The Clinical Use of Serum Biomarkers in Traumatic Brain Injury: A Systematic Review Stratified by Injury Severity

Al-Adli, Nadeem; Akbik, Omar S.; Rail, Benjamin; Montgomery, Eric Y.; Caldwell, Christie; Barrie, Umaru; Vira, Shaleen; Tamimi, Mazin Al; Bagley, Carlos A.; Aoun, Salah G.

doi:10.1016/j.wneu.2021.08.073

Cited by 10 publications

(13 citation statements)

References 115 publications

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“…Biomarkers are specific proteins that are used as indicators of the status of different physiological processes in an individual [33][34][35][36][37][38][39]. Biomarkers are often used to determine the stage or severity of an underlying disease or injury [40][41][42][43][44][45][46]. TBI presents as a multifactorial series of events that affect a variety of cells within the central nervous system (CNS) including neurons, microglia, astrocytes, oligodendrocytes and endothelial cells [47,48].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Biomarkers of Traumatic Brain Injury

et al. 2022

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Traumatic brain injury (TBI) has a complex pathology in which the initial injury releases damage associated proteins that exacerbate the neuroinflammatory response during the chronic secondary injury period. One of the major pathological players in the inflammatory response after TBI is the inflammasome. Increased levels of inflammasome proteins during the acute phase after TBI are associated with worse functional outcomes. Previous studies reveal that the level of inflammasome proteins in biological fluids may be used as promising new biomarkers for the determination of TBI functional outcomes. In this study, we provide further evidence that inflammatory cytokines and inflammasome proteins in serum may be used to determine injury severity and predict pathological outcomes. In this study, we analyzed blood serum from TBI patients and respective controls utilizing Simple Plex inflammasome and V-PLEX inflammatory cytokine assays. We performed statistical analyses to determine which proteins were significantly elevated in TBI individuals. The receiver operating characteristics (ROC) were determined to obtain the area under the curve (AUC) to establish the potential fit as a biomarker. Potential biomarkers were then compared to documented patient Glasgow coma scale scores via a correlation matrix and a multivariate linear regression to determine how respective biomarkers are related to the injury severity and pathological outcome. Inflammasome proteins and inflammatory cytokines were elevated after TBI, and the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, tumor necrosis factor (TNF)-α, IL-4 and IL-6 were the most reliable biomarkers. Additionally, levels of these proteins were correlated with known clinical indicators of pathological outcome, such as the Glasgow coma scale (GCS). Our results show that inflammatory cytokines and inflammasome proteins are promising biomarkers for determining pathological outcomes after TBI. Additionally, levels of biomarkers could potentially be utilized to determine a patient’s injury severity and subsequent pathological outcome. These findings show that inflammation-associated proteins in the blood are reliable biomarkers of injury severity that can also be used to assess the functional outcomes of TBI patients.

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Section: Introductionmentioning

confidence: 99%

Inflammatory Biomarkers of Traumatic Brain Injury

et al. 2022

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“…UCH-L1 appears to be useful in cases of severe TBI [ 19 , 35 , 37 , 41 ]. This protein is upregulated following neuronal damage [ 19 , 27 , 42 ].…”

Section: Reviewmentioning

confidence: 99%

“…This protein is upregulated following neuronal damage [ 19 , 27 , 42 ]. Elevated levels of UCH-L1 have been found in patients who have findings consistent with DAI on neuroimaging when compared with patients who suffered focal injuries [ 19 , 37 , 41 ]. Elevated levels also appear to be associated with increased mortality and worse long-term memory performance [ 19 , 37 , 43 , 44 ].…”

Section: Reviewmentioning

confidence: 99%

“…Elevated levels of UCH-L1 have been found in patients who have findings consistent with DAI on neuroimaging when compared with patients who suffered focal injuries [ 19 , 37 , 41 ]. Elevated levels also appear to be associated with increased mortality and worse long-term memory performance [ 19 , 37 , 43 , 44 ]. Importantly, this biomarker has limited to no value when used alone in cases of mild-to-moderate TBI [ 19 , 35 ].…”

Section: Reviewmentioning

confidence: 99%

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Blood-Based Biomarkers in Traumatic Brain Injury: A Narrative Review With Implications for the Legal System

McBride,

Eltman,

Swanson

2023

Cureus

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Traumatic brain injury (TBI) is an increasingly recognized diagnosis with significant, and often costly, associated consequences. Yet, despite their increased recognition, TBIs remain underdiagnosed. This issue is especially prominent in the context of mild TBI (mTBI), where there often exists little to no objective evidence of brain injury. In recent years, considerable effort has been made to better define and interpret known objective markers of TBI, as well as identify and explore new ones. An area of particular interest has focused on research related to blood-based biomarkers of TBI. Advancements in our understanding of TBI-related biomarkers can make it possible to characterize the severity of TBI with greater accuracy, improve our understanding of staging within both the injury process and the recovery process, and help us develop quantifiable metrics representative of reversal and recovery from a brain injury following trauma. Proteomic and non-proteomic blood-based biomarkers are being studied extensively and have shown promise for these purposes. Developments in this realm have significant implications not only for clinical care but also for legislation, as well as civil and criminal litigation. Despite their substantial potential, most of these biomarkers are not yet ready for use within the clinical setting, and therefore, are not appropriate for use within the legal or policy-making systems at this time. Given that existing standardization for the accurate and reliable use of TBI biomarkers is currently insufficient for use within either the clinical or legal realms, such data can be vulnerable to misuse and can even result in the abuse of the legal system for unwarranted gain. Courts will need to carefully evaluate the information presented in their role as gatekeepers of the admissibility of scientific evidence within the legal process. Ultimately, the development of biomarkers should lead to improved clinical care following TBI exposure, coherent and informed laws surrounding TBI, and more accurate and just results in litigation surrounding TBI-related sequelae.

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“…The extensive body of literature regarding TBI and trauma (reviewed in 4 , 5 ) demonstrates that the resulting inflammatory processes are complex, individual-specific, injury-specific and associated with morbidity and mortality 6 . The cellular and molecular mediators of the innate and adaptive immune system do not function in isolation, but rather through dynamic interactions to either stimulate or suppress inflammation 7 .…”

Section: Introductionmentioning

confidence: 99%

Central role for neurally dysregulated IL-17A in dynamic networks of systemic and local inflammation in combat casualties

Zamora

Forsberg

Shah

et al. 2023

Sci Rep

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Dynamic Network Analysis (DyNA) and Dynamic Hypergraphs (DyHyp) were used to define protein-level inflammatory networks at the local (wound effluent) and systemic circulation (serum) levels from 140 active-duty, injured service members (59 with TBI and 81 non-TBI). Interleukin (IL)-17A was the only biomarker elevated significantly in both serum and effluent in TBI vs. non-TBI casualties, and the mediator with the most DyNA connections in TBI wounds. DyNA combining serum and effluent data to define cross-compartment correlations suggested that IL-17A bridges local and systemic circulation at late time points. DyHyp suggested that systemic IL-17A upregulation in TBI patients was associated with tumor necrosis factor-α, while IL-17A downregulation in non-TBI patients was associated with interferon-γ. Correlation analysis suggested differential upregulation of pathogenic Th17 cells, non-pathogenic Th17 cells, and memory/effector T cells. This was associated with reduced procalcitonin in both effluent and serum of TBI patients, in support of an antibacterial effect of Th17 cells in TBI patients. Dysregulation of Th17 responses following TBI may drive cross-compartment inflammation following combat injury, counteracting wound infection at the cost of elevated systemic inflammation.

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The Clinical Use of Serum Biomarkers in Traumatic Brain Injury: A Systematic Review Stratified by Injury Severity

Cited by 10 publications

References 115 publications

Inflammatory Biomarkers of Traumatic Brain Injury

Inflammatory Biomarkers of Traumatic Brain Injury

Blood-Based Biomarkers in Traumatic Brain Injury: A Narrative Review With Implications for the Legal System

Central role for neurally dysregulated IL-17A in dynamic networks of systemic and local inflammation in combat casualties

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