Dataset Information

Inflammasome proteins as biomarkers of traumatic brain injury.

ABSTRACT:

Background

The inflammasome plays an important role in the inflammatory innate immune response after central nervous system (CNS) injury. Inhibition of the inflammasome after traumatic brain injury (TBI) results in improved outcomes by lowering the levels of caspase-1 and interleukin (IL)-1b. We have previously shown that inflammasome proteins are elevated in the cerebrospinal fluid (CSF) of patients with TBI and that higher levels of these proteins were consistent with poorer outcomes after TBI when compared to patients that presented these inflammasome proteins at lower levels.

Methods and findings

Here we extend our work by analyzing serum from 21 TBI patients and CSF from 18 TBI patients compared to 120 serum samples and 30 CSF samples from no-TBI donor controls for the expression of caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin(IL)-1b and IL-18. Analysis was carried out using the Ella Simple Plex system (Protein Simple) to determine the sensitivity and specificity of inflammasome proteins as biomarkers of TBI. Receiver operator characteristic (ROC) curves, confidence intervals and likelihood ratios for each biomarker was determined. ROC curves, confidence intervals, sensitivity and specificity for each biomarker examined revealed that caspase-1 (0.93 area under the curve (AUC)) and ASC (0.90 AUC) in serum and ASC (1.0 AUC) and IL-18 (0.84 AUC) in CSF are promising biomarkers of TBI pathology. Importantly, higher protein levels (above 547.6 pg/ml) of ASC (0.91 AUC) were consistent with poorer outcomes after TBI as determined by the Glasgow Outcome Scale-Extended (GOSE).

Conclusion

These findings indicate that inflammasome proteins are excellent diagnostic and predictive biomarkers of TBI.

SUBMITTER: Kerr N

PROVIDER: S-EPMC6312377 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Inflammasome proteins as biomarkers of traumatic brain injury.

Kerr Nadine N Lee Stephanie W SW Perez-Barcena Jon J Crespi Catalina C Ibañez Javier J Bullock M Ross MR Dietrich W Dalton WD Keane Robert W RW de Rivero Vaccari Juan Pablo JP

PloS one 20181231 12

<h4>Background</h4>The inflammasome plays an important role in the inflammatory innate immune response after central nervous system (CNS) injury. Inhibition of the inflammasome after traumatic brain injury (TBI) results in improved outcomes by lowering the levels of caspase-1 and interleukin (IL)-1b. We have previously shown that inflammasome proteins are elevated in the cerebrospinal fluid (CSF) of patients with TBI and that higher levels of these proteins were consistent with poorer outcomes a ...[more]

PMID: 30596792

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Project description: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.

Project description:Traumatic brain injury (TBI) affects millions of people of all ages around the globe. TBI is notoriously hard to diagnose at the point of care, resulting in incorrect patient management, avoidable death and disability, long-term neurodegenerative complications, and increased costs. It is vital to develop timely, alternative diagnostics for TBI to assist triage and clinical decision-making, complementary to current techniques such as neuroimaging and cognitive assessment. These could deliver rapid, quantitative TBI detection, by obtaining information on biochemical changes from patient's biofluids. If available, this would reduce mis-triage, save healthcare providers costs (both over- and under-triage are expensive) and improve outcomes by guiding early management. Herein, we utilize Raman spectroscopy-based detection to profile a panel of 18 raw (human, animal, and synthetically derived) TBI-indicative biomarkers (N-acetyl-aspartic acid (NAA), Ganglioside, Glutathione (GSH), Neuron Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase L1 (UCHL1), Cholesterol, D-Serine, Sphingomyelin, Sulfatides, Cardiolipin, Interleukin-6 (IL-6), S100B, Galactocerebroside, Beta-D-(+)-Glucose, Myo-Inositol, Interleukin-18 (IL-18), Neurofilament Light Chain (NFL)) and their aqueous solution. The subsequently derived unique spectral reference library, exploiting four excitation lasers of 514, 633, 785, and 830 nm, will aid the development of rapid, non-destructive, and label-free spectroscopy-based neuro-diagnostic technologies. These biomolecules, released during cellular damage, provide additional means of diagnosing TBI and assessing the severity of injury. The spectroscopic temporal profiles of the studied biofluid neuro-markers are classed according to their acute, sub-acute, and chronic temporal injury phases and we have further generated detailed peak assignment tables for each brain-specific biomolecule within each injury phase. The intensity ratios of significant peaks, yielding the combined unique spectroscopic barcode for each brain-injury marker, are compared to assess variance between lasers, with the smallest variance found for UCHL1 (σ2 = 0.000164) and the highest for sulfatide (σ2 = 0.158). Overall, this work paves the way for defining and setting the most appropriate diagnostic time window for detection following brain injury. Further rapid and specific detection of these biomarkers, from easily accessible biofluids, would not only enable the triage of TBI, predict outcomes, indicate the progress of recovery, and save healthcare providers costs, but also cement the potential of Raman-based spectroscopy as a powerful tool for neurodiagnostics.

Dataset Information

Inflammasome proteins as biomarkers of traumatic brain injury.

Background

Methods and findings

Conclusion

Publications

Inflammasome proteins as biomarkers of traumatic brain injury.

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