Correlation of Blood Biomarkers and Biomarker Panels with Traumatic Findings on Computed Tomography after Traumatic Brain Injury

Posti, Jussi P.; Takala, Riikka; Lagerstedt, Linnéa; Dickens, Alex M.; Hossain, Iftakher; Mohammadian, Mehrbod; Ala-Seppälä, Henna; Frantzén, Janek; Gils, Mark van; Hutchinson, Peter J.; Katila, Ari; Maanpää, Henna Riikka; Menon, David; Newcombe, Virginia; Tallus, Jussi; Hrusovsky, Kevin; Wilson, David H.; Gill, Jessica; Sánchez, Jean Charles; Tenovuo, Olli; Zetterberg, Henrik; Blennow, Kaj

doi:10.1089/neu.2018.6254

Cited by 58 publications

(75 citation statements)

References 33 publications

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“…Among these, elevated blood Aβ40 and Aβ42 fragments have been detected acutely and chronically after mTBI (Lejbman et al, 2016;Bogoslovsky et al, 2017). However, blood Aβ levels appear to lack specificity for TBI (Posti et al, 2019). As such, in both mTBI and PTSD, there is a current need for biomarkers to help characterize biological changes differentially associated with each disorder in order to improve clinical detection and monitoring of long-term consequences of mTBI and PTSD.…”

Section: Introductionmentioning

confidence: 99%

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

et al. 2020

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The differential diagnosis between mild Traumatic Brain Injury (mTBI) sequelae and Post-Traumatic Stress Disorder (PTSD) is challenging due to their symptomatic overlap and co-morbidity. As such, there is a need to develop biomarkers which can help with differential diagnosis of these two conditions. Studies from our group and others suggest that blood and brain lipids are chronically altered in both mTBI and PTSD. Therefore, examining blood lipids presents a minimally invasive and cost-effective approach to identify promising biomarkers of these conditions. Using liquid chromatography-mass spectrometry (LC-MS) we examined hundreds of lipid species in the blood of healthy active duty soldiers (n = 52) and soldiers with mTBI (n = 21), PTSD (n = 34) as well as co-morbid mTBI and PTSD (n = 13) to test whether lipid levels were differentially altered with each. We also examined if the apolipoprotein E (APOE) ε4 allele can affect the association between diagnosis and peripheral lipid levels in this cohort. We show that several lipid classes are altered with diagnosis and that there is an interaction between diagnosis and the ε4 carrier status on these lipids. Indeed, total lipid levels as well as both the degree of unsaturation and chain lengths are differentially altered with diagnosis and ε4 status, specifically long chain unsaturated triglycerides (TG) and both saturated and mono-unsaturated diglycerides (DG). Additionally, an examination of lipid species reveals distinct profiles in each diagnostic group stratified by ε4 status, mainly in TG, saturated DG species and polyunsaturated phosphatidylserines. In summary, we show that peripheral lipids are promising biomarker candidates to assist with the differential diagnosis of mTBI and PTSD. Further, ε4 carrier status alone and in interaction with diagnosis has a strong influence on peripheral lipid levels. Therefore, examining ε4 status along with peripheral lipid levels could help with differential diagnosis of mTBI and PTSD.

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Section: Introductionmentioning

confidence: 99%

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

et al. 2020

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“…Currently, strategies for diagnosing and treating TBI in patients are limited [12]. Imaging tests (computed tomography, CT or magnetic resonance imaging, MRI) are generally applied to diagnose and classify TBI in clinical practice but are limited because of low sensitivity in patients with mild injuries [13,14]. Cerebrospinal fluid (CSF) or blood tests are useful in the assessment of the severity of the injury and subsequent recovery of TBI patients by detecting protein or miRNA components in the peripheral blood [14].…”

Section: Introductionmentioning

confidence: 99%

“…Imaging tests (computed tomography, CT or magnetic resonance imaging, MRI) are generally applied to diagnose and classify TBI in clinical practice but are limited because of low sensitivity in patients with mild injuries [13,14]. Cerebrospinal fluid (CSF) or blood tests are useful in the assessment of the severity of the injury and subsequent recovery of TBI patients by detecting protein or miRNA components in the peripheral blood [14]. For instance, protein tests that can detect cytokines, chemokines, tau, calcium-binding protein S100B, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), ubiquitin carboxyterminal hydrolase L1 (UCH-L1), and myelin basic protein (MBP) are candidates for classification and prognostication of TBI patients [15].…”

Section: Introductionmentioning

confidence: 99%

Plasma Exosome-derived MicroRNAs as Novel Biomarkers of Traumatic Brain Injury in Rats

Wang

Zhang

et al. 2020

Int. J. Med. Sci.

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Traumatic brain injury (TBI) is a widespread central nervous system (CNS) condition and a leading cause of death, disability, and long-term disability including seizures and emotional and behavioral issues. To date, applicable diagnostic biomarkers have not been elucidated. MicroRNAs (miRNAs) are enriched and stable in exosomes in plasma. Therefore, we speculated that miRNAs in plasma exosomes might serve as novel biomarkers for TBI diagnosis and are also involved in the pathogenesis of TBI. In this study, we first isolated exosomes from peripheral blood plasma in rats with TBI and then investigated the alterations in miRNA expression in exosomes by high-throughput RNA sequencing. As a result, we identified 50 significantly differentially expressed miRNAs, including 31 upregulated and 19 downregulated miRNAs. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the most highly correlated pathways that were identified were the MAPK signaling pathway, regulation of actin cytoskeleton, Rap1 signaling pathway and Ras signaling pathway. This study provides novel perspectives on miRNAs in peripheral blood plasma exosomes, which not only could be used as biomarkers of TBI diagnosis but could also be manipulated as therapeutic targets of TBI.

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“…In studies of sports-related mTBI evaluating concussed professional ice hockey players and boxers after a bout, tau and neurofilament L are elevated in the blood, and in the former group and in a manner similar to SNTF, predict the persistence of post-concussion symptoms based on the length of the delay in return to play. On the other hand, studies published to date of tau and NFL as candidate markers for TBI treated in the emergency department have included cases with discernable intracranial lesions on head CT scan, thus precluding evaluation of these markers for prognosis of mTBI (30)(31)(32). Strikingly, SNTF, tau, and neurofilament L are all important structural proteins of the axon whose blood levels rise after sports-related concussion (26)(27)(28), supporting the hypothesis that they all represent surrogate blood biomarkers for the diffuse axonal injury underlying functionally deleterious mTBI.…”

Section: Discussionmentioning

confidence: 99%

“…However, studies of tau and NFL as prognostic markers for mTBI treated in the emergency department included complicated TBI cases with intracranial lesions discernable on non-contrast head CT scan, which may be prognostic for worse long-term outcomes (29). Thus far, neither marker has shown utility in this setting for the prognosis of uncomplicated mTBI (30)(31)(32). Biomarkers tied to brain elements other than the axon also have been investigated as candidates for mTBI.…”

Section: Introductionmentioning

confidence: 99%

Serum SNTF, a Surrogate Marker of Axonal Injury, Is Prognostic for Lasting Brain Dysfunction in Mild TBI Treated in the Emergency Department

et al. 2020

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Mild traumatic brain injury (mTBI) causes persisting post-concussion syndrome for many patients without abnormalities on conventional neuroimaging. Currently, there is no method for identifying at-risk cases at an early stage for directing concussion management and treatment. SNTF is a calpain-derived N-terminal proteolytic fragment of spectrin (α II-spectrin1-1176) generated in damaged axons following mTBI. Preliminary human studies suggest that elevated blood SNTF on the day of mTBI correlates with white matter disruption and lasting brain dysfunction. Here, we further evaluated serum SNTF as a prognostic marker for persistent brain dysfunction in uncomplicated mTBI patients treated in a Level I trauma center emergency department. Compared with healthy controls (n = 40), serum SNTF increased by 92% within 24 h of mTBI (n = 95; p < 0.0001), and as a diagnostic marker exhibited 100% specificity and 37% sensitivity (AUC = 0.87). To determine whether the subset of mTBI cases positive for SNTF preferentially developed lasting brain dysfunction, serum levels on the day of mTBI were compared with multiple measures of brain performance at 90 days post-injury. Elevated serum SNTF correlated significantly with persistent impairments in cognition and sensory-motor integration, and predicted worse performance in each test on a case by case basis (AUC = 0.68 and 0.76, respectively). SNTF also predicted poorer recovery of cognitive stress function from 30 to 90 days (AUC = 0.79-0.90). These results suggest that serum SNTF, a surrogate marker for axonal injury after mTBI, may have potential for the rapid prognosis of lasting post-concussion syndrome and impaired functional recovery following CT-negative mTBI. They provide further evidence linking axonal injury to persisting brain dysfunction after uncomplicated mTBI. A SNTF blood test, either alone or combined with other markers of axonal injury, may have important utilities for research, prognosis, management and treatment of concussion.

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Correlation of Blood Biomarkers and Biomarker Panels with Traumatic Findings on Computed Tomography after Traumatic Brain Injury

Cited by 58 publications

References 33 publications

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

Plasma Exosome-derived MicroRNAs as Novel Biomarkers of Traumatic Brain Injury in Rats

Serum SNTF, a Surrogate Marker of Axonal Injury, Is Prognostic for Lasting Brain Dysfunction in Mild TBI Treated in the Emergency Department

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