Differential Gene Expression Associated with Meningeal Injury in Acute Mild Traumatic Brain Injury

Livingston, Whitney S.; Gill, Jessica; Cota, Martin; Olivera, Anlys; O'Keefe, Jessica L.; Martin, Christiana; Latour, Lawrence L.

doi:10.1089/neu.2016.4479

Cited by 15 publications

(12 citation statements)

References 29 publications

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“…The NF-κB pathway has been implicated in the regulation of proinflammatory cytokines during meningitis (51) and in bloodbrain barrier permeability (52). Moreover, the NF-κB pathway has been found to be dysregulated in clinical studies of acute and subacute TBI (7)(8)(9)(10). Upregulation of AKT1 in this sample suggests activation of the NF-κB pathway; a finding that supports these prior studies, although the specific role of AKT1 in blast effects on the central nervous system remains to be examined.…”

Section: Discussionsupporting

confidence: 73%

“…Differential gene expression is reported in a small number of clinical TBI studies (7)(8)(9)(10), with few studies relevant to blast TBI (11)(12)(13). Gene expression regulation is imperative to appropriate cellular response to external mechanical, environmental, or biological stimuli, and the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) complex is a main transcription factor of these adaptive gene expression changes (14).…”

Section: Introductionmentioning

confidence: 99%

“…Within clinical studies of TBI, changes in the NF-κB network are reported in a limited number of studies (7)(8)(9)(10); however, they have not yet been examined in biTBI. Preclinical studies of blast exposures have demonstrated altered gene expression, including cognitive impairment (20,21) and immune function (22).…”

Section: Introductionmentioning

confidence: 99%

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A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism

et al. 2020

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Blast exposure is common in military personnel during training and combat operations, yet biological mechanisms related to cell survival and function that coordinate recovery remain poorly understood. This study explored how moderate blast exposure influences gene expression; specifically, gene-network changes following moderate blast exposure. On day 1 (baseline) of a 10-day military training program, blood samples were drawn, and health and demographic information collected. Helmets equipped with bilateral sensors worn throughout training measured overpressure in pounds per square inch (psi). On day 7, some participants experienced moderate blast exposure (peak pressure ≥5 psi). On day 10, 3 days post-exposure, blood was collected and compared to baseline with RNA-sequencing to establish gene expression changes. Based on dysregulation data from RNA-sequencing, followed by top gene networks identified with Ingenuity Pathway Analysis, a subset of genes was validated (NanoString). Five gene networks were dysregulated; specifically, two highly significant networks: (1) Cell Death and Survival (score: 42), including 70 genes, with 50 downregulated and (2) Cell Structure, Function, and Metabolism (score: 41), including 69 genes, with 41 downregulated. Genes related to ubiquitination, including neuronal development and repair: UPF1, RNA Helicase and ATPase (UPF1) was upregulated while UPF3 Regulator of Nonsense Transcripts Homolog B (UPF3B) was downregulated. Genes related to inflammation were upregulated, including AKT serine/threonine kinase 1 (AKT1), a gene coordinating cellular recovery following TBIs. Moderate blast exposure induced significant gene expression changes including gene networks involved in (1) cell death and survival and (2) cellular development and function. The present findings may have implications for understanding blast exposure pathology and subsequent recovery efforts.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism

et al. 2020

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“…Examination of gene activity through genetic expression analyses allows for the unbiased identification of pathways related to brain injury, including proteomic candidates. Previous studies in civilians with acute nonblast injuries, 2 as well as in military personnel with a mix of blunt force TBIs and blast-induced TBIs (biTBIs), 3 suggest that gene activities change following head injuries; however, previous studies have not acquired baseline samples, resulting in an inability to control for individual variability. The objective of this study was to identify biological pathways implicated in biTBIs in a cohort of military personnel who participated in a blast-related training.…”

mentioning

confidence: 99%

Moderate blast exposure alters gene expression and levels of amyloid precursor protein

et al. 2017

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Objective:To explore gene expression after moderate blast exposure (vs baseline) and proteomic changes after moderate- (vs low-) blast exposure.Methods:Military personnel (N = 69) donated blood for quantification of protein level, and peak pressure exposures were detected by helmet sensors before and during a blast training program (10 days total). On day 7, some participants (n = 29) sustained a moderate blast (mean peak pressure = 7.9 psi) and were matched to participants with no/low-blast exposure during the training (n = 40). PAXgene tubes were collected from one training site at baseline and day 10; RNA-sequencing day 10 expression was compared with each participant's own baseline samples to identify genes and pathways differentially expressed in moderate blast-exposed participants. Changes in amyloid precursor protein (APP) from baseline to the day of blast and following 2 days were evaluated. Symptoms were assessed using a self-reported form.Results:We identified 1,803 differentially expressed genes after moderate blast exposure; the most altered network was APP. Significantly reduced levels of peripheral APP were detected the day after the moderate blast exposure and the following day. Protein concentrations correlated with the magnitude of the moderate blast exposure on days 8 and 9. APP concentrations returned to baseline levels 3 days following the blast, likely due to increases in the genetic expression of APP. Onset of concentration problems and headaches occurred after moderate blast.Conclusions:Moderate blast exposure results in a signature biological profile that includes acute APP reductions, followed by genetic expression increases and normalization of APP levels; these changes likely influence neuronal recovery.

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“…We also see BBB disruption in American football players as a result of exposure to "subconcussive" head impacts [96]. A range of inflammatory genetic markers have been reported in the subset of individuals after mTBI with evidence of meningeal enhancement on MRI [97]. There is sufficient evidence to support BBB dysfunction following TBI; however, the extent and time course of disruption following human mTBI remains poorly understood.…”

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 98%

Concussion Pathophysiology and Injury Biomechanics

Romeu-Mejia¹,

Giza

Goldman

2019

Curr Rev Musculoskelet Med

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Purpose of Review The concussion public health burden has increased alongside our knowledge of the pathophysiology of mild traumatic brain injury (mTBI). The purpose of this review is to summarize our current understanding of mTBI pathophysiology and biomechanics and how these underlying principles correlate with clinical manifestations of mTBI. Recent Findings Changes in post-mTBI glutamate and GABA concentrations seem to be region-specific and timedependent. Genetic variability may predict recovery and symptom severity while gender differences appear to be associated with the neuroinflammatory response and neuroplasticity. Ongoing biomechanical research has shown a growing body of evidence in support of an "individual-specific threshold" for mTBI that varies based on individual intrinsic factors. Summary The literature demonstrates a well-characterized timeframe for mTBI pathophysiologic changes in animal models while work in this area continues to grow in humans. Current human research shows that these underlying post-mTBI effects are multifactorial and may correlate with symptomatology and recovery. While wearable sensor technology has advanced biomechanical impact research, a definitive concussion threshold remains elusive.

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Differential Gene Expression Associated with Meningeal Injury in Acute Mild Traumatic Brain Injury

Cited by 15 publications

References 29 publications

A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism

A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism

Moderate blast exposure alters gene expression and levels of amyloid precursor protein

Concussion Pathophysiology and Injury Biomechanics

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