About the AuthorCHRISTOPHER A. SHAW Department of Ophthalmology and Visual Sciences, University of British Columbia, Canada

• Preface xvAcknowledgments xxiPart I The Dynamics of Neurological Disease 11 The Dynamics of Neurological Disease: Current Views and Key Issues 31.1 Introduction 41.2 The Complexity of Human Neurological Diseases 41.3 The Nervous System as an Archetypical Complex System 91.4 CNS Signaling Failures: Implications for Neurological Disease 141.5 History and Key Characteristics of the Age-Dependent Neurological Diseases 141.6 The Fractal Nature of Complexity in the CNS 16Endnotes 172 Clinical and Economic Features of Age-Related Neurological Diseases 192.1 Introduction 192.2 Parkinson’s Disease 192.3 Amyotrophic Lateral Sclerosis 292.4 Alzheimer’s Disease 402.5 Summary of the Data on the Progressive, Age-Related Neurological Diseases 472.6 Neural Loci and Mechanisms of Action 48Endnote 493 Spectrums of Neurological Disease, Clusters, and Ubiquity 513.1 Introduction 513.2 Spectrums of Neurological Disease 513.3 The Dimension of the Problem when Assessing Potential Causal Factors in Neurological Diseases 543.4 Neurological Disease Clusters 573.5 Ubiquity 603.6 Nested Complex Systems: Proximal versus Distal Events as They May Relate to Neurological Diseases 603.7 The Path to “Curing” Neurological Diseases 634 Complexity, Cascading Failures, and Neurological Diseases 674.1 Introduction 674.2 Introduction to Complexity Theory and Complex Systems 674.3 Computer Programs and Computer Crashes 694.4 Biosemiosis in the CNS (Part 1) 704.5 Complexity in the CNS and the Impact of Genetic and Environmental Insults 734.6 Tipping Points and Time Lines of Disease Progression 775 Genetic Determinants of Neurological Disease 795.1 Introduction 805.2 Causality versus Coincidence 805.3 Actions of Mutant Genes in Neurological Disease 825.4 Genetic Mutations Linked to Parkinson’s Disease 845.5 Genetic Mutations Linked to ALS 865.6 Genetic Mutations Linked to Alzheimer’s Disease 925.7 Genes and Neurological Disease: Some General Considerations 946 Environmental Determinants of Neurological Disease and Gene–Toxin Interactions 976.1 Introduction 986.2 Toxins and Neurological Diseases 986.3 Aluminum and Neurological Disease 1016.4 Single- vs. Multiple-Hit Models of Neurological Disease: Gene–Toxin Interactions 1146.5 Genetic Susceptibility Factors 1176.6 Biosemiosis (Part 2) 1236.7 Gene–Toxin Interactions and Cascading Failures 1246.8 Genes and Toxins in Neurological Disease: Penultimate Thoughts 1246.9 And, Finally, the Microbiome 125Endnote 1257 The Mystery and Lessons of ALS-PDC 1277.1 Introduction 1277.2 Neurological Disease Clusters and ALS-PDC 1287.3 History and Features of ALS-PDC 1297.4 Cycad and ALS-PDC 1357.5 Amino Acid Toxins in Cycad and ALS-PDC 1407.6 Non-Amino Acid Toxins Linked to ALS-PDC 1437.7 Aluminum and Ionic Etiologies for ALS-PDC 1477.8 Still Other Molecules Causal to ALS-PDC 1487.9 What is the Current View on the Importance of ALS-PDC? 1487.10 Complexity of Neurological Diseases as Viewed from Guam 151Endnote 151Part II Age and Time Lines of Neurological Disease 1538 Neurological Disease Models and their Discontents: Validity, Replicability, and the Decline Effect 1558.1 Introduction 1558.2 Modeling Human Neurological Diseases: Possibilities and Pitfalls 1568.3 Considerations Regarding Model Systems 1588.4 Model Systems and their Discontents 1598.5 Is There an Ideal Model for Studying Neurological Diseases? General Considerations 1688.6 Specific Considerations for Ideal Model-System Approaches in ALS 1708.7 Alternative Views of Neurological Disease and Model-Systems Approaches: Multiple-Hit Etiologies 1729 The Progression and the Time Line of Neurological Disease 1759.1 Introduction 1759.2 Creating Disease Time Lines: The Framingham Study 1769.3 Time Lines of Neurological Disease 1769.4 Back to a Multiple-Hit Disease Consideration 1809.5 Haecceity and Quiddity in Context to Biosemiosis and Multiple Hits 1819.6 Some Final Thoughts on Time Lines of Neurological Disease: Differentiation and Neurogenesis 182Endnote 18310 Development, Aging, and Neurological Disease 18510.1 Introduction 18510.2 The Fetal Basis of Adult Disease Hypothesis 18610.3 ASD as a Developmental Neurological Disorder 18810.4 Toxins and Developmental CNS Disorders 19310.5 Developmental versus Mature CNS Disorders 193Endnotes 194Part III Interactions and Synergies in Neurological Disease 19511 CNS–Immune System Interactions and Autoimmunity 19711.1 Introduction 19811.2 Immunity and the CNS, an Introduction to a Complex Topic 19811.3 CNS–Immune System Interactions: More Detailed Considerations 20211.4 Autoimmunity 20511.5 Immune System Signaling Errors and Autoimmunity in ASD and Other Neurological Disorders 20811.6 Laterality and Autoimmunity in Neurological Diseases 21211.7 Other System Disorders in Neurological Diseases: More Evidence for Autoimmunity? 21511.8 Are There Infectious Disease Links to Neurological Diseases? 21512 The Impact of Synergy of Factors in Neurological Disease 21912.1 Introduction 21912.2 Synergistic and Additive Effects in General and as Applied to CNS Diseases 21912.3 Gene–Environment (Toxin) Interactions in Non-neuronal Systems 22112.4 Gene–Environment (Toxin) Interactions in Neurological Disease 22412.5 Levels of Complexity in Gene–Toxin Interactions: Implications for Current and Future Therapeutics 226Part IV Transition and Politics in Neurological Disease 22913 The Current Status of Neurological Disease Treatments 23113.1 Introduction 23113.2 Current Therapeutic Approaches to Treating Neurological Diseases 23213.3 Summary 242Endnote 24314 The Future of Translational Research in Neurological Disease 24514.1 Introduction 24514.2 Comparing Traumatic Brain Injury to Neurological Diseases 24614.3 ALS and Polio: Comparing the Nature of Neural Degeneration and Progression in the Two Diseases 24914.4 Neurological Diseases as Spectrum Disorders: Implications for Therapy 25214.5 Cystic Fibrosis and Gene Therapy 25414.6 Restoring CNS Function: What is the Bottom Line? 25514.7 Biosemiosis (Part 3) and True Narrative Representations 25515 Defining the Limits for Neurological Disease Treatments 25915.1 Introduction 25915.2 The Complexity of the Human CNS versus One View of the Philosophy of Science 26015.3 Examples of Unique Individuality: From Pilgrimages to Nature 26115.4 Therapeutic Windows for the Treatment of Neurological Diseases 266Endnotes 27016 The Politics and Economics of Neurological Disease 27116.1 Introduction 27116.2 The Problems with Single-Hit Models of Neurological Disease 27216.3 Summarizing the Main Themes by Chapter 27416.4 Can the Amount of Money Spent Change these Outcomes for Neurological Disease Treatment? 27616.5 General Considerations for the Future of Neurological Disease Research 28016.6 The Advent of Modern Dentistry and Dental Prophylaxis 28416.7 Addressing Neurological Diseases at the Individual and Population Levels 286Endnotes 290Glossary 291References 301Index 355

About the AuthorCHRISTOPHER A. SHAW Department of Ophthalmology and Visual Sciences, University of British Columbia, Canada

• Preface xvAcknowledgments xxiPart I The Dynamics of Neurological Disease 11 The Dynamics of Neurological Disease: Current Views and Key Issues 31.1 Introduction 41.2 The Complexity of Human Neurological Diseases 41.3 The Nervous System as an Archetypical Complex System 91.4 CNS Signaling Failures: Implications for Neurological Disease 141.5 History and Key Characteristics of the Age-Dependent Neurological Diseases 141.6 The Fractal Nature of Complexity in the CNS 16Endnotes 172 Clinical and Economic Features of Age-Related Neurological Diseases 192.1 Introduction 192.2 Parkinson’s Disease 192.3 Amyotrophic Lateral Sclerosis 292.4 Alzheimer’s Disease 402.5 Summary of the Data on the Progressive, Age-Related Neurological Diseases 472.6 Neural Loci and Mechanisms of Action 48Endnote 493 Spectrums of Neurological Disease, Clusters, and Ubiquity 513.1 Introduction 513.2 Spectrums of Neurological Disease 513.3 The Dimension of the Problem when Assessing Potential Causal Factors in Neurological Diseases 543.4 Neurological Disease Clusters 573.5 Ubiquity 603.6 Nested Complex Systems: Proximal versus Distal Events as They May Relate to Neurological Diseases 603.7 The Path to “Curing” Neurological Diseases 634 Complexity, Cascading Failures, and Neurological Diseases 674.1 Introduction 674.2 Introduction to Complexity Theory and Complex Systems 674.3 Computer Programs and Computer Crashes 694.4 Biosemiosis in the CNS (Part 1) 704.5 Complexity in the CNS and the Impact of Genetic and Environmental Insults 734.6 Tipping Points and Time Lines of Disease Progression 775 Genetic Determinants of Neurological Disease 795.1 Introduction 805.2 Causality versus Coincidence 805.3 Actions of Mutant Genes in Neurological Disease 825.4 Genetic Mutations Linked to Parkinson’s Disease 845.5 Genetic Mutations Linked to ALS 865.6 Genetic Mutations Linked to Alzheimer’s Disease 925.7 Genes and Neurological Disease: Some General Considerations 946 Environmental Determinants of Neurological Disease and Gene–Toxin Interactions 976.1 Introduction 986.2 Toxins and Neurological Diseases 986.3 Aluminum and Neurological Disease 1016.4 Single- vs. Multiple-Hit Models of Neurological Disease: Gene–Toxin Interactions 1146.5 Genetic Susceptibility Factors 1176.6 Biosemiosis (Part 2) 1236.7 Gene–Toxin Interactions and Cascading Failures 1246.8 Genes and Toxins in Neurological Disease: Penultimate Thoughts 1246.9 And, Finally, the Microbiome 125Endnote 1257 The Mystery and Lessons of ALS-PDC 1277.1 Introduction 1277.2 Neurological Disease Clusters and ALS-PDC 1287.3 History and Features of ALS-PDC 1297.4 Cycad and ALS-PDC 1357.5 Amino Acid Toxins in Cycad and ALS-PDC 1407.6 Non-Amino Acid Toxins Linked to ALS-PDC 1437.7 Aluminum and Ionic Etiologies for ALS-PDC 1477.8 Still Other Molecules Causal to ALS-PDC 1487.9 What is the Current View on the Importance of ALS-PDC? 1487.10 Complexity of Neurological Diseases as Viewed from Guam 151Endnote 151Part II Age and Time Lines of Neurological Disease 1538 Neurological Disease Models and their Discontents: Validity, Replicability, and the Decline Effect 1558.1 Introduction 1558.2 Modeling Human Neurological Diseases: Possibilities and Pitfalls 1568.3 Considerations Regarding Model Systems 1588.4 Model Systems and their Discontents 1598.5 Is There an Ideal Model for Studying Neurological Diseases? General Considerations 1688.6 Specific Considerations for Ideal Model-System Approaches in ALS 1708.7 Alternative Views of Neurological Disease and Model-Systems Approaches: Multiple-Hit Etiologies 1729 The Progression and the Time Line of Neurological Disease 1759.1 Introduction 1759.2 Creating Disease Time Lines: The Framingham Study 1769.3 Time Lines of Neurological Disease 1769.4 Back to a Multiple-Hit Disease Consideration 1809.5 Haecceity and Quiddity in Context to Biosemiosis and Multiple Hits 1819.6 Some Final Thoughts on Time Lines of Neurological Disease: Differentiation and Neurogenesis 182Endnote 18310 Development, Aging, and Neurological Disease 18510.1 Introduction 18510.2 The Fetal Basis of Adult Disease Hypothesis 18610.3 ASD as a Developmental Neurological Disorder 18810.4 Toxins and Developmental CNS Disorders 19310.5 Developmental versus Mature CNS Disorders 193Endnotes 194Part III Interactions and Synergies in Neurological Disease 19511 CNS–Immune System Interactions and Autoimmunity 19711.1 Introduction 19811.2 Immunity and the CNS, an Introduction to a Complex Topic 19811.3 CNS–Immune System Interactions: More Detailed Considerations 20211.4 Autoimmunity 20511.5 Immune System Signaling Errors and Autoimmunity in ASD and Other Neurological Disorders 20811.6 Laterality and Autoimmunity in Neurological Diseases 21211.7 Other System Disorders in Neurological Diseases: More Evidence for Autoimmunity? 21511.8 Are There Infectious Disease Links to Neurological Diseases? 21512 The Impact of Synergy of Factors in Neurological Disease 21912.1 Introduction 21912.2 Synergistic and Additive Effects in General and as Applied to CNS Diseases 21912.3 Gene–Environment (Toxin) Interactions in Non-neuronal Systems 22112.4 Gene–Environment (Toxin) Interactions in Neurological Disease 22412.5 Levels of Complexity in Gene–Toxin Interactions: Implications for Current and Future Therapeutics 226Part IV Transition and Politics in Neurological Disease 22913 The Current Status of Neurological Disease Treatments 23113.1 Introduction 23113.2 Current Therapeutic Approaches to Treating Neurological Diseases 23213.3 Summary 242Endnote 24314 The Future of Translational Research in Neurological Disease 24514.1 Introduction 24514.2 Comparing Traumatic Brain Injury to Neurological Diseases 24614.3 ALS and Polio: Comparing the Nature of Neural Degeneration and Progression in the Two Diseases 24914.4 Neurological Diseases as Spectrum Disorders: Implications for Therapy 25214.5 Cystic Fibrosis and Gene Therapy 25414.6 Restoring CNS Function: What is the Bottom Line? 25514.7 Biosemiosis (Part 3) and True Narrative Representations 25515 Defining the Limits for Neurological Disease Treatments 25915.1 Introduction 25915.2 The Complexity of the Human CNS versus One View of the Philosophy of Science 26015.3 Examples of Unique Individuality: From Pilgrimages to Nature 26115.4 Therapeutic Windows for the Treatment of Neurological Diseases 266Endnotes 27016 The Politics and Economics of Neurological Disease 27116.1 Introduction 27116.2 The Problems with Single-Hit Models of Neurological Disease 27216.3 Summarizing the Main Themes by Chapter 27416.4 Can the Amount of Money Spent Change these Outcomes for Neurological Disease Treatment? 27616.5 General Considerations for the Future of Neurological Disease Research 28016.6 The Advent of Modern Dentistry and Dental Prophylaxis 28416.7 Addressing Neurological Diseases at the Individual and Population Levels 286Endnotes 290Glossary 291References 301Index 355

About the AuthorCHRISTOPHER A. SHAW Department of Ophthalmology and Visual Sciences, University of British Columbia, Canada

• Preface xvAcknowledgments xxiPart I The Dynamics of Neurological Disease 11 The Dynamics of Neurological Disease: Current Views and Key Issues 31.1 Introduction 41.2 The Complexity of Human Neurological Diseases 41.3 The Nervous System as an Archetypical Complex System 91.4 CNS Signaling Failures: Implications for Neurological Disease 141.5 History and Key Characteristics of the Age-Dependent Neurological Diseases 141.6 The Fractal Nature of Complexity in the CNS 16Endnotes 172 Clinical and Economic Features of Age-Related Neurological Diseases 192.1 Introduction 192.2 Parkinson’s Disease 192.3 Amyotrophic Lateral Sclerosis 292.4 Alzheimer’s Disease 402.5 Summary of the Data on the Progressive, Age-Related Neurological Diseases 472.6 Neural Loci and Mechanisms of Action 48Endnote 493 Spectrums of Neurological Disease, Clusters, and Ubiquity 513.1 Introduction 513.2 Spectrums of Neurological Disease 513.3 The Dimension of the Problem when Assessing Potential Causal Factors in Neurological Diseases 543.4 Neurological Disease Clusters 573.5 Ubiquity 603.6 Nested Complex Systems: Proximal versus Distal Events as They May Relate to Neurological Diseases 603.7 The Path to “Curing” Neurological Diseases 634 Complexity, Cascading Failures, and Neurological Diseases 674.1 Introduction 674.2 Introduction to Complexity Theory and Complex Systems 674.3 Computer Programs and Computer Crashes 694.4 Biosemiosis in the CNS (Part 1) 704.5 Complexity in the CNS and the Impact of Genetic and Environmental Insults 734.6 Tipping Points and Time Lines of Disease Progression 775 Genetic Determinants of Neurological Disease 795.1 Introduction 805.2 Causality versus Coincidence 805.3 Actions of Mutant Genes in Neurological Disease 825.4 Genetic Mutations Linked to Parkinson’s Disease 845.5 Genetic Mutations Linked to ALS 865.6 Genetic Mutations Linked to Alzheimer’s Disease 925.7 Genes and Neurological Disease: Some General Considerations 946 Environmental Determinants of Neurological Disease and Gene–Toxin Interactions 976.1 Introduction 986.2 Toxins and Neurological Diseases 986.3 Aluminum and Neurological Disease 1016.4 Single- vs. Multiple-Hit Models of Neurological Disease: Gene–Toxin Interactions 1146.5 Genetic Susceptibility Factors 1176.6 Biosemiosis (Part 2) 1236.7 Gene–Toxin Interactions and Cascading Failures 1246.8 Genes and Toxins in Neurological Disease: Penultimate Thoughts 1246.9 And, Finally, the Microbiome 125Endnote 1257 The Mystery and Lessons of ALS-PDC 1277.1 Introduction 1277.2 Neurological Disease Clusters and ALS-PDC 1287.3 History and Features of ALS-PDC 1297.4 Cycad and ALS-PDC 1357.5 Amino Acid Toxins in Cycad and ALS-PDC 1407.6 Non-Amino Acid Toxins Linked to ALS-PDC 1437.7 Aluminum and Ionic Etiologies for ALS-PDC 1477.8 Still Other Molecules Causal to ALS-PDC 1487.9 What is the Current View on the Importance of ALS-PDC? 1487.10 Complexity of Neurological Diseases as Viewed from Guam 151Endnote 151Part II Age and Time Lines of Neurological Disease 1538 Neurological Disease Models and their Discontents: Validity, Replicability, and the Decline Effect 1558.1 Introduction 1558.2 Modeling Human Neurological Diseases: Possibilities and Pitfalls 1568.3 Considerations Regarding Model Systems 1588.4 Model Systems and their Discontents 1598.5 Is There an Ideal Model for Studying Neurological Diseases? General Considerations 1688.6 Specific Considerations for Ideal Model-System Approaches in ALS 1708.7 Alternative Views of Neurological Disease and Model-Systems Approaches: Multiple-Hit Etiologies 1729 The Progression and the Time Line of Neurological Disease 1759.1 Introduction 1759.2 Creating Disease Time Lines: The Framingham Study 1769.3 Time Lines of Neurological Disease 1769.4 Back to a Multiple-Hit Disease Consideration 1809.5 Haecceity and Quiddity in Context to Biosemiosis and Multiple Hits 1819.6 Some Final Thoughts on Time Lines of Neurological Disease: Differentiation and Neurogenesis 182Endnote 18310 Development, Aging, and Neurological Disease 18510.1 Introduction 18510.2 The Fetal Basis of Adult Disease Hypothesis 18610.3 ASD as a Developmental Neurological Disorder 18810.4 Toxins and Developmental CNS Disorders 19310.5 Developmental versus Mature CNS Disorders 193Endnotes 194Part III Interactions and Synergies in Neurological Disease 19511 CNS–Immune System Interactions and Autoimmunity 19711.1 Introduction 19811.2 Immunity and the CNS, an Introduction to a Complex Topic 19811.3 CNS–Immune System Interactions: More Detailed Considerations 20211.4 Autoimmunity 20511.5 Immune System Signaling Errors and Autoimmunity in ASD and Other Neurological Disorders 20811.6 Laterality and Autoimmunity in Neurological Diseases 21211.7 Other System Disorders in Neurological Diseases: More Evidence for Autoimmunity? 21511.8 Are There Infectious Disease Links to Neurological Diseases? 21512 The Impact of Synergy of Factors in Neurological Disease 21912.1 Introduction 21912.2 Synergistic and Additive Effects in General and as Applied to CNS Diseases 21912.3 Gene–Environment (Toxin) Interactions in Non-neuronal Systems 22112.4 Gene–Environment (Toxin) Interactions in Neurological Disease 22412.5 Levels of Complexity in Gene–Toxin Interactions: Implications for Current and Future Therapeutics 226Part IV Transition and Politics in Neurological Disease 22913 The Current Status of Neurological Disease Treatments 23113.1 Introduction 23113.2 Current Therapeutic Approaches to Treating Neurological Diseases 23213.3 Summary 242Endnote 24314 The Future of Translational Research in Neurological Disease 24514.1 Introduction 24514.2 Comparing Traumatic Brain Injury to Neurological Diseases 24614.3 ALS and Polio: Comparing the Nature of Neural Degeneration and Progression in the Two Diseases 24914.4 Neurological Diseases as Spectrum Disorders: Implications for Therapy 25214.5 Cystic Fibrosis and Gene Therapy 25414.6 Restoring CNS Function: What is the Bottom Line? 25514.7 Biosemiosis (Part 3) and True Narrative Representations 25515 Defining the Limits for Neurological Disease Treatments 25915.1 Introduction 25915.2 The Complexity of the Human CNS versus One View of the Philosophy of Science 26015.3 Examples of Unique Individuality: From Pilgrimages to Nature 26115.4 Therapeutic Windows for the Treatment of Neurological Diseases 266Endnotes 27016 The Politics and Economics of Neurological Disease 27116.1 Introduction 27116.2 The Problems with Single-Hit Models of Neurological Disease 27216.3 Summarizing the Main Themes by Chapter 27416.4 Can the Amount of Money Spent Change these Outcomes for Neurological Disease Treatment? 27616.5 General Considerations for the Future of Neurological Disease Research 28016.6 The Advent of Modern Dentistry and Dental Prophylaxis 28416.7 Addressing Neurological Diseases at the Individual and Population Levels 286Endnotes 290Glossary 291References 301Index 355