Advances in Multiple Sclerosis and Experimental Demyelinating Diseases (eBook)

Preface 5
Contents 11
Contributors 13
Benign Multiple Sclerosis: A Distinct Clinical Entity with Therapeutic Implications 15
1 Introduction 16
2 Natural History of Multiple Sclerosis: Disability Progression 16
3 Benign MS: A Fallacy or a Distinct Clinical Entity? 17
4 Does Benign MS Stay Benign with Increasing Disease Duration? 18
5 Other Clinical Predictors of MS Outcome 20
6 Neuroimaging Studies in Benign MS 21
7 The Currently FDA-Approved Disease-Modifying Agents: Efficacy, Mode of Action, and Side Effects 23
8 Should All MS Patients Be Treated with Disease- Modifying Therapies? 27
References 28
Pathological Heterogeneity of Idiopathic Central Nervous System Inflammatory Demyelinating Disorders 32
1 Introduction 33
2 Heterogeneity of Multiple Sclerosis White Matter Lesions 34
3 Remyelination in MS 44
4 The Clinicopathologic Spectrum of CNS Idiopathic Inflammatory Demyelinating Disorders 45
Conclusions 51
References 51
Multiple Sclerosis Genetics 57
1 Introduction 58
2 Major Histocompatibility Complex and Multiple Sclerosis 59
3 Genetic Analyses 61
4 Microarray Studies 69
5 Future Directions 73
References 75
Imaging of Remyelination and Neuronal Health 85
Abbreviations 86
1 Introduction 86
2 Conventional MRI of Remyelination 88
3 Magnetization Transfer Imaging of Remyelination 92
4 Diffusion Imaging of Remyelination 95
5 Spectroscopy of Remyelination 98
6 Other Imaging Modalities 100
Conclusions 102
References 102
Immunological Aspects of Axon Injury in Multiple Sclerosis 105
1 Introduction 106
2 Changes in Axon Function During Demyelination 106
3 Axonal Degeneration During Demyelination 115
4 Immune-Mediated Mechanisms of Axon Injury During Demyelination 119
5 Stress and the Naked Axon – A Hypothesis 130
References 130
The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease 144
1 Introduction 145
2 Multiple Classes of Protease Implicated in MS 146
3 Functional Roles of Proteases in MS 158
4 Novel Hypothesis Regarding Role of Proteases in MS 167
5 Proteases as Targets for Rationale Drug Design 168
Conclusion 170
References 170
Genetic Analysis of CNS Remyelination 187
1 Introduction 188
2 Mouse Models of Demyelinating Disease 189
3 Cellular Events in Remyelination 190
4 Genetic Analysis in the Mouse 190
5 Reverse Genetic Analysis of CNS Remyelination 192
6 Forward Genetic Analysis of CNS Remyelination 197
References 200
Remyelination in Experimental Models of Toxin- Induced Demyelination 203
1 Introduction 204
2 Demyelinating Toxins 206
3 What is the Place of Toxin Models in the Study of CNS Demyelination and Remyelination? 215
References 218
Remyelination-Promoting Human IgMs: Developing a Therapeutic Reagent for Demyelinating Disease 223
1 Multiple Sclerosis is a Disease of Myelin 224
2 Remyelination as a Normal Reparative Response 224
3 Strategies to Augment Remyelination 226
4 Antibodies Directed Against CNS Antigens Can be Pathogenic or Reparative 229
5 Human Antibodies that Promote Remyelination 231
6 Role of Anti-CNS Antibodies in Endogenous Repair 233
7 A Recombinant Human IgM Promotes Remyelination in vivo at Doses Comparable to Growth Factors 233
8 The IgM Character of Remyelination Promoting Antibodies is Vital for Function 236
9 Mechanisms of Antibody-Mediated CNS Repair 237
10 Therapeutic Goal: Alter the Balance of Inflammation to Favor Regeneration 239
References 240
Neuroimaging of Demyelination and Remyelination Models 250
1 Introduction 251
2 Conventional MRI Studies 253
3 Advanced MRI Methods for Visualizing Demyelinating Diseases 260
4 T1 and T2 Relaxometry 264
5 Magnetic Resonance Spectroscopy 265
6 Cell-Specific Contrast Agents 266
7 Imaging of Remyelination in MS Models 269
8 Conclusions and Future Directions 271
References 272
Hormonal Influences in Multiple Sclerosis 276
1 Introduction 277
2 Glucocorticoids 278
3 Female Hormones of Reproduction and MS 284
4 Testosterone and DHEA 295
5 Vitamin D 298
6 Thyroid Hormone 301
7 Leptin and Ghrelin 305
8 Conclusions 307
References 308
Statins and Demyelination 321
1 Introduction 322
2 Mechanism of Action 322
3 Statins in Treatment of Experimental Autoimmune Encephalomyelitis 323
4 Statins in Treatment of MS 326
References 329
Role of Uric Acid in Multiple Sclerosis 333
1 Uric Acid in Evolution 333
2 Uric Acid and Free Radicals 335
3 Role of Free Radicals in Multiple Sclerosis: Lessons from Experimental Allergic Encephalomyelitis and Other Models 336
4 Serum Uric Acid Levels in Patients with Multiple Sclerosis 338
5 Possible Mechanisms of Uric Acid Action in Multiple Sclerosis, Protection of Blood– Brain Barrier Integrity 343
6 Treatment of MS Patients by Raising UA Levels 344
Conclusions 346
References 346
Neuromyelitis Optica: Clinical Syndrome and the NMO- IgG Autoantibody Marker 351
1 All that Relapses is not MS 352
2 NMO is Distinct: The Clinical Clues 354
3 A Tool: Discovery of a Biomarker and Its Target 355
4 Uncertainties (Boundaries, Forme Frustes, OSMS vs NMO, etc.) 357
5 Toward an Understanding of NMO Pathogenesis 359
6 How Has Current Knowledge Affected the Therapeutic Approach to NMO? 361
Conclusion 362
References 363
Index 365