Front Cover 1
Omega-3 Fatty Acids in Brain and Neurological Health 4
Copyright Page 5
Contents 6
Preface 12
List of Contributors 14
Acknowledgments 18
1 Enhanced Longevity and Role of Omega-3 Fatty Acids 20
Introduction 20
Longevity 20
Food Restriction for Enhanced Longevity 21
Calorie Restriction for Longevity 21
Smoking and Reduced Longevity 21
Genetics, a Key Modifier of Longevity 22
Genetic Diseases and Longevity 22
Genomics 23
Environmental Factors and Longevity 23
Animal Tests and Longevity 24
Omega-3 Fatty Acids and Longevity 24
References 25
Further Reading 26
2 Molecular Gerontology: Principles and Perspectives for Interventions 28
Introduction 28
Homeostasis Versus Homeodynamics 28
Molecular Basis of Aging 29
Free Radical Theory of Aging 29
Protein Error Theory of Aging 30
From FRTA and PETA to Higher Order Theories 30
Genetics, Post-Genetics, and Epigenetics of Aging 30
Epigenetics of Aging 31
Aging Interventions 31
Gene Therapy 31
Manipulating the Milieu 33
Hormetics, Hormesis, and Hormetins 33
References 34
3 Peroxisomal Pathways, their Role in Neurodegenerative Disorders and Therapeutic Strategies 38
Peroxisomes 38
Ether Lipid Synthesis 38
a-oxidation 39
ß-oxidation 39
Peroxisomal Pathologies 42
Leukodystrophies 43
X-linked Adrenoleukodystrophy 43
Lipid and Steroid Hormone Modifications 44
Biological Markers of X-ALD 44
Therapeutic Strategies 44
Fatty Acids and Dietary Intervention 45
Hormone Replacement Therapy 46
Gene Therapy 46
Demyelination and Other Leukodystrophies 46
Conclusion 47
References 47
4 Unregulated Lipid Peroxidation in Neurological Dysfunction 50
Introduction 50
Lipid Oxidation Biomarkers for Neurological Dysfunction 51
Lipid Peroxidation Products from Linoleic Acid 51
Lipid Peroxidation Products from AA 51
Hydroxyeicosatetraenoic Acids 51
F2-Isoprostanes 52
Isofurans 52
Lipid Peroxidation Products from Docosahexaenoic Acid 53
Neuroprostanes 53
Neurofurans 53
Lipid Peroxidation-Derived Short-Chain Aldehydes 53
Lipid Peroxidation Products from Cholesterol 54
Neurological Dysfunction Associated with Lipid Peroxidation 56
Mechanisms of Free Radical Production in Neurological Disorders 57
Alzheimer’s Disease 57
Parkinson’s Disease 57
Amyotrophic Lateral Sclerosis 60
Stroke 61
Down Syndrome 61
Other Neurological Dysfunctions in Childhood 62
Therapeutic Intervention with Antioxidants for Neurological Dysfunction 62
References 63
Additional References 70
5 Obesity, Western Diet Intake, and Cognitive Impairment 76
Obesity and Cognitive Impairment 76
Western Diet Intake and Cognitive Impairment 77
Western Diet Intake and Cognitive Impairment: Underlying Neuroendocrine Mechanisms 78
Summary 80
References 80
6 Genetic Risk Factors for Diabetic Neuropathy 82
Diabetes Mellitus and Its Complications 82
Diabetic Neuropathy: General Characteristics 82
Risk Factors for Diabetic Neuropathy and pathophysiological Mechanisms 82
Genetic Risk Factors for Diabetic Neuropathy 83
Potential Use of Genetic Risk Factors in Clinical Practice 85
References 86
7 n-3 Fatty Acid-Derived Lipid Mediators against Neurological Oxidative Stress and Neuroinflammation 88
Overview 88
DHA in the Brain 89
EPA-Derived Lipid Mediators in the Brain 90
DHA-derived Lipid Mediators in the Brain 92
DHA-derived D-series Resolvins 92
DHA-derived Protectins and Neuroprotectins 92
Effect of EPA and DHA in Neurological Disorders 95
Conclusion 97
References 97
8 The Impact of Omega-3 Fatty Acids on Quality of Life 100
Introduction 100
Assessment of QoL 100
Current Evidence on Omega-3 Fatty Acids and QoL 101
Evidence from Observational Studies 101
Evidence from Clinical Trials 102
Discussion 102
Conclusion and Recommendations 103
References 103
9 Mammalian Fatty Acid Amides of the Brain and CNS 106
Introduction 106
Primary Fatty Acid Amides 106
N-Acylethanolamines (NAEs) 109
N-Acyl Amino Acids (NAAs) 112
NAGs, a Specific Class of the NAAs 113
N-Acyl Taurines, a Specific Class of the NAAs 116
Other N-Acyl Amino Acids 117
N-Acyldopamines 118
The Relevance of the Fatty Acid Amides to Neurological Disease 118
Acknowledgements 121
References 121
10 Low Omega-3 Fatty Acids Diet and the Impact on the Development of Visual Connections and Critical Periods of Plasticity 128
Introduction 128
Nutrition and the Impact of Omega-3 Fatty Acids on Brain Development 128
The Development of Visual Topographical Maps 131
Critical Periods for Brain Development 132
Role of Omega-3 on Development of Central Visual Connections 133
References 136
11 The Effects of Omega-3 Polyunsaturated Fatty Acids on Maternal and Child Mental Health 140
Introduction 140
The Role of Omega-3 Fatty Acids in Neurotransmission 140
DHA and Maternal Mental Health 141
Postpartum Depression 141
Omega-3 Fatty Acids in Postpartum Depression 142
Omega-3 Fatty Acids and Child Mental Health 142
Neurodevelopmental Outcomes: Infancy through Childhood 142
Infancy 142
Childhood 143
Childhood Developmental Disorders 143
Attention Deficit Hyperactivity Disorder 144
Childhood Depression 144
Autistic Spectrum Disorders 145
Conclusion 145
References 146
12 Pain as Modified by Polyunsaturated Fatty Acids 150
Introduction 150
Factors Involved in the Supply and Physiological Function of Fatty Acids in the Brain 151
Blood–Brain Barrier 151
Fatty Acid Transporter Protein 152
Fatty Acid Binding Protein 152
Long-Chain Fatty Acid Receptor GPR40 153
Toll Like Receptor 4 153
Involvement of Lipids, Fatty Acids, and Their Metabolites in Pain Regulation 153
Dietary Lipids 153
Omega-3 Fatty Acids 154
DHA 154
Metabolites Derived from Omega-3 Fatty Acids 155
Omega-6 Fatty Acids and Their Metabolites 157
Prostaglandins 157
Leukotrienes 159
Platelet-Activating Factor 159
Lysophosphatidic Acid 160
Future Prospects 160
References 161
13 Fish Oil Supplementation Prevents Age-Related Memory Decline: Involvement of Nuclear Hormone Receptors 166
Introduction 166
Effects of Aging on Incorporation of Docosahexaenoic Acid in Brain Phospholipids 166
Effects of Aging on DHA Biosynthesis 167
DHA is Involved in Learning and Memory 168
Dietary Fish Oil and Prevention of Age-Related Memory Decline 169
Animal Studies 169
Human Studies 171
DHA Improves Synaptic Plasticity During Aging: Involvement of Retinoid X Receptors and Peroxisome Proliferator-Activated Re... 172
Summary and Concluding Remarks 174
References 176
14 Role of Omega-3 Fatty Acids in Brain and Neurological Health with Special Reference to Clinical Depression 182
Introduction 182
Omega-3 Fatty Acids 182
Factors that Interfere with Conversion of ALA 183
Omega-3 to Omega-6 Ratio 183
Genetic Factors 184
Dietary and Lifestyle Factors 184
Saturated fat – trans-fat 184
Caffeine, Nicotine, Alcohol, Sugar 184
Stress 184
Co-nutrients 184
Status of Omega-3 Fatty Acids in Clinical Depression 184
Nutrient Co-Factor Deficiencies 185
Zinc Deficiency 185
Selenium Deficiency 185
Folic Acid Deficiency 185
Antioxidants 185
Vitamin B6, Tryptophan, and Serotonin 186
Omega-3 Fatty Acids 186
Neurological Alterations in Depression 186
Possible Mechanisms for Links Between Omega-3 Fatty Acids and Depression 188
Omega-3 Fatty Acids Affect Cell Membrane Integrity and Fluidity 188
Omega-3 Fatty Acids Decrease the Production of Pro-Inflammatory Cytokines 189
Omega-3 Fatty Acids and Hippocampal Neurogenesis 189
Impact of Diet on AHN 189
Clinical Trials Supporting the Role of Omega-3 Fatty Acids in MDD 190
Conversion of ALA to EPA and DHA from Flax Seed Oil 192
Probable Mode of Action of Flax Seed Oil in Depression 192
Conclusion 194
References 195
Further Reading 198
15 Omega-3 Fatty Acid Supplementation for Major Depression with Chronic Disease 200
Introduction 200
Omega-3 Fatty Acids 200
Major Depressive Disorder 201
Omega-3 Fatty Acids and Depression 201
Effects of Omega-3 Fatty Acids on Depression with Cardiovascular Disorders 202
Effects of Omega-3 Fatty Acids on Depression with Diabetes 202
Effects of Omega-3 Fatty Acids on Depression and Pregnancy 203
Effects of Omega-3 Fatty Acids on Depression and Old Age 203
Effect of Omega-3 Fatty Acids on Anxiety and Depression in Students 203
Summary 204
References 204
16 The Effectiveness of Fish Oil as a Treatment for ADHD 206
A review of the Literature 206
Purpose 207
Analyzing the Studies 207
Findings 207
The Effect of Fish Oil on the Behavioral/Physical Symptoms of ADHD 209
Omega 3 209
Omega-3 and Omega-6 210
Combination of Essential Fatty Acids and other Supplements 211
Fatty Acid Levels in Blood of Patients with ADHD 212
Omega 3 212
No Supplements were Given 212
Conclusion 212
Final Thought 217
References 217
Further Reading 218
17 Fatty Acids and the Aging Brain 220
Introduction 220
Physiologic Brain Aging 221
Structural Changes 221
Macro-Structural Changes 221
Micro-Structural Changes 222
Chemical Changes 222
Dopamine 222
Serotonin 222
Glutamate 223
Cognitive Changes 223
Changes in Attention 223
Changes in Memory 223
Changes in Orientation 224
Changes in Perception 224
Changes in Executive Control 224
Fatty Acids and Brain Aging 224
Fatty Acid Basics: An Introduction to the Biochemistry of Fatty Acids 224
Fatty Acid Composition of the Brain 225
Omega Fatty Acids 225
Function of Omega-3 Fatty Acids in the Brain 225
Neural Mechanisms 225
Neurogenesis 225
Neurotransmission 226
Reduction of Amyloid-ß Production 226
Increasing Brain-Derived Neurotrophic Factor 226
Vascular Mechanisms 226
Reduction of Inflammation 226
Lowering of Thrombosis 226
Blood Pressure Reduction 227
Lowering Triglyceride Levels 227
Sources of Omega Fatty Acids 227
Omega Fatty Acid Metabolism 227
Pathological Brain Aging 228
Alzheimer’s Disease 228
Disease Characteristics 228
Structural Differences from Normal Aging 228
Chemical Differences 229
Cognitive Differences 229
Disease Mechanisms 229
Vascular Dementia 230
Disease Characteristics 230
Structural Changes 230
Cognitive Changes 230
Chemical Changes 230
Disease Mechanisms 230
Mixed Dementia 230
Protective Effect of Omega-3 Fatty Acids against Dementia 231
Conclusion 232
References 232
Further Reading 238
18 Cerebrovascular Changes: The Role of Fat and Obesity 240
Introduction 240
Vascularization of the Brain 240
The Blood–Brain Barrier 241
Effects of a High Fat Diet and Obesity on Overall Health and Proposed Mechanisms 241
Clinical Studies: Vascular Changes Due to a High Fat Diet and Obesity 242
Animal Studies: Vascular Changes Due to a High Fat Diet and Obesity 243
Impact of Omega-3 Fatty Acids on Vascular Health 245
Conclusion 245
References 246
19 Effects of Omega-3 Fatty Acids on Alzheimer’s Disease 250
Introduction 250
Omega-3 Fatty Acids Biology in Health 250
Alzheimer’s Disease 250
Omega-3 Fatty Acid: a Role in Alzheimer’s Disease? 251
DHA Deficiency and Neurological Function Affected by Diabetes in Alzheimer’s Disease 251
Animal Models, Diabetes, and Alzheimer’s Disease 252
Omega-3 Fatty Acids in Prevention and Treatment of Alzheimer’s Disease 253
References 254
20 Substantia Nigra Modulation by Essential Fatty Acids 256
Importance of Essential Fatty Acids as Neuroprotectors During Brain Development and Aging 256
Substantia Nigra Vulnerability to Neurodegeneration 257
Substantia Nigra Dopamine Cell Populations Display Differential Vulnerability to Lesions 258
Repercussion of EFA Deficiency or Supplementation on Midbrain Dopaminergic Systems 259
Potential Mechanisms Involved in Substantia Nigra Dopamine Cell Loss Induced by EFA Dietary Restriction 260
Acknowledgments 264
References 264
Further Reading 268
21 The Role of Omega-3 Fatty Acids in Hippocampal Neurogenesis 270
Introduction 270
Adult Neurogenesis 271
Measurement of Neurogenesis (Markers of Proliferation) 271
Omega-3 PUFAs and Hippocampal Neurogenesis 272
Developmental Neurogenesis 272
Adult Hippocampal Neurogenesis 273
Mechanisms of Action 273
References 278
22 Imaging Brain DHA Metabolism in Vivo, in Animals, and Humans 284
Introduction 284
Quantitative Imaging of Brain DHA Metabolism in Rodents 284
Incorporation of Circulating PUFAs into Brain Membrane Lipids 284
Methods and models for determining PUFA incorporation into brain 286
Imaging Membrane Synthesis 287
Neuroplasticity with Ocular Enucleation 287
Brain Tumor Imaging 287
Upregulated DHA and AA Releasing Enzymes in an Animal Model of the Metabolic Syndrome 288
Neurotransmission 288
Human Mutations and Mouse Knockouts of iPLA2ß 289
Quantitative Imaging of Brain DHA Metabolism in Human Subjects 290
Baseline Brain DHA Incorporation 290
Upregulated Incorporation Coefficients in Chronic Alcoholics 290
Summary and Conclusions 291
Acknowledgments 292
References 292
23 Obesity and Migraine in Children 296
Introduction 296
Epidemiological Relationship Between Migraine and Obesity 296
Comorbidity 297
Cognitive Profile, Migraine, and Obesity 298
Proposed Mechanism for the Relationship Between Obesity and Migraine 298
Lifestyle Factors 299
Influence of Weight Loss on Chronic Headache in Obese People and Effects of the Preventive Treatment of Migraine on Weight ... 300
Conclusions 302
References 302
24 Dietary Omega-3 Sources during Pregnancy and the Developing Brain: Lessons from Studies in Rats 306
Introduction 306
ALA Supplementation and Brain Fatty Acid Composition 307
Long-chain Omega-3 PUFA Supplementation and Brain Fatty Acid Composition 310
Direct Comparison of ALA and Long-chain Omega-3 PUFA Supplementation on Brain Fatty Acid Composition 316
Conclusions 316
References 320
25 Omega-3 Fatty Acids and Cognitive Behavior 322
Introduction 322
Infants and Children 322
Maternal Supplementation 323
Supplementation During Infancy 326
Supplementation During Childhood 328
Young Adults 330
Older Adults 333
Epidemiological Studies: The Association Between Omega-3 PUFA Intake, Omega-3 PUFA Levels, and Cognitive Decline 333
RCTs: Healthy Older Adults 338
RCTs: Older Adults with Mild Cognitive Impairment or Alzheimer’s Disease 338
Conclusion 341
References 341
26 Lipids and Lipid Signaling in Drosophila Models of Neurodegenerative Diseases 346
Introduction 346
Drosophila as a Model System of Neurodegenerative Diseases 346
Genetic Tools for Making Neurodegenerative Disease Models in Drosophila 346
P-Element-Mediated Mutagenesis 346
UAS-GAL4-Based Gene Expression System 347
Reporters for Amyloid Precursor Protein .-secretase Activity in Drosophila 348
Representative Drosophila Models for Neurodegenerative Diseases 348
Effects of Lipids and Lipid Signaling on Drosophila Models of Neurodegenerative Diseases 349
Effects of PUFA and Cholesterol Levels on Drosophila AD Models Expressing Human Aß42 349
Effect of Phosphatidylethanolamine Depletion on .-secretase-Mediated APP Processing in Transgenic Drosophila 351
Effects of Lipid Signaling Enzyme Diacylglycerol Kinase e Inhibition on Mutant Huntingtin Toxicity 351
Drosophila Mutant of Very Long-Chain Acyl Coenzyme a Synthetase and Glyceryl Trioleate Oil 351
Lipids, TRP Channels, and Neurodegeneration in Drosophila 352
Points to Consider When Drosophila Models are Used for Studying the Role of Lipids 353
Perspective 353
References 354
27 Polyunsaturated Fatty Acids in Relation to Sleep Quality and Depression in Obstructive Sleep Apnea Hypopnea Syndrome 356
Introduction 356
OSAHS 356
Sleepiness 357
OSAHS and Associated Complications 357
Polyunsaturated Fatty Acids 357
PUFAs and Health 358
Depression 359
Link Between PUFAs and Depression in OSAHS 359
Sleep Quality 361
Link Between PUFAs and Sleep Quality in OSAHS 361
Conclusion 364
References 364
Further Reading 366
28 Omega-3 Fatty Acids in Intellectual Disability, Schizophrenia, Depression, Autism, and Attention-Deficit Hyperactivity D... 368
Introduction 368
Background 368
Plasma Lipids in Adults with Intellectual Disability and the Efficacy of Omega-3 Fatty Acids 369
Adrenoleukodystrophy and Adrenomyeloneuropathy 369
Fatty Acid, Lipid, and Cholesterol Levels 370
Plasma Lipids in Schizophrenia and the Efficacy of Omega-3 Fatty Acids 371
Plasma Lipids in Depressive Illness and Efficacy of Omega-3 Fatty Acids 372
Plasma Lipids in Autism and Efficacy of Omega-3 Fatty Acids 373
Plasma Lipids in ADHD and Efficacy of Omega-3 Fatty Acids 374
Conclusions 374
References 375
29 Effect of Omega-3 Fatty Acids on Aggression 378
Introduction 378
First Trial of Omega-3 PUFAs and Aggression in Young Adults 378
Effect of Omega-3 PUFAs on Aggression in Schoolchildren 379
Effect of Omega-3 PUFAs on Aggression in the Elderly 379
Effect of Omega-3 PUFAs on Aggression in Prisoners 380
Effect of Omega-3 PUFAs on Aggression in Patients with ADHD 380
Association Between Omega-3 PUFAs and Hostility in Patients with Schizophrenia 380
Mechanism of Action of Omega-3 PUFAs 380
Serotonin 380
Noradrenalin 381
Cortical-Hippocampal-Amygdala Pathway 381
Endocannabinoids 381
Brain-Derived Neurotrophic Factor 381
Conclusion 381
References 383
30 Multiple Sclerosis: Modification by Fish Oil 386
Introduction 386
Overview 386
Cellular Level of Multiple Sclerosis 387
Omega-3 Supplementation of MS Patients 388
Varying Results Amongst Researchers 388
Summary 389
Acknowledgement 390
References 390
31 Deuterium Protection of Polyunsaturated Fatty Acids against Lipid Peroxidation: A Novel Approach to Mitigating Mitochond... 392
Introduction 392
PUFAs in Mitochondrial Membranes and Oxidative Stress 392
Mitochondrial Dysfunction, Oxidative Stress, and PD 394
Isotope Protection of PUFAS Against autoxidation 395
Yeast Models Confirm the Non-Linear Protective Effect of D-PUFAs in vivo 397
Isotope Reinforcement of PUFA in Pre-Clinical PD Modeling 397
Pre-Clinical Efficacy 399
Conclusion 399
References 400
32 Obesity, Cognitive Functioning, and Dementia: A Lifespan Prospective 404
Introduction 404
Weight-Related Variables and Dementia 404
Prospective Studies with a Focus on Dementia 406
Prospective Studies Focusing on Cognitive Functioning 407
Weight and Cognitive Function: Role of CVD Factors 408
Interactions of Obesity and CVD Risk Factors 409
Controls and Potential Mediators 409
Initial Summary 410
MetS 410
Mechanisms: General 411
Early Influences on Relations between Obesity and Cognition 412
Morbid Obesity and Clinically Important Cognitive Deficit 413
Treatment of Overweight and Obesity 414
Treatment of Obesity with Omega-3 Fatty Acids 415
Omega-3 Fatty Acid Mechanisms for Reducing Weight Loss 416
Methodologies: General Issues 416
Measurement of Cognitive Function 416
Diagnosis of Dementia 417
Formal Definitions of Mild Cognitive Impairment 417
Prospective Designs 417
Neuroimaging Studies 417
Trials 417
Final Summary and Conclusions 417
References 418
33 Dairy Products and Cognitive Functions 422
Introduction 422
Review of the Literature 422
Early Cross-Sectional and Prospective Research Findings in Associations between Dairy and Cognition 424
Cross-Sectional Studies 424
Prospective Studies 424
Summary of These Study Findings 424
Focused Dairy–Cognition Studies 428
Cross-Sectional Studies 428
Randomized Controlled Trials 429
Discussion 429
Limitations of this Literature 429
Assessment of Cognitive Functioning 430
Control of Confounding Variables 430
Dietary Assessment 430
Mechanisms of Action 430
Epidemiological and Clinical Significance 431
Summary 432
Directions for Future Research 432
References 432
34 Obesity and Chronic Low Back Pain: A Kinematic Approach 436
Introduction 436
Quantitative Movement Analysis 437
Equipment 437
Obesity and LBP: Our Experience 438
Gait Analysis 438
Trunk Movement 440
Quantification of Functional Limitation 440
Quantification of the Effects of Osteopathic Manipulative Treatment 443
Conclusions 444
References 444
Further Reading 446
35 Fatty Acids and the Hippocampus 448
Introduction 448
Fatty Acids and Memory/Hippocampus 448
SFAs, Memory, and the Hippocampus – Evidence from Animal Models 448
Neurological Impact of Saturated Fat Consumption 449
BDNF 449
Oxidative Stress 449
Neuroinflammation 450
SFAs, Memory, and the Hippocampus – Human Data 450
Omega-3 Fatty Acids, Memory, and the Hippocampus – Evidence from Animal Studies 451
Can Omega-3 Fatty Acids Remediate Damage to the Hippocampus in Humans? 452
Omega-3 Fatty Acids and Depression 452
Omega-3 Fatty Acids and their Effect on Memory and Cognition 453
Conclusion on Human Data 453
General Conclusion: Fatty Acids and their Impact on the Hippocampus 454
Fatty Acids and AD 454
SFAs and Risk of AD 454
Putative Causal Basis for Link between SFAs and AD 454
Omega-3 Fatty Acids, Cognitive Decline, and Dementia 455
Global Prevalence 455
Matched Group Studies 455
Longitudinal Studies of Cognitive Decline 456
Cognitive Decline and Self-Report Measures of Dietary Intake 456
Dementia Diagnosis and Self-Report Measures of Dietary Intake 456
Cognitive Decline and Plasma Lipid Estimates 457
Dementia Diagnosis and Plasma Lipid Estimates 457
Prevention and Treatment Studies 457
Human Data – Conclusions 458
Omega-3 Fatty Acids, AD, and Memory Impairment – Evidence from Animal Models 458
General Discussion 459
References 460
Further Reading 464
36 Fish Oil Supplements, Contaminants, and Excessive Doses 466
Introduction 466
Mercury 466
Lead 468
Selenium 468
Arsenic 469
Cadmium 470
PCBs 470
Dichlorodiphenyltrichloroethane 471
Dieldrin 471
Conclusion 472
Acknowledgment 472
References 472
37 Introduction to Fish Oil Oxidation, Oxidation Prevention, and Oxidation Correction 474
Introduction 474
Oxidation Process 474
Oxidation Indicators 474
Prevention of Oxidation and Oxidative Stability 476
Oxidation Correction 477
Summary 478
References 478
Further Reading 479
Index 480