Оглавление
Группа авторов. Spectrums of Amyotrophic Lateral Sclerosis
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
Spectrums of Amyotrophic Lateral Sclerosis. Heterogeneity, Pathogenesis and Therapeutic Directions
Contributors
Foreword
Preface
Acknowledgments
CHAPTER 1 Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development
INTRODUCTION
CLINICAL HETEROGENEITY OF ALS. Familial and Sporadic ALS
Age of Onset
Survival
Classic ALS, LMN Form, and UMN Form
Site of Onset
Diagnosis of ALS
ALS and Its Relationship with Frontotemporal Dementia and Myopathies
PLEIOTROPY OF ALS GENES
GENETIC MODELS TO STUDY ALS. In Vivo Models
In Vitro Models
CONCLUSION
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 2 Genetic Basis of ALS
INTRODUCTION
GENES CAUSING ALS
Superoxide Dismutase 1 (SOD1)
TAR DNA‐Binding Protein 43 (TDP‐43)
Fused in Sarcoma (FUS)
Chromosome 9 Open Reading Frame 72 (C9orf72)
RECENTLY DISCOVERED GENES
Annexin A11 (ANXA11)
Glycosyltransferase 8 Domain Containing 1 (GLT8D1)
Stathmin‐2 (STMN2)
ASPECTS OF ALS HERITABILITY
Sporadic vs. Familial
Penetrance and the Oligogenic Hypothesis
Multistep Model
NONCODING VARIATION
Regulatory and Intronic Variants
Epigenetics
CONCLUSIONS
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 3 Susceptibility Genes and Epigenetics in Sporadic ALS
INTRODUCTION
ENVIRONMENTAL ASSOCIATIONS IN sALS
GENETIC BASIS OF sALS
IDENTIFICATION OF sALS SUSCEPTIBILITY GENES
CANDIDATE sALS SUSCEPTIBILITY GENES
UNC13A
DPP6
C21orf2
EPIGENETIC MECHANISMS IN sALS
Methylation in sALS
miRNAs in sALS
Post‐Translational Histone Modification in sALS
Epigenetic Analysis in Monozygotic sALS Twins
MODIFICATIONS TO THE EPIGENOME BY ENVIRONMENTAL FACTORS
In Utero Environmental Exposures
Environmental in Utero Epigenomic Alterations
Post Utero Exposures
CONCLUSION
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 4 The Lessons of ALS‐PDC – Environmental Factors in ALS Etiology
INTRODUCTION
KOCH'S POSTULATES IN THE SEARCH OF ETIOLOGICAL ALS FACTORS
NEUROLOGICAL DISEASE CLUSTERS
THE NATURAL HISTORY OF ALS‐PDC
INVESTIGATING ETIOLOGICAL FACTORS
IDENTIFIED CYCAD TOXIN/TOXICANTS
ALUMINUM AND IONIC ETIOLOGIES FOR ALS‐PDC
OTHER MOLECULES THAT MIGHT HAVE BEEN INVOLVED IN ALS‐PDC
A PUTATIVE VIRAL ETIOLOGY FOR ALS‐PDC ON GUAM AND ALS IN GENERAL
THE CONTINUING IMPORTANCE OF ALS‐PDC
SUMMARY AND CONCLUSIONS
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
NOTE
CHAPTER 5 The Microbiome of ALS – Does It Start from the Gut?
INTRODUCTION
RECENT STUDIES
Animal and in vitro Studies
Clinical Studies
HOW COULD THE MICROBIOME CONTRIBUTE TO ALS?
Gut Barrier and Membrane Permeability
Inflammation and Immune Response
Neurotoxins
Energy Metabolism
MICROBIOME MODULATION AS A POTENTIAL THERAPEUTIC AVENUE
CONCLUSION
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 6 Protein Aggregation in Amyotrophic Lateral Sclerosis
INTRODUCTION
PATHOLOGICAL PROTEIN INCLUSIONS ASSOCIATED WITH ALS
Protein Homeostasis and Misfolded Protein Partitioning in ALS
CONSEQUENCES OF PROTEIN AGGREGATION IN ALS
THE PRIMARY AGGREGATING PROTEINS IN ALS
Superoxide Dismutase‐1 (SOD1)
Transactivation Response DNA Binding Protein 43 (TDP‐43)
Fused in Sarcoma (FUS)
PRION‐LIKE PROPAGATION OF PROTEIN AGGREGATION IN ALS
CONCLUSION
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 7 Evidence for a Growing Involvement of Glia in Amyotrophic Lateral Sclerosis
INTRODUCTION. NON‐NEURONAL CELLS PLAY IMPORTANT ROLES IN NEURODEGENERATION INCLUDING IN ALS. Glial Cells and Their Established Functions
Neurodegeneration and the Role of Glial Cells
Glia in ALS
Glial Dysfunction Is a Common Hallmark of ALS Patients
GLIAL ACTIVATION IN ALS MODELS. Major Pathological Forms of ALS
Microglia‐Related ALS Pathology
Microglia in SOD1‐ALS Pathology
Microglia in TDP‐43‐ALS Pathology
Microglia in FUS‐ALS Pathology
Astrocyte‐Related ALS Pathology
Oligodendrocyte‐Related ALS Pathology and Glial Inclusion Formation
GLIAL INCLUSION FORMATION IN ALS. Oligodendrocytes
Astrocytes
THE ROLE OF GLIAL CELLS IN SOD1 PATHOLOGY MIGHT BE DIFFERENT FROM OTHER FORMS OF ALS
CONCLUSION
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 8 Animal Models of ALS – Current and Future Perspectives
INTRODUCTION
THE CLINICAL MANIFESTATIONS OF ALS
Limb Onset
Bulbar Onset
Respiratory Onset
CURRENT AND EXPERIMENTAL PHARMACOLOGICAL INTERVENTIONS
Riluzole
Edaravone
Future Directions for Pharmacological Interventions
CAUSATIVE FACTORS IN THE DEVELOPMENT OF ALS. Genetic Factors
Environmental and Epigenetic Factors
Gut and Microbial Factors
ANIMAL MODELS OF ALS
One‐hit Models of ALS
Multi‐hit Models of ALS
FUTURE MODEL DEVELOPMENT
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 9 Clinical Trials in ALS – Current Challenges and Strategies for Future Directions
INTRODUCTION
CHALLENGES IN ALS CLINICAL TRIALS
DISEASE HETEROGENEITY
LACK OF ESTABLISHED BIOMARKERS
LIMITATIONS OF CONVENTIONAL OUTCOME MEASURES
ALSFRS‐R
FVC/SVC
HHD
Survival vs. Function
PHASE II TRIAL “PARADOX”
PATIENT RECRUITMENT AND RETENTION
ASSUMPTIONS FOR LEAD‐IN PHASES
NAVIGATING REGULATORY NUANCES
FUTURE DIRECTIONS
ADVANCES IN DISEASE UNDERSTANDING AND ASSESSMENT
Disease Heterogeneity
Emerging Biomarkers
Novel Outcome Measures
NEW APPROACHES TO TRIAL DESIGN. Cautious Phase II Design
Adaptive Trial Design
Platform Trials
Bayesian Statistics
EDUCATION
PEOPLE MAKE OR BREAK A TRIAL
Conclusion
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 10 Future Priorities and Directions in ALS Research and Treatment
INTRODUCTION
ETIOLOGICAL HETEROGENEITY OF ALS
ALS RISK FACTORS
CELLULAR DYSFUNCTION IN ALS
ALS AS A “TREATABLE” DISEASE
THE IMPORTANCE OF EFFECTIVE BIOMARKERS
FUTURE THERAPEUTIC AVENUES FOR A HETEROGENEOUS DISEASE
ONGOING CLINICAL TRIALS USING CuATSM
CONCLUSIONS AND THE ROAD FORWARD IN ALS RESEARCH AND TREATMENT
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
R
S
T
U
V
W
Y
Z
WILEY END USER LICENSE AGREEMENT
