Preface
Contents
Contributors
Part I: Pathophysiological Fingerprints of MS and Related Neuroimmunological Disorders
Chapter 1: Pathophysiological Bases of Autoimmune-Initiated/Mediated Neurodegeneration
1 Introduction
2 Basic Mechanisms of Immune-Mediated Tissue Injury in the CNS
3 CNS Inflammation Driven by MHC Class II Restricted CD4+ T-Lymphocytes
4 Direct Cellular Cytotoxicity through Autoreactive MHC Class I Restricted CD8+ T-Cells
5 CD8+ Tissue Resident Memory T-Cells May Drive Chronic CNS Inflammation, when Antigen Clearance Is Incomplete
6 The Role of B-Cells in Brain Inflammation
7 T-Cell Mediated Encephalomyelitis Modified by Pathogenic Autoantibodies
8 Can Autoantibodies Alone Induce Brain Disease, Inflammation, or Tissue Damage?
9 Conclusions
References
Chapter 2: Translational Animal Models for MS and Related Neuroimmunological Disorders
1 Introduction
2 Methods
2.1 EAE: Active Immunization Model
2.2 Adoptive Transfer Model
2.3 Transgenic Approaches
2.4 CD8+ T Cell Model
2.5 EAE Models of Progressive MS Forms
2.6 TheilerΒ΄s Murine Encephalomyelitis Virus (TMEV)
2.7 Models of Toxic Demyelination
2.8 Further Experimental Autoimmune Diseases
3 Alternatives to EAE, New Approaches
4 Conclusion
References
Chapter 3: White Matter Pathology
1 Introduction
2 Focal Lesions
3 Normal-Appearing White Matter
4 Imaging of Pathologies
4.1 Inflammation
4.2 Demyelination and Remyelination
4.3 Axonal damage and Loss
5 Novel Diffusion-Based Methods for Imaging of Microstructural Integrity
References
Chapter 4: Pathophysiology of Grey Matter Affection in MS
1 Introduction
1.1 Grey Matter Pathology in Multiple Sclerosis
1.2 General Assets for Studying GM Properties
2 Methods for Assessing Mesoscopic GM Integrity
2.1 Common Preprocessing Steps for Structural MRI Data
2.2 Volume-Based Analyses
2.3 Surface-Based Morphometry
2.3.1 FreeSurfer
2.3.2 Alternative Tools to Derive Surface-Based Structural Morphometrics
3 MRI-Derived Markers of GM Microstructure
3.1 Diffusion-Derived Metrics
3.2 Additional Markers of GM Pathology
4 Conclusion
References
Chapter 5: Translational Characterization of the Glia Role in Multiple Sclerosis
1 Introduction
1.1 Morphology and Physiology of Glial Cells
1.1.1 Astrocytes
1.1.2 Oligodendrocytes
1.1.3 NG2 Glia
1.1.4 Microglia
2 Methods Used to Characterize the Role of Glia in Multiple Sclerosis
2.1 Histology and Microscopy Techniques
2.1.1 Immunohistochemistry
2.2 Electrophysiology Techniques
2.2.1 Extracellular Recording
2.2.2 Intracellular Recording
2.2.3 Patch Clamp Recording
2.3 Imaging Techniques
2.3.1 Structural Imaging
Microglia/Macrophage Imaging
2.3.2 Molecular Imaging
3 Role of Glial cells in Multiple Sclerosis: Insights from the Bench
3.1 Role of Astrocytes
3.2 Role of Oligodendrocytes and NG2 Glia
3.3 Role of Microglia
4 Glial cells as Therapeutic Targets: Translation to the Bedside
4.1 Targeting Astrocytes
4.2 Targeting Oligodendrocytes
4.3 Targeting Microglia
5 Conclusion
References
Chapter 6: Translational Value of CSF and Blood Markers of Autoimmunity and Neurodegeneration
1 Introduction
2 Current Knowledge and Pitfalls in Rating Disease Activity in Patients with Multiple Sclerosis
3 Methodological Approaches
3.1 Single Molecule Array Technique (Simoa)
4 Distinct Inflammatory Components and Biomarkers
4.1 Markers of Acute Inflammatory Disease Activity
4.2 Markers of Chronic Neurodegenerative Processes
5 Conclusion
References
Part II: Animal Models of Neuroinflammation
Chapter 7: Spontaneous Mouse Models of Neuroinflammation
1 Introduction
2 Materials
2.1 Animals
2.2 Antigen
2.3 Growth Medium
2.4 Primers
2.5 Other Reagents
3 Method
3.1 Preparation of Emulsion and Immunization
3.2 Isolation and Culture of T Cells
3.3 T Cell Hybridoma Generation
3.4 Selection of Antigen-Specific T Cell Hybridoma Clones
3.5 TCR Repertoire Analysis
3.6 Verification of Expression and Response in 58Ξ±-Ξ²-Cells
3.6.1 Cloning of Fused TCR Ξ± and Ξ² Chains
3.6.2 Retroviral Expression of TCR in 58Ξ±-Ξ²- Cells
3.7 Pronuclear Injection and Characterization of TCR Transgenic Mice
3.8 Evaluation of Spontaneous EAE
3.8.1 Classic Paralytic EAE
3.8.2 Ataxic EAE
4 Notes
5 Limitations
6 Concluding Remarks
References
Chapter 8: Chronic Progressive Models
1 Introduction
2 Animal Models
2.1 Active EAE Induced by a Fusion Protein (MBP-PLP)
2.2 TheilerΒ΄s Murine Encephalomyelitis Virus Infection of SJL Mice
2.3 OSE Model
2.3.1 Material and Methods
Mice and Housing
Phenotyping of Blood Specimen Via Flow Cytometry
Phenotype and Classifying Criteria
2.3.2 Pathological Manifestations
2.3.3 Advantages and Limitations of the OSE Model
Advantages
Limitations of the Model
2.4 NOD-EAE Model
2.4.1 Phenotypic Characteristics and Pathological Manifestations
2.4.2 Material and Methods
Mice
Procedure of Disease Induction
Handling and Classifying Criteria
2.4.3 Advantages and Limitations of the Model
Advantages
Limitations of the Model
3 Concluding Remarks
References
Chapter 9: Electrophysiological Measurements for Brain Network Characterization in Rodents
1 Introduction
2 Electrophysiology In Vitro (Ex Vivo)
2.1 Materials and Methods
2.1.1 Brain Slice Preparation
2.1.2 Single-Cell Electrophysiological Recordings
2.1.3 Patterns of Single-Cell Recordings
2.1.4 Performing Neuronal Network Electrophysiological Recordings
2.1.5 Patterns of Neuronal Network Recordings
2.2 Exemplary Results
3 Drawbacks and Limitations
4 Electrophysiology In Vivo
4.1 Material and Methods
4.2 Implantation of Electrodes for Single-Unit Activity Recordings
4.3 Neuronal Activity Recording and Analysis
5 Conclusions
References
Part III: Translation of Functional Domain Abnormalities from Human to Mice
Chapter 10: Translation of Functional Domain Abnormalities from Human to Mouse Motor System
1 Introduction
1.1 Anatomical Organization, Circuitry, and Functionality of the Motor System
1.1.1 Primary Motor Cortex (M1)
1.1.2 Supplementary Motor Area (SMA)
1.1.3 Premotor Cortex (PMC)
1.1.4 Prefrontal Cortex (PFC)
1.1.5 Basal Ganglia
1.1.6 Thalamus
1.1.7 Cerebellum
1.1.8 Spinal Cord
2 Materials and Methods for Measuring Motor System Impairment in MS
2.1 Functional Abnormalities in Motor Regions: Evidence from Functional Imaging
2.1.1 fMRI
2.1.2 E/MEG
2.2 Abnormalities in Evoked Potentials and Their Relation to Motor System
3 Where Do We Stand in the Human-to-Mouse Translation?
4 Conclusions
References
Chapter 11: Characterization of the Somatosensory System
1 Introduction
2 Evoked Responses and the Complementarity of Electroencephalography and Magnetoencephalography
2.1 SEP and SEF Generation Process
2.2 Complementarity of EEG and MEG
3 Head Model Generation
4 Forward and Inverse Problems in Bioelectromagnetism
4.1 Inverse Problem in EEG and MEG Source Analysis
4.2 Optimization Methods for Targeted Multichannel TES and TMS
4.3 Bioelectromagnetic Forward Problems
5 Application for the Characterization of the Somatosensory System
6 Translation to Clinical Applications in Multiple Sclerosis and Epilepsy
7 Conclusion
References
Chapter 12: Translational Research in Neuroimmunology: Cognition
1 Introduction
2 Neuroimmunology and Cognition
3 Attention
3.1 Tests Measuring Attention
4 Memory
4.1 Tests Assessing Memory
5 Executive Functions
5.1 Assessing Executive Functions
6 Visuospatial Functions
6.1 Tests of Visuospatial Functions
7 Examining Cognition in Nonhuman Subjects
7.1 Barnes Maze
8 CANTAB
9 Conclusion
References
Chapter 13: Models for Assessing Anxiety and Depression in Multiple Sclerosis: from Mouse to Man
1 Introduction
2 Material and Methods for Measuring Anxiety and Depression in Rodents
2.1 Anxiety
2.1.1 Elevated Plus Maze (EPM)
2.1.2 Open Field (OF)
2.1.3 Further Anxiety Tests
2.2 Depression
2.2.1 Forced Swim Test (FST)
2.2.2 Tail Suspension Test (TST)
2.2.3 Further Depression Tests
2.3 Genetic Mouse Models of Anxiety and Depression
3 Notes for Animal Experiments
4 Material and Methods for Measuring Anxiety and Depression in Patients
4.1 Anxiety
5 Depression
6 Assessment in MS Patients
7 Experimental Approaches to Assess Anxiety and Depression in Humans
8 Conclusion
References
Part IV: Exploring Translational Paths in MS with Brain Imaging: Small Animal to Human Imaging Tools
Chapter 14: Human Structural MRI
1 Introduction
2 Conventional Structural MRI
3 Advanced Imaging of Lesions
4 Normal-Appearing Tissue Damage
5 Structural Disconnection
6 Atrophy
7 Conclusion
References
Chapter 15: Human Functional MRI
1 Introduction
2 Basic Principles of Functional MRI Techniques
3 Methods to Investigate Task-Related Functional Activity in MS
3.1 Analysis of Active Task fMRI
3.1.1 The General Linear Model
3.1.2 Functional and Effective Connectivity
4 Resting State fMRI
4.1 Basic Principles
4.2 Methods to Investigate RS FC in MS
4.2.1 Local Methods
4.2.2 Functional Integration Methods
4.2.3 Dynamic RS FC
5 Functional MRI to Understand MS Pathophysiology
5.1 Active Task fMRI
5.2 Resting State fMRI
5.2.1 Resting State FC
5.2.2 Graph Theory Analysis
5.2.3 Dynamic FC
6 Functional MRI to Monitor Pharmacologic and Rehabilitative Treatments
6.1 Pharmacologic Treatments
6.2 Rehabilitative Treatments
7 Conclusions
References
Chapter 16: Functional Studies in Rodents
1 Introduction
2 Technical Requirements of the Experimental Setting
2.1 fMRI Methods
2.1.1 BOLD
2.1.2 CBV
2.1.3 CBF
2.1.4 Diffusion-Weighted fMRI
2.1.5 Manganese-Enhanced MRI (MEMRI)
2.2 Anesthesia
2.2.1 ISO
2.2.2 MED
2.2.3 ISO/MED
2.2.4 Awake Imaging
2.3 Animal Physiology/Monitoring
2.3.1 Body Temperature
2.3.2 Respiration
2.4 Data Analysis
2.4.1 Preprocessing
2.4.2 Processing of Stimulus-Evoked fMRI
2.4.3 Processing of rsfMRI
3 Application of fMRI in MS Models
4 Conclusion
References
Chapter 17: Noninvasive Electrophysiology
1 Introduction
2 Noninvasive Electrophysiology in Animal Models
3 Noninvasive Electrophysiology in the Diagnosis of Multiple Sclerosis
4 Noninvasive Electrophysiology in the Prognosis of Multiple Sclerosis
5 Noninvasive Electrophysiology in Assessing Pharmacological Effects in Multiple Sclerosis
6 Conclusion
References
Part V: Translational View on Therapeutic Strategies
Chapter 18: Targeting Acute Inflammation
1 Introduction
2 Recent Insights into the Pathogenesis of Multiple Sclerosis
2.1 Mechanisms of Neuronal Injury
2.1.1 Immune Cell-Mediated Neuronal/Axonal Injury
2.1.2 Axonal/Neuronal Degeneration as a Consequence of Inflammatory Demyelination
3 Potential Therapeutic Strategies Targeting Acute Inflammation
3.1 Ξ²-HMG-CoA Reductase
3.2 NF-ΞΊB
3.3 Sphingosine 1-Phosphate Receptors
3.4 PPARΞ³
3.5 Matrix Metalloproteinases
3.6 Ion Channel Blockade
3.7 Cannabinoid Receptors
3.8 Estrogen Receptors
3.9 Ξ±4 Integrin
4 Conclusion
References
Chapter 19: Translational Aspects of Immunotherapeutic Targets in Multiple Sclerosis
1 Introduction
2 Multifaceted Immunomodulation
2.1 Glatiramer Acetate (GA)
2.2 Interferon Beta (IFN-Ξ²)
3 Inhibition of Leukocyte Trafficking
3.1 Fingolimod/Siponimod
3.2 Natalizumab
4 Continuous Lymphocyte Depletion
4.1 Teriflunomide
4.2 Dimethyl Fumarate (DMF)
5 Interval Lymphocyte Depletion
5.1 Alemtuzumab
5.2 Ocrelizumab
6 Conclusion
References
Chapter 20: Therapeutic Strategies to Potentially Cure Multiple Sclerosis: Insights into the Mechanisms of Autologous Hematopo...
1 Introduction
2 Methodology
3 Immunological Mechanism of Self-Tolerance Following AHSCT
4 Clinical Studies of AHCT in MS
5 Adverse Events and Mortality Rates
6 Optimization and Recommendations
7 Conclusion
References
Chapter 21: Symptomatic MS Therapy
Abbreviations
1 Introduction
2 Fatigue
3 Neuropsychiatric Syndromes
4 Cognitive Impairment
5 Bladder, Bowel, and Sexual Dysfunction
6 Movement Disorders
7 Spasticity
8 Eye Movement Abnormalities
9 Gait Impairment
References
Index