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

In the paper

“Several lines of evidence point to a relationship between single-incident TBI and AD (10, 11).”

What the sources say

• Supported

  The epidemiological-link section reports that studies associate a history of TBI with later AD, while acknowledging that some studies found no association. The paper also describes AD-like pathology after TBI and explicitly examines how a single TBI may trigger such changes. (LLM, conf=0.92)

  cites [10] Johnson, 2010, Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease?, Nat Rev Neurosci source
• Supported

  The Introduction links TBI to increased Alzheimer’s disease incidence in epidemiological studies. The Discussion adds that survivors of a single TBI have shown amyloid plaques and neurofibrillary tangles, providing another line of evidence for the relationship. Page numbers are not available in our copy. (LLM, conf=0.92)

  cites [11] Johnson, 2013, Inflammation and white matter degeneration persist for years after a single traumatic brain injury, Brain source

In the paper

“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).”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [30] DeKosky, 2007, Association of increased cortical soluble Aβ42 levels with diffuse plaques after severe brain injury in humans, Arch Neurol source

In the paper

“Second, many animal studies show increased production and accumulation of amyloid precursor protein (APP), Aβ, and pathological tau following TBI (16, 21–28).”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  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)

  cites [25] Tran, 2011, Distinct temporal and anatomical distributions of amyloid-β and tau abnormalities following controlled cortical impact in transgenic mice, PLoS One sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [26] Itoh, 2009, Expression of amyloid precursor protein after rat traumatic brain injury, Neurol Res source
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“First, numerous population-based studies demonstrate that head injury during adulthood increases the risk of AD later in life (12–19)”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Guo, 2000, Head injury and the risk of AD in the MIRAGE study, Neurology source
• Partly supported

  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)

  cites [13] Schofield, 1997, Alzheimer’s disease after remote head injury: an incidence study, J Neurol Neurosurg Psychiatry sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [14] Plassman, 2000, Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias, Neurology source
• Partly supported

  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)

  cites [15] LoBue, 2017, Traumatic brain injury history is associated with earlier age of onset of Alzheimer disease, Clin Neuropsychol sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [18] Li, 2016, Traumatic brain injury and age at onset of cognitive impairment in older adults, J Neurol sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [19] Yang, 2015, Accumulation of amyloid in cognitive impairment after mild traumatic brain injury, J Neurol Sci source

In the paper

“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).”

What the sources say

• Supported

  The citation group (69–71) is attached to the claim about distinct genetic and transcriptomic profiles, not the later inference about roles in the injured CNS, which has separate citations. In Results (‘Environment-specific gene expression’), RNA-Seq shows substantial expression differences between microglia and other macrophage populations; the Discussion (‘Tuning enhancer landscapes and gene expression to context-specific functions’) also describes distinct active enhancer sets. (LLM, conf=0.90)

  cites [69] Gosselin, 2014, Environment drives selection and function of enhancers controlling tissue-specific macrophage identities, Cell source
• ?Could not verify

  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)

  cites [70] Butovsky, 2014, Identification of a unique TGF-β-dependent molecular and functional signature in microglia, Nat Neurosci sourceExperimental — accuracy not yet measured
• Supported

  The Results sections on genome-wide assays and gene expression report high-throughput RNA-seq and chromatin profiling of brain microglia alongside other macrophage populations, finding distinct expression patterns. The inference about roles in the injured CNS is attached to a different citation group (72–74), so it is not attributed to this paper here. (LLM, conf=0.88)

  cites [71] Lavin, 2014, Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment, Cell source
• Supported

  The citation to this paper is attached to the claim that the two cell types likely have different roles in the affected CNS, not to the preceding high-throughput-sequencing claim. The Abstract (page unavailable) reports that monocyte-derived macrophages initiate demyelination while microglia clear debris in EAE, supporting distinct roles in an inflamed CNS. (LLM, conf=0.91)

  cites [72] Yamasaki, 2014, Differential roles of microglia and monocytes in the inflamed central nervous system, J Exp Med source
• Supported

  The citation to this source is attached to the claim that microglia and peripheral macrophages have different roles in the injured CNS, not to the preceding claim about sequencing. The Abstract and Discussion describe distinct responses after spinal cord injury: microglia act early and process debris while remaining viable; peripheral macrophages predominate later and are less capable of handling CNS debris. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [74] Ajami, 2011, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Nat Neurosci source

In the paper

“These changes are directly associated with an altered and time-dependent inflammatory profile in microglia (80).”

What the sources say

• Supported

  The Discussion reports that, after mild TBI, CX3CR1-deficient mice show a protective M2 microglial profile during the acute phase but a pronounced inflammatory M1 profile during the chronic phase. It associates these time-dependent profiles with changes in neuronal damage. The provided passages do not give page numbers. (LLM, conf=0.90)

  cites [80] Febinger, 2015, Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury, J Neuroinflammation source

In the paper

“For example, APP expression increases in striatal and hippocampal axons along with cortical and thalamic neurons within the first 24 h after experimental impact and fluid percussion TBI (121–123)”

What the sources say

• Partly supported

  The Discussion (page not available in our copy) reports increased APP/APLP immunoreactivity in the thalamus at 1 hour and in the striatum, hippocampus, and injured cortex by 2 hours after lateral fluid-percussion injury. This paper does not study impact injury, and the Results place increased staining in cortical and thalamic neuronal cell bodies at 48 hours or later, not within the first 24 hours. It measures APP/APLP accumulation and immunoreactivity rather than establishing increased APP expression. (LLM, conf=0.88)

  cites [121] Pierce, 1996, Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [122] Bramlett, 1997, Temporal and regional patterns of axonal damage following traumatic brain injury: a beta-amyloid precursor protein immunocytochemical study in rats, J Neuropathol Exp Neurol source
• ?Not checked — no full text of the sourcecites [123] Van Den Heuvel, 1998, Diffuse neuronal perikaryon amyloid precursor protein immunoreactivity in a focal head impact model, Acta Neurochir Suppl source

In the paper

“Indeed, the complex neuroanatomy and neurophysiology of the human brain, such as cortical folding, substantial white matter, and specific pathophysiology compared to the rodent brain, may facilitate distinct post-injury neuropathology (137).”

What the sources say

• Supported

  Section 1.3 states that the gyrencephalic brains, substantial white matter, and pathophysiological features of humans and other large mammals may be key to specific features of trauma-induced neuropathology. The same section contrasts these features with rodent brains and explains why rodent models may not reproduce all aspects of clinical TBI. (LLM, conf=0.95)

  cites [137] Cullen, 2016, A porcine model of traumatic brain injury via head rotational acceleration, Methods Mol Biol source

In the paper

“A longstanding concern with many clinical studies is reliance on self-report and use of diagnostic verbiage in medical records to identify a correlation between TBI and post-injury development of AD (32).”

What the sources say

• Supported

  The paper states that most epidemiologic studies used self-reports to establish TBI history and relied on billing codes for clinical AD diagnoses. It identifies both practices as limitations in studying the TBI–AD relationship (passage 1, section labeled Abstract). (LLM, conf=0.93)

  cites [32] Weiner, 2017, Traumatic brain injury may not increase the risk of Alzheimer disease, Neurology source

In the paper

“Although Aβ deposition is apparent following rotational acceleration TBI in pigs (132, 133) and rabbits (134)”

What the sources say

• Supported

  This source is cited for the pig finding; the rabbit finding has a separate citation. The Results (‘Aβ in Plaques’) report Aβ-containing plaque-like profiles 3–10 days after rotational-acceleration injury in pigs, though they were found in only about one third of injured animals. (LLM, conf=0.90)

  cites [132] Smith, 1999, Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig, J Neuropathol Exp Neurol source
• Supported

  This source is one of the citations attached to the pig finding, not the separately cited rabbit finding. The Brain Injury section describes rotational acceleration in pigs, and the Discussion reports Aβ plaques six months after injury. (LLM, conf=0.93)

  cites [133] Chen, 2004, Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma, Am J Pathol source
• ?Not checked — no full text of the sourcecites [134] Hamberger, 2003, Redistribution of neurofilaments and accumulation of beta-amyloid protein after brain injury by rotational acceleration of the head, J Neurotrauma source

In the paper

“aged microglia displayed an exaggerated pro-inflammatory response referred to as “microglial priming” first described in a model of prion disease (92).”

What the sources say

• Partly supported

  The Introduction and Discussion describe microglial priming and an exaggerated response to inflammatory challenge in mice with prion disease. They do not establish that aged microglia display this response; the studied condition is chronic neurodegeneration, not aging. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [92] Cunningham, 2005, Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration, J Neurosci sourceExperimental — accuracy not yet measured

In the paper

“To date, no effective interventions are available to improve recovery following TBI (42–44).”

What the sources say

• ?Not checked — no full text of the sourcecites [42] McConeghy, 2012, A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury, CNS Drugs source
• ?Not checked — no full text of the sourcecites [43] Janowitz, 2010, Exploring new routes for neuroprotective drug development in traumatic brain injury, Sci Transl Med source
• Partly supported

  The Conclusions state that no single pharmacological therapy has been shown to unequivocally improve clinical outcomes after TBI. The claim extends that narrower, qualified finding to all interventions; the Results also report functional-outcome benefits for eight therapies in the studies reviewed. Page numbers were not supplied for these passages. (LLM, conf=0.88)

  cites [44] Gruenbaum, 2016, Pharmacologic neuroprotection for functional outcomes after traumatic brain injury: a systematic review of the clinical literature, CNS Drugs sourceExperimental — accuracy not yet measured

In the paper

“Despite preclinical studies providing evidence for successful pharmacologic intervention, more than 30 phase-III clinical trials have failed to improve secondary injury outcome measures after TBI (35–37).”

What the sources say

• Partly supported

  The Introduction says several TBI trials failed to demonstrate significant improvement in outcomes despite promising preclinical data. It does not establish that more than 30 of those trials were phase III or that they failed specifically on secondary-injury outcome measures; its figure of over 200 refers to randomized TBI therapy trials generally. (LLM, conf=0.86)

  cites [35] Narayan, 2002, Clinical trials in head injury, J Neurotrauma sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports encouraging preclinical results and says no multicenter phase III trial of a neuroprotective agent had convincingly shown benefit. But the trial-results discussion reports significant effects in 7 of 10 trials of therapeutic strategies and 3 of 23 trials of neuroprotective agents; the paper does not say that more than 30 trials failed. Its reviewed trials primarily measured clinical outcome, not specifically secondary-injury outcome measures. (LLM, conf=0.90)

  cites [36] Maas, 2010, Clinical trials in traumatic brain injury: past experience and current developments, Neurotherapeutics sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [37] Schouten, 2007, Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature, Curr Opin Crit Care source

In the paper

“By 30 DPI, however, these Cx3cr1−/− mice have worse cognitive dysfunction and neuronal loss compared to wild-type controls.”

What the sources say

• Supported

  The Abstract’s Results state that at 30 days post-TBI, injured CX3CR1−/− mice had greater cognitive dysfunction and neuronal death than injured wild-type mice. The Methods identify the injury as mild controlled cortical impact, and the Results section on neuronal survival reports fewer surviving neurons in the knockout mice at 30 days. Page numbers are not supplied in our copy. (LLM, conf=0.94)

  cites [80] Febinger, 2015, Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury, J Neuroinflammation source

In the paper

“Considering the failure of prospective studies with NSAID treatment (111), the beneficial effects of NSAIDs is presumed to be related to pre-morbid function.”

What the sources say

• Supported

  The citation is attached to the failure of prospective NSAID treatment studies, not to the citing authors’ subsequent inference about pre-morbid function. The paper’s discussion reports that earlier NSAID treatment and secondary-prevention trials showed no benefit; its own trial likewise found no improvement in cognitive function. Our copy does not provide a page number for the discussion passage. (LLM, conf=0.92)

  cites [111] Martin, 2008, Cognitive function over time in the Alzheimer’s disease anti-inflammatory prevention trial (ADAPT), Arch Neurol source

In the paper

“For example, multiple reports indicate that there are endogenous differences in rodent and human APP (136), which could significantly alter the production on Aβ after TBI.”

What the sources say

• Supported

  The passage accompanying Figure 1 in the Discussion identifies three amino acid differences between rodent and human Aβ and describes different processing of endogenous mouse and human APP. The citation is attached to the statement about species differences; the subsequent possibility concerning Aβ production after TBI is the citing authors’ inference. (LLM, conf=0.91)

  cites [136] Jankowsky, 2007, Rodent A beta modulates the solubility and distribution of amyloid deposits in transgenic mice, J Biol Chem source

In the paper

“a majority of rodent studies fail to show this association in non-transgenic animals using CCI, FPI, and weight drop models (121, 122, 124, 125, 135).”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports no Aβ deposits after lateral fluid-percussion injury in rats and describes a weight-drop study with no evidence of Aβ deposits. It does not address CCI or establish that a majority of rodent studies found no deposition. (LLM, conf=0.84)

  cites [121] Pierce, 1996, Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [122] Bramlett, 1997, Temporal and regional patterns of axonal damage following traumatic brain injury: a beta-amyloid precursor protein immunocytochemical study in rats, J Neuropathol Exp Neurol source
• ?Not checked — no full text of the sourcecites [124] Ciallella, 2002, Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [125] Masumura, 2000, Altered expression of amyloid precursors proteins after traumatic brain injury in rats: in situ hybridization and immunohistochemical study, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [135] Lewén, 1996, Changes in microtubule-associated protein 2 and amyloid precursor protein immunoreactivity following traumatic brain injury in rat: influence of MK-801 treatment, Brain Res source

In the paper

“While the age-related pro-inflammatory response to immune challenge is decreased in macrophages (91)”

What the sources say

• Supported

  In “TLR signalling and cytokine production in aged monocytes and macrophages,” the review reports reduced TLR-induced production of the pro-inflammatory cytokines TNF and IL-6 by macrophages from aged mice. This supports the attributed claim, although the evidence described here concerns particular immune challenges and mouse macrophage populations. (LLM, conf=0.88)

  cites [91] Shaw, 2013, Age-dependent dysregulation of innate immunity, Nat Rev Immunol source

In the paper

“Third, recent genetic studies implicate inflammatory genes and pathways (CD33, TREM2, HLA-DRB5-DRB1) in late-onset disease pathology (112–115).”

What the sources say

• Supported

  The Abstract (page not specified) reports an association between CD33 variants and Alzheimer’s disease and identifies CD33 as a susceptibility locus with a putative immune-system function. This supports the CD33 portion of the multi-cited sentence; the sentence does not assign TREM2 or HLA-DRB5-DRB1 specifically to this paper. (LLM, conf=0.90)

  cites [112] Hollingworth, 2011, Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease, Nat Genet source
• Partly supported

  The Discussion (page not specified) links TREM2 to immune and inflammatory signaling and reports that its variants predispose to Alzheimer’s disease. The introductory passage (page not specified) lists CD33 among genes implicated by studies of late-onset disease. Our copy does not identify HLA-DRB5-DRB1, so it does not support that part of the sentence. (LLM, conf=0.88)

  cites [113] Guerreiro, 2013, TREM2 variants in Alzheimer’s disease, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion (page not available in our copy) link a TREM2 variant to Alzheimer’s disease risk and discuss inflammation; the Discussion also reports an association for CD33. The paper does not address HLA-DRB5-DRB1, so it does not support the full gene list attributed to the citation group. (LLM, conf=0.88)

  cites [114] Jonsson, 2013, Variant of TREM2 associated with the risk of Alzheimer’s disease, N Engl J Med sourceExperimental — accuracy not yet measured
• Supported

  The Abstract (page unavailable) identifies HLA-DRB5-DRB1 as an Alzheimer’s disease susceptibility region and links it to immune response and inflammation. It also reports a TREM2 risk variant and discusses CD33 in relation to late-onset Alzheimer’s disease, while noting that this study did not replicate the CD33 association in its stage 2 analysis. Together, these passages support the qualified claim that genetic studies implicate these genes and pathways. (LLM, conf=0.86)

  cites [115] Lambert, 2013, Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease, Nat Genet source

In the paper

“Excessive or chronic neuroinflammation is linked to progressive changes, including atrophy, neuronal loss, and axonal degeneration (84, 103–105).”

What the sources say

• ?Not checked — no full text of the sourcecites [84] Smith, 1997, Progressive atrophy and neuron death for one year following brain trauma in the rat, J Neurotrauma source
• Partly supported

  The Innate immunity section (page not provided) links excessive or prolonged microglial activation to impaired neuronal survival and progressive degeneration after traumatic brain injury. The Introduction also describes neuronal apoptosis and death, but the cited passages do not specifically link chronic neuroinflammation to atrophy or axonal degeneration. (LLM, conf=0.86)

  cites [103] Dardiotis, 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The discussion (page unavailable) reports both inflammatory recruitment and neuronal degeneration after traumatic brain injury, but says diffuse diencephalic degeneration can occur without leukocyte infiltration and describes the processes as distinct. The study follows rats for up to 72 hours; it does not establish a link between excessive or chronic neuroinflammation and progressive atrophy or axonal degeneration. (LLM, conf=0.86)

  cites [104] Soares, 1995, Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [105] Nonaka, 1999, Prolonged activation of NF-kappaB following traumatic brain injury in rats, J Neurotrauma source

In the paper

“These findings are consistent with human studies that report increased mRNA expression of microglial markers OX-6 and CD68 at 1 year post-injury (11)”

What the sources say

• Partly supported

  The Activated microglia and Long-term survival sections report immunohistochemical staining for CR3/43 and CD68 in human TBI cases, including persistent CD68-reactive microglia. They do not report increased mRNA expression of OX-6 or CD68 at one year post-injury; the long-term findings concern protein staining and morphology, including cases 2–8 years after injury. Page numbers are not available in our copy. (LLM, conf=0.86)

  cites [11] Johnson, 2013, Inflammation and white matter degeneration persist for years after a single traumatic brain injury, Brain sourceExperimental — accuracy not yet measured

In the paper

“Together, these studies indicate that chronic neuroinflammation could provoke tau pathology thereby worsening neuronal injury and long-term outcome.”

What the sources say

• ?Not checked — no full text of the sourcecites [149] Collins-Praino, 2016, Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury?, Brain Behav Immun source
• ?Not checked — no full text of the sourcecites [150] Ballatore, 2007, Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders, Nat Rev Neurosci source
• ?Not checked — no full text of the sourcecites [151] Miyasaka, 2010, Microtubule destruction induces tau liberation and its subsequent phosphorylation, FEBS Lett source
• ?Not checked — no full text of the sourcecites [153] Ojo, 2013, Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice, J Neuropathol Exp Neurol source
• ?Not checked — no full text of the sourcecites [154] Dressler, 2007, Neuronal and glial apoptosis in human traumatic brain injury, Int J Legal Med source
• Partly supported

  In “Microglial phagocytosis in Alzheimer disease” (page unavailable), the paper reports that early microglial activation was associated with synapse loss before tangle formation in a tauopathy mouse model. It does not establish that chronic neuroinflammation provokes tau pathology or worsens long-term outcomes. (LLM, conf=0.82)

  cites [155] Neumann, 2009, Debris clearance by microglia: an essential link between degeneration and regeneration, Brain sourceExperimental — accuracy not yet measured

In the paper

“Nonetheless, a recent report indicates that 30 mild TBI’s do not alter Aβ and tau pathology in 18-month-old 3xTg mice (59).”

What the sources say

• Partly supported

  The Effect of rmTBI on Amyloid and Tau Pathology reports no change in Aβ levels or tau phosphorylation in 18-month-old 3xTg-AD mice. But it explicitly says those mice received 20 rmTBIs, not 30; the Figure 8 and 9 captions also specify 20. The claim attributes the correct finding to the wrong injury count. (LLM, conf=0.94)

  cites [59] Winston, 2016, Dendritic spine loss and chronic white matter inflammation in a mouse model of highly repetitive head trauma, Am J Pathol sourceExperimental — accuracy not yet measured

In the paper

“Only two reports examining repetitive TBI in Tg2576 mice showed increased Aβ in addition to behavioral impairment at chronic post-injury time points (165, 233).”

What the sources say

• Supported

  This paper is one report of repetitive TBI in Tg2576 mice with both increased Aβ deposition and cognitive impairment at a chronic time point. The Amyloid deposition and Neurobehavioral analysis sections report these findings at 16 weeks after injury; the cited paper does not need to establish the citing sentence’s count of two reports. (LLM, conf=0.91)

  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
• Supported

  This paper is one of the reports the sentence cites. Its Aβ ELISA results (p. 4) show higher Aβ1-40 and Aβ1-42 in repetitively injured Tg2576 mice than in sham controls, and its neurobehavioral results (p. 4) report cognitive impairment. Both were assessed eight weeks after injury; the paper does not establish the citing authors’ count of reports. (LLM, conf=0.92)

  cites [233] Conte, 2004, Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury, J Neurochem source

In the paper

“emphasize the distinct temporal inflammatory response to TBI in APP/PS1 mice (16).”

What the sources say

• Supported

  The Discussion reports that, after mild TBI, astrocyte activation and cytokine responses in APP/PS1 knock-in mice began later and persisted longer than in injured wild-type mice. The results section also reports a different temporal pattern of proinflammatory cytokine gene expression, although cytokine protein levels followed largely similar patterns in the two groups. (LLM, conf=0.93)

  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

In the paper

“While the use of these agents is limited in experimental TBI studies, several groups have reported that microglial elimination [via colony-stimulating factor 1 receptor (CSF1R) inhibition] improves behavioral performance and synaptic functioning independent of Aβ accumulation in multiple transgenic mouse models of AD (3xTg, 5xFAD, APP/PS1) (236–238).”

What the sources say

• Partly supported

  The Results on 5xfAD mice report that CSF1R inhibition eliminated microglia and increased mushroom-spine density; the Discussion reports unchanged amyloid-β levels and plaque load. But the behavioral result was only a trend toward improved contextual memory (P = 0.0813), and the paper measured spine structure rather than synaptic functioning directly. The other mouse models appear in a sentence supported by multiple citations, not as models studied in this paper. (LLM, conf=0.87)

  cites [236] Spangenberg, 2016, Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology, Brain sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable in our copy) report that CSF1R inhibition improved behavior and prevented synaptic degeneration in APP/PS1 mice without changing amyloid-β levels. But GW2580 blocked microglial proliferation rather than eliminating microglia, and this paper tested APP/PS1 mice, not 3xTg or 5xFAD mice. (LLM, conf=0.90)

  cites [237] Olmos-Alonso, 2016, Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology, Brain sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract Results and Results section report improved learning and memory in CSF1R-inhibitor-treated 3xTg-AD mice, with unchanged Aβ levels and plaque loads. This paper does not report improved synaptic functioning; it studies 3xTg-AD mice, while the sentence’s other model-specific findings may be covered by its other citations. (LLM, conf=0.87)

  cites [238] Dagher, 2015, Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice, J Neuroinflammation sourceExperimental — accuracy not yet measured

In the paper

“Thus, the production of Aβ is a complex process and accumulating evidence indicates that soluble Aβ oligomers, not Aβ plaques alone, are the disease-causing species that induce substantial neurotoxicity including synaptic dysfunction and behavioral impairment [see review in Ref. (138)].”

What the sources say

• Supported

  The original amyloid cascade hypothesis section identifies small soluble Aβ oligomers, rather than fibrils, as the most pathogenically relevant Aβ-derived toxins. The Neurological consequences section reports impaired synaptic plasticity and memory formation after oligomer injections, supporting the claim’s reference to synaptic dysfunction and behavioral impairment. Page numbers were not available in our copy. (LLM, conf=0.91)

  cites [138] Ferreira, 2011, The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease, Neurobiol Learn Mem source

In the paper

“Recent data demonstrate that TBI induces a primed microglial phenotype, defined by altered morphology and increased expression of MHC-II and CD68 (204, 208).”

What the sources say

• Partly supported

  The Results section on TBI-associated microglia priming reports altered microglial morphology and increased MHC-II expression 30 days after diffuse TBI in mice. The paper does not report increased CD68 after TBI; its Introduction mentions CD68 as a marker in other models of microglial priming. (LLM, conf=0.90)

  cites [204] Fenn, 2014, Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia, Biol Psychiatry sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports increased MHC-II and CD68 after diffuse brain injury and describes this as evidence of microglial priming. But Results §3.9 finds no increase in Iba-1 proportional area from TBI alone at 30 days; the clearest measured microglial morphology changes followed LPS challenge. Thus the paper supports priming and the marker expression, but not unequivocally altered microglial morphology induced by TBI alone. (LLM, conf=0.86)

  cites [208] Muccigrosso, 2016, Cognitive deficits develop 1month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge, Brain Behav Immun sourceExperimental — accuracy not yet measured

In the paper

“For example, TBI in the APP/PS1 knock-in mouse model of AD results in a delayed neuroinflammatory response compared to wild-type control mice subjected to CHI (16).”

What the sources say

• Supported

  The Introduction reports delayed onset of neuroinflammatory responses in injured APP/PS1 knock-in mice compared with injured wild-type mice. The Discussion (Figure 7 summary) specifies that much of the cytokine, microglial, and astrocyte response was delayed until seven days after closed head injury. (LLM, conf=0.94)

  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

In the paper

“These results indicate that Aβ maintains both pathological and beneficial properties which are dependent on the type of CNS injury and the inflammatory context, namely lymphoid or brain tissue.”

What the sources say

• Supported

  The Discussion states that Aβ may have pathological or beneficial properties in response to different CNS injuries. It also says Aβ’s role depends on whether the inflammatory targets and source are in secondary lymphoid tissues or the glial-rich environment of the brain. (LLM, conf=0.94)

  cites [142] Grant, 2012, Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis, Sci Transl Med source

In the paper

“Collectively, these results indicate that there is a direct relationship between neuroinflammation and functional recovery”

What the sources say

• Partly supported

  The Discussion reports that inhibiting proinflammatory cytokine upregulation prevented chronic cognitive impairment after head injury in an Alzheimer-relevant mouse model, linking the neuroinflammatory response to neurological outcomes. That supports a relationship in this model, but not an unqualified, direct relationship with functional recovery generally. (LLM, conf=0.82)

  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 sourceExperimental — accuracy not yet measured

In the paper

“A similar trend was observed in the chemokines CCL2, CCL3, CCL4, and CCL5.”

What the sources say

• Supported

  In the Results section on the temporal cytokine and chemokine response (page not supplied), the authors report measuring four CC chemokines and finding an early response in injured WT mice but a peak at 7 days in injured APP/PS1 KI mice. Figure 3c and Table 1 identify the measured chemokines as CCL2, CCL3, CCL4, and CCL5. This supports the stated similar temporal trend. (LLM, conf=0.88)

  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

In the paper

“In addition, mRNA expression of CCR2, CD68, and MHC-II, characteristically expressed by macrophages, was delayed in APP/PS1 mice compared to wild-type controls following TBI.”

What the sources say

• Partly supported

  The section on the temporal neuroinflammatory response (page unavailable) reports a CCR2 spike at one month, greatest in injured APP/PS1 mice, and CD68 and MHC-II peaks at seven days in that group. It does not establish that CCR2 expression was delayed relative to injured wild-type mice. It also describes CD68 and MHC-II as markers of microglia/macrophage activation, rather than characterizing all three markers as macrophage-specific. (LLM, conf=0.83)

  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 sourceExperimental — accuracy not yet measured

In the paper

“These data indicate that the presence of wild-type hTau is sufficient to alter the macrophage response to single-incident TBI.”

What the sources say

• Supported

  The Discussion states that wild-type human tau alters the microglial/macrophage response to a single TBI. The Results also report an increased acute response in hTau mice compared with controls. (LLM, conf=0.95)

  cites [183] Kokiko-Cochran, 2017, Traumatic brain injury in hTau model mice: enhanced acute macrophage response and altered long-term recovery, J Neurotrauma source

In the paper

“these studies highlight a physiological role for Aβ in innate immunity”

What the sources say

• Partly supported

  The Results section reports that administered Aβ affects myeloid cells, including macrophages and dendritic cells, and the Discussion describes an anti-inflammatory effect in EAE mice. But the Introduction says the physiological role of peripheral Aβ is not completely understood; effects of administered Aβ do not establish a physiological role in innate immunity. (LLM, conf=0.83)

  cites [142] Grant, 2012, Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis, Sci Transl Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that Aβ-derived peptides reduce inflammatory markers in experimental autoimmune encephalomyelitis and suggests that amyloid-forming proteins may contain inflammation in MS lesions. It does not establish a physiological role for Aβ in innate immunity; that extends the paper’s findings and its tentative account of a role in lesions. (LLM, conf=0.82)

  cites [143] Steinman, 2014, Janus faces of amyloid proteins in neuroinflammation, J Clin Immunol sourceExperimental — accuracy not yet measured
• Supported

  The Discussion says the study’s cell and animal models generated data consistent with a normal physiological role for Aβ as an antimicrobial peptide and a protective role in innate immunity. The citing sentence’s wording, “highlight a physiological role,” is a fair paraphrase of that finding. (LLM, conf=0.88)

  cites [144] Kumar, 2016, Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease, Sci Transl Med source

In the paper

“While several clinical studies report that higher cerebral spinal fluid (CSF) levels of Aβ42 predict improved neurological recovery following severe TBI (139, 140)”

What the sources say

• Partly supported

  The Results passage in our copy (labeled Abstract; page unavailable) reports that brain interstitial-fluid Aβ rose as neurological status improved, including in TBI patients. It reports a much weaker association for ventricular CSF Aβ (r = 0.20). Although the paper measured Aβ42 in pooled samples, it does not establish that higher CSF Aβ42 predicts subsequent neurological recovery. (LLM, conf=0.88)

  cites [139] Brody, 2008, Amyloid-beta dynamics correlate with neurological status in the injured human brain, Science sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [140] Franz, 2003, Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury, Neurology source

In the paper

“and reduces the time to onset of AD (20).”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Nemetz, 1999, Traumatic brain injury and time to onset of Alzheimer’s disease: a population-based study, Am J Epidemiol source

In the paper

“The disease is characterized by key neuropathological features, including extracellular accumulation of beta-amyloid (Aβ) protein in senile plaques (6)”

What the sources say

• ?Not checked — no full text of the sourcecites [6] Glenner, 1984, Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem Biophys Res Commun source

In the paper

“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.”

In the paper

“Intracellular aggregation of MAPT in NFTs was only present in a subset of older subjects (31).”

What the sources say

• ?Not checked — no full text of the sourcecites [31] Ikonomovic, 2004, Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury, Exp Neurol source

In the paper

“The post-injury inflammatory response is a key mediator in long-term recovery from traumatic brain injury (TBI).”

• Also stated in: § Post-Injury Neuroinflammation and Aging · hedged

  “Accumulating evidence implicates the post-injury inflammatory response as a key mediator in long-term recovery from TBI.”

In the paper

“Importantly, both amyloid and neurofibrillary changes begin during preclinical AD when cognitive deficits are not apparent (8).”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Braak, 1991, Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections, Brain Pathol source

In the paper

“Additional data demonstrate that post-injury microglia are “primed” and become hyper-reactive following a subsequent acute immune challenge thereby worsening recovery.”

In the paper

“For example, phagocytosis and chemotaxis diminish in both microglia and macrophages during aging.”

In the paper

“Second, retrospective studies demonstrate that sustained NSAID treatment during mid-life significantly decreases the risk of AD (109, 110).”

What the sources say

• ?Not checked — no full text of the sourcecites [109] Beard, 1998, Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease: a case-control study in Rochester, Minnesota, 1980 through 1984, Mayo Clin Proc source
• ?Not checked — no full text of the sourcecites [110] In’t Veld, 1998, NSAIDs and incident Alzheimer’s disease. The Rotterdam study, Neurobiol Aging source

In the paper

“Collectively, these studies indicate that interruption of post-injury monocytic infiltration has both beneficial and detrimental consequences depending on the outcome measures evaluated.”

In the paper

“Injury severity may also be a critical mediator in outcome.”

In the paper

“however, white matter demyelination injury provokes a reduced macrophage response in older rodents compared to younger controls (102).”

What the sources say

• ?Not checked — no full text of the sourcecites [102] Zhao, 2006, Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination, Neurobiol Aging source

In the paper

“For example, Aβ accumulation is observed in patients with dementia pugilistica which reflects traumatic injury as a result of repetitive brain insults.”

In the paper

“Chronic inflammation is a potential common denominator in both TBI and AD.”

In the paper

“Existing brain pathology and secondary immune challenges may be critical in shaping post-injury disease pathogenesis.”

In the paper

“and imaging studies showing increased binding of PK-[11C](R)PK11195 ligand, expressed by activated microglia, between 11 months and 17 years post-injury (86).”

What the sources say

• ?Not checked — no full text of the sourcecites [86] Ramlackhansingh, 2011, Inflammation after trauma: microglial activation and traumatic brain injury, Ann Neurol source

In the paper

“Indeed, many prevalent immunohistochemical markers do not identify whether or not a reactive macrophage is of microglial or monocytic origin.”

In the paper

“Age-related changes in the function of microglia and macrophages may influence outcome after TBI.”

In the paper

“Macrophage-mediated neuroinflammation is also a prominent feature of many age-related neurodegenerative diseases including AD (87).”

What the sources say

• ?Not checked — no full text of the sourcecites [87] Rawji, 2016, Immunosenescence of microglia and macrophages: impact on the ageing central nervous system, Brain source

In the paper

“In other words, secondary injury cascades can act concurrently and synergize to influence outcome (3).”

What the sources say

• ?Not checked — no full text of the sourcecites [3] Maas, 2008, Moderate and severe traumatic brain injury in adults, Lancet Neurol source

In the paper

“and lends support to the notion that a persistent post-injury macrophage response is detrimental to outcome.”

In the paper

“Chronic microglial and astrocytic reactivity, as defined by altered morphology, persists in sub-cortical brain regions months to years post-injury.”

In the paper

“Many types of CNS injury, including TBI, induce the expression of APP.”

In the paper

“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).”

In the paper

“Primary damage occurs as a result of the physical and mechanical forces of brain injury and includes brain contusion, hemorrhage, hematoma, and axonal injury (3).”

What the sources say

• ?Not checked — no full text of the sourcecites [3] Maas, 2008, Moderate and severe traumatic brain injury in adults, Lancet Neurol source

In the paper

“In summary, these models of experimental TBI induce a temporal inflammatory response that is consistent with what is observed in human head injury, and increased injury severity is positively correlated with BBB disruption and infiltration of peripheral cells (63).”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Simon, 2017, The far-reaching scope of neuroinflammation after traumatic brain injury, Nat Rev Neurol source

In the paper

“When in the reactive macrophage state, it is difficult to distinguish microglia and peripheral monocytes.”

In the paper

“Experimental models of TBI have historically been referred to as focal or diffuse, but increasing evidence indicates that even focal brain injuries cause diffuse damage that is not restricted to the site of injury.”

In the paper

“Collectively, these data indicate that aging before and after TBI could significantly influence outcome.”

In the paper

“Consequently, the validity of TBI-AD experiments in non-transgenic rodents is unclear.”

In the paper

“TBI is not an isolated event within the inflammatory milieu.”

In the paper

“Traumatic axonal injury (TAI) is an additional source of accumulating APP (127, 128).”

What the sources say

• ?Not checked — no full text of the sourcecites [127] Povlishock, 1993, Pathobiology of traumatically induced axonal injury in animals and man, Ann Emerg Med source
• ?Not checked — no full text of the sourcecites [128] Maxwell, 1993, Ultrastructural evidence of axonal shearing as a result of lateral acceleration of the head in non-human primates, Acta Neuropathol source

In the paper

“Consequently, peripheral cells, such as neutrophils, monocytes, T-cells, and dendritic cells, enter the brain within days post-injury.”

In the paper

“This conserved response is, therefore, viewed as a critical mediator of post-injury outcome.”

In the paper

“Follow-up experiments revealed that CCI TBI in aged PDAPP mice caused a regression of established Aβ deposits (41).”

What the sources say

• ?Not checked — no full text of the sourcecites [41] Nakagawa, 2000, Brain trauma in aged transgenic mice induces regression of established abeta deposits, Exp Neurol source

In the paper

“Moreover, acute transient interruption of the microglial response to TBI is beneficial to outcome.”

In the paper

“There is a persuasive body of evidence showing a significant inflammatory component in AD as well.”

In the paper

“Thus, Aβ may have a specific temporal profile in single and repetitive models of TBI.”

In the paper

“Experimental TBI, regardless of model, consistently induces an inflammatory response including microglial/macrophage reactivity.”

In the paper

“Together, these studies emphasize the temporal inflammatory response to a single brain injury and confirm that alteration of this response can influence outcome.”

In the paper

“Together these studies indicate that interruption of CCL2/CCR2 signaling offers therapeutic potential to improve outcome following TBI”

In the paper

“which has been replicated in multiple follow-up studies using CCI as well as midline and lateral FPI (124–126).”

What the sources say

• ?Not checked — no full text of the sourcecites [124] Ciallella, 2002, Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [125] Masumura, 2000, Altered expression of amyloid precursors proteins after traumatic brain injury in rats: in situ hybridization and immunohistochemical study, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [126] Murakami, 1998, Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus, J Neurotrauma source

In the paper

“Finally, location and timing of injury may mediate Aβ pathology.”

In the paper

“Amyloid precursor protein accumulation does not result in Aβ deposition in many experimental studies though.”

In the paper

“In summary, these models of experimental TBI induce a temporal inflammatory response that is consistent with what is observed in human head injury, and increased injury severity is positively correlated with BBB disruption and infiltration of peripheral cells (63).”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Simon, 2017, The far-reaching scope of neuroinflammation after traumatic brain injury, Nat Rev Neurol source

In the paper

“Taken together, these findings indicate that the immune response to and recovery from TBI is not absolute and very much influenced by multiple factors.”

In the paper

“Fourth, alterations in inflammatory cells and molecules are reported in multiple different mouse models of AD.”

In the paper

“Together these data confirm that TBI induces persistent macrophage inflammation”

In the paper

“Collectively, human studies show that post-injury tau pathology varies in response to severity, type, and number of brain injuries as well as the time point of post-injury analysis.”

In the paper

“Accumulating evidence shows that transient interruption of the macrophage response to TBI could improve outcome.”

In the paper

“results from non-transgenic rodent studies remain variable.”

In the paper

“Third, additional factors must account for the resistance of rodents to develop Aβ and tau pathology after TBI.”

In the paper

“The presence of Aβ and tau pathology appears to be dependent on the injury model used and the post-injury time point.”

In the paper

“the inter-injury time interval may be critical in this response.”

In the paper

“Thus, abnormal processing of tau is not necessarily the primary mechanism of disease pathogenesis.”

In the paper

“the combined effect of amyloid and tau pathology following TBI is complex and likely dependent on multiple factors that are time- and injury severity-dependent.”

In the paper

“Pre-injury peripheral immune challenge at sub-threshold levels (red line) attenuates the post-injury macrophage-related inflammatory response to TBI.”

In the paper

“Importantly, in both instances LPS administration altered outcome from TBI.”

In the paper

“Increasing evidence, as described in the following sections, clearly shows that pre- and post-injury immune stressors that elicit macrophage reactivity influence response to and recovery from TBI.”

In the paper

“many older neuropsychologically healthy individuals display amyloid deposition (145, 146)”

What the sources say

• ?Not checked — no full text of the sourcecites [145] Dickson, 1992, Identification of normal and pathological aging in prospectively studied nondemented elderly humans, Neurobiol Aging source
• ?Not checked — no full text of the sourcecites [146] Katzman, 1988, Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques, Ann Neurol source

In the paper

“a breakdown in communication between microglia and neurons likely sets the stage for neuropathology.”

In the paper

“a universal experimental model of repetitive TBI is not established.”

In the paper

“higher levels of CSF Aβ oligomers predict poor neurological recovery (141).”

What the sources say

• ?Not checked — no full text of the sourcecites [141] Gatson, 2013, Detection of β-amyloid oligomers as a predictor of neurological outcome after brain injury, J Neurosurg source

In the paper

“post-TBI infection that stimulates an inflammatory response may have a significant effect in long-term recovery.”

In the paper

“age-related Aβ accumulation may play a critical role in the brain’s ability to respond to and recover from traumatic injury.”

In the paper

“the role of Aβ in mediating response to and recovery from TBI is largely unknown”

In the paper

“Single TBI (dotted black line) results in acute macrophage-related neuroinflammation that subsides over time.”

In the paper

“Together, these studies implicate soluble tau aggregates as mediators of pathological spreading throughout the brain termed “cistauosis.””

In the paper

“One group considered this question and determined that timing of LPS treatment mediated a beneficial or detrimental post-injury effect in rats.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“A robust and persistent neuroinflammatory response may then be sufficient to promote phosphorylation, aggregation, and subsequent neurodegeneration; key features of AD (149–151).”

What the sources say

• ?Not checked — no full text of the sourcecites [149] Collins-Praino, 2016, Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury?, Brain Behav Immun source
• ?Not checked — no full text of the sourcecites [150] Ballatore, 2007, Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders, Nat Rev Neurosci source
• ?Not checked — no full text of the sourcecites [151] Miyasaka, 2010, Microtubule destruction induces tau liberation and its subsequent phosphorylation, FEBS Lett source

In the paper

“Mounting evidence indicates that neuroinflammation and microglial priming is a factor in repetitive TBI as well.”

In the paper

“TBI in the presence of Aβ (solid red line) results in an acute blunted macrophage response that increases at chronic post-injury time points.”

In the paper

“Studies with CCR2 and CX3CR1 knock-in/knock-out mice demonstrate that permanent interruption of the microglial or macrophage response to TBI does not offer optimal protection after injury.”

In the paper

“TBI induces a persistent pro-inflammatory profile in microglia”

In the paper

“pre-injury immune challenge significantly alters response to and recovery from brain injury, in part, via modulation of macrophage reactivity and cytokine production.”

In the paper

“First, the inflammatory response to TBI is not absolute and is influenced by previous and subsequent inflammatory challenges.”

In the paper

“Together, these studies indicate that choice of experimental TBI model and rodent model (rat or mouse, transgenic or non-transgenic) influence the temporal appearance of post-injury amyloid and tau pathology through independent mechanisms.”

In the paper

“the cell-specific role of microglia and monocytes remains unknown.”

In the paper

“progressive tau pathology occurs in response to repetitive or blast TBI.”

In the paper

“tau oligomers may represent the most toxic and pathologically relevant aggregate.”

In the paper

“the data support a neuroprotective role of reactive microglia”

In the paper

“Over time, macrophage-related neuroinflammation increases with normal health burden.”

In the paper

“Post-injury peripheral immune challenge (solid blue line) causes a hyper-active macrophage response correlating with behavioral dysfunction.”

In the paper

“Non-transgenic mice exposed to repetitive mild TBI consistently show increased APP, phosphorylated tau, and behavioral impairment at chronic post-injury time points (232).”

What the sources say

• ?Not checked — no full text of the sourcecites [232] Edwards, 2017, Amyloid-beta and tau pathology following repetitive mild traumatic brain injury, Biochem Biophys Res Commun source

In the paper

“Aβ alone is not predictive of AD”

What the sources say

• ?Not checked — no full text of the sourcecites [145] Dickson, 1992, Identification of normal and pathological aging in prospectively studied nondemented elderly humans, Neurobiol Aging source
• ?Not checked — no full text of the sourcecites [146] Katzman, 1988, Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques, Ann Neurol source

In the paper

“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.”

In the paper

“Together, these data indicate that chronic neuroinflammation mediates AD-related pathology following repetitive TBI”

In the paper

“no studies could be found that define inter-injury macrophage changes in experimental models of repetitive TBI.”

In the paper

“Collectively, these data indicate that genetic predisposition to AD drives independent mechanisms that promote post-injury amyloid and tau pathology.”

In the paper

“Similarly, only transgenic tau mouse models [T44 (one mouse), hTau] displayed NFT pathology following repetitive TBI (153, 234).”

What the sources say

• ?Not checked — no full text of the sourcecites [153] Ojo, 2013, Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice, J Neuropathol Exp Neurol source
• ?Not checked — no full text of the sourcecites [234] Yoshiyama, 2005, Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model, J Neurotrauma source

In the paper

“Based on the abovementioned results, one might suggest that the validity of TBI-AD experiments in APP-transgenic rodents is unclear as well.”

In the paper

“Together, these studies indicate that primed microglia potentiate brain pathology and behavioral decline in aging and after CNS injury.”

In the paper

“Thus, accumulation of Aβ and tau phosphorylation could be viewed as part of the injury process instead of a result of the injury.”

In the paper

“The presence of pathological proteins (e.g., amyloid and tau oligomers or fibrils) in transgenic rodents at the time of TBI is sufficient to promote aggregation.”

In the paper

“Traumatic brain injury (TBI) in the presence of pathological tau (solid blue line) results in an enhanced macrophage response to TBI that remains elevated at chronic post-injury time points.”

In the paper

“TBI occurring in the absence of tau or Aβ (dotted black line) results in acute macrophage-related neuroinflammation that subsides over time.”

In the paper

“Together, these data are similar to single TBI experimental studies and show that TBI alone is not sufficient to induce amyloid or tau aggregation in non-transgenic rodents.”

In the paper

“These data indicate that tau phosphorylation is a conserved response to TBI regardless of primary insult”

In the paper

“these studies lend support to the notion that infection may be associated with development of AD.”

In the paper

“Collectively, these studies confirm the vulnerability of the brain to tau pathology following single-incident TBI.”

In the paper

“Collectively, these results indicate that tau alone possesses neurotoxic properties that mediate recovery following TBI.”