Spectrums of amyotrophic lateral sclerosis : heterogeneity, pathology, and therapeutic directions

목차 (Table of Contents)

• 자료제공 :
• Contributors xiii
• Preface xvii
• Acknowledgments xix
• Foreword xxi
• CHAPTER 1 Clinical Heterogeneity of ALS - Implications for Models and Therapeutic Development 1
• Serena Lattante and Mario Sabatelli
• Introduction 1
• Clinical Heterogeneity of ALS 2
• Familial and Sporadic ALS 2
• Age of Onset 3
• Survival 3
• Classic ALS, LMN Form, and UMN Form 4
• Site of Onset 4
• Diagnosis of ALS 5
• ALS and Its Relationship with Frontotemporal
• Dementia and Myopathies 5
• Pleiotropy of ALS Genes 6
• Genetic Models to Study ALS 8
• In Vivo Models 8
• In Vitro Models 9
• Conclusion 10
• Conflict of Interest 11
• Copyright and Permission Statement 11
• References 11
• CHAPTER 2 Genetic Basis of ALS 17
• Jay P. Ross, Patrick A. Dion, and Guy A. Rouleau
• Introduction 17
• Genes Causing ALS 18
• Superoxide Dismutase 1 (SOD1) 18
• TAR DNA-Binding Protein 43 (TDP-43) 19
• Fused in Sarcoma (FUS) 19
• Chromosome 9 Open Reading Frame 72 (C9orf72) 20
• Recently Discovered Genes 21
• Annexin A11 (ANXA11) 21
• Glycosyltransferase 8 Domain Containing 1 (GLT8D1) 23
• Stathmin-2 (STMN2) 23
• Aspects of ALS Heritability 24
• Sporadic vs. Familial 24
• Penetrance and the Oligogenic Hypothesis 24
• Multistep Model 25
• Noncoding Variation 25
• Regulatory and Intronic Variants 25
• Epigenetics 26
• Conclusions 27
• Acknowledgments 27
• Conflict of Interest 27
• Copyright and Permission Statement 28
• References 28
• CHAPTER 3 Susceptibility Genes and Epigenetics in Sporadic ALS 35
• Jessica R. Morrice, Christopher A. Shaw,
• and Cheryl Y. Gregory-Evans
• Introduction 35
• Environmental Associations in sALS 36
• Genetic Basis of sALS 38
• Identification of sALS Susceptibility Genes 39
• Candidate sALS Susceptibility Genes 40
• Unc13a 40
• Dpp6 40
• C21orf2 41
• Epigenetic Mechanisms in sALS 41
• Methylation in sALS 41
• miRNAs in sALS 42
• Post-Translational Histone Modification in sALS 43
• Epigenetic Analysis in Monozygotic sALS Twins 44
• Modifications to the Epigenome by Environmental Factors 44
• In Utero Environmental Exposures 45
• Environmental in Utero Epigenomic Alterations 45
• Post Utero Exposures 45
• Conclusion 46
• Conflict of Interest 46
• Copyright and Permission Statement 47
• References 47
• CHAPTER 4 The Lessons of ALS-PDC - Environmental Factors
• in ALS Etiology 57
• Christopher A. Shaw and Thomas E. Marler
• Introduction 57
• Koch's Postulates in the Search of Etiological ALS Factors 58
• Neurological Disease Clusters 59
• The Natural History of ALS-PDC 60
• Investigating Etiological Factors 62
• Identified Cycad Toxicants 67
• Aluminum and Ionic Etiologies for ALS-PDC 69
• Other Molecules That Might Have Been Involved in ALS-PDC 70
• A Putative Viral Etiology for ALS-PDC on Guam
• and ALS in General 70
• The Continuing Importance of ALS-PDC 71
• Summary and Conclusions 73
• Acknowledgments 74
• Conflict of Interest 74
• Copyright and Permission Statement 74
• References 75
• CHAPTER 5 The Microbiome of ALS - Does It Start from the Gut? 81
• Audrey Labarre and Alex Parker
• Introduction 81
• Recent Studies 82
• Animal and in vitro Studies 82
• Clinical Studies 91
• How Could the Microbiome Contribute to ALS? 92
• Gut Barrier and Membrane Permeability 93
• Inflammation and Immune Response 94
• Neurotoxins 95
• Energy Metabolism 96
• Microbiome Modulation as a Potential Therapeutic Avenue 96
• Conclusion 97
• Conflict of Interest 97
• Copyright and Permission Statement 97
• References 98
• Chapter 6 Protein Aggregation in Amyotrophic Lateral Sclerosis 105
• Christen G. Chisholm, Justin J. Yerbury,
• and Luke McAlary
• Introduction 105
• Pathological Protein Inclusions Associated with ALS 106
• Protein Homeostasis and Misfolded Protein
• Partitioning in ALS 107
• Consequences of Protein Aggregation in ALS 108
• The Primary Aggregating Proteins in ALS 110
• Superoxide Dismutase-1 (SOD1) 110
• Transactivated Response DNA Binding
• Protein 43 (TDP-43) 111
• Fused in Sarcoma (FUS) 111
• Prion-like Propagation of Protein Aggregation in ALS 112
• Conclusion 113
• Acknowledgments 114
• Conflict of Interest 114
• Copyright and Permission Statement 114
• References 114
• CHAPTER 7 Evidence for a Growing Involvement of Glia
• in Amyotrophic Lateral Sclerosis 123
• Rowan A. W. Radford, Andres Vidal-Itriago,
• Natalie M. Scherer, Albert Lee, Manuel Graeber,
• Roger S. Chung, and Marco Morsch
• Introduction 123
• Non-neuronal Cells Play Important Roles
• in Neurodegeneration Including in ALS 123
• Glial Cells and Their Established Functions 123
• Neurodegeneration and the Role of Glial Cells 124
• Glia in ALS 124
• Glial Dysfunction Is a Common Hallmark
• of ALS Patients 125
• Glial Activation in ALS Models 126
• Major Pathological Forms of ALS 126
• Microglia-Related ALS Pathology 126
• Microglia in SOD1-ALS Pathology 126
• Microglia in TDP-43-ALS Pathology 127
• Microglia in FUS-ALS Pathology 128
• Astrocyte-Related ALS Pathology 128
• Oligodendrocyte-Related ALS Pathology
• and Glial Inclusion Formation 129
• Glial Inclusion Formation in ALS 130
• Oligodendrocytes 130
• Astrocytes 131
• The Role of Glial Cells in SOD1 Pathology Might Be
• Different from Other Forms of ALS 131
• Conclusion 132
• Acknowledgments 134
• Conflict of Interest 134
• Copyright and Permission Statement 134
• References 134
• CHAPTER 8 Animal Models of ALS - Current and Future
• Perspectives 143
• Robert A. Deziel, Amber L. Marriott, Denis G. Kay,
• and Daphne A. Gill
• Introduction 143
• The Clinical Manifestations of ALS 143
• Limb Onset 144
• Bulbar Onset 144
• Respiratory Onset 144
• Current and Experimental Pharmacological Interventions 145
• Riluzole 145
• Edaravone 146
• Future Directions for Pharmacological Interventions 146
• Causative Factors in the Development of ALS 146
• Genetic Factors 146
• Environmental and Epigenetic Factors 148
• Gut and Microbial Factors 148
• Animal Models of ALS 150
• One-hit Models of ALS 150
• Multi-hit Models of ALS 151
• Future Model Development 153
• Acknowledgments 153
• Conflict of Interest 154
• Copyright and Permission Statement 154
• References 154
• CHAPTER 9 Clinical Trials in ALS - Current Challenges
• and Strategies for Future Directions 161
• Kristiana Salmon and Angela Genge 161
• Introduction 161
• Challenges in ALS Clinical Trials 162
• Disease Heterogeneity 162
• Lack of Established Biomarkers 163
• Limitations of Conventional Outcome Measures 163
• ALSFRS-R 163
• FVC/SVC 164
• HHD 164
• Survival vs. Function 164
• Phase II Trial "Paradox" 165
• Patient Recruitment and Retention 166
• Assumptions for Lead-In Phases 166
• Navigating Regulatory Nuances 167
• Future Directions 167
• Advances in Disease Understanding and Assessment 168
• Disease Heterogeneity 168
• Emerging Biomarkers 168
• Novel Outcome Measures 169
• New Approaches to Trial Design 170
• Cautious Phase II Design 170
• Adaptive Trial Design 171
• Platform Trials 172
• Bayesian Statistics 172
• Education 173
• People Make or Break a Trial 173
• Conclusion 174
• Acknowledgments 175
• Conflict of Interest 175
• Copyright and Permission Statement 175
• References 175
• CHAPTER 10 Future Priorities and Directions in ALS Research and Treatment 181
• Jessica R. Morrice, Michael Kuo,
• and Christopher A. Shaw
• Introduction 181
• Etiological Heterogeneity of ALS 182
• ALS Risk Factors 183
• Cellular Dysfunction in ALS 185
• ALS as a "Treatable" Disease 186
• The Importance of Effective Biomarkers 187
• Future Therapeutic Avenues for a Heterogeneous Disease 188
• Ongoing Clinical Trials Using CuATSM 188
• Conclusions and the Road Forward in ALS Research and Treatment 190
• Conflict of Interest 191
• Copyright and Permission Statement 191
• References 191
• Index 000