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The pig as a preclinical traumatic brain injury model: current models, functional outcome measures, and translational detection strategies.

ABSTRACT: Traumatic brain injury (TBI) is a major contributor of long-term disability and a leading cause of death worldwide. A series of secondary injury cascades can contribute to cell death, tissue loss, and ultimately to the development of functional impairments. However, there are currently no effective therapeutic interventions that improve brain outcomes following TBI. As a result, a number of experimental TBI models have been developed to recapitulate TBI injury mechanisms and to test the efficacy of potential therapeutics. The pig model has recently come to the forefront as the pig brain is closer in size, structure, and composition to the human brain compared to traditional rodent models, making it an ideal large animal model to study TBI pathophysiology and functional outcomes. This review will focus on the shared characteristics between humans and pigs that make them ideal for modeling TBI and will review the three most common pig TBI models-the diffuse axonal injury, the controlled cortical impact, and the fluid percussion models. It will also review current advances in functional outcome assessment measures and other non-invasive, translational TBI detection and measurement tools like biomarker analysis and magnetic resonance imaging. The use of pigs as TBI models and the continued development and improvement of translational assessment modalities have made significant contributions to unraveling the complex cascade of TBI sequela and provide an important means to study potential clinically relevant therapeutic interventions.

SUBMITTER: Kinder HA

PROVIDER: S-EPMC6334610 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The pig as a preclinical traumatic brain injury model: current models, functional outcome measures, and translational detection strategies.

Kinder Holly A HA Baker Emily W EW West Franklin D FD

Neural regeneration research 20190301 3

Traumatic brain injury (TBI) is a major contributor of long-term disability and a leading cause of death worldwide. A series of secondary injury cascades can contribute to cell death, tissue loss, and ultimately to the development of functional impairments. However, there are currently no effective therapeutic interventions that improve brain outcomes following TBI. As a result, a number of experimental TBI models have been developed to recapitulate TBI injury mechanisms and to test the efficacy ...[more]

PMID: 30539807

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Project description:IntroductionThe high failure rate of clinical trials in traumatic brain injury (TBI) may be attributable, in part, to the use of untested or insensitive measurement instruments. Of more than 1,000 clinical outcome assessment measures (COAs) for TBI, few have been systematically vetted to determine their performance within specific "contexts of use (COU)." As described in guidance issued by the U.S. Food and Drug Administration (FDA), the COU specifies the population of interest and the purpose for which the COA will be employed. COAs are commonly used for screening, diagnostic categorization, outcome prediction, and establishing treatment effectiveness. COA selection typically relies on expert consensus; there is no established methodology to match the appropriateness of a particular COA to a specific COU. We developed and pilot-tested the Evidence-Based Clinical Outcome assessment Platform (EB-COP) to systematically and transparently evaluate the suitability of TBI COAs for specific purposes.Methods and findingsFollowing a review of existing literature and published guidelines on psychometric standards for COAs, we developed a 6-step, semi-automated, evidence-based assessment platform to grade COA performance for six specific purposes: diagnosis, symptom detection, prognosis, natural history, subgroup stratification and treatment effectiveness. Mandatory quality indicators (QIs) were identified for each purpose using a modified Delphi consensus-building process. The EB-COP framework was incorporated into a Qualtrics software platform and pilot-tested on the Glasgow Outcome Scale-Extended (GOSE), the most widely-used COA in TBI clinical studies.ConclusionThe EB-COP provides a systematic methodology for conducting more precise, evidence-based assessment of COAs by evaluating performance within specific COUs. The EB-COP platform was shown to be feasible when applied to a TBI COA frequently used to detect treatment effects and can be modified to address other populations and COUs. Additional testing and validation of the EB-COP are warranted.

Project description:Adolescent traumatic brain injury (TBI) is a major public health concern, resulting in >35,000 hospitalizations in the United States each year. Although neuroimaging is a primary diagnostic tool in the clinical assessment of TBI, our understanding of how specific neuroimaging findings relate to outcome remains limited. Our study aims to identify imaging biomarkers of long-term neurocognitive outcome after severe adolescent TBI. Twenty-four adolescents with severe TBI (Glasgow Coma Scale ≤8) enrolled in the ADAPT (Approaches and Decisions after Pediatric TBI) study were recruited for magnetic resonance imaging (MRI) scanning 1-2 years post-injury at 13 participating sites. Subjects underwent outcome assessments ∼1-year post-injury, including the Wechsler Abbreviated Scale of Intelligence (IQ) and the Pediatric Glasgow Outcome Scale-Extended (GOSE-Peds). A typically developing control cohort of 38 age-matched adolescents also underwent scanning and neurocognitive assessment. Brain-image segmentation was performed on T1-weighted images using Freesurfer. Brain and ventricular cerebrospinal fluid volumes were used to compute a ventricle-to-brain ratio (VBR) for each subject, and the corpus callosum cross-sectional area was determined in the midline for each subject. The TBI group demonstrated higher VBR and lower corpus callosum area compared to the control cohort. After adjusting for age and sex, VBR was significantly related with GOSE-Peds score in the TBI group (n = 24, p = 0.01, cumulative odds ratio = 2.18). After adjusting for age, sex, intracranial volume, and brain volume, corpus callosum cross-sectional area correlated significantly with IQ score in the TBI group (partial cor = 0.68, n = 18, p = 0.007) and with PSI (partial cor = 0.33, p = 0.02). No association was found between VBR and IQ or between corpus callosum and GOSE-Peds. After severe adolescent TBI, quantitative MRI measures of VBR and corpus callosum cross-sectional area are associated with global functional outcome and neurocognitive outcomes, respectively.

Project description:BackgroundTraumatic brain injuries (TBI) are associated with high risk of morbidity and mortality. Early outcome prediction in patients with TBI require reliable data input and stable prognostic models. The aim of this investigation was to analyze different CT classification systems and prognostic calculators in a representative population of TBI-patients, with known outcomes, in a neurointensive care unit (NICU), to identify the most suitable CT scoring system for continued research.Materials and methodsWe retrospectively included 158 consecutive patients with TBI admitted to the NICU at a level 1 trauma center in Sweden from 2012 to 2016. Baseline data on admission was recorded, CT scans were reviewed, and patient outcome one year after trauma was assessed according to Glasgow Outcome Scale (GOS). The Marshall classification, Rotterdam scoring system, Helsinki CT score and Stockholm CT score were tested, in addition to the IMPACT and CRASH prognostic calculators. The results were then compared with the actual outcomes.ResultsGlasgow Coma Scale score on admission was 3-8 in 38%, 9-13 in 27.2%, and 14-15 in 34.8% of the patients. GOS after one year showed good recovery in 15.8%, moderate disability in 27.2%, severe disability in 24.7%, vegetative state in 1.3% and death in 29.7%. When adding the variables from the IMPACT base model to the CT scoring systems, the Stockholm CT score yielded the strongest relationship to actual outcome. The results from the prognostic calculators IMPACT and CRASH were divided into two subgroups of mortality (percentages); ≤50% (favorable outcome) and > 50% (unfavorable outcome). This yielded favorable IMPACT and CRASH scores in 54.4 and 38.0% respectively.ConclusionThe Stockholm CT score and the Helsinki score yielded the closest relationship between the models and the actual outcomes in this consecutive patient series, representative of a NICU TBI-population. Furthermore, the Stockholm CT score yielded the strongest overall relationship when adding variables from the IMPACT base model and would be our method of choice for continued research when using any of the current available CT score models.

Dataset Information

The pig as a preclinical traumatic brain injury model: current models, functional outcome measures, and translational detection strategies.

Publications

The pig as a preclinical traumatic brain injury model: current models, functional outcome measures, and translational detection strategies.

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