BOOK
Acute Brain Impairment
Philip V Peplow | Svetlana A Dambinova | Thomas A Gennarelli | Bridget Martinez
(2017)
Additional Information
Book Details
Abstract
A rise in the number of young and old patients suffering from a stroke or traumatic brain injury has led to the need for better drug development and treatment, as well as diagnosis and prevention of ischemic stroke and traumatic brain injury. This book provides a comprehensive overview of scientific advancements in these areas.
Chapters provide the latest knowledge in neuroscience, biotechnology, and personalized medicine applicable to acute brain injuries. Development of neuroprotective drugs is treated in detail. Chemical biomarkers for detection, imaging and preventative strategies are covered to provide medicinal chemists with a broad view of translational aspects of the field.
This book will be useful to postgraduate students and researchers in medicinal chemistry and pharmacology as well as specialists in the acute brain injury field.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Preface | vii | ||
| Dedication | viii | ||
| Contents | ix | ||
| Chapter 1 Transient Ischemic Attack, Traumatic Brain Injury, and Ischemic Stroke: Risk Factors and Treatments | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Definition of TIA, TBI, and Stroke | 2 | ||
| 1.3 Incidence of TIA, TBI, and Stroke | 3 | ||
| 1.4 Risk Factors for TIA and Stroke | 4 | ||
| 1.4.1 Age | 4 | ||
| 1.4.2 Gender | 4 | ||
| 1.4.3 Race | 4 | ||
| 1.4.4 Hypertension | 4 | ||
| 1.4.5 Diabetes Mellitus | 5 | ||
| 1.4.6 Smoking | 5 | ||
| 1.4.7 Previous Stroke | 5 | ||
| 1.4.8 TIA | 5 | ||
| 1.4.9 Atrial Fibrillation | 6 | ||
| 1.4.10 Atherosclerosis of Carotid Arteries | 6 | ||
| 1.4.11 Coronary Artery Disease | 6 | ||
| 1.4.12 Obesity | 6 | ||
| 1.4.13 Diet | 6 | ||
| 1.4.14 Physical Activity | 6 | ||
| 1.4.15 Blood Lipids | 7 | ||
| 1.4.16 Hormone Replacement Therapy | 7 | ||
| 1.5 Treatment of TIA and Ischemic Stroke | 7 | ||
| 1.5.1 Thrombolysis | 7 | ||
| 1.5.2 Antiplatelet Therapy | 7 | ||
| 1.5.3 Anticoagulant Therapy | 8 | ||
| 1.5.4 Statin Therapy | 8 | ||
| 1.5.5 Neuroprotective Therapy | 9 | ||
| 1.5.6 Thrombectomy | 9 | ||
| 1.6 Hemorrhagic Transformation | 9 | ||
| 1.7 Treatment of TBI | 10 | ||
| 1.8 Conclusion | 11 | ||
| References | 11 | ||
| Chapter 2 Inflammatory Changes in Cerebral Ischemic Injury: Cellular and Molecular Involvement | 15 | ||
| 2.1 Introduction | 15 | ||
| 2.2 Damage-associated Molecular Patterns in Ischemic Brain Tissue | 16 | ||
| 2.3 Toll-like Receptors as DAMP Receptors | 18 | ||
| 2.4 Inflammatory Cytokines and Mediators | 19 | ||
| 2.5 Infiltrating Immune Cells in the Ischemic Brain | 21 | ||
| 2.6 T Cells in Ischemic Brain Injury | 21 | ||
| 2.7 Resolution of Post-ischemic Inflammation | 23 | ||
| 2.8 Conclusion | 25 | ||
| References | 25 | ||
| Chapter 3 Biomarkers of Acute Brain Injury and Surrogate Endpoints in Traumatic Brain Injury and Stroke Translational Studies | 34 | ||
| 3.1 Epidemiology of Acute Traumatic Brain Injury and Stroke | 34 | ||
| 3.2 Brain Injury Biomarkers and Surrogate Endpoints in Clinical Trials | 36 | ||
| 3.3 Biomarkers of Astroglial Injury | 37 | ||
| 3.3.1 S100β | 37 | ||
| 3.3.2 Glial Fibrillary Acidic Protein | 38 | ||
| 3.4 Biomarkers of Neuronal Injury | 39 | ||
| 3.4.1 Neuron-specific Enolase | 39 | ||
| 3.4.2 Ubiquitin C-terminal Hydrolase | 40 | ||
| 3.5 Biomarkers of Axonal Injury | 41 | ||
| 3.5.1 αII-spectrin Breakdown Products | 41 | ||
| 3.5.2 Tau Protein | 41 | ||
| 3.5.3 Neurofilaments | 42 | ||
| 3.6 Conclusion | 42 | ||
| References | 43 | ||
| Chapter 4 Difficulties of Translating Outcomes from Animal Studies to Clinical Trials | 51 | ||
| 4.1 Introduction | 51 | ||
| 4.2 Differences among Animal Models of Stroke, TIA, and TBI in the Type and Extent of Cerebral Injury | 52 | ||
| 4.3 Differences between Humans and Animal Stroke Models | 56 | ||
| 4.4 Differences in the Ways That Studies Are Conducted in Humans and Animal Models | 57 | ||
| 4.5 Differences in Primary Functional Outcomes Measured in Clinical Trials and Animal Studies | 58 | ||
| 4.6 Strategies to Improve the Quality of Animal and Clinical Studies of Stroke Therapies | 58 | ||
| 4.7 Conclusion | 60 | ||
| References | 61 | ||
| Chapter 5 Neuroprotective Therapies for Ischemic Stroke | 64 | ||
| 5.1 Introduction | 64 | ||
| 5.2 Metabolic Alterations that Increase the Risk of Developing Stroke | 65 | ||
| 5.3 Pathophysiology and Possible Therapeutic Strategies | 65 | ||
| 5.3.1 Energy Failure | 66 | ||
| 5.3.2 Barrier Dysfunction | 68 | ||
| 5.3.3 Excitotoxicity | 69 | ||
| 5.3.4 Oxidative Stress | 69 | ||
| 5.3.5 Inflammation | 70 | ||
| 5.3.6 Immunomodulation | 73 | ||
| 5.4 Conclusion | 75 | ||
| References | 75 | ||
| Chapter 6 The Molecular Neuroprotective Strategies in Cerebral Ischemia: An Insight into Emerging Treatments for Oxidative Stress | 82 | ||
| 6.1 Introduction | 82 | ||
| 6.2 Free Radical Release and Oxidative Stress in Cerebral Ischemia | 83 | ||
| 6.3 Endogenous Anti-oxidant Defense Mechanisms and Therapeutic Targets | 84 | ||
| 6.3.1 SODs in Cerebral Ischemia | 84 | ||
| 6.3.2 NOX Regulates ROS Generation in Ischemic Stroke | 87 | ||
| 6.3.3 Activation of Nrf2/ARE Signaling Alleviates Oxidative Stress | 87 | ||
| 6.3.4 Other Endogenous Oxidative Stress Targets in Ischemic Stroke | 89 | ||
| 6.4 Sequestering Oxidative Stress-induced Apoptosis and Necrosis Post-ischemia | 89 | ||
| 6.4.1 Apoptosis Regulation and the Mechanistic Targets | 90 | ||
| 6.4.2 Targeting Necrosis in Cerebral Ischemia | 91 | ||
| 6.5 Exogenous Anti-oxidants to Decrease ROS Generation | 92 | ||
| 6.6 Neuronal Restoration Strategies Following Cerebral Ischemia | 96 | ||
| 6.6.1 Cellular Therapy | 96 | ||
| 6.6.2 Endogenous Neurogenesis | 97 | ||
| 6.6.3 Ischemic Preconditioning | 98 | ||
| 6.7 Conclusion | 99 | ||
| Abbreviations | 99 | ||
| References | 100 | ||
| Chapter 7 Identification of MicroRNAs as Targets for Treatment of Ischemic Stroke | 105 | ||
| 7.1 Introduction | 105 | ||
| 7.2 Mechanisms of Neuronal Injury in Ischemic Stroke | 106 | ||
| 7.2.1 MiRs and the Regulation of Apoptosis | 109 | ||
| 7.2.2 Autophagy, Anoikis, and miRs | 110 | ||
| 7.2.3 Excitotoxicity | 111 | ||
| 7.3 Heat Shock Proteins and MiRs | 112 | ||
| 7.4 MiRs and Glia in Ischemic Stroke | 114 | ||
| 7.4.1 Astrocytes | 114 | ||
| 7.4.2 Microglia | 116 | ||
| 7.5 Clinical Utility of MiRs in Ischemic Stroke | 117 | ||
| 7.6 Conclusions | 121 | ||
| Acknowledgments | 121 | ||
| References | 121 | ||
| Chapter 8 Combined Drug-Diagnostic Test Co-development for Predicting and Preventing Brain Impairments | 128 | ||
| 8.1 Introduction | 128 | ||
| 8.2 Companion Diagnostic Precedent | 129 | ||
| 8.2.1 Public Health Perspective | 129 | ||
| 8.2.2 Personalized or Precision Medicine | 130 | ||
| 8.2.3 Drug-test Co-development Approach for Brain Impairments | 132 | ||
| 8.3 Regulatory Criteria for Drug-test Co-development | 133 | ||
| 8.3.1 FDA Rx/CDx Concept | 133 | ||
| 8.3.2 Intended Use and Indication of Use | 133 | ||
| 8.3.3 Trends in Point-of-care Testing and Rx | 134 | ||
| 8.4 Advantages of Combined Brain Impairment Drug-Diagnostic Test use in the Clinical Setting | 135 | ||
| 8.4.1 Optimization of Neuro-critical Care by Rx/CDx | 135 | ||
| 8.4.2 Rx/CDx for Preventing and Predicting Chronic CVDs | 136 | ||
| 8.5 Conclusion | 137 | ||
| References | 137 | ||
| Chapter 9 Advances in Diagnostics and Treatment of Neurotoxicity after Sports-related Injuries | 141 | ||
| 9.1 Introduction | 141 | ||
| 9.2 Reversible and Irreversible Cerebrovascular Changes after mTBI | 143 | ||
| 9.2.1 The NVU Concept | 143 | ||
| 9.2.2 Alterations in Small- and Medium-sized Vessels | 143 | ||
| 9.3 BBB Dysfunction and Neuroinflammation after mTBI | 144 | ||
| 9.3.1 Compromised BBB | 144 | ||
| 9.3.2 Neuroinflammation | 146 | ||
| 9.3.3 Vasogenic and Cytotoxic Edema Formation | 146 | ||
| 9.4 Focal and Traumatic Axonal Injury Correlates with Altered CBF | 146 | ||
| 9.4.1 Traumatic Axonal Injury and Altered CBF | 146 | ||
| 9.4.2 Radiological Findings in mTBI | 147 | ||
| 9.5 Biomarkers for Acute and Chronic Conditions after mTBI | 148 | ||
| 9.5.1 Prospective Biomarkers of NVU | 148 | ||
| 9.5.2 GluR Peptide and Ab Translational Research | 149 | ||
| 9.6 Conventional Treatment Options for mTBI | 150 | ||
| 9.6.1 Trends in Emergent Pharmacological Agents for mTBI | 150 | ||
| 9.6.2 Non-pharmacological Treatment Options for Concussions | 153 | ||
| 9.7 Conclusion | 154 | ||
| References | 155 | ||
| Chapter 10 Functional Predictors for Prognosis and Recovery after Mild Traumatic Brain Injury | 162 | ||
| 10.1 Introduction | 162 | ||
| 10.2 Mild Traumatic Brain Injury | 163 | ||
| 10.3 Standardized Evaluation Tools | 163 | ||
| 10.3.1 Neuropsychological Evaluation | 164 | ||
| 10.3.2 Vestibular/Balance | 165 | ||
| 10.4 Pre-injury Risk Factors/Conditions | 166 | ||
| 10.4.1 Post-injury Risk Factors for Poor Recovery | 168 | ||
| 10.4.2 Rehabilitation Factors for Recovery | 168 | ||
| 10.5 Summary and Future Directions | 169 | ||
| 10.5.1 Assessment Modalities and Multidisciplinary Team Approach | 169 | ||
| 10.5.2 Future Directions and Emerging mTBI Assessment Tools | 169 | ||
| 10.6 Conclusion | 171 | ||
| References | 171 | ||
| Chapter 11 Predictors for Prognosis and Recovery from Unconsciousness Due to Brain Trauma | 176 | ||
| 11.1 Introduction | 176 | ||
| 11.2 Coma and Post-comatose Unconsciousness | 177 | ||
| 11.2.1 Consciousness and Unconsciousness | 177 | ||
| 11.2.2 Post-traumatic Coma and Scales | 177 | ||
| 11.2.3 Post-comatose Unconsciousness | 178 | ||
| 11.3 Structural and Functional Basis of Unconsciousness | 179 | ||
| 11.3.1 Neuroimaging and Novel Magnetic Resonance Imaging-based Classification of sTBI | 179 | ||
| 11.3.2 Cerebral Blood Flow Mapping | 181 | ||
| 11.3.3 Neurotransmitter Aspects of Unconsciousness | 183 | ||
| 11.4 Prognostic Value of Neuroimaging for Coma and Unconsciousness | 184 | ||
| 11.4.1 MRI Features and Predictors in Unconsciousness | 184 | ||
| 11.4.2 Prognostic Value of Non-structural Neuroimaging Data (functional MRI) | 187 | ||
| 11.4.3 Neurometabolic Imaging and Prognostic Value of Unconsciousness | 189 | ||
| 11.5 Neurochemical Basis of Coma and Prognostic Biomarkers of Outcome | 190 | ||
| 11.6 Conclusion | 192 | ||
| Acknowledgments | 194 | ||
| References | 194 | ||
| Chapter 12 Neurotoxicity in Spinal Cord Impairments | 198 | ||
| 12.1 Introduction | 198 | ||
| 12.2 Pathological Features of SC Impairments | 199 | ||
| 12.2.1 Hemodynamic Aspects of SC Injury | 199 | ||
| 12.2.2 Biochemical Alterations in Acute and Chronic Conditions | 201 | ||
| 12.2.3 Radiological Patterns of SC Impairments | 203 | ||
| 12.3 Potential Biomarkers of SC Impairments | 204 | ||
| 12.3.1 Neuronal Markers in SCI | 204 | ||
| 12.3.2 Biomarkers of Inflammation | 205 | ||
| 12.3.3 Neurotoxicity Markers for SC Ischemia and SCI | 205 | ||
| 12.4 Therapy Options for SC Impairments | 207 | ||
| 12.4.1 Acute States | 207 | ||
| 12.4.2 Chronic Conditions | 207 | ||
| 12.4.3 Trends in Treatment Optimization | 209 | ||
| 12.5 Conclusion | 209 | ||
| Abbreviations | 210 | ||
| References | 210 | ||
| Chapter 13 Advanced Approaches in Stem Cell Therapy for Stroke and Traumatic Brain Injury | 214 | ||
| 13.1 Introduction | 214 | ||
| 13.2 Origins and Sources of SCs | 215 | ||
| 13.3 Transplantation of SCs in Animal Models of Stroke and TBI | 217 | ||
| 13.4 SC Therapy in Stroke and TBI: Clinical Trials | 222 | ||
| 13.4.1 Stroke | 222 | ||
| 13.4.2 Traumatic Brain Injury | 231 | ||
| 13.5 Conclusion | 234 | ||
| References | 234 | ||
| Chapter 14 Testing and Mechanisms of Neuroprotective Agents for Cerebral Ischemic Injury in Clinical Trials, 2010-2016 | 242 | ||
| 14.1 Introduction | 242 | ||
| 14.2 Neuroprotective Agents | 243 | ||
| 14.2.1 Magnesium | 243 | ||
| 14.2.2 Minocycline | 247 | ||
| 14.2.3 Lovastatin | 248 | ||
| 14.2.4 Citalopram | 250 | ||
| 14.2.5 Donepezil | 250 | ||
| 14.2.6 Citicoline | 251 | ||
| 14.2.7 Tocotrienols | 252 | ||
| 14.2.8 Cyclosporine | 253 | ||
| 14.2.9 Cutamesine (SA4503) | 253 | ||
| 14.2.10 Intra-arterial Administration of Neuroprotective Drugs as an Adjunct to Mechanical Thrombectomy—Verapamil and Beyond | 254 | ||
| References | 256 | ||
| Chapter 15 Difficulties in Clinical Trials to Treat Traumatic Brain Injury and Stroke | 263 | ||
| 15.1 Introduction | 263 | ||
| 15.2 Why Translation Has Failed: Reasons for Failure in the Translation from Animal to Human Studies | 264 | ||
| 15.2.1 Animal Models | 265 | ||
| 15.2.2 Assumptions Made in Translation: Time of Administration, Mechanism, Dosing and Publication Bias | 267 | ||
| 15.2.3 Clinical Trials and Their Problems | 267 | ||
| 15.3 Conclusions: Recommendations to Improve Translation | 272 | ||
| References | 274 | ||
| Chapter 16 Challenges in Using Biomarkers in Central Nervous System Applications | 276 | ||
| 16.1 Introduction | 276 | ||
| 16.2 Biases and Pitfalls in Choice of Biomarkers | 277 | ||
| 16.2.1 Peculiarities in Primary Biomarker Testing | 277 | ||
| 16.2.2 Selection of Indicators for Secondary Injuries | 278 | ||
| 16.2.3 Biomarkers of Autoimmune Response | 279 | ||
| 16.3 Possible Omissions in Brain Biomarker Testing | 279 | ||
| 16.3.1 Single vs. Multiple Biomarker Testing | 279 | ||
| 16.3.2 Translational Study Design Considerations | 280 | ||
| 16.3.3 Determining Study Power | 281 | ||
| 16.4 Biological Fluid Testing Drawbacks | 282 | ||
| 16.4.1 Biological Fluid Selection | 282 | ||
| 16.4.2 Sample Preparation and Storage | 283 | ||
| 16.5 Conclusion | 285 | ||
| References | 285 | ||
| Chapter 17 Resolving Difficult Case Scenarios by Incorporating Stroke Biomarkers in Clinical Decision-making | 289 | ||
| 17.1 Introduction | 289 | ||
| 17.2 Blood-based Stroke Biomarkers in Clinical Scenarios | 292 | ||
| 17.2.1 Hemorrhagic Transformation | 292 | ||
| 17.2.2 Malignant Cerebral Infarction | 296 | ||
| 17.2.3 Early Neurologic Deterioration | 298 | ||
| 17.2.4 Stroke Diagnosis | 299 | ||
| 17.2.5 Thrombus Formation | 301 | ||
| 17.2.6 Stroke Etiology | 304 | ||
| 17.2.7 Stroke Risk | 306 | ||
| 17.2.8 Atrial Fibrillation | 306 | ||
| 17.3 Conclusions | 308 | ||
| Acknowledgments | 308 | ||
| References | 308 | ||
| Chapter 18 Development of Novel Test Platforms for the Assessment of Brain Injury | 315 | ||
| 18.1 Introduction | 315 | ||
| 18.2 Diagnostic Approaches to Brain Injury | 316 | ||
| 18.2.1 Currently Available Brain Injury Assays | 316 | ||
| 18.2.2 Roadmap for Assay Development | 316 | ||
| 18.3 Immunochemical Assays Development | 318 | ||
| 18.3.1 Unique Reagents for Brain Biomarker Detection | 318 | ||
| 18.3.2 Assay Design | 319 | ||
| 18.3.3 Assay Platform | 321 | ||
| 18.4 POCT for Brain Injury Assessments | 324 | ||
| 18.4.1 Laboratory-based Testing and POCT | 324 | ||
| 18.4.2 Emerging Assay Technologies | 324 | ||
| 18.5 Conclusion | 325 | ||
| References | 325 | ||
| Chapter 19 Advancements and Challenges in Hyperacute Stroke Translational Research | 327 | ||
| 19.1 Introduction | 327 | ||
| 19.2 Metabolic Impairments and Diagnostic Imaging | 328 | ||
| 19.2.1 Selected Metabolic Biomarkers and Emerging Technologies | 329 | ||
| 19.2.2 Diagnostic Biomarkers of Imaging | 331 | ||
| 19.3 Revascularization in Hyperacute Stroke | 333 | ||
| 19.4 Pitfalls in Neuroprotective Translational Research | 334 | ||
| 19.5 Challenges in Neuroregenerative Translational Research | 336 | ||
| 19.6 Conclusion | 337 | ||
| References | 338 | ||
| Subject Index | 341 |