Current status of fluid biomarkers in mild traumatic brain injury
Section snippets
Biofluids for mTBI biomarkers
Blood (serum and plasma) is a preferred biofluid for biomarker discover because of the ease of access, ease of processing, relatively homogenous samples, and the large amount of normative data available (Lundblad, 2003). However, because it comes into contact with all tissues and organs, blood can present difficulties in identifying the source of a protein and can also present challenges in terms of sensitivity and dynamic range (Good et al., 2007).
Most mTBI studies have evaluated potential
The hypothesis-driven approach:
Based on the success of serum troponin-T as a biomarker for myocardial damage, (Mair et al., 1992), a search began for biomarkers of brain injury. Putative candidates were identified based on their relatively high abundance in cells or cellular compartments known to be affected in TBI, and protein concentrations in blood or CSF were evaluated.
Early TBI biomarker candidates were lactate dehydrogenase and creatine kinase BB. However, these did not have sufficient specificity, sensitivity, or
The unbiased approach
The above hypothesis-driven biomarkers have largely been evaluated in moderate to severe TBI. For mTBI, diagnosis is more challenging because of the less severe symptoms and typically negative conventional imaging results. As discussed above, evaluation of existing biomarkers reveals some promising candidates to assist in the diagnosis of mTBI, although many challenges remain. Several studies included multiple injury levels and did not analyze the mild injury data independently. Mild traumatic
Phage display
Phage display is a method to select peptides, proteins or antibodies with specific binding properties. It is most widely used to investigate protein-protein interactions, receptor- and antibody-binding sites, and for selecting antibodies against a range of antigens (Bradbury, 2010). It uses bacteriophages (viruses that infect bacteria) in which DNA encoding peptides or proteins is inserted into the gene encoding a coat protein of a filamentous phage such as M13 phage. Libraries of
Biomarkers in urine
Urine is easily obtained, particularly in the post-acute phase where it could be self-collected. However, quantitation of urinary biomarkers is problematic as they can very dependent upon flow rates. Urinary S100B measurement revealed elevations in children and adults with severe TBI and strong correlations with serum S100B levels (Berger and Kochanek, 2006, Hallen et al., 2010, Rodriguez-Rodriguez et al., 2012). However, a separate study of pediatric TBI found similar S100B levels in urine
Conclusions
Millions of people are affected by mTBI and its sequelae, but mTBI is difficult to diagnose. It lacks a consensus definition, relies on subjective self-reported symptoms, and is insensitive to commonly available imaging modalities. An objective and quantifiable measure of mTBI, such as a serum biomarker, is needed. Suitable biomarkers would aid in diagnosis, prognosis, return to play/duty assessments, therapeutic evaluations, and provide additional knowledge regarding mTBI pathophysiology. Most
Acknowledgements
The author’s research was supported by NIH grants R21 NS084088 and RO1 NS062993.
References (227)
- et al.
Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast
Free Radic. Biol. Med.
(2013) microRNAs: tiny regulators with great potential
Cell
(2001)- et al.
Reference values for venous and capillary S100B in children
Clin. Chim. Acta
(2011) - et al.
Association of increased S100B, S100A6 and S100P in serum levels with acute coronary syndrome and also with the severity of myocardial infarction in cardiac tissue of rat models with ischemia-reperfusion injury
Atherosclerosis
(2011) - et al.
Protein gene product 9.5 (PGP 9.5) is not a specific marker of neural and nerve sheath tumors: an immunohistochemical study of 95 mesenchymal neoplasms
Mod. Pathol.
(2003) - et al.
Systematic review of return to work after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis
Arch. Phys. Med. Rehabil.
(2014) - et al.
Systematic review of the prognosis after mild traumatic brain injury in adults: cognitive, psychiatric, and mortality outcomes: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis
Arch. Phys. Med. Rehabil.
(2014) - et al.
Biomarkers for the diagnosis, prognosis, and evaluation of treatment efficacy for traumatic brain injury
Neurotherapeutics
(2010) - et al.
Circulating miRNAs as sensitive and specific biomarkers for the diagnosis and monitoring of human diseases: promises and challenges
Clin. Biochem.
(2013) - et al.
An acidic protein isolated from fibrous astrocytes
Brain Res.
(1971)
Astroglia: important mediators of traumatic brain injury
Prog. Brain Res.
Biomarkers in melanoma
Ann. Oncol.
Validity of serum tau protein levels in pediatric patients with minor head trauma
Am. J. Emerg. Med.
Reverse phase protein microarray technology in traumatic brain injury
J. Neurosci. Methods
Antioxidant therapies for traumatic brain injury
Neurotherapeutics
Temporally resolved differential proteomic analysis of human ventricular CSF for monitoring traumatic brain injury biomarker candidates
J. Neurosci. Methods
The demonstration of new human brain-specific proteins by high-resolution two-dimensional polyacrylamide gel electrophoresis
J. Neurol. Sci.
Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting
J. Emerg. Nurs.
Neuron-specific enolase increases in plasma during and immediately after extracorporeal circulation
Ann. Thorac. Surg.
The value of serum tau protein for the diagnosis of intracranial injury in minor head trauma
Am. J. Emerg. Med.
Novel differential neuroproteomics analysis of traumatic brain injury in rats
Mol. Cell. Proteomics
Proteomic biomarkers for blast neurotrauma: targeting cerebral edema, inflammation, and neuronal death cascades
J. Neurotrauma
Long-term consequences of single and multiple mild blast exposure on select physiological parameters and blood-based biomarkers
Electrophoresis
Analysis of serum and plasma identifies differences in molecular coverage, measurement variability, and candidate biomarker selection
Proteomics Clin. Appl.
High serum S100B levels for trauma patients without head injuries
Neurosurgery
The phosphorylated axonal form of the neurofilament subunit NF-H (pNF-H) as a blood biomarker of traumatic brain injury
J. Neurotrauma
Mild traumatic brain injury: a neuropsychiatric approach to diagnosis, evaluation, and treatment
Neuropsychiatr. Dis. Treat.
Probing microRNAs with microarrays: tissue specificity and functional inference
RNA
Enzymatic changes in serum and cerebrospinal fluid in neurological injury
J. Neurosurg.
Principles for return to learn after concussion
Int. J. Clin. Pract.
MicroRNA let-7i is a promising serum biomarker for blast-induced traumatic brain injury
J. Neurotrauma
Expression and localization of myelin basic protein in oligodendrocytes and transfected fibroblasts
J. Neurochem.
Chronic stress, salivary cortisol response, interpersonal relatedness, and depression among community-dwelling survivors of traumatic brain injury
J. Neurosci. Nurs.
Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children
Pediatr. Res.
Serum S-100B and cleaved-tau are poor predictors of long-term outcome after mild traumatic brain injury
Brain Inj.
Serum biochemical markers for post-concussion syndrome in patients with mild traumatic brain injury
J. Neurotrauma
The use of serum biomarkers to predict outcome after traumatic brain injury in adults and children
J. Head Trauma Rehabil.
Urinary S100B concentrations are increased after brain injury in children: A preliminary study
Pediatr. Crit. Care Med.
Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children
J. Neurosurg.
Identification of inflicted traumatic brain injury in well-appearing infants using serum and cerebrospinal markers: a possible screening tool
Pediatrics
Multiplex assessment of serum biomarker concentrations in well-appearing children with inflicted traumatic brain injury
Pediatr. Res.
Serum concentrations of ubiquitin C-terminal hydrolase-L1 and alphaII-spectrin breakdown product 145 kDa correlate with outcome after pediatric TBI
J. Neurotrauma
Neuroimaging biomarkers in mild traumatic brain injury (mTBI)
Neuropsychol. Rev.
Biomarkers and surrogate endpoints: preferred definitions and conceptual framework
Clin. Pharmacol. Ther.
Myelin basic protein: a multifunctional protein
Cell. Mol. Life Sci.
Coping styles, cortisol reactivity, and performance in a vigilance task of patients with persistent postconcussive symptoms after a mild head injury
Int. J. Neurosci.
Regional neurodegeneration and gliosis are amplified by mild traumatic brain injury repeated at 24-hour intervals
J. Neuropathol. Exp. Neurol.
The use of phage display in neurobiology
Curr. Prot. Neurosci, (Crawley J.N. e al., eds)
Guidelines for the management of severe traumatic brain injury
J. Neurotrauma
Mild traumatic brain injury
Mt Sinai J. Med.
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2021, Brain, Behavior, and ImmunityCitation Excerpt :Characterizing inflammation in the peripheral blood can help uncover the potential systemic consequences of brain injury and reveal the inflammatory status of the brain (Jeter et al., 2013; Kim et al., 2018; Kulbe and Geddes, 2016; Wang et al., 2005; Zetterberg et al., 2013). Many groups have been able to successfully detect significant increases in inflammatory markers in the blood following TBI and established associations or correlations with other injury parameters and outcomes (Jeter et al., 2013; Kim et al., 2018; Kulbe and Geddes, 2016; Wang et al., 2005; Zetterberg et al., 2013). Many of the cytokines/chemokines we measured in this study are considered pro-inflammatory (Gyoneva and Ransohoff, 2015).