Spectrums of Amyotrophic Lateral Sclerosis

1 Cover

2 Title Page

3 Copyright Page

4 Dedication Page

5 Contributors

6 Foreword

7 Preface

8 Acknowledgments

9 CHAPTER 1: Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development INTRODUCTION CLINICAL HETEROGENEITY OF ALS PLEIOTROPY OF ALS GENES GENETIC MODELS TO STUDY ALS CONCLUSION CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

10 CHAPTER 2: Genetic Basis of ALS INTRODUCTION GENES CAUSING ALS RECENTLY DISCOVERED GENES ASPECTS OF ALS HERITABILITY NONCODING VARIATION CONCLUSIONS ACKNOWLEDGMENTS CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

11 CHAPTER 3: Susceptibility Genes and Epigenetics in Sporadic ALS INTRODUCTION ENVIRONMENTAL ASSOCIATIONS IN sALS GENETIC BASIS OF sALS IDENTIFICATION OF sALS SUSCEPTIBILITY GENES CANDIDATE sALS SUSCEPTIBILITY GENES EPIGENETIC MECHANISMS IN sALS MODIFICATIONS TO THE EPIGENOME BY ENVIRONMENTAL FACTORS CONCLUSION CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

12 CHAPTER 4: The Lessons of ALS‐PDC – Environmental Factors in ALS Etiology INTRODUCTION KOCH'S POSTULATES IN THE SEARCH OF ETIOLOGICAL ALS FACTORS NEUROLOGICAL DISEASE CLUSTERS THE NATURAL HISTORY OF ALS‐PDC INVESTIGATING ETIOLOGICAL FACTORS IDENTIFIED CYCAD TOXIN/TOXICANTS ALUMINUM AND IONIC ETIOLOGIES FOR ALS‐PDC OTHER MOLECULES THAT MIGHT HAVE BEEN INVOLVED IN ALS‐PDC A PUTATIVE VIRAL ETIOLOGY FOR ALS‐PDC ON GUAM AND ALS IN GENERAL THE CONTINUING IMPORTANCE OF ALS‐PDC SUMMARY AND CONCLUSIONS ACKNOWLEDGMENTS CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

13 CHAPTER 5: The Microbiome of ALS – Does It Start from the Gut? INTRODUCTION RECENT STUDIES HOW COULD THE MICROBIOME CONTRIBUTE TO ALS? MICROBIOME MODULATION AS A POTENTIAL THERAPEUTIC AVENUE CONCLUSION CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

14 CHAPTER 6: Protein Aggregation in Amyotrophic Lateral Sclerosis INTRODUCTION PATHOLOGICAL PROTEIN INCLUSIONS ASSOCIATED WITH ALS CONSEQUENCES OF PROTEIN AGGREGATION IN ALS THE PRIMARY AGGREGATING PROTEINS IN ALS PRION‐LIKE PROPAGATION OF PROTEIN AGGREGATION IN ALS CONCLUSION ACKNOWLEDGMENTS CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

15 CHAPTER 7: Evidence for a Growing Involvement of Glia in Amyotrophic Lateral Sclerosis INTRODUCTIONNON‐NEURONAL CELLS PLAY IMPORTANT ROLES IN NEURODEGENERATION INCLUDING IN ALS GLIAL ACTIVATION IN ALS MODELS GLIAL INCLUSION FORMATION IN ALS THE ROLE OF GLIAL CELLS IN SOD1 PATHOLOGY MIGHT BE DIFFERENT FROM OTHER FORMS OF ALS CONCLUSION ACKNOWLEDGMENTS CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

16 CHAPTER 8: Animal Models of ALS – Current and Future Perspectives INTRODUCTION THE CLINICAL MANIFESTATIONS OF ALS CURRENT AND EXPERIMENTAL PHARMACOLOGICAL INTERVENTIONS CAUSATIVE FACTORS IN THE DEVELOPMENT OF ALS ANIMAL MODELS OF ALS FUTURE MODEL DEVELOPMENT ACKNOWLEDGMENTS CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

17 CHAPTER 9: Clinical Trials in ALS – Current Challenges and Strategies for Future Directions INTRODUCTION CHALLENGES IN ALS CLINICAL TRIALS DISEASE HETEROGENEITY LACK OF ESTABLISHED BIOMARKERS LIMITATIONS OF CONVENTIONAL OUTCOME MEASURES PHASE II TRIAL “PARADOX” PATIENT RECRUITMENT AND RETENTION ASSUMPTIONS FOR LEAD‐IN PHASES NAVIGATING REGULATORY NUANCES FUTURE DIRECTIONS ADVANCES IN DISEASE UNDERSTANDING AND ASSESSMENT NEW APPROACHES TO TRIAL DESIGN EDUCATION PEOPLE MAKE OR BREAK A TRIAL ACKNOWLEDGMENTS CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

18 CHAPTER 10: Future Priorities and Directions in ALS Research and Treatment INTRODUCTION ETIOLOGICAL HETEROGENEITY OF ALS ALS RISK FACTORS CELLULAR DYSFUNCTION IN ALS ALS AS A “TREATABLE” DISEASE THE IMPORTANCE OF EFFECTIVE BIOMARKERS FUTURE THERAPEUTIC AVENUES FOR A HETEROGENEOUS DISEASE ONGOING CLINICAL TRIALS USING CuATSM CONCLUSIONS AND THE ROAD FORWARD IN ALS RESEARCH AND TREATMENT CONFLICT OF INTEREST COPYRIGHT AND PERMISSION STATEMENT REFERENCES

19 Index

20 End User License Agreement

1 Chapter 1 TABLE 1.1 Spectrum of clinical disease phenotypes associated with genetic var...

2 Chapter 5TABLE 5.1 Summary of key findings linking ALS and the microbiome.

3 Chapter 9TABLE 9.1 Common adaptive trial designs.

1 Chapter 2 FIGURE 2.1 Timeline of ALS gene discovery and the rate of genetically explai...

2 Chapter 3 FIGURE 3.1 Risk factors in proposed etiologies for sALS. Susceptibility gene...

3 Chapter 4FIGURE 4.1 People with lytico (ALS) and bodig (PDC) on Guam. (a) A woman bed...FIGURE 4.2 (a) Decline by birth year in the numbers of newly diagnosed ALS, ...FIGURE 4.3 Pedigrees of four typical, unrelated families of Umatac village i...FIGURE 4.4 Cycad tree ( Cycas micronesica K.D. Hill) on Guam.FIGURE 4.5 Venn diagram showing suggested interactions of genes and toxicant...

4 Chapter 5FIGURE 5.1 Main hypotheses explaining the role of the microbiome in ALS. The...

5 Chapter 6FIGURE 6.1 Schematic of protein misfolding and aggregation process and the a...

6 Chapter 7FIGURE 7.1 Schematic of the time course of how glial cells have been reporte...

7 Chapter 9FIGURE 9.1 Platform trials allow the evaluation of multiple therapies under ...FIGURE 9.2 Platform trials reduce the number of participants assigned to the...

1 Cover Page

2 Title Page

3 Copyright

4 Dedication

5 Contributors

6 Foreword

7 Preface

8 Acknowledgments

9 Table of Contents

10 Begin Reading

11 Index

12 WILEY END USER LICENSE AGREEMENT

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