amyloid deposition, and lipid peroxidation, but do not report tau phosphorylation or aggregation. Searches for tau phosphorylation and neurofibrillary tangles found only a general mention of tangles as an Alzheimer’s disease hallmark, not a finding after single TBI. Page numbers were unavailable in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [166] Smith, 2003, Tau immunohistochemistry in acute brain injury, Neuropathol Appl Neurobiol source

  • May combine two claims.

    Premisecitation

    Low and moderate doses of valganciclovir reduced CD11b cell populations with no effect on axonal injury, silver staining, or APP accumulation at sub-acute post-injury time points.

    “In these experiments, low and moderate doses of valganciclovir reduced CD11b cell populations with no effect on axonal injury, silver staining, or APP accumulation at sub-acute post-injury time points (241).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [241] Bennett, 2014, Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury, J Neurotrauma source

      In the subacute-effects section (21 days; page unavailable), low-dose valganciclovir reduced microglial cells, with no difference in silver staining. The paper reports unchanged APP staining and axonal injury for intermediate-dose treatment at 7 days, not 21 days. At 21 days, intermediate-dose treatment caused tissue loss, and silver staining was not quantified, so the claim extends the no-effect finding beyond the reported results. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In typical cases of AD, NFTs spread from the medial temporal lobes and hippocampus to the neocortex.

    “NFTs spread from the medial temporal lobes and hippocampus to the neocortex (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Braak, 1997, Frequency of stages of Alzheimer-related lesions in different age categories, Neurobiol Aging source

  • May combine two claims.

    Interpretationreasoning

    There is a biological link between TBI and AD pathology, but the exact molecular pathways underlying this relationship are poorly understood and post-injury mechanisms that facilitate Aβ and tau pathology remain under investigation.

    “These and other studies indicate that there is a biological link between TBI and AD pathology, but the exact molecular pathways underlying this relationship are poorly understood and post-injury mechanisms that facilitate Aβ and tau pathology remain under investigation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Alzheimer's disease is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time.

    “Alzheimer’s disease is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Alzheimer, 1907, Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschrift fur Psychiatr, Und Psych Medizin

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Post-injury neuroinflammation is a malleable response that is closely associated with development of AD-like pathology, thereby supporting a relationship between TBI, neuroinflammation, and development of AD.

    “This review will consider post-injury neuroinflammation as a malleable response that is closely associated with development of AD-like pathology, thereby supporting a relationship between TBI, neuroinflammation, and development of AD.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    TBI is recognized as an environmental risk factor for many neurodegenerative diseases such as AD, Parkinson's disease, and chronic traumatic encephalopathy.

    “Indeed, TBI is recognized as an environmental risk factor for many neurodegenerative diseases such as AD, Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In typical cases of AD, Aβ spreads from the frontal and temporal lobes to the hippocampus and limbic system.

    “In typical cases of AD, Aβ spreads from the frontal and temporal lobes to the hippocampus and limbic system.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Braak, 1997, Frequency of stages of Alzheimer-related lesions in different age categories, Neurobiol Aging source

  • May combine two claims.

    Interpretationreasoning

    The brain's immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery will be altered.

    “Collectively, the studies described in this review suggest that the brain’s immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery”
    • Also stated in: § Inflammation as a Mediator of Post-Injury Outcome · plain
      “We propose that the brain’s immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, progressive impairments will be evident.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    AD is characterized by intracellular aggregation of microtubule-associated protein tau (MAPT, tau) in neurofibrillary tangles (NFTs).

    “and intracellular aggregation of microtubule-associated protein tau (MAPT, tau) in neurofibrillary tangles (NFTs) (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Kidd, 1963, Paired helical filaments in electron microscopy of Alzheimer’s disease, Nature source

  • May combine two claims.

    Interpretationreasoning

    These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology.

    “These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges.

    “Moreover, the immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Inflammation is a malleable response to TBI that changes with aging, which suggests that it could be critical in mediating post-injury outcome.

    “Moreover, inflammation is a malleable response to TBI that changes with aging which suggests that it could be critical in mediating post-injury outcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    APP accumulates in traumatized axons after all severities of TBI and has been detected many months post-injury.

    “For example, APP accumulates in traumatized axons after all severities of TBI and has been detected many months post-injury (129–131).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [129] Blumbergs, 1995, Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury, J Neurotrauma source
    • cites [130] Blumbergs, 1994, Staining of amyloid precursor protein to study axonal damage in mild head injury, Lancet source
    • cites [131] Gentleman, 1995, Axonal injury: a universal consequence of fatal closed head injury?, Acta Neuropathol source

  • May combine two claims.

    Premisecitation

    Secondary damage develops hours and days after the primary damage, but is not necessarily dependent on the primary injury itself.

    “Secondary damage develops hours and days after the primary damage, but is not necessarily dependent on the primary injury itself.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Maas, 2008, Moderate and severe traumatic brain injury in adults, Lancet Neurol source

  • May combine two claims.

    Interpretationnone given

    TBI induces a widespread neuroinflammatory response that can promote recovery if controlled for a defined time period.

    “TBI induces a widespread neuroinflammatory response that can promote recovery if controlled for a defined time period.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    PDAPP transgenic mice display age-related cognitive impairment, synaptic dysfunction, Aβ accumulation, and tau phosphorylation.

    “These PDAPP transgenic mice display age-related cognitive impairment, synaptic dysfunction, Aβ accumulation, and tau phosphorylation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Age-related immune changes and those that occur during AD share many similarities and the distinction between the two processes remains unclear.

    “Consequently, age-related immune changes and those that occur during AD share many similarities and the distinction between the two processes remains unclear (89).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Heneka, 2010, Neuroinflammatory processes in Alzheimer’s disease, J Neural Transm source

  • May combine two claims.

    Premisecitation

    CX3CR1 deficiency results in early protection but chronic worsening of CCI TBI-induced deficits due in part to a decrease in anti-inflammatory cytokines on CD11b+ sorted cells at 28 DPI.

    “Subsequent work by a separate group confirms these results and demonstrates that CX3CR1 deficiency results in early protection but chronic worsening of CCI TBI-induced deficits due in part to a decrease in anti-inflammatory cytokines on CD11b+ sorted cells at 28 DPI (81).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Zanier, 2016, Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice, J Neurotrauma source

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

    Premisenone given

    Monomeric Aβ aggregates to form oligomers, protofibrils, and fibrils that accumulate in the characteristic Aβ plaque of AD.

    “Monomeric Aβ aggregates to form oligomers, protofibrils, and fibrils that accumulate in the characteristic Aβ plaque of AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Microglia and astrocyte reactivity increases within days post-injury, but altered and reactive morphology diminishes by 10-14 days post-injury.

    “Similarly, microglia and astrocyte reactivity increases within days post-injury, but altered and reactive morphology diminishes by 10–14 days post-injury.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    In normal physiological conditions, the BBB prevents entry of peripheral monocytes into the brain parenchyma.

    “In normal physiological conditions, the BBB prevents entry of peripheral monocytes into the brain parenchyma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    After TBI, microglia and monocyte-derived macrophages adopt a similar morphology, upregulate similar inflammatory surface markers, and increase production of similar inflammatory cytokines.

    “For example, after TBI, microglia and monocyte-derived macrophages adopt a similar morphology, upregulate similar inflammatory surface markers, and increase production of similar inflammatory cytokines.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Post-injury inflammation poses both beneficial and detrimental consequences that need to be balanced.

    “It is necessary to acknowledge that post-injury inflammation poses both beneficial and detrimental consequences that need to be balanced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Chronic post-injury neuroinflammation may be sufficient to induce or facilitate AD-related pathology.

    “Collectively, these results suggest that chronic post-injury neuroinflammation may be sufficient to induce or facilitate AD-related pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Accumulating data indicate that pre- and post-injury immune challenges may influence the microglial and macrophage response to brain injury and influence post-injury pathology and behavioral recovery.

    “Accumulating data indicate that pre- and post-injury immune challenges may influence the microglial and macrophage response to brain injury and influence post-injury pathology and behavioral recovery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several experimental studies have failed to show that TBI induces or worsens AD-related pathology, with some even reporting a reduction in post-injury Aβ accumulation in transgenic mice.

    “Finally, several experimental studies have failed to show that TBI induces or worsens AD-related pathology (38, 39) with some even reporting a reduction in post-injury Aβ accumulation in transgenic mice (40, 41).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [38] Kokiko-Cochran, 2016, Altered Neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer’s disease, J Neurotrauma source
    • cites [39] Collins, 2015, The effect of focal brain injury on beta-amyloid plaque deposition, inflammation and synapses in the APP/PS1 mouse model of Alzheimer’s disease, Exp Neurol source
    • cites [40] Nakagawa, 1999, Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Abeta deposition during aging, J Comp Neurol source
    • cites [41] Nakagawa, 2000, Brain trauma in aged transgenic mice induces regression of established abeta deposits, Exp Neurol source

  • May combine two claims.

    Premisecitation

    Microglia, monocytes, and astrocytes as well as inflammatory cytokines and chemokines are elevated in the AD brain.

    “First, microglia, monocytes, and astrocytes as well as inflammatory cytokines and chemokines are elevated in the AD brain (108).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Minter, 2016, The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease, J Neurochem source

  • May combine two claims.

    Premisecitation

    Post-injury neuroinflammation is characterized by activation of brain-resident microglia, infiltration of peripheral immune cells, astrogliosis, and increased synthesis and release of pro- and anti-inflammatory molecules which can persist for months to years after the initial insult.

    “Post-injury neuroinflammation is characterized by activation of brain-resident microglia, infiltration of peripheral immune cells, astrogliosis, and increased synthesis and release of pro- and anti-inflammatory molecules which can persist for months to years after the initial insult (106, 107).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [106] Başkaya, 1997, The biphasic opening of the blood-brain barrier in the cortex and hippocampus after traumatic brain injury in rats, Neurosci Lett source
    • cites [107] Morganti-Kossmann, 2007, Modulation of immune response by head injury, Injury source

  • May combine two claims.

    Premisecitation

    Inflammation following TBI is a complex and dynamic response of both the central and peripheral nervous systems, which is influenced by age, sex, injury location and severity, secondary injury cascades, and genetics.

    “Inflammation following TBI is a complex and dynamic response of both the central and peripheral nervous systems, which is influenced by age, sex, injury location and severity, secondary injury cascades, and genetics (63).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Simon, 2017, The far-reaching scope of neuroinflammation after traumatic brain injury, Nat Rev Neurol source

  • May combine two claims.

    Interpretationreasoning

    In both sets of experiments, the reduction in Aβ pathology was accompanied by increased neuronal death and memory impairment, ultimately bringing into question the neurotoxic properties of Aβ alone.

    “In both sets of experiments, the reduction in Aβ pathology was accompanied by increased neuronal death and memory impairment, ultimately bringing into question the neurotoxic properties of Aβ alone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Post-injury macrophage recruitment substantially decreases in Ccr2−/− mice following CCI TBI and correlates with improved behavioral outcome.

    “Similarly, post-injury macrophage recruitment substantially decreases in Ccr2−/− mice following CCI TBI and correlates with improved behavioral outcome (75).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Hsieh, 2014, CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury, J Neurotrauma source

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

    Premisenone given

    The neuroinflammatory response to injury occurs in a temporally distinct manner.

    “While no single model recapitulates all aspects of human TBI, the neuroinflammatory response to injury occurs in a temporally distinct manner.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Inflammatory cytokines and chemokines are immediately released after moderate TBI and peak within hours post-injury.

    “Inflammatory cytokines and chemokines are immediately release after moderate TBI and peak within hours post-injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Genetic deletion of CCL2 attenuates lesion volume, reduces macrophage recruitment and astrogliosis, and improves functional outcome compared to controls after CHI.

    “Genetic deletion of CC ligand-2 (CCL2), the cognate ligand for CCR2, attenuates lesion volume, reduces macrophage recruitment and astrogliosis, and improves functional outcome compared to controls after CHI (60).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Semple, 2010, Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice, J Cereb Blood Flow Metab source

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

    Premisenone given

    Disruption and dysfunction of the BBB after TBI facilitates monocyte infiltration.

    “Disruption and dysfunction of the BBB after TBI facilities monocyte infiltration though.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LPS treatment 1 day after repetitive mild TBI (3 TBI's, 5 days apart) increased macrophage reactivity but decreased production of inflammatory cytokines and reduced neuronal injury.

    “For example, LPS treatment 1 day after repetitive mild TBI (3 TBI’s, 5 days apart) increased macrophage reactivity but decreased production of inflammatory cytokines and reduced neuronal injury (235).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Corrigan, 2017, Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation, Brain Behav Immun source

  • May combine two claims.

    Interpretationreasoning

    The presence or absence of tau phosphorylation alone is not sufficient to define tau pathology and may represent a transient effect of TBI.

    “the presence or absence of tau phosphorylation alone is not sufficient to define tau pathology and may represent a transient effect of TBI.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The cumulative effect of aging and TBI in microglial priming remains unknown.

    “the cumulative effect of aging and TBI in microglial priming remains unknown”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both Aβ and tau phosphorylation are reported in normal aging and could, therefore, influence the brain's response to TBI without causing AD.

    “Both Aβ and tau phosphorylation are reported in normal aging and could, therefore, influence the brain’s response to TBI without causing AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Aβ and tau phosphorylation are reported in normal aging.

  • May combine two claims.

    Interpretationnone given

    The presence of low-molecular weight Aβ aggregates may substantially alter the neuroinflammatory environment and influence outcome following TBI.

    “Based on recent evidence, the presence of these low-molecular weight aggregates may substantially alter the neuroinflammatory environment and influence outcome following TBI.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The cumulative effect of aging and TBI in microglial priming may be critical in determining the relationship between TBI and development of age-related neurodegenerative disease such as AD.

    “may be critical in determining the relationship between TBI and development of age-related neurodegenerative disease such as AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    A common mechanism may mediate post-injury amyloid and tau pathology in a temporally distinct manner which may vary between transgenic and non-transgenic rodent models.

    “Alternatively, a common mechanism may mediate post-injury amyloid and tau pathology in a temporally distinct manner which may vary between transgenic and non-transgenic rodent models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These studies highlight the potential therapeutic relevance of targeting microglia and macrophages to modulate post-injury outcome and further indicate that neuroinflammation is a critical mediator of post-injury pathology.

    “Nonetheless, these studies highlight the potential therapeutic relevance of targeting microglia and macrophages to modulate post-injury outcome and further indicate that neuroinflammation is a critical mediator of post-injury pathology.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    TBI induces an acute increase in oligomeric Aβ, but the long-term consequences of this increase and the effect on specific cell types or brain region pathology remains unknown.

    “Although these studies indicate that TBI induces an acute increase in oligomeric Aβ, the long-term consequences of this increase and the effect on specific cell types or brain region pathology remains unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The role of amyloid is underexplored in experimental models of repetitive TBI, which is predominantly characterized by tau pathology.

    “the role of amyloid is underexplored in experimental models of repetitive TBI, which is predominantly characterized by tau pathology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Subtle alterations in the inflammatory response to TBI are possible and can influence outcome.

    “Certainly, there is a specific cascade of inflammatory events that occur after TBI, but these studies indicate that subtle alterations in this response are possible and can influence outcome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is a specific cascade of inflammatory events that occur after TBI.

  • May combine two claims.

    Premisecitation

    Delayed LPS treatment 5 days after repetitive TBI increased inflammatory cytokines, worsened neuronal damage including phosphorylation and aggregation of tau, and impaired behavioral recovery.

    “Delayed LPS treatment 5 days after repetitive TBI increased inflammatory cytokines, worsened neuronal damage including phosphorylation and aggregation of tau, and impaired behavioral recovery (235).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Corrigan, 2017, Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation, Brain Behav Immun source

  • May combine two claims.

    Interpretationcitation

    These results highlight the temporal immune response to TBI and indicate that delayed post-injury immune challenges are detrimental to outcome.

    “These results highlight the temporal immune response to TBI and indicate that delayed post-injury immune challenges are detrimental to outcome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Macrophage reactivity was only reported in 1 of these 4 studies, and indicated that repetitive TBI in aged hTau mice resulted in increased CD45 immunoreactivity in the cortex, corpus callosum, and hippocampus 3 weeks post-injury.

    “Macrophage reactivity was only reported in 1 of these 4 studies, and indicated that repetitive TBI in aged hTau mice resulted in increased CD45 immunoreactivity in the cortex, corpus callosum, and hippocampus 3 weeks post-injury (153).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Ojo, 2013, Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice, J Neuropathol Exp Neurol source

  • May combine two claims.

    Interpretationreasoning

    The first TBI is the priming event and subsequent brain injuries cause an exaggerated inflammatory response that promotes pathology.

    “the first TBI is the priming event and subsequent brain injuries cause an exaggerated inflammatory response that promotes pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Repetitive post-injury immune challenge increases macrophage-related neuroinflammation and correlates with the advanced neuropathology.

    “Repetitive post-injury immune challenge (dotted blue line), similar to what is observed in repetitive TBI, increases macrophage-related neuroinflammation and correlates with the advanced neuropathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Many APP-transgenic models express mutant APP at higher levels than endogenous APP and maintain genetic risk variants that cause familial AD which is fairly uncommon.

    “Indeed, many of these models express mutant APP at higher levels than endogenous APP and maintain genetic risk variants that cause familial AD which is fairly uncommon.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    This could be due, in part, to intrinsic differences between human and rodent APP and tau.

    “This could be due, in part, to intrinsic differences between human and rodent APP and tau.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Animal models of repetitive mild TBI are described in a recent review that includes references to development of post-injury Aβ and tau pathology.

    “Animal models of repetitive mild TBI are described in a recent review, which includes references to development of post-injury Aβ and tau pathology (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Edwards, 2017, Amyloid-beta and tau pathology following repetitive mild traumatic brain injury, Biochem Biophys Res Commun source

  • May combine two claims.

    Interpretationcitation

    The glial response to TBI is altered in the presence of Aβ and correlates with altered functional recovery.

    “demonstrate that the glial response to TBI is altered in the presence of Aβ and correlates with altered functional recovery (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Kokiko-Cochran, 2016, Altered Neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer’s disease, J Neurotrauma source

  • May combine two claims.

    Interpretationnone given

    Accumulation of Aβ and tau phosphorylation are routinely considered primary dependent variables in experimental studies, but these pathological features do not often correlate with neuronal loss or behavioral impairment.

    “Second, accumulation of Aβ and tau phosphorylation are routinely considered primary dependent variables in experimental studies, but these pathological features do not often correlate with neuronal loss or behavioral impairment.”
    Quote in the paperNot a substantial claim
78 of 78

  • The paper relies on this without support.

    The molecular mechanisms that link TBI to development of neurodegenerative disease remain underexplored and few studies account for age-specific pathological response to and recovery from brain injury.

    “The molecular mechanisms that link TBI to development of neurodegenerative disease remain underexplored and few studies account for age-specific pathological response to and recovery from brain injury.”

  • The paper relies on this without support.

    The roles of monocyte sub-populations in mediating outcome from TBI remain unknown without detailed follow-up studies.

    “Without detailed follow-up studies, the roles of monocyte sub-populations in mediating outcome from TBI remain unknown.”

  • The paper relies on this without support.

    The role of soluble Aβ oligomers in post-injury pathology has received limited attention.

    “Surprisingly, the role of soluble Aβ oligomers in post-injury pathology has received limited attention.”

  • The paper relies on this without support.

    No single experimental TBI model recapitulates all aspects of human TBI.

    “While no single model recapitulates all aspects of human TBI, the neuroinflammatory response to injury occurs in a temporally distinct manner.”

  • The paper relies on this without support.

    Findings from rodent models of TBI and AD are informative about human TBI-AD pathology.

    “the relevance of these abnormal proteins as mediators of response to and recovery from TBI remains applicable.”

  • The paper relies on this without support.

    The presence of Aβ and tau pathology in animal models is relevant to human AD.

    “the relevance of these abnormal proteins as mediators of response to and recovery from TBI remains applicable.”

  • The paper relies on this without support.

    Both TBI and AD are complex neurodegenerative pathologies that elicit a central and peripheral immune response.

    “Both TBI and AD are complex neurodegenerative pathologies that elicit a central and peripheral immune response.”

  • The paper relies on this without support.

    There is a specific cascade of inflammatory events that occur after TBI.

    “Certainly, there is a specific cascade of inflammatory events that occur after TBI, but these studies indicate that subtle alterations in this response are possible and can influence outcome.”

  • The paper relies on this without support.

    The severity of repetitive TBI is typically referred to as 'mild,' but the number of injuries varies from 2 to 10 across several days or weeks.

    “While severity of repetitive TBI is typically referred to as “mild,” the number of injuries varies from 2 to 10 across several days or weeks.”

  • The paper relies on this without support.

    Aβ and tau phosphorylation are reported in normal aging.

    “Both Aβ and tau phosphorylation are reported in normal aging and could, therefore, influence the brain’s response to TBI without causing AD.”

  • The paper relies on this without support.

    Multiple mouse models of AD display an altered inflammatory response to TBI.

    “Given that multiple mouse models of AD display an altered inflammatory response to TBI, it is possible that accumulation of pathological proteins alters the neuroinflammatory environment in a way influences the brain’s response to injury.”
11 of 11

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.

  • Study year conflicts with its reference

    Minor

    The text calls reference 142 a 2013 study, while the reference entry dates it to 2012.

  • Rat-study description cites a mouse study

    Minor

    The text groups reference 186 among studies reporting these findings in rats, but reference 186 identifies its subjects as mice.

2 of 2

Cites

Flagged first, then by citations

1 of the 249 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Alzheimer, 1907, Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschrift fur Psychiatr, Und Psych Medizin, 64, 146

Cited by

Sorted by citations

Related

Authors
Kokiko-Cochran, O. N., & Godbout, J. P.
Affiliations
The Ohio State University Wexner Medical Center (US)
ORCID
Godbout, Jonathan P.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-04-09
Volume
9
Pages
672-672
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.00672
PMC
PMC5900037
OpenAlex
W2797989008
Cited by
128
References
249
Citations by year
2026: 8 · 2025: 11 · 2024: 18 · 2023: 17 · 2022: 19 · 2021: 20 · 2020: 16 · 2019: 15 · 2018: 4
FWCI
2.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (R56-NS090311, R01-AG-51902)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Keywords
traumatic brain injury, Alzheimer's disease, neuroinflammation, microglia, macrophages, amyloid-beta, tau phosphorylation, microglial priming, neurodegeneration, neuropsychiatric complications, injury recovery
MeSH terms
Brain Injuries, Traumatic, Aging, Alzheimer Disease, Animals, Humans, Inflammation, Macrophages, tau Proteins, Amyloidogenic Proteins

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 2026-10-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-30.

Cited sources are checked by gpt-6-sol.

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 ›

Are you an author, or do you see a problem with this page? Request a review