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An update on diagnostic and prognostic biomarkers for traumatic brain injury.

ABSTRACT: INTRODUCTION:Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (?II-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.

SUBMITTER: Wang KK

PROVIDER: S-EPMC6359936 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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An update on diagnostic and prognostic biomarkers for traumatic brain injury.

Wang Kevin K KK Yang Zhihui Z Zhu Tian T Shi Yuan Y Rubenstein Richard R Tyndall J Adrian JA Manley Geoff T GT

Expert review of molecular diagnostics 20180123 2

<h4>Introduction</h4>Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, includi ...[more]

PMID: 29338452

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Project description:Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency departments (EDs) of the Johns Hopkins Hospital (JHH; n?=?76) and San Francisco General Hospital (SFGH, n?=?80), and a control group of JHH ED patients without TBI (n?=?150). Findings were subsequently validated in the prospective, multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study (n?=?159). We investigated the association between BDNF, glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and recovery from TBI at 6 months in the TRACK-TBI Pilot cohort. Incomplete recovery was defined as having either post-concussive syndrome or a Glasgow Outcome Scale Extended score <8 at 6 months. Median day-of-injury BDNF concentrations (ng/mL) were lower among TBI cases (JHH TBI, 17.5 and SFGH TBI, 13.8) than in JHH controls (60.3; p?=?0.0001). Among TRACK-TBI Pilot subjects, median BDNF concentrations (ng/mL) were higher in mild (8.3) than in moderate (4.3) or severe TBI (4.0; p?=?0.004. In the TRACK-TBI cohort, the 75 (71.4%) subjects with very low BDNF values (i.e., <the 1st percentile for non-TBI controls, <14.2?ng/mL) had higher odds of incomplete recovery than those who did not have very low values (odds ratio, 4.0; 95% confidence interval [CI]: 1.5-11.0). The area under the receiver operator curve for discriminating complete and incomplete recovery was 0.65 (95% CI: 0.52-0.78) for BDNF, 0.61 (95% CI: 0.49-0.73) for GFAP, and 0.55 (95% CI: 0.43-0.66) for UCH-L1. The addition of GFAP/UCH-L1 to BDNF did not improve outcome prediction significantly. Day-of-injury serum BDNF is associated with TBI diagnosis and also provides 6-month prognostic information regarding recovery from TBI. Thus, day-of-injury BDNF values may aid in TBI risk stratification.

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:Purpose: High throughput small RNA-Seq analysis from circulating biofluids is crucial in driving the discovery of non-invasive miRNA biomarkers for TBI. In this study, we focused our analysis on acute post-TBI alterations in plasma miRNA profiles in adult, male Sprague-Dawley rats. We compared the plasma miRNA profiles from naive, sham-operated controls and rats with mild and severe TBI. The aim was to identify a miRNA signature that would distinguish the rats with mTBI from the naive and sham-operated controls. Next, we compared the rats with mild and severe TBIs to investigate if a dose-dependent increase would occur in the plasma miRNA levels with corresponding increase in injury severities. Finally, we analysed if the sham surgery itself results in alterations in circulating miRNA profiles, by comparing the naive and sham-operated controls. Methods: TBI was induced with the lateral fluid percussion injury (FPI) model. Tail-vein plasma was collected at 2 days post-TBI from 31 adult male, Sprague-Dawley rats (5 naive, 8 sham-operated controls, 10 mTBI and 8 sTBI) under inhalation of isoflurane anesthesia. Small RNA-Seq was performed from plasma samples of a subset of 20 rats (5 cases each from naive, sham-operated controls, mTBI and sTBI groups). For each case, RNA was isolated from 200 µL plasma using the miRNeasy serum/plasma kit. The extracted RNA was subjected to qPCR-based quality control (QC). Small RNA library preparation was performed with the QIASeq miRNA library kit for Illumina NGS systems. Single-end sequencing of 75 bp reads was performed at a depth of 12M, with one sample/lane in the Illumina NextSeq 550. One naive plasma sample failed at the library preparation step. Hence, small RNA-Seq was succesful for 19/20 cases. The raw fastq files obtained from small RNA-Seq were first manually inspected with FastQC (v0.11.3) to check the overall quality of the sequencing data. For primary quantification of read counts, the fastq files were then uploaded to the Qiagen Geneglobe Data analysis center (DAC), a freely available web resource to analyze data from Qiagen’s QIASeq NGS library kits (https://geneglobe.qiagen.com/in/analyze/). Mapping was performed in the DAC portal with bowtie, using the rat reference genome RGSC Rnor_6.0. Annotation of miRNAs was performed with miRBase v21. Following primary quantification, differential expression analysis for miRNAs was performed with DESeq2 (v1.22.2) in R environment (v3.5.3). Logistic regression (LR) with feature selection utilizing nested leave-one-out cross-validation was also performed to identify miRNAs (“features”) contributing most to groupwise differences (differences between naïve, sham, mTBI, sTBI, sTBI + mTBI and naïve + sham). Results: A total of 748 miRNAs were detected across all samples, out of which 723 (97%) were expressed in all the four groups (naive, sham-operated, mTBI and sTBI). Based on the differential expression and logistic regression analyses, we identified five miRNA candidates that contributed most to the seperation between the mTBI and naive groups: rno-miR-9a-3p, rno-miR-153-3p, rno-miR-15a-3p, rno-miR-136-3p and rno-miR-434-3p. We validated the small RNA-Seq data for these miRNA candidates with miRCURY reverse transcriptase quantitative PCR (RT-qPCR). We could succesfully validate elevated levels of miR-9a-3p, miR-136-3p and miR-434-3p in the mTBI group in comparison to naive. When analysed from the whole cohort, the elevated levels of these miRNAs were consistently observed in the mTBI group compared to the naive, both with RT-qPCR and droplet digital PCR (ddPCR). Further, all the three miRNAs revealed elevated plasma levels in the sTBI group in comparison to the mTBI. Conclusions: Elevated plasma miRNA signature of miR-9a-3p, miR-136-3p and miR-434-3p distinguishes rats with mTBI from the naive, in the lateral FPI model of TBI. Further, all these miRNAs exhibit a dose-dependent increase in plasma levels with increase in injury severities.

Project description:The diagnosis of mild traumatic brain injury (TBI) is challenging in the acute setting because the symptoms are nonspecific and often transient, or they develop with a delay. In these cases, the criteria for acute head imaging are frequently not fulfilled. This may lead to missed diagnoses in emergency care. There is a need for developing a rapid diagnostic test to verify the presence of TBI using body fluids. Blood, urine, and saliva samples from 11 adult patients (mean age 64 years, SD 24 years) with acute and clinically diagnosed TBI, and 12 healthy volunteers were collected at Turku University Hospital during a period of 5 months. The injuries necessitated hospitalization for at least one day. The TBIs were classified mild in nine cases and severe in two cases. The mean period between the trauma and the time for obtaining the samples was 27 h, SD 11 h. The samples were analyzed in an ISO-certified laboratory for the number of lectin-bound glycan molecules indicating destruction of nerve tissue. The screening was performed on several possible glycans for binding, and the measurement by degree of fluorescence. In the analysis, the group of patients with TBI was compared with healthy volunteers. The results showed a significant decrease (p < 0.05, Wilcoxon rank-sum two-sided test) in the level of two glycans in plasma, but no significant increase for any glycan; in saliva, one glycan showed a significant increase in the TBI group; in urine, three glycans were significantly different between the groups (one showed an increase, whereas two showed a decrease). The results support the idea of conducting more research on how diagnostic glycans could be detected in body fluids after TBI. As a proof-of-concept, significant changes in the concentration of five glycans were found in plasma, saliva, and urine between TBI patients and healthy controls. This may enable the development of a rapid body fluid-based point-of-care test to identify patients with TBI after a head injury.

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An update on diagnostic and prognostic biomarkers for traumatic brain injury.

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An update on diagnostic and prognostic biomarkers for traumatic brain injury.

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