Biomarkers for Traumatic Brain Injury -- Contents -- List of Contributors -- Chapter 1 Clinical Relevance of Biomarkers for Traumatic Brain Injury -- 1.1 Introduction -- 1.2 Epidemiology and Health Care Economics -- 1.3 Diagnosis -- 1.4 Potential Clinical Applications of TBI Biomarkers -- 1.5 Human Biomarkers for TBI -- 1.6 Future Directions -- References -- Chapter 2 Magnetic Resonance Imaging Biomarkers of Mild Traumatic Brain Injury -- 2.1 Introduction -- 2.2 Search Criteria and Results -- 2.3 Clinical CT and MRI -- 2.3.1 Susceptibility Weighted Imaging (SWI) of Hemorrhagic Lesions -- 2.4 Diffusion Tensor Imaging (DTI) of Axonal Injury -- 2.4.1 Imaging at Different Pathological Stages -- 2.4.2 Correlation Between DTI-Derived WM Injury Topography and Neuropsychological De cits -- 2.4.3 Pros and Cons of Different Analytical Approaches -- 2.4.4 DTI Caveat -- 2.5 In Vivo 1H MR Spectroscopic Imaging -- 2.6 Perfusion Imaging -- 2.7 Delivering Improved Care to Patients with mTBI -- 2.8 Conclusions -- References -- Chapter 3 Immunoexcitotoxicity as a Central Mechanism of Chronic Traumatic Encephalopathy - A Unifying Hypothesis -- 3.1 Introduction -- 3.2 Clinical Features of Chronic Traumatic Encephalopathy -- 3.3 Pathological Features of Chronic Traumatic Encephalopathy -- 3.4 Microglial Priming and Activation with TBI -- 3.4.1 Immunoexcitotoxicity -- 3.4.2 The Aging Brain and Immunoexcitotoxicity -- 3.4.3 White Matter Damage with Immunoexcitotoxicity -- 3.5 Animals and Human Studies Showing Delayed, Progressive Axonal Injury -- 3.5.1 Macrophage Recruitment to the CNS -- 3.6 Immunoexcitotoxicity and Hyperphosphorylation of Tau -- 3.7 Conclusions -- References -- Chapter 4 Neurodegradomics: The Source of Biomarkers for Mild Traumatic Brain Injury -- 4.1 Introduction -- 4.2 Neurodegradomics: The Source of Brain Biomarkers -- 4.2.1 Blood-Brain Barrier.

4.2.2 Brain Microvessels -- 4.2.3 Brain Microglial System -- 4.2.4 Brain Proteolysis -- 4.3 Glutamate-Induced Neurotoxicity (Excitotoxicity) Triggers Secondary Brain Injury -- 4.3.1 Biomarkers of Glutamate-Induced Neurotoxicity -- 4.3.2 ''Bottom Up'' Approach -- 4.3.3 ''Top Down'' Approach -- 4.4 Glutamate Receptor Biomarkers in Peripheral Fluids -- 4.4.1 Natural Antigens and Antibodies Responses to Brain Damage -- 4.4.2 Autoantibodies and Autoimmune Reactions to CNS Injury -- 4.5 Conclusions -- References -- Chapter 5 Neurotoxicity Biomarkers in Experimental Acute and Chronic Brain Injury -- 5.1 Introduction: Neurotoxicity Biomarkers in Experimental Brain Injuries -- 5.2 NMDA and AMPA Receptor Antigens after Experimental Concussion -- 5.2.1 Effect of Concussion Injury on Behavior and Neurological State -- 5.2.2 Assessment of Brain Damage and Blood-Brain Barrier (BBB) Integrity -- 5.2.3 Cortical NMDA and AMPA Receptor mRNA Expression and Receptor Subunit Densities -- 5.2.4 Proteolytic Receptor Fragments in Peripheral Fluids -- 5.3 AMPA Receptor Antibodies in Chronic Consequences after Experimental Concussion -- 5.3.1 Distant Effect of Concussion Injury -- 5.3.2 AMPA Receptor Subunit mRNA Expression and Protein Densities in Hippocampus -- 5.3.3 Detection of AMPA Receptor Subunit Antibodies in Serum -- 5.4 Effects of Endogenous Peptide Inhibitor of AMPAR on Cortical Impact -- 5.4.1 Endogenous Peptide Factor of Glutamate Receptors -- 5.4.2 Pharmacological Properties and Functional Activity of Synthetic Peptides -- 5.4.3 Preclinical Studies of Glyzargin Effects -- 5.5 Conclusions -- Acknowledgments -- References -- Chapter 6 Mitochondrial Dysfunctions and Markers of Spinal Cord Injury -- 6.1 Introduction -- 6.2 Brain and Spinal Cord Mitochondria Respond Differently to Trauma -- 6.2.1 Metabolic Differences between Spinal Cord and Brain Mitochondria.

6.2.2 Relationships between Respiration and the Mitochondrial Calcium Retention Capacity -- 6.2.3 Distinctive Properties of ROS Generation in Brain and Spinal Cord Mitochondria -- 6.2.4 Activation of Glutamate Receptors Stimulates Acute Excitotoxic Death of Neurons and Oligodendrocytes in Spinal Cord Injury -- 6.3 The Concept of Primary and Secondary Acute Spinal Cord Injury -- 6.4 Early Markers of Spinal Cord Injury -- 6.4.1 Neuron-Speci c Enolase -- 6.4.2 S-100 Protein -- 6.5 Early Involvement of Mitochondria in Spinal Cord Injury -- 6.6 Conclusions -- References -- Chapter 7 Biomarkers of Neuroglial Injury in Rat Models of Combat TBI: Primary Blast Over-Pressure Compared to ''Composite'' Blast -- 7.1 Introduction -- 7.2 Materials and Methods -- 7.2.1 Hardware Design and Setup -- 7.2.2 Animal Exposure to a Controlled Blast Wave -- 7.2.3 Blood and Tissue Collection -- 7.2.4 Silver Staining Assessment of Neurodegeneration in Rat Brain -- 7.2.5 Western Blot Analysis of Brain Tissues -- 7.2.6 Statistics -- 7.3 Results and Discussion -- 7.3.1 Rat Models of Blast Exposure Using External Shock Tube: Primary Blast Load versus ''Composite'' Blast Exposure -- 7.3.2 Neural Injury and Gliosis in Rat Brain after Different Blast Exposures Assessed by Silver Staining and Immunohistochemistry (IHC) -- 7.3.3 Serum Levels of Biomarkers of Neuroglial Injury Following Blast Exposure -- 7.4 Conclusions -- Acknowledgements -- References -- Chapter 8 Biomarkers for Subtle Brain Dysfunction -- 8.1 Introduction -- 8.2 Biomarkers for Concussions -- 8.3 Neurotoxicity Biomarkers in Sport-Related Concussions -- 8.3.1 Healthy Volunteers and Club Sport Athlete Characteristics -- 8.3.2 Neurocognitive Testing and Neuroimaging -- 8.3.3 Reference Values of Neurotoxicity Biomarker Assays -- 8.3.4 AMPAR Peptide/Antibodies -- 8.3.5 NR2 Peptide/Antibodies.

8.4 Risk Assessment of Secondary Ischemic Events -- 8.5 Risk Assessment of Cerebral Hematoma and Hemorrhage -- 8.6 Risk of Abnormal Cerebral Spiking Activity -- 8.7 Conclusions -- References -- Chapter 9 Feasibility Studies of Neurotoxicity Biomarkers for Assessment of Traumatic Brain Injury -- 9.1 Introduction -- 9.2 Biomarkers of Chronic Encephalopathy -- 9.3 Mild TBI in Trauma Unit Setting -- 9.3.1 Human Subject Characteristics -- 9.3.2 AMPAR Peptide and Antibody -- 9.3.3 NR2 Peptide and Antibody -- 9.4 Mild TBI in the Military Setting -- 9.4.1 Clinical and Neuroimaging Findings -- 9.4.2 Cognitive Evaluation -- 9.4.3 AMPAR Peptide in Plasma of Active Duty Personnel -- 9.5 Post-Traumatic Epilepsy in Active Duty Personnel Following Moderate TBI -- 9.5.1 Study Participants -- 9.5.2 Anatomical and Functional Assessments of Epileptiform Activity -- 9.5.3 AMPAR Antibodies in Serum of Persons with Post-Traumatic Epilepsy and Temporal Lobe Epilepsy -- 9.6 Conclusions -- References -- Chapter 10 Astroglial Proteins as Biomarkers of Intracerebral Hemorrhage -- 10.1 Introduction -- 10.2 Intracerebral Hemorrhage: Epidemiology and Pathophysiology -- 10.3 Hematoma Expansion and Cellular Destruction -- 10.4 Astroglial Proteins as Biomarkers of Intracerebral Hemorrhage -- 10.4.1 Protein S100B -- 10.4.2 Glial Fibrillary Acidic Protein (GFAP) -- 10.5 Discussion -- References -- Chapter 11 Protein S100B in Traumatic Brain Injury -- 11.1 Introduction -- 11.2 Protein S100B: Methods of Analysis -- 11.3 Protein S100B in Minor Head Injury -- 11.3.1 De nition of Minor Head Injury -- 11.3.2 Speci city and Sensitivity -- 11.4 Protein S100B in Severe Traumatic Brain Injury -- 11.4.1 Outcome Measures -- 11.4.2 Repeated Measurements -- 11.4.3 Multi-Trauma -- 11.5 Protein S100B in Children -- 11.6 Health Economics Aspects of S100B in Traumatic Brain Injury -- References.

Chapter 12 Utilities of TBI Biomarkers in Various Clinical Settings -- 12.1 Introduction -- 12.2 Biomarker Discovery: Methods and Results -- 12.2.1 Proteomics/Systems Biology in the Area of Neurotrauma -- 12.2.2 Data Mining Coupled Neurosystems Biology Analysis in Brain Injury -- 12.3 Strategy for Regulatory Approval by FDA -- 12.3.1 FDA Regulation -- 12.3.2 Quality System Regulation Requirements -- 12.4 Biomarker-based Diagnosis, Management, and Outcome Prediction of Patients with Severe TBI -- 12.4.1 Primary Damage and Acute Diagnosis in Severe TBI -- 12.4.2 Biomarkers in the Management of Severe TBI -- 12.4.3 Biomarkers for Prediction of Outcome and Prognosis -- 12.5 Conclusions -- References -- Chapter 13 Future Trends in Biomarker Immunoassay Development -- 13.1 Introduction -- 13.2 TBI Biomarkers: Assay Requirements -- 13.2.1 Clinical Indications -- 13.2.2 Preliminary Assay Performance Characteristics -- 13.2.3 Peculiarities of Brain Biomarkers for Immunoassays -- 13.3 Diagnostic Challenges in Development of Immunoassays for TBI -- 13.3.1 Specimen Choice -- 13.3.2 Choice of Immunoassay Architecture -- 13.3.3 Immunoassay Format -- 13.3.4 Technology Optimization -- 13.4 Safety Regulatory Stages for Immunoassays -- 13.4.1 Analytical Phase -- 13.4.2 Clinical Phase I and II -- 13.4.3 Clinical Laboratory Testing -- 13.5 Future Trends in Immunoassay Development -- 13.5.1 Advantages of the Combined Drug/Test Use -- 13.5.2 Diagnostics of Co-Morbid Neurological Conditions -- 13.5.3 Biomarkers and Personalized Medicine -- 13.6 Conclusions -- References -- Subject Index.