Temporal MRI characterization, neurobiochemical and neurobehavioral changes in a mouse repetitive concussive head injury model

Yang, Zhihui; Wang, Ping; Morgan, Drake; Lin, Dan; Pan, Jianchun; Lin, Fan; Strang, Kevin H.; Selig, Tyler M.; Pérez, Pablo D.; Febo, Marcelo; Chang, Binggong; Rubenstein, Richard; Wang, Kevin

doi:10.1038/srep11178

Cited by 57 publications

(66 citation statements)

References 33 publications

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“…These models include midline fluid percussion injury (mFPI) [9] and closed head impact acceleration models [10, 11]. Modifications of these models are used to induce repeated head injuries and mild TBI [12, 13]. Animal models are integral in developing our understanding of the pathophysiology of TBI.…”

Section: Introduction To Traumatic Brain Injurymentioning

confidence: 99%

Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury

Witcher

Eiferman

Godbout

2015

Trends in Neurosciences

186

157

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Traumatic brain injury (TBI) can lead to secondary neuropsychiatric problems that develop and persist years after injury. Mounting evidence indicates that neuroinflammatory processes progress after the initial head injury and worsen with time. Microglia contribute to this inflammation by maintaining a primed profile long after the acute effects of the injury have dissipated. This may set the stage for glial dysfunction and hyperactivity to challenges including subsequent head injury, stress, or induction of a peripheral immune response. The purpose of this review is to discuss the evidence that microglia become primed following TBI and how this corresponds with vulnerability to a “second hit” and subsequent neuropsychiatric and neurodegenerative complications.

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Section: Introduction To Traumatic Brain Injurymentioning

confidence: 99%

Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury

Witcher

Eiferman

Godbout

2015

Trends in Neurosciences

186

157

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“…21 However, to our knowledge, the profile of P-tau in blood samples in humans with mild and moderate TBI has yet to be defined. Incorporating the 3 tau indices to distinguish abnormal cranial computed tomography (CT) (pathoanatomic lesions) from normal CT findings would aid in the diagnosis and prognosis for acute TBI.…”

mentioning

confidence: 99%

Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau–Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers

et al. 2017

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IMPORTANCEAnnually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated. OBJECTIVETo examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI. DESIGN, SETTING, AND PARTICIPANTSIn the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean [SD], 176.4 [44.5] days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.MAIN OUTCOMES AND MEASURES Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification. RESULTSIn the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale [GCS] score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, Յ12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, Յ4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).CONCLUSIONS AND RELEVANCE Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained el...

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“…46,47 We developed a closed cortical impact procedure resulting in consistent, increased levels of brain pTau. [48][49][50] C57Bl/ 6 mice (males, 8-10 weeks old) were anesthetized using 1-4% isoflurane. The superior aspects of the head were shaved and the mouse positioned within a stereotactic frame, on top of a 2-cm-thick Type E foam padding (Foam to Size, Ash-land, VA) to allow for the acceleration-deceleration component of injury.…”

Section: Mouse Modelmentioning

confidence: 99%

Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy

et al. 2020

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Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder caused by repetitive trauma to the central nervous system (CNS) suffered by soldiers, contact sport athletes, and civilians following accident-related trauma. CTE is a CNS tauopathy, with trauma-induced inflammation leading to accumulation of hyperphosphorylated forms of the microtubule-binding protein Tau (pTau), resulting in neurofibrillary tangles and progressive loss of neurons. At present, there are no therapies to treat CTE. We hypothesized that direct CNS administration of an adeno-associated virus (AAV) vector coding for an anti-pTau antibody would generate sufficient levels of anti-pTau in the CNS to suppress pTau accumulation thus interrupting the pathogenic process. Using a serotype AAVrh.10 gene transfer vector coding for a monoclonal antibody directed against pTau, we demonstrate the feasibility of this strategy in a murine CTE model in which pTau accumulation was elicited by repeated traumatic brain injury (TBI) using a closed cortical impact procedure over 5 days. Direct delivery of AAVrh.10 expression vectors coding for either of the two different anti-pTau antibodies to the hippocampus of these TBI mice significantly reduced pTau levels across the CNS. Using doses that can be safely scaled to humans, the data demonstrate that CNS administration of AAVrh.10anti-pTau is effective, providing a new strategy to interrupt the CTE consequences of TBI.

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Temporal MRI characterization, neurobiochemical and neurobehavioral changes in a mouse repetitive concussive head injury model

Cited by 57 publications

References 33 publications

Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury

Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury

Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau–Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers

Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy

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