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.
Contents
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 ComplexityTheory 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 GeneticMutations Linked to ALS 86
5.6 GeneticMutations 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: PenultimateThoughts 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 IsThere 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 SystemInteractions 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 FutureTherapeutics 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 TherapeuticWindows 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
