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

In the paper

“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).”

What the sources say

• Disputed

  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.

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

In the paper

“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).”

What the sources say

• Supported

  This source supports the CCX872 portion of the two-citation sentence. The Animals section describes a CCI injury; the macrophage-accumulation results (Fig. 5c) report a 50% reduction with CCX872, and the cognitive-dysfunction results (Fig. 8) report improved learning and memory after TBI. The RS504393 and weight-drop findings are not the part attributed to this source. (LLM, conf=0.91)

  cites [76] Morganti, 2015, CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury, J Neurosci source
• ?Not checked — no full text of the sourcecites [77] Liu, 2013, Chemokine CCL2 induces apoptosis in cortex following traumatic brain injury, J Mol Neurosci source

In the paper

“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).”

What the sources say

• Partly supported

  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)

  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 [31] Ikonomovic, 2004, Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury, Exp Neurol source

In the paper

“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).”

What the sources say

• Supported

  The “Evidence of Microglial Priming with Age” section defines a primed profile using the same three features: higher baseline inflammatory markers and mediators, a lower threshold for switching to a pro-inflammatory state, and an exaggerated response after immune activation. The claim is a close paraphrase of that definition. (LLM, conf=0.95)

  cites [93] Norden, 2015, Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease, Neuropharmacology source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [116] Bhaskar, 2010, Regulation of tau pathology by the microglial fractalkine receptor, Neuron sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  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)

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

  The Introduction distinguishes resident microglia from monocyte-derived macrophages and describes different apparent roles in Aβ clearance. The Discussion likewise reports distinct responses in AD mouse models. The citation is attached to the distinct-roles statement; the subsequent implication for long-term outcome is the citing authors’ inference. (LLM, conf=0.88)

  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

In the paper

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

What the sources say

• Partly supported

  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)

  cites [80] Febinger, 2015, Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury, J Neuroinflammation sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [82] Carbonell, 1998, Adaptation of the fluid percussion injury model to the mouse, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [83] Carbonell, 1999, Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse, Acta Neuropathol source
• ?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

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

  cites [85] Pierce, 1998, Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats, Neuroscience sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The roundtable discussion on pathoanatomic heterogeneity and laboratory models describes animal models designed for particular focal or diffuse injuries and says they do not capture the full spectrum of injury severity or the variability of human injuries and recovery. That supports the limitation attributed to this paper. The concluding phrase about restricted translation is attached to citation (46), not this source. (LLM, conf=0.86)

  cites [45] Saatman, 2008, Classification of traumatic brain injury for targeted therapies, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [46] Margulies, 2009, Combination therapies for traumatic brain injury: prospective considerations, J Neurotrauma source

In the paper

“For example, myeloid cells are instrumental in maintaining CNS homeostasis; however, aging significantly alters their properties (88).”

What the sources say

• Supported

  The Introduction describes microglia as CNS immune cells that maintain homeostasis. It also reports age-related changes in their inflammatory activity, while section 6 describes changes in their morphology and responses to injury. (LLM, conf=0.88)

  cites [88] Harry, 2013, Microglia during development and aging, Pharmacol Ther source

In the paper

“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).”

What the sources say

• Supported

  The Introduction identifies APOE ε4 as implicated in late-onset Alzheimer’s disease. The Discussion reports an association between APOE ε4 and unfavorable long-term functional outcome after TBI, while noting that non-genetic confounders could affect the estimated association. It found no significant association at six months. (LLM, conf=0.87)

  cites [33] Li, 2015, The association between apolipoprotein E and functional outcome after traumatic brain injury, Medicine (Baltimore) source
• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [94] Perry, 2014, Microglial priming in neurodegenerative disease, Nat Rev Neurol source
• ?Not checked — no full text of the sourcecites [95] Flanary, 2007, Evidence that aging and amyloid promote microglial cell senescence, Rejuvenation Res source
• Partly supported

  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)

  cites [96] Cohen, 2014, Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner, EMBO J sourceExperimental — accuracy not yet measured

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).”

What the sources say

• Supported

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

  cites [78] Gyoneva, 2015, Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury, J Neuroinflammation source

In the paper

“Secondary damage includes excitotoxicity (64), oxidative stress (65), and widespread neuroinflammation (63).”

What the sources say

• Supported

  Only “excitotoxicity” is attributed to this paper by citation (64); oxidative stress and neuroinflammation have separate citations. The Introduction (page unavailable) says increased extracellular glutamate initiates secondary injury cascades and can make neuronal tissue vulnerable to excitotoxicity. (LLM, conf=0.91)

  cites [64] Dorsett, 2017, Glutamate neurotransmission in rodent models of traumatic brain injury, J Neurotrauma source
• Supported

  Citation (65) is attached to oxidative stress, not to excitotoxicity or neuroinflammation. The Introduction identifies oxygen radical-induced oxidative damage as a validated secondary-injury mechanism in traumatic brain injury. (LLM, conf=0.93)

  cites [65] Hall, 2010, Antioxidant therapies for traumatic brain injury, Neurotherapeutics source
• ?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

“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.”

What the sources say

• Partly supported

  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)

  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

“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).”

What the sources say

• Partly supported

  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)

  cites [240] Rice, 2017, Microglial repopulation resolves inflammation and promotes brain recovery after injury, Glia sourceExperimental — accuracy not yet measured

In the paper

“A recent highly repetitive mouse model of TBI including 30 injuries has also been characterized (59).”

What the sources say

• Supported

  The Discussion describes the authors' new mouse model of repetitive mild TBI, designed to deliver up to 30 head impacts. The Neuronal Architecture Changes after mTBI section reports exposing mice to 30 injuries, so the cited paper is the model the sentence identifies. (LLM, conf=0.95)

  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

In the paper

“The co-occurrence of TBI and APP mutation in the clinical setting is rare (29) thereby restricting the results of many of these studies.”

What the sources say

• Partly supported

  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)

  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

In the paper

“supporting the notion that tau oligomers are neurotoxic and contribute to tau spreading throughout the brain (180).”

What the sources say

• Supported

  The Discussion (page not provided) reports that injected TBI-derived tau oligomers caused spatial-memory deficits in mice and were detected beyond the injection site. It interprets those findings as suggesting that the oligomers may spread to other brain regions, matching the citing sentence’s hedged claim. (LLM, conf=0.93)

  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

In the paper

“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.”

What the sources say

• Supported

  The results section reports that MW151 suppressed the injury-induced pro-inflammatory cytokine response in APP/PS1 KI mice, and Figure 6 reports that treated injured mice made fewer errors than vehicle-treated injured mice. The Discussion describes the inflammatory response as extended and says treatment during that phase prevented cognitive impairment. The measured cytokine suppression was at day 10 after injury; the paper does not claim cytokines remained elevated at day 32. (LLM, conf=0.91)

  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 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).”

What the sources say

• Supported

  The Results report that CCI increased soluble and insoluble Aβ40 and Aβ42 in the injured cortex of 3xTg mice at 1 day postinjury. The Discussion says the brain cleared the injury-induced Aβ accumulations within 7 days. The Results also note that a greater proportion of Aβ remained insoluble at day 7, a distinction the claim does not address. (LLM, conf=0.90)

  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

In the paper

“Similarly, CSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines (239).”

What the sources say

• Partly supported

  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)

  cites [239] Rice, 2015, Elimination of microglia improves functional outcomes following extensive neuronal loss in the hippocampus, J Neurosci sourceExperimental — accuracy not yet measured

In the paper

“Together, these studies demonstrate that single TBI induces acute tau phosphorylation but not aggregation.”

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
• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [166] Smith, 2003, Tau immunohistochemistry in acute brain injury, Neuropathol Appl Neurobiol source

In the paper

“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).”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“NFTs spread from the medial temporal lobes and hippocampus to the neocortex (9).”

What the sources say

• ?Not checked — no full text of the sourcecites [9] Braak, 1997, Frequency of stages of Alzheimer-related lesions in different age categories, Neurobiol Aging source

In the paper

“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.”

In the paper

“Alzheimer’s disease is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time (5).”

What the sources say

• Not checked yetcites [5] Alzheimer, 1907, Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschrift fur Psychiatr, Und Psych Medizin

In the paper

“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.”

In the paper

“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).”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [9] Braak, 1997, Frequency of stages of Alzheimer-related lesions in different age categories, Neurobiol Aging source

In the paper

“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.”

In the paper

“and intracellular aggregation of microtubule-associated protein tau (MAPT, tau) in neurofibrillary tangles (NFTs) (7).”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Kidd, 1963, Paired helical filaments in electron microscopy of Alzheimer’s disease, Nature source

In the paper

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

In the paper

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

In the paper

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

In the paper

“For example, APP accumulates in traumatized axons after all severities of TBI and has been detected many months post-injury (129–131).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [130] Blumbergs, 1994, Staining of amyloid precursor protein to study axonal damage in mild head injury, Lancet source
• ?Not checked — no full text of the sourcecites [131] Gentleman, 1995, Axonal injury: a universal consequence of fatal closed head injury?, Acta Neuropathol source

In the paper

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

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

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

In the paper

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

In the paper

“Consequently, age-related immune changes and those that occur during AD share many similarities and the distinction between the two processes remains unclear (89).”

What the sources say

• ?Not checked — no full text of the sourcecites [89] Heneka, 2010, Neuroinflammatory processes in Alzheimer’s disease, J Neural Transm source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [81] Zanier, 2016, Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice, J Neurotrauma source

In the paper

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

In the paper

“Similarly, microglia and astrocyte reactivity increases within days post-injury, but altered and reactive morphology diminishes by 10–14 days post-injury.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Kokiko-Cochran, 2016, Altered Neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer’s disease, J Neurotrauma source
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?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

“First, microglia, monocytes, and astrocytes as well as inflammatory cytokines and chemokines are elevated in the AD brain (108).”

What the sources say

• ?Not checked — no full text of the sourcecites [108] Minter, 2016, The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease, J Neurochem source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [107] Morganti-Kossmann, 2007, Modulation of immune response by head injury, Injury source

In the paper

“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).”

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

“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 the paper

“Similarly, post-injury macrophage recruitment substantially decreases in Ccr2−/− mice following CCI TBI and correlates with improved behavioral outcome (75).”

What the sources say

• ?Not checked — no full text of the sourcecites [75] Hsieh, 2014, CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury, J Neurotrauma source

In the paper

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

In the paper

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

In the paper

“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).”

What the sources say

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

In the paper

“Disruption and dysfunction of the BBB after TBI facilities monocyte infiltration though.”

In the paper

“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).”

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

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

In the paper

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

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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).”

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

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

In the paper

“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).”

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

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

“demonstrate that the glial response to TBI is altered in the presence of Aβ and correlates with altered functional recovery (38).”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Kokiko-Cochran, 2016, Altered Neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer’s disease, J Neurotrauma source

In the paper

“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.”