Neural Dynamics of Neurological Disease

The emerging understanding of age-related neurological disorders suggests that notions of a single causal gene/toxin being responsible is likely incorrect. Neurological disorders probably arise due to a unique intersection of multiple genetic and toxic factors, combined with additional contributions of age, stage of development, immune system actions, and more. This perspective leads to the view that rather than reflecting only one pathway to end-state disease, each is a spectrum disorder, and every individual case is therefore unique.

Neural Dynamics of Neurological Disease argues for a fundamental rethinking of what we think we know about neurological disorders, how they arise and progress, and, crucially, what might be done to "cure" them. It first introduces the concept of neural dynamics of neurological disease, then examines various diseases and gives examples of the interplay of elements such as neural systems, cell types, and biochemical pathways that can contribute to disease. The concluding chapters point the way to how the emerging notion of neurological disease as a dynamic process may lead to more successful treatment options.

Providing a cross-disciplinary approach to understanding the origin and progression of neurological disease, Neural Dynamics of Neurological Disease is a timely and valuable resource for neuroscientists, researchers, and clinicians.

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

Preface xv

Acknowledgments xxi

Part I The Dynamics of Neurological Disease 1

1 The Dynamics of Neurological Disease: Current Views and Key Issues 3

1.1 Introduction 4

1.2 The Complexity of Human Neurological Diseases 4

1.3 The Nervous System as an Archetypical Complex System 9

1.4 CNS Signaling Failures: Implications for Neurological Disease 14

1.5 History and Key Characteristics of the Age-Dependent Neurological Diseases 14

1.6 The Fractal Nature of Complexity in the CNS 16

Endnotes 17

2 Clinical and Economic Features of Age-Related Neurological Diseases 19

2.1 Introduction 19

2.2 Parkinson’s Disease 19

2.3 Amyotrophic Lateral Sclerosis 29

2.4 Alzheimer’s Disease 40

2.5 Summary of the Data on the Progressive, Age-Related Neurological Diseases 47

2.6 Neural Loci and Mechanisms of Action 48

Endnote 49

3 Spectrums of Neurological Disease, Clusters, and Ubiquity 51

3.1 Introduction 51

3.2 Spectrums of Neurological Disease 51

3.3 The Dimension of the Problem when Assessing Potential Causal Factors in Neurological Diseases 54

3.4 Neurological Disease Clusters 57

3.5 Ubiquity 60

3.6 Nested Complex Systems: Proximal versus Distal Events as They May Relate to Neurological Diseases 60

3.7 The Path to “Curing” Neurological Diseases 63

4 Complexity, Cascading Failures, and Neurological Diseases 67

4.1 Introduction 67

4.2 Introduction to Complexity Theory and Complex Systems 67

4.3 Computer Programs and Computer Crashes 69

4.4 Biosemiosis in the CNS (Part 1) 70

4.5 Complexity in the CNS and the Impact of Genetic and Environmental Insults 73

4.6 Tipping Points and Time Lines of Disease Progression 77

5 Genetic Determinants of Neurological Disease 79

5.1 Introduction 80

5.2 Causality versus Coincidence 80

5.3 Actions of Mutant Genes in Neurological Disease 82

5.4 Genetic Mutations Linked to Parkinson’s Disease 84

5.5 Genetic Mutations Linked to ALS 86

5.6 Genetic Mutations Linked to Alzheimer’s Disease 92

5.7 Genes and Neurological Disease: Some General Considerations 94

6 Environmental Determinants of Neurological Disease and Gene–Toxin Interactions 97

6.1 Introduction 98

6.2 Toxins and Neurological Diseases 98

6.3 Aluminum and Neurological Disease 101

6.4 Single- vs. Multiple-Hit Models of Neurological Disease: Gene–Toxin Interactions 114

6.5 Genetic Susceptibility Factors 117

6.6 Biosemiosis (Part 2) 123

6.7 Gene–Toxin Interactions and Cascading Failures 124

6.8 Genes and Toxins in Neurological Disease: Penultimate Thoughts 124

6.9 And, Finally, the Microbiome 125

Endnote 125

7 The Mystery and Lessons of ALS-PDC 127

7.1 Introduction 127

7.2 Neurological Disease Clusters and ALS-PDC 128

7.3 History and Features of ALS-PDC 129

7.4 Cycad and ALS-PDC 135

7.5 Amino Acid Toxins in Cycad and ALS-PDC 140

7.6 Non-Amino Acid Toxins Linked to ALS-PDC 143

7.7 Aluminum and Ionic Etiologies for ALS-PDC 147

7.8 Still Other Molecules Causal to ALS-PDC 148

7.9 What is the Current View on the Importance of ALS-PDC? 148

7.10 Complexity of Neurological Diseases as Viewed from Guam 151

Endnote 151

Part II Age and Time Lines of Neurological Disease 153

8 Neurological Disease Models and their Discontents: Validity, Replicability, and the Decline Effect 155

8.1 Introduction 155

8.2 Modeling Human Neurological Diseases: Possibilities and Pitfalls 156

8.3 Considerations Regarding Model Systems 158

8.4 Model Systems and their Discontents 159

8.5 Is There an Ideal Model for Studying Neurological Diseases? General Considerations 168

8.6 Specific Considerations for Ideal Model-System Approaches in ALS 170

8.7 Alternative Views of Neurological Disease and Model-Systems Approaches: Multiple-Hit Etiologies 172

9 The Progression and the Time Line of Neurological Disease 175

9.1 Introduction 175

9.2 Creating Disease Time Lines: The Framingham Study 176

9.3 Time Lines of Neurological Disease 176

9.4 Back to a Multiple-Hit Disease Consideration 180

9.5 Haecceity and Quiddity in Context to Biosemiosis and Multiple Hits 181

9.6 Some Final Thoughts on Time Lines of Neurological Disease: Differentiation and Neurogenesis 182

Endnote 183

10 Development, Aging, and Neurological Disease 185

10.1 Introduction 185

10.2 The Fetal Basis of Adult Disease Hypothesis 186

10.3 ASD as a Developmental Neurological Disorder 188

10.4 Toxins and Developmental CNS Disorders 193

10.5 Developmental versus Mature CNS Disorders 193

Endnotes 194

Part III Interactions and Synergies in Neurological Disease 195

11 CNS–Immune System Interactions and Autoimmunity 197

11.1 Introduction 198

11.2 Immunity and the CNS, an Introduction to a Complex Topic 198

11.3 CNS–Immune System Interactions: More Detailed Considerations 202

11.4 Autoimmunity 205

11.5 Immune System Signaling Errors and Autoimmunity in ASD and Other Neurological Disorders 208

11.6 Laterality and Autoimmunity in Neurological Diseases 212

11.7 Other System Disorders in Neurological Diseases: More Evidence for Autoimmunity? 215

11.8 Are There Infectious Disease Links to Neurological Diseases? 215

12 The Impact of Synergy of Factors in Neurological Disease 219

12.1 Introduction 219

12.2 Synergistic and Additive Effects in General and as Applied to CNS Diseases 219

12.3 Gene–Environment (Toxin) Interactions in Non-neuronal Systems 221

12.4 Gene–Environment (Toxin) Interactions in Neurological Disease 224

12.5 Levels of Complexity in Gene–Toxin Interactions: Implications for Current and Future Therapeutics 226

Part IV Transition and Politics in Neurological Disease 229

13 The Current Status of Neurological Disease Treatments 231

13.1 Introduction 231

13.2 Current Therapeutic Approaches to Treating Neurological Diseases 232

13.3 Summary 242

Endnote 243

14 The Future of Translational Research in Neurological Disease 245

14.1 Introduction 245

14.2 Comparing Traumatic Brain Injury to Neurological Diseases 246

14.3 ALS and Polio: Comparing the Nature of Neural Degeneration and Progression in the Two Diseases 249

14.4 Neurological Diseases as Spectrum Disorders: Implications for Therapy 252

14.5 Cystic Fibrosis and Gene Therapy 254

14.6 Restoring CNS Function: What is the Bottom Line? 255

14.7 Biosemiosis (Part 3) and True Narrative Representations 255

15 Defining the Limits for Neurological Disease Treatments 259

15.1 Introduction 259

15.2 The Complexity of the Human CNS versus One View of the Philosophy of Science 260

15.3 Examples of Unique Individuality: From Pilgrimages to Nature 261

15.4 Therapeutic Windows for the Treatment of Neurological Diseases 266

Endnotes 270

16 The Politics and Economics of Neurological Disease 271

16.1 Introduction 271

16.2 The Problems with Single-Hit Models of Neurological Disease 272

16.3 Summarizing the Main Themes by Chapter 274

16.4 Can the Amount of Money Spent Change these Outcomes for Neurological Disease Treatment? 276

16.5 General Considerations for the Future of Neurological Disease Research 280

16.6 The Advent of Modern Dentistry and Dental Prophylaxis 284

16.7 Addressing Neurological Diseases at the Individual and Population Levels 286

Endnotes 290

Glossary 291

References 301

Index 355

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