Trials for Cerebellar Ataxias: From Cellular Models to Human Therapies

Preface
The List of Referees
Contents
Part I: Basic Science of Cerebellum and Ataxias
Functional Anatomy of the Cerebellum
1 Introduction
2 Macroscopic Anatomy of the Cerebellum
2.1 Outer Shape and Orientation
2.2 The White Matter of the Cerebellum
2.3 Cerebellar Nuclei
2.4 Cerebellar Lobules in the Vermis
2.5 Lobules in the Hemisphere
2.6 Unfolded Schemes of the Cerebellar Cortex
3 Neuronal Components and Circuitry of the Cerebellum
3.1 Purkinje Cells and Climbing Fibers
3.2 Molecular Layer Interneurons
3.3 Granule Cells, Parallel Fibers, and Mossy Fibers
3.4 Golgi Cells and Other Inhibitory Cells in the Granular Layer
3.5 Glial Cells in the Cerebellar Cortex
3.6 Neurons in the Cerebellar Nuclei
4 Afferent Axonal Projections of the Cerebellum
4.1 Climbing Fibers Originating from the Inferior Olive
4.2 Mossy Fiber Axons
4.3 Distribution Pattern of Major Mossy Fiber Axons in the Cerebellar Cortex
4.4 Other Afferent Projections to the Cerebellar Cortex
4.5 Afferents of the Cerebellar Nuclei
5 Compartments or Modules of the Cerebellum
5.1 Cerebellar Modules Determined by Projections of Climbing Fibers and Purkinje Cell Axons
5.2 Longitudinal Stripes of Molecular Expression in the Cerebellar Cortex
5.3 Compartmentalization of the Cerebellar Nuclei
6 Output Projections of the Cerebellum
6.1 Somatomotor System
6.2 Oculomotor System
6.3 Various Non-Motor Output Pathways
6.4 Inhibitory Output Projection from the Cerebellar Nuclei
7 Functional Localization in the Cerebellum
7.1 Functional Localization of Vermal Areas
7.1.1 Lobules I–VIa and VIII
7.1.2 Lobules VIb–c and VII
7.1.3 Lobule IXa–b
7.1.4 Lobules IXc and X
7.2 Functional Localization of Paravermal and Hemispheric Areas
7.2.1 Rostral and Caudal Lobules
7.2.2 Medial Paravermal Area of Lobules VI and VII (Lateral A Module)
7.2.3 Ansiform Area (Crus I in Rodents, Crus I + II in Primates)
7.2.4 Paraflocculus
7.2.5 Flocculus
8 Concluding Remarks
References
Cerebellar Physiology
1 Introduction
2 Basic Cerebellar Structure
2.1 Gross Cerebellar Structure
2.2 Cerebellar Inputs
2.2.1 Basic Anatomy of Climbing Fiber Projections and Olivo-Cortico-Nuclear Circuits
2.2.2 Basic Anatomy of Mossy Fiber Projections
2.2.3 Neuromodulatory Inputs
2.3 Non-uniformity in Cerebellar Anatomy
3 Cellular Physiology
3.1 Cortical Circuits
3.1.1 Inputs to the Granule Cell Layer
3.1.2 Parallel Fiber Inputs to the Molecular Layer
3.1.3 Purkinje Cell Simple Spikes and Complex Spikes
3.1.4 Purkinje Cell Targets Within the Cerebellar Cortex
3.2 Purkinje Cell Control of Cerebellar Nuclei
3.3 Zebrin Stripes
3.4 Synaptic Plasticity
3.4.1 Parallel Fiber–Purkinje Cell Synaptic Plasticity
3.4.2 Zebrin II and Synaptic Plasticity
3.4.3 Plasticity at Cerebellar Nuclei Synapses
4 Systems Physiology
4.1 Somatotopic Organization
4.2 Physiologically Defined Olivocerebellar Pathways
4.3 Spinocerebellar Mossy Fibers
4.4 Cerebro-Cerebellar Pathways
5 Behavioral Physiology
5.1 Limb Control
5.1.1 Locomotion
5.1.2 Reaching
5.2 Eye Movements
5.3 Associative Learning
5.3.1 Eyeblink Conditioning
5.3.2 Vestibulo-Ocular Reflex
5.3.3 Higher-Order Learning
5.3.4 Climbing Fibers and Learning
6 The Cerebellum as a Feedforward Controller
7 Summary
References
Cerebellar Biochemistry/Pharmacology
1 Introduction
2 Interactions Between Purkinje Cells and Other Cerebellar Cells
2.1 Parallel and Climbing Fibers (Granule Cells and Inferior Olive Neurons)
2.2 Basket Cells
2.3 Glial Cells
3 Importance of Protein Degradation Systems in Cerebellar Purkinje Cells
3.1 Classification of Protein Degradation Systems
3.2 Ubiquitin-Proteasome System in Cerebellar Purkinje Cells
3.3 Autophagy-Lysosome Pathways in Cerebellar Purkinje Cells
4 Endogenous Modulators of Purkinje Cells
4.1 Thyrotropin-Releasing Hormone (TRH)
4.2 Thyroid Hormones (THs)
4.3 Glutamate Receptor δ2 (GluRδ2) and D-Serine
4.4 Nitric Oxide (NO)
4.5 Hydrogen Sulfide and D-Cysteine
5 Concluding Remarks
References
Genetics of Dominant Ataxias
1 Introduction
2 Genetic Diagnosis
3 ADCA Pathological Mechanisms
3.1 Abnormal Repeat Expansions
3.2 Channelopathies and Alteration of the Signal Transduction Pathways
3.2.1 Specific Ion Channel Alterations
3.2.2 Alteration of the Synaptic Machinery
3.3 Abnormal Gene Expression
3.4 Disorders of Lipid Metabolism
3.5 Other Mechanisms
4 Phenotype–Genotype Correlations
5 Biomarkers and Treatment
6 Conclusions
Bibliography
Autosomal and X-Linked Degenerative Ataxias: From Genetics to Promising Therapeutics
1 Introduction
2 Classification
3 Friedreich Ataxia (FRDA)
3.1 Clinical Features
3.2 Pathophysiology
3.3 Diagnosis and Treatment
3.4 Current Clinical Research
4 Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)
4.1 Clinical Features
4.2 Pathophysiology
4.3 Diagnosis and Treatment
4.4 Current Clinical Research
5 SYNE-1-Related Ataxia (ARCA1 – SCAR8)
5.1 Clinical Features
5.2 Pathophysiology
5.3 Diagnosis and Treatment
5.4 Current Clinical Research
6 Ataxia Telangiectasia (AT)
6.1 Clinical Features
6.2 Pathophysiology
6.3 Diagnosis and Treatment
6.4 Current Clinical Research
7 Ataxia with Oculomotor Apraxia Type 1 (AOA1)
7.1 Clinical Features
7.2 Pathophysiology
7.3 Diagnosis and Treatment
7.4 Current Clinical Research
8 Ataxia with Oculomotor Apraxia Type 2 (AOA2)
8.1 Clinical Features
8.2 Pathophysiology
8.3 Diagnosis and Treatment
8.4 Current Clinical Research
9 Ataxia with Vitamin E Deficiency (AVED)
9.1 Clinical Features
9.2 Pathophysiology
9.3 Diagnosis and Treatment
9.4 Current Clinical Research
10 Spastic Paraplegia Type 7 (SPG7) Ataxia
10.1 Clinical Features
10.2 Pathophysiology
10.3 Diagnosis and Treatment
10.4 Current Clinical Research
11 X-Linked Ataxias
11.1 Clinical Features
11.2 Pathophysiology
11.3 Diagnosis and Treatment
11.4 Current Clinical Research
12 Preclinical and Future Therapeutic Advances
12.1 Nucleic Acid-Based Drugs
12.2 Gene Therapy and Genome Editing
12.3 Epigenetic
12.4 Stem Cells
12.5 Vaccines
13 Conclusion
References
Seeking Therapies for Spinocerebellar Ataxia: From Gene Silencing to Systems-Based Approaches
1 Introduction
2 Complex Issues in SCA3 to Consider as Therapies Are Sought
2.1 SCA3 Is Dominantly Inherited, but Elements Beyond Toxic Gain of Function Likely Contribute
2.2 SCA3 Is a Neurodegenerative Disease, but Neurons Are Not the Only Involved Cell Type
2.3 Proteotoxicity of the ATXN3 Disease Protein Is Important, but Not the Only Contributor to Disease
2.4 SCA3 Affects the Brain, but Little Is Known About Disease in Other Organs
2.5 The ATXN3 Disease Protein Maybe Small, but Its Function Is Complex and Far-Reaching
2.6 Studies of Overexpressed or Transgenic ATXN3 Have Shed Important Light on Disease Mechanisms but May Not Mirror the Human Disease State
2.7 ATXN3 Maybe the Obvious Target in SCA3, but Targets Beyond and Downstream of ATXN3 Also Need to Be Explored
2.8 Most Research in SCA3 Has Focused on Disease Effects at the Cellular Level, but Network-Level Effects Remain Understudied
3 Screens to Identify Targetable Pathways for Potential Therapy
4 Human Stem Cells as a New Tool for Mechanistic and Translational Studies
5 Impaired Connectivity as a Druggable SCA Target: Insight into Systems-Based Approach
6 Conclusion and the Future of SCA3 Therapeutics
References
Ion Channel Genes and Ataxia
1 Introduction
2 Cerebellar Circuitry and Importance of Ion Channels
3 Ataxia Related to Mutations in Potassium Channel Genes
3.1 Ataxia Related to Voltage-Gated Potassium Channels
3.2 Kv1-Related Ataxia
3.2.1 KCNA1-Related Ataxia/Episodic Ataxia Type 1 (EA1)
3.2.2 KCNA2-Related Ataxia
3.3 Kv3-Related Ataxia
3.3.1 KCNC1-Related Ataxia/Myoclonic Epilepsy and Ataxia Due to KCNC1 (MEAK)
3.3.2 KCNC3-Related Ataxia/Spinocerebellar Ataxia Type 13 (SCA13)
3.4 KCND3-Related Ataxia/Spinocerebellar Ataxia Type (SCA19/22)
3.5 KCNJ10-Related Ataxia/SeSAME Syndrome
3.6 KCNMA1-Related Ataxia
4 Ataxia Related to Mutations in Calcium Channel Genes
4.1 Ataxia Related to Voltage-Gated Calcium Channels
4.2 CACNA1A-Related Ataxia
4.2.1 Episodic Ataxia Type 2 (EA2)
4.2.2 Spinocerebellar Ataxia Type 6 (SCA6)
4.3 CACNA1G-Related Ataxia/Spinocerebellar Ataxia Type 42 (SCA42)
4.4 CACNB4-Related Ataxia/Episodic Ataxia Type 5 (EA5)
4.5 ITPR1-Related Ataxias
4.5.1 Spinocerebellar Ataxia Type 15 (SCA15)
4.5.2 Spinocerebellar Ataxia Type 16 (SCA16)
4.5.3 Spinocerebellar Ataxia Type 29 (SCA29)
4.5.4 Gillespie Syndrome (GS)
4.6 TRPC3-Related Ataxia/Spinocerebellar Ataxia Type 41 (SCA41)
5 Ataxia Related to Mutations in Sodium Channel Genes
5.1 Ataxia Related to Voltage-Gated Sodium Channels
5.2 SCN1A-Related Ataxia/Dravet Syndrome
5.3 SCN2A-Related Ataxia
5.4 SCN8A-Related Ataxia
6 Ataxia Related to Mutations Genes Encoding Na+/K+ ATPase
6.1 ATP1A3-Related Ataxia/CAPOS Syndrome
7 Other Ion Channel Disorders
7.1 SLC1A3-Related Ataxia/Episodic Ataxia Type 6 (EA6)
7.2 Ataxia Related to Mutations in ANO10/Autosomal Recessive Cerebellar Ataxia Type 3 (ARCA3)
8 Conclusion
References
Part II: Biomarkers and Tools of Trials
How to Design a Therapeutic Trial in SCAs
1 Introduction
2 Lessons from Clinical Trials Performed in SCAs
2.1 Pharmacological Interventions
2.2 Rehabilitation Interventions
3 Fundamental Aspects to Consider in SCA Clinical Trial
3.1 Participant Number and Trial Duration
3.2 Selection of SCA Population
3.3 Outcome Measures
3.4 Trial Designs
3.5 Clinical Trial in Preclinical Stage SCA
4 Conclusions
References
Therapy Development for Spinocerebellar Ataxia: Rating Scales and Biomarkers
1 Introduction
2 Rating Scales (Table 1)
2.1 Scales for Motor Dysfunction
2.2 Scales for Performance
2.3 Scales for Non-motor Symptoms
2.4 Scales for Functional Capacity and Quality of Life
3 Biomarkers
3.1 Neuroimaging Biomarkers
3.1.1 MRI
3.1.2 MRS
3.1.3 Functional MRI (fMRI)
3.1.4 PET
3.1.5 SPECT
3.2 Fluid Biomarkers
3.3 Physiology Biomarkers
4 Conclusion
References
Clinical Rating Scales for Ataxia
1 Introduction
2 Clinical Rating Scales for Ataxia—Remarks on Validation
3 ICARS—The International Cooperative Ataxia Rating Scale
4 UMSARS—The Unified Multiple Systems Atrophy Rating Scale
5 FARS—The Friedreich Ataxia Rating Scale
6 SARA—Scale for the Assessment and Rating of Ataxia
7 NESSCA—Neurological Examination Score for Spinocerebellar Ataxia
8 BARS—The Brief Ataxia Rating Scale
9 CCAS Scale—Cerebellar Cognitive Affective Syndrome Scale
10 INAS—Inventory of Non-Ataxia Symptoms
11 Disability Staging
11.1 Mobility Stages (Klockgether et al. 1998)
11.2 UMSARS Part IV: Global Disability Scale (Wenning et al. 2004)
11.3 FARS—Functional Staging of Ataxia (Subramony et al. 2005)
12 Remote Assessment of Ataxia
13 Functional Composite Scores
14 Instrumented Motor Testing
15 Patient-Reported Outcomes for Ataxias
15.1 Generic PRO of hrQOL
15.2 PRO Specific for Ataxias
15.3 FAIS—Friedreich’s Ataxia Impact Scale
15.4 PROM-Ataxia
16 Summary and Perspectives
17 Future Directions for Clinical Scales
References
Scale for Ocular Motor Disorders in Ataxia (SODA): Procedures and Basic Understanding
1 Background and Justification
2 Ten Rules of Accurate and Effective Examination of Eye Movements and Vestibular Function
2.1 Rule 1: Assuring That the Preliminaries Are Met
2.2 Rule 2: Organization in the Clinic, Keeping the Distance Between the Patient and the Visual Target
2.3 Rule 3: Color of the Visual Target Should Be Bright
2.4 Rule 4: Ocular Alignment
2.5 Rule 5: Age-Related Changes and Effects of Medications
2.6 Rule 6: Stabilize the Patient’s Head
2.7 Rule 7: Pay Attention to the Eyelids
2.8 Rule 8: Use an Ophthalmoscope if Needed
2.9 Rule 9: Look at the Bridge of the Nose
2.10 Rule 10: Head Impulses Should Be Brief but Fast
3 Organizational Components of SODA
3.1 Ocular Alignment
3.2 Fixation Deficits (Saccadic Intrusions)
3.3 Jerk Nystagmus
3.3.1 Gaze-Evoked Nystagmus
3.3.2 Downbeat Nystagmus
3.3.3 Upbeat Nystagmus
3.3.4 Positional Nystagmus
3.4 VOR
3.5 Saccades
3.6 Pursuits and VOR Cancellation
References
Cerebellar Learning in the Prism Adaptation Task
1 Clinical Practice
2 Prism Adaptation Task
3 Adaptability Index (AI)
4 Findings in Basic Science for the Cerebellum
5 Internal Models in the Cerebellum
6 Tandem Internal Models
7 Indexes for Tandem Internal Model
8 Summary/Importance of Collaboration Between Clinicians and Basic Scientists
References
Blood and CSF Biomarkers in Autosomal Dominant Cerebellar Ataxias
1 Introduction
2 Biological Biomarkers
2.1 Neurofilament Light Chain
2.2 Tau
2.3 Astrocytosis and Gliosis
2.4 Ataxin-Specific Bioassays
2.5 Oxidative Stress Biomarkers
2.6 Inflammation Biomarkers
2.7 Insulin/Insulin-Like Growth Factor 1 (IGF-1) System
2.8 Co-chaperone Protein
3 Biomarkers in Development
3.1 Brain Cholesterol Metabolism
3.2 Metabolic Profile
3.3 Micro-RNAs
3.4 Sirtuin-1
4 Conclusion
References
Part III: Autosomal Dominant Cerebellar Ataxias
Riluzole in Progressive Cerebellar Ataxias
1 Introduction
2 Symptomatic Effects of Riluzole in Progressive Ataxias
3 Future Perspectives
References
ASOs Against ATXN2 in Preclinical and Phase 1 Trials
1 SCA2 Clinical Characteristics
1.1 SCA2 Models
1.2 Pcp2-ATXN2 Transgenic Mice
1.3 SCA2 BAC Transgenic Mice
2 ASO Development Targeting Wild-Type and mt ATXN2
2.1 Atxn2 Knockout Mice
2.2 Establishing Cerebellar RNA and Protein Markers for Preclinical Studies
2.3 RNA-Based SCA2 Therapeutics
3 ALS and ATXN2 ASO Phase 1 Study
3.1 Phase 1 Clinical Trial (BIIB105)
4 Conclusions and Outlook
References
Antisense Oligonucleotide Therapy Against SCA3
1 Introduction
2 Antisense Oligonucleotide Therapy Targeting Strategies
2.1 Targeting the ATXN3 Transcript for RNA Degradation: RNase H1-Dependent Mechanism
2.2 ASOs Targeting RNA Processing: RNase H1-Independent Mechanism
3 ASO Delivery Methods to the CNS
3.1 Direct Invasive CNS Delivery
3.2 Indirect Noninvasive CNS Delivery
4 Limiting ASO Off-Targets
5 Hurdles for Moving SCA3 ASO Application to the Clinic
References
Spinocerebellar Ataxia Type 7: From Mechanistic Pathways to Therapeutic Opportunities
1 Introduction
2 SCA7 Molecular Cascade
2.1 Ataxin-7 Function
2.2 PolyQ Ataxin-7 Toxicity
2.3 Dysregulation of the SIRT1/NAD+—PPARγ/PGC-1α Regulatory Axis
2.4 PARP1 Hyperactivation and Increased DNA Damage
3 Targets for Therapeutic Interventions
3.1 Calcium-Activated Potassium Channels
3.2 SIRT1/NAD+ Pathway
3.2.1 SIRT1 Direct Activation
3.2.2 NAD+ Replenishment
3.3 PPAR:RXR:PGC-1α Pathway
3.3.1 PPARγ Activation
3.3.2 PPARδ Activation
3.3.3 RXR Activation
3.4 DNA Damage
3.5 Reducing Ataxin-7 Expression
3.5.1 RNAi Effectors
3.5.2 Antisense Oligonucleotides (ASOs)
4 Concluding Remarks
References
Experimental Neurotransplantation for Cerebellar Ataxias
1 Introduction
2 Specific Features of Neurotransplantation and Cerebellar Transplantation
3 Mechanisms of Action of Cerebellar Transplants
3.1 Cell Substitution
3.2 Cell Rescue
3.3 Support of Residual Cerebellar Function
3.4 Provision of Trophic Factors and Other Molecules Produced by Grafted Cells
4 Graft Sources and Types
4.1 Fetal Cerebellar Tissue
4.2 Mesenchymal Stem Cells
4.3 Embryonic, Carcinoma, Adult, and Induced Pluripotent Stem Cells
5 Graft Survival, Differentiation, Migration, and Axon Growth in the Host Tissue
5.1 Factors Determining Graft Survival
5.2 Differentiation of Grafted Cells
5.3 Migration and Synaptic Integration of Grafted Cells
6 Examples of Mouse Model Studies
6.1 Grafting Fetal (Embryonic) Cerebellar Tissue
6.2 Neural Precursor or Neural Stem Cell Transplantation
6.3 Cerebellar Parenchymal Injection of Stem Cells
6.4 Intravenous or Cerebroventricular Infusion of MSCs
6.5 Administration of Stem Cell Products
7 Comments on Clinical Applications of Neurotransplantation for Cerebellar Ataxias
8 Conclusion
References
Development of Mesenchymal Stem Cells Therapy for the Treatment of Polyglutamine SCA: From Bench to Bedside
1 Introduction
2 Polyglutamine Spinocerebellar Ataxia
3 Derivation, Characterization, and Properties of Mesenchymal Stem Cells
4 General MoAs of Mesenchymal Stem Cells as a Potential Therapeutic Agent
4.1 Paracrine Effects
4.2 Immunomodulation
5 Potential Mechanisms of MSCs Therapies in Neurodegenerative Diseases and PolyQ SCAs
5.1 MSCs Enhance the Abnormal Protein Aggregation Clearance
5.2 MSCs Enhance Antioxidant Capability and Exert Anti-apoptosis Effect
5.3 MSCs Exert Neuroprotective Effect Through Neurotrophic Factor Secretion
5.4 MSCs Modulate the Neuroinflammation Through Their Immunomodulatory Effects
5.5 MSCs Restore Bioenergetic Systems Through Increasing Mitochondria Mass and Enhancing Aerobic Glycolysis
6 MSCs Clinical Studies in PolyQ SCAs
7 Opportunities and Challenges of Stem Cell Therapy for SCA
7.1 Multiple Neuroprotective MoAs of MSCs Make Them a Potential Good Therapy for SCAs
7.2 Limited Number and Scale of Clinical Trials Compromise the Outcomes
7.3 Cell-Based Drug Development Is Unconventional and Regulatory Path Is Still Evolving
8 Conclusion
References
Cerebello-Spinal tDCS as Rehabilitative Intervention in Neurodegenerative Ataxia
1 Introduction
2 Transcranial Direct Current Stimulation for the Treatment of Cerebellar Ataxias
2.1 tDCS Techniques
2.2 Clinical Studies
3 Conclusions
References
Cerebellar Transcranial Magnetic Stimulation in Cerebellar Ataxias
1 Introduction
2 Principles of Transcranial Magnetic Stimulation
3 The Cerebellum as a Window to the Whole Brain
4 Clinical Outcomes
5 Neurophysiological and Biochemical Outcomes
6 Targets and Coils
7 Little Brain, Big Expectations: A Glimpse into the Future
8 Conclusions
References
Physical Therapy in Cerebellar Ataxia
1 What Is Ataxia
2 What Is Not Ataxia
3 Limb Ataxia
4 Postural and Gait Ataxia
5 Balance Training for Gait Ataxia
6 Motor Learning in Cerebellar Disease
7 Compensatory Strategies
8 Other Considerations
9 Future Directions
10 Summary
References
Part IV: Autosomal Recessive Cerebellar Ataxias
Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy
1 Friedreich’s Ataxia
1.1 Friedreich’s Ataxia: A Multisystemic Disorder
1.2 The Genetic Cause of Friedreich’s Ataxia: From GAA Expansion to Gene Silencing
2 Frataxin Plays a Major Role in Fe-S Clusters Biogenesis
2.1 The Frataxin Protein
2.2 Fe-S Clusters Biogenesis: A Conserved Mechanism Driven by Frataxin?
2.3 ISC Deficiency on Fe-S Clusters Delivery
3 Cellular and Molecular Pathogenesis
3.1 Hallmarks of FA Pathophysiology: A Vicious Cycle Empowered by Fe-S Deficit
3.2 Ferroptosis: A Major Cell Death Mechanism in FA?
3.3 NRF2: The Master Regulator of Stress Is Affected in FA
4 Treatment Strategies Targeting Downstream Events
4.1 Omaveloxolone: Targeting the NRF2 Pathway
4.2 Vatiquinone (EPI-743): A Cytoprotective Effect Against Ferroptosis
5 Therapeutic Approaches Aimed at Increasing Frataxin Levels
5.1 Current Epigenetic-Based FA Therapeutic Strategies
5.2 Gene Therapy
5.3 Protein Replacement Therapy
References
Therapeutic Use of Interferon Gamma in Friedreich Ataxia
1 Interferon Gamma in FRDA Clinical Trials
1.1 The Design of Studies
1.2 Protocols, Primary and secondary outcome meaasures of Safety and Efficacy
1.3 Open Label Trial of High Dose IFNγ with Objective Indicators of Efficacy
2 Conclusion
References
Metabolic Treatments of Cerebellar Ataxia
1 Introduction to Metabolic Diseases
2 Metabolic Forms of Cerebellar Ataxia
3 Metabolic Treatments of Cerebellar Ataxia
3.1 Dietary Intervention
3.2 Supplementation Therapies
3.3 Metabolite-Lowering Therapies
3.4 Chaperone and Replacement Therapies
4 Conclusion
References
Clinical Trials in Fragile X-Associated Tremor/Ataxia Syndrome
1 Introduction
2 Clinical Trials in FXTAS
3 Memantine
4 Allopregnanolone
5 Citicoline
6 Treadmill Training
7 Conclusions
References
Part V: Sporadic Ataxias
Therapeutic Strategies in Immune-Mediated Cerebellar Ataxias
1 Introduction
2 Available Treatment Options for Each Subtype of IMCAs
2.1 IMCAs with Autoimmunity Triggered by Another Condition
2.1.1 Post-infectious Cerebellitis
2.1.2 Miller Fisher Syndrome
2.1.3 Gluten Ataxia
2.1.4 Opsoclonus Myoclonus Syndrome
2.1.5 Paraneoplastic Cerebellar Degeneration
2.2 IMCAs with Autoimmunity Not Triggered by Another Condition
2.2.1 Anti-GAD Ataxia
2.2.2 Primary Autoimmune Cerebellar Ataxia
3 General Principles in Therapeutic Strategies
3.1 The Response to Immunotherapy
3.2 Subsequent Recovery and Cerebellar Reserve
4 Conclusion
References
Coenzyme Q10 in Multiple System Atrophy
1 An Overview of Multiple System Atrophy
2 Multiplex Family with Multiple System Atrophy
3 Discovery of COQ2 as a Genetic Factor for Familial Multiple System Atrophy
4 Discovery of COQ2 as a Genetic Risk Factor for Sporadic MSA
5 Coenzyme Q10
6 Toward Clinical Trials of Drugs for MSA
7 Ubiquinol as a Drug for MSA
8 Conclusion
References
State of the Art and History of Therapeutics in Ataxias
1 Introduction
2 Methods
3 Results
4 Discussion
Appendix 1
Appendix 2
References
Index