Biomarkers for Traumatic Brain Injury

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Biomarkers for Traumatic Brain Injury
Copyright
Contents
List of Contributors
Foreword: The hit that would change football forever
	Traumatic brain injury event
	Detection of traumatic brain injury
	Changes to playing style to avoid traumatic brain injury
Section I: Introduction
1 Introduction—scope of the problem
	1.1 Scope of the problem
	1.2 Candidate biomarkers
	1.3 Blood biomarkers for traumatic brain injury
	1.4 Nonblood biomarkers
	1.5 Conclusions
	Disclaimers and Acknowledgments
	References
2 The need for traumatic brain injury markers
	2.1 Introduction
	2.2 Context
	2.3 Probabilities, decision-making, and test thresholds
	2.4 Acute assessment of patients with traumatic brain injury in the emergency department
	2.5 Identification of those patients who will have ongoing problems following traumatic brain injury and the prediction of ...
	2.6 Issues for children
	2.7 Issues for women
	2.8 Issues for future research to consider
		2.8.1 Summary—the importance of being able to predict post-concussion symptoms
		2.8.2 Promising areas of predictive biomarker research
	References
3 Regulatory considerations for diagnostics and biomarkers of traumatic brain injury
	3.1 Background
	3.2 Risk-based classification of medical devices
		3.2.1 Class I—Low-risk devices
		3.2.2 Class II—Moderate-risk devices—premarket notification—510(k) program
		3.2.3 Special 510(k)
		3.2.4 Abbreviated 510(k)
		3.2.5 Class III—High-risk devices—premarket approval
	3.3 Non-standard regulatory pathways
		3.3.1 Humanitarian use devices for rare disorders
		3.3.2 De novo 510(k)
		3.3.3 Use of real-world data in device clearance/approvals—a new initiative
		3.3.4 Oversight of laboratory developed tests
	3.4 Evolving European regulatory framework
	3.5 Elements of Food and Drug Administration review and regulation—case study of two traumatic brain injury-related devices
		3.5.1 Case study 1: ImPACT and ImPACT pediatric
			3.5.1.1 Test battery validity
			3.5.1.2 Reliability
		3.5.2 Case study 2: Banyan brain trauma indicator
	3.6 User fees and their impact on Food and Drug Administration
Section II: Pathophysiology of TBI
4 Peripheral markers of TBI and blood−brain barrier disruption
	4.1 Introduction
	4.2 Biomarkers’ properties
		4.2.1 Nucleic acids as biomarkers
			4.2.1.1 Genetics of posttraumatic events
			4.2.1.2 Cell death and cfDNA are posttraumatic events
			4.2.1.3 MicroRNAs as biomarkers
				4.2.1.3.1 BBB, protein markers, and TBI
	4.3 Conclusions
	Reference
5 The role of autoimmunity after traumatic brain injury
	5.1 Introduction
	5.2 Traumatic brain injury may induce autoimmune disorders
	5.3 How the immune system responds to traumatic brain injury? Role of innate and adaptive immune responses
		5.3.1 Innate immune response to traumatic brain injury: role of cytokines and chemokines
		5.3.2 Innate immune response after traumatic brain injury: role of immune cells
		5.3.3 Adaptive immunity after traumatic brain injury
	5.4 Mechanism of autoimmunity development after traumatic brain injury
		5.4.1 Autoantigens and autoantibodies
		5.4.2 Role of B and T cells in traumatic brain injury-induced autoimmunity
			5.4.2.1 B cells and autoantibody production
			5.4.2.2 T cells and traumatic brain injury-induced autoimmunity
	5.5 Autoantibodies as putative biomarkers
	5.6 Conclusion
	References
6 Traumatic brain injury: glial fibrillary acidic protein posttranslational modification
	Abbreviations
	6.1 Introduction
	6.2 The protein posttranslational modification, citrullination
	6.3 Role of citrullination in the polymerization of glial fibrillary acidic protein
	6.4 Citrullination of glial fibrillary acidic protein as a hallmark mechanism in the pathogenesis of traumatic brain injury
	6.5 Citrullination: method of detection
	6.6 Conclusion and future research
	References
Section III: TBI biomarkers in medical practice
7 Economics of traumatic brain injury biomarkers
	7.1 Introduction
		7.1.1 Traumatic brain injury biomarkers
		7.1.2 Economic evaluations of traumatic brain injury biomarkers
		7.1.3 Current traumatic brain injury standard of care: computed tomography and magnetic resonance imaging
		7.1.4 Creating benchmark cost data for traumatic brain injury biomarkers
	7.2 Methods
		7.2.1 Procedures
		7.2.2 Measurements
			7.2.2.1 Clinically diagnosed traumatic brain injury
			7.2.2.2 CT and MRI utilization and costs
			7.2.2.3 Veterans Health Administration health services costs
			7.2.2.4 Comorbid conditions
		7.2.3 Analysis
	7.3 Results
	7.4 Discussion
		7.4.1 Study limitations
		7.4.2 Implications for policy and practice
		7.4.3 Directions for future research
	References
8 Electrophysiology monitoring
	8.1 Introduction
	8.2 The autonomic nervous system
		8.2.1 Effect of traumatic brain injury on the autonomic nervous system
		8.2.2 Autonomic nervous system biomarkers in traumatic brain injury
		8.2.3 Autonomic nervous system biomarkers in traumatic brain injury rehabilitation
	8.3 Event-related potentials
		8.3.1 Early event-related potential components
		8.3.2 Late event-related potential components
		8.3.3 P300 event-related potential component
		8.3.4 N2 event-related potential component
		8.3.5 Event-related potentials as biomarkers in traumatic brain injury
			8.3.5.1 Moderate-to-severe traumatic brain injury
			8.3.5.2 Mild traumatic brain injury
		8.3.6 Event-related potentials as biomarkers in traumatic brain injury recovery
	8.4 Conclusion
	References
9 Traumatic brain injury therapeutics
	9.1 Airway and ventilator management
	9.2 Sedation and analgesia
	9.3 Hyperosmolar therapy
	9.4 External ventricular devices
	9.5 Decompressive craniectomy/craniotomy
	9.6 Therapeutic hypothermia
	9.7 Seizure prophylaxis
	References
Section IV: Classical TBI biomarkers
10 S100 biomarkers in patients with traumatic brain injury
	10.1 Introduction
	10.2 Biomarker family S100
		10.4.1 General characteristics
		10.4.2 Biological functions
		10.4.3 Family member S100B
			10.4.1.1 Special characteristics of S100B
			10.4.1.2 Mechanism of pathologic increase of S100B
			10.4.1.3 Half-life and elimination of S100B
	10.3 Clinical applications of S100B
		10.4.4 Applications in dermatology
		10.4.5 Applications in neurosurgery
	10.4 Current state of research regarding neurosurgical implications of S100B
		10.4.6 Studies regarding diagnostic application of S100B
			10.4.1.4 Influence of alcohol intoxication on diagnostic outcome
			10.4.1.5 β-error in diagnostics
		10.4.7 Studies regarding half-life and elimination of S100B
		10.4.8 Studies regarding extracerebral sources of S100B
		10.4.9 Prognostic value of S100B
	10.5 Conclusion
	References
11 Pathophysiology and clinical implementation of traumatic brain injury biomarkers: neuron-specific enolase
	11.1 Introduction
	11.2 Neuron-specific enolase basics—physiology and pathophysiology
	11.3 Neuron-specific enolase as a biomarker in pathological conditions
	11.4 Neuron-specific enolase after ischemic brain damage
	11.5 Neuron-specific enolase in brain trauma
		11.5.1 Mild traumatic brain injury
	11.6 Moderate and severe traumatic brain injury
	11.7 Neuron-specific enolase in children
	11.8 Limitations of neuron-specific enolase as a traumatic brain injury biomarker
	11.9 Conclusion
	References
12 Traumatic brain injury biomarkers glial fibrillary acidic protein/ubiquitin C-terminal hydrolase L1
	12.1 Computed tomography imaging
	12.2 Ubiquitin C-terminal hydrolase L1 and glial fibrillary acidic protein
	12.3 Predetermined cutoff and validation
	12.4 Biomarker performance
		12.4.1 Vignette
	12.5 Specificity of glial fibrillary acidic protein/ubiquitin C-terminal hydrolase L1
		12.5.1 Vignette
	12.6 Glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 trends over time
	12.7 Use in m-traumatic brain injury
		12.7.1 Vignette
	12.8 Future directions
	References
13 Neurofilaments light chain/Neurofilaments heavy chain
	13.1 Introduction
	13.2 Neurofilament for traumatic brain injury diagnosis
	13.3 Neurofilament levels for detecting secondary brain injury
	13.4 Neurofilament levels for outcome prediction in patients with traumatic brain injury
	13.5 Serum biomarkers of cardiac arrest/ultimate ischemic brain damage
	13.6 Conclusion
	References
14 Tau protein, biomarker for traumatic brain injury
	14.1 Introduction
	14.2 Pathophysiology
	14.3 Tau as a biomarker in cerebral spinal fluid
	14.4 Tau as a biomarker in the blood
	14.5 Conclusion
	References
Section V: Novel TBI biomarkers
15 Neurogranin
	15.1 Historical background
	15.2 Physiologic function
	15.3 Pathophysiology of brain disorders
		15.3.1 Neurodegeneration
		15.3.2 Neuroinflammation
		15.3.3 Neuropsychiatric conditions
		15.3.4 Neurovascular
	15.4 Neurogranin and traumatic brain injury
	15.5 Conclusions
	References
16 Myelin basic protein in traumatic brain injury
	16.1 Myelin basic protein
		16.1.1 Myelin and multiple sclerosis
		16.1.2 Summary and future study
	References
Section VI: Analytical testing consideration
17 Antibody selection, evaluation, and validation for analysis of traumatic brain injury biomarkers
	17.1 Introduction
	17.2 Finding the right antibody for a specific research application
	17.3 Antibody evaluation and initial characterization
	17.4 Immunological test method characteristics and validation
	17.5 Diagnostic sensitivity and specificity, positive predictive value, negative predictive value, positive and negative li...
	17.6 Antibodies for traumatic brain injury
	17.7 What to report in a research publication
	17.8 Concluding remarks
	References
18 Sensitive immunoassay testing platforms
	18.1 Brief introduction to traumatic brain injury and current state of testing
	18.2 Brief overview of neural tissue and cell types
	18.3 Discussion of biomarkers and their limitations in testing for mild/moderate traumatic brain injury
		18.3.1 Fluid type
		18.3.2 Food and Drug Administration—approved laboratory test and limitations
		18.3.3 Biomarkers more specific to axonal injury/mild or moderate traumatic brain injury
	18.4 The need for multiplexed and sensitive assays
		18.4.1 Why do we need multiplexed assays?
		18.4.2 The barriers of traumatic brain injury biomarker testing in blood: the need for ultrasensitive assays
	18.5 Digital enzyme-linked immunosorbent assay using single-molecule arrays
		18.5.1 Measurement principles
		18.5.2 Performance
		18.5.3 Applications in neurology/traumatic brain injury
	18.6 Single-molecule counting
		18.6.1 Measurement principles
		18.6.2 Performance
		18.6.3 Applications in neurology/traumatic brain injury
	18.7 Concluding remarks
	References
19 Clinical mass spectrometry and its applications in traumatic brain injuries
	19.1 Introduction of mass spectrometry platform
	19.2 Fundamentals of clinical mass spectrometry
		19.2.1 Types of ionization methods
			19.2.1.1 Electrospray ionization
			19.2.1.2 Atmospheric pressure chemical ionization
			19.2.1.3 Atmospheric pressure photoionization
			19.2.1.4 Matrix-assisted laser desorption ionization
		19.2.2 Mass analyzers
			19.2.2.1 Overview
			19.2.2.2 Time of flight mass analyzers
			19.2.2.3 Triple-quadrupole mass analyzers
	19.3 Clinical applications of mass spectrometry
		19.3.1 Overview
		19.3.2 Clinical toxicology: drugs of abuse and pain management
		19.3.3 Endocrinology/steroid hormones
		19.3.4 Therapeutic drug monitoring
		19.3.5 Targeted mass spectrometer assay for clinical proteomics
	19.4 Comparing immunoassays to clinical mass spectrometer
		19.4.1 Specificity
		19.4.2 Sensitivity
		19.4.3 Multiplexing capability
		19.4.4 Cost
	19.5 The role of clinical mass spectrometry in the analysis of traumatic brain injury
		19.5.1 Traumatic brain injury—a brief overview
		19.5.2 Current status of mass spectrometry-based traumatic brain injury research
			19.5.2.1 Overview
			19.5.2.2 Lipidomics and metabolomics in traumatic brain injury research
			19.5.2.3 Neuroproteomics in TBI research
	19.6 New developments: FDA approval on the brain trauma indicator (Banyan BTI)
	19.7 Future of clinical mass spectrometry in the diagnosis of traumatic brain injury
		19.7.1 Challenges: from discovery research to the clinic
		19.7.2 Opportunities: targeted mass spectrometry assays for traumatic brain injury biomarker validation and future clinical...
	19.8 Summary
	References
20 Surface plasmon resonance
	20.1 Introduction
	20.2 History
	20.3 The sensorgram
	20.4 Grating-coupled Surface plasmon resonance
	20.5 Surface plasmon resonance-based sensors
		20.5.1 Localized surface plasmon resonance
		20.5.2 Surface plasmon resonance-MS
		20.5.3 Surface plasmon resonance imaging
		20.5.4 Surface plasmon field-enhanced fluorescence spectroscopy
	20.6 Biosensing applications of surface plasmon field-enhanced fluorescence spectroscopy
		20.6.1 Cardiac troponin
		20.6.2 D-dimer
		20.6.3 Traumatic brain injury-related biomarkers
			20.6.3.1 Glial fibrillary acidic protein
			20.6.3.2 Neurogranin
		20.6.4 Grating-coupled Surface plasmon field-enhanced fluorescence spectroscopy
	20.7 Conclusion
	References
21 Point-of-care testing for concussion and traumatic brain injury
	21.1 Introduction to point-of-care testing
	21.2 Point-of-care testing for traumatic brain injury
		21.2.1 Ease-of-use
		21.2.2 Testing by nonmedical personnel
		21.2.3 Use-case scenarios
	References
	Further reading
Section VII: Non-blood TBI biomarker strategy
22 Clinical risk factors of traumatic brain injury
	22.1 Introduction
	22.2 Clinical risk factors in traumatic brain injury
		22.2.1 Severity of traumatic brain injury and guideline-based treatment in high volume centers
		22.2.2 Cranial imaging in patients with traumatic brain injury
		22.2.3 Prehospital treatment – avoidance of secondary brain injury
		22.2.4 In-hospital treatment – emergency department
		22.2.5 In-hospital treatment – emergency surgical intervention
		22.2.6 Predictive factors for prognosis of outcome in traumatic brain injury
	References
23 Saliva biomarkers of traumatic brain injury
	23.1 Biomarkers of traumatic brain injury
	23.2 Stress response profiling: a new method for unbiased discovery of traumatic brain injury biomarkers
	23.3 Homeostatic pathways monitored by stress response profiling biomarkers
		23.3.1 Redox stress response
		23.3.2 Cellular detoxification
		23.3.3 Protein chaperoning
		23.3.4 DNA repair and modification
		23.3.5 Adhesion, cytoskeleton, extracellular matrix, and exosomes
		23.3.6 Cell cycle and energy metabolism
		23.3.7 Apoptosis and autophagy
		23.3.8 Neuroendocrine signaling
		23.3.9 Immunity
		23.3.10 Microbial stress response
		23.3.11 Osmotic stress response
	23.4 Pathway signature of traumatic brain injury
	23.5 Saliva specimen for traumatic brain injury biomarkers
		23.5.1 Standard saliva specimen
		23.5.2 Whole saliva specimen
		23.5.3 Biomarker assays for whole saliva
	23.6 Saliva biomarkers of mild traumatic brain injury
	23.7 Saliva biomarkers of severe traumatic brain injury
	23.8 Conclusions
	Future directions
	References
24 Digital neurocognitive testing
	References
25 Electroencephalographic as a biomarker of concussion
	25.1 Why should electroencephalographic be considered for use as a biomarker of concussion?
	25.2 Standard clinical electroencephalographic using visual inspection
	25.3 Evoked potentials
		25.3.1 Brain stem auditory evoked potentials
		25.3.2 Visual evoked potentials
		25.3.3 Cognitive evoked potentials/event related potentials
	25.4 Spectral analysis
	25.5 3D electroencephalographic mapping—standardized low-resolution electromagnetic tomographic activity
	25.6 Discriminant analyses methods
	25.7 Practical application of electroencephalographic in the clinical setting
		25.7.1 Case #1
		25.7.2 Case #2
	25.8 Future directions of electroencephalographic technologies in the field of concussion identification and management
	References
	Further reading
26 Neuropsychological testing
	26.1 Neuropsychological tests
	26.2 Memory
		26.2.1 Brief Visuospatial Memory Test
		26.2.2 Rey Auditory Verbal Learning Test
	26.3 Processing speed
		26.3.1 Trail Making Test Part A
		26.3.2 Wechsler Adult Intelligence Scale IV processing speed index
	26.4 Executive function
		26.4.1 Controlled Oral Word Association Test
		26.4.2 Wechsler Adult Intelligence Scale IV Complete
		26.4.3 1D-KEFS color word interference
		26.4.4 Trail Making Test Part B
	26.5 Mood, postconcussive syndrome, posttraumatic stress disorder tests
		26.5.1 Patient Health Questionnaire-9 and Center for Epidemiologic Studies Depression Scale
		26.5.2 PTSD checklist for DSM-5
		26.5.3 Rivermead Post-Concussion Symptoms Questionnaire
	26.6 Biomarkers
		26.6.1 Glial fibrillary acidic protein
		26.6.2 Ubiquitin C-terminal hydrolase L1
		26.6.3 Tau
		26.6.4 Neuron-specific enolase
		26.6.5 S-100β
		26.6.6 Brain-derived neurotrophic factor
	26.7 Conclusion
		Subject
	References
27 Outpatient risk stratification for traumatic brain injury
	References
28 Peptidomics and traumatic brain injury: biomarker utilities for a theragnostic approach
	28.1 Introduction
	28.2 Peptidome in biofluids as biomarkers
	28.3 Serum
	28.4 Cerebrospinal fluid
	28.5 Plasma
	28.6 Urine
	28.7 Saliva
	28.8 Tissue
	28.9 Tear
	28.10 Microvesicles and exosomes
	28.11 Fractionation and separation
	28.12 Peptide identification and data analysis
	28.13 Peptidomic approach for discovery of novel proteolytic peptides in traumatic brain injury
	28.14 Current mass spectrometric peptidomic technologies
	28.15 Concluding remarks
	References
29 Autoantibodies in central nervous system trauma: new frontiers for diagnosis and prognosis biomarkers
	29.1 Introduction
	29.2 The immunological events following central nervous system injury
		29.2.1 Initial signaling
		29.2.2 Microglial activation
		29.2.3 Peripheral innate immune activation
		29.2.4 Adaptive immunity in traumatic brain injury and spinal cord injury
		29.2.5 Role of autoimmunity
		29.2.6 Neurotoxic waste removal via the glymphatic system is impaired posttraumatic brain injury
		29.2.7 Autoantibodies as biomarkers in central nervous system trauma
		29.2.8 List of identified autoantibodies
			29.2.8.1 Myelin basic protein
			29.2.8.2 GFAP
			29.2.8.3 S100β protein
			29.2.8.4 Acetylcholine receptor (α7 ACR)
			29.2.8.5 Peroxiredoxin 6
			29.2.8.6 Glutamate receptors (GluR1 and NR2A)
			29.2.8.7 Other personalized autoantigens
		29.2.9 Evaluation of autoantibodies as central nervous system injury biomarkers
	29.3 Activation of B cells exacerbates secondary central nervous system injury
	29.4 B cells as therapeutic targets for central nervous system injury
	29.5 Conclusion
	References
Index
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