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Precision Medicine in Neurodegenerative Disorders
Part II
1st Edition - February 16, 2023
Editor: Alberto J. Espay
Hardback ISBN:
9 7 8 - 0 - 3 2 3 - 8 5 5 5 5 - 6
eBook ISBN:
9 7 8 - 0 - 3 2 3 - 9 0 0 6 5 - 2
Precision Medicine in Neurodegenerative Disorders, Part Two, Volume 193 in the Handbook of Clinical Neurology deals with the "How" in the reconfiguration of our approach to… Read more
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Precision Medicine in Neurodegenerative Disorders, Part Two, Volume 193 in the Handbook of Clinical Neurology deals with the "How" in the reconfiguration of our approach to slow accelerated brain aging. The book rethinks animal models on which therapies are tested, outlines the progress and expected changes in biological subtyping efforts using lysosomal, endosomal, mitochondrial, immune dysregulation, and inflammatory mechanisms of disease pathophysiology, and the growing role of microbiome in shaping disease. The volume separates the potentially disease-modifying neurorescue and neurorestoration, (e.g., gene therapy and cell replacement therapy) from true precision "medicine"–matching biology with the mechanism of intervention of interest.
Specific chapters are dedicated to the promise and challenges of extracellular vesicles for both diagnosis and treatment, the growing application of digital measures and other evaluations of clinical response, the nuts and bolts of novel adaptive clinical trial designs, and the regulatory changes needed to facilitate drug development for disease-modification purposes.
- Summarizes theory and research on precision medicine in neurodegenerative disorders
- Covers basic biology, clinical trials and therapeutics
- Includes disease mechanisms, genetic subtypes, and more
Clinical neurologists
- Cover image
- Title page
- Table of Contents
- Copyright
- Handbook of Clinical Neurology 3rd Series
- Foreword
- In Memoriam–Michael Parkinson
- Preface
- Contributors
- Part 3: Basic science development
- Chapter 1: Role of rodent models in advancing precision medicine for Parkinson's disease
- Abstract
- Introduction
- Challenges to Subgrouping in PD
- Rationale for Modeling PD in Rodents
- Genetic Models of Parkinson's Disease
- Inducible α-Synuclein Overexpressing Models
- Neurotoxin Models of Parkinson's Disease
- Conclusion
- References
- Chapter 2: The allure and pitfalls of the prion-like aggregation in neurodegeneration
- Abstract
- Introduction
- Origins of the Idea of Prions
- Extending the Thermodynamic Hypothesis to Protein Unfolding
- Thermodynamic Hypothesis vs the Prion Hypothesis for Amyloid Aggregation
- Is the Prion Hypothesis the Luminiferous Ether of Biology?
- Conclusions
- Disclosures
- References
- Chapter 3: The shift to a proteinopenia paradigm in neurodegeneration
- Abstract
- Introduction
- GOF Mythology
- GOF Contradictions
- Solving the GOF Contradictions
- Paradigm Shift
- Disclosures
- References
- Chapter 4: Disease mechanisms as subtypes: Lysosomal dysfunction in the endolysosomal Parkinson's disease subtype
- Abstract
- Background on Parkinson's Disease
- Lysosome Structure and Function
- Structure of the Lysosome
- Regulation of Lysosomal Biogenesis
- Endosomal Pathway in Health and Disease
- Endosomal Biology in Neurodegeneration
- Lysosomes in Immune Cells: Phagocytosis and Antigen Presentation
- Immune Cell Lysosomal Dysfunction in Parkinson's Disease
- Microglial Phagocytosis in Parkinson's Disease
- LRRK2 at the Lysosome in Immune Cells
- GBA at the Lysosome in Immune Cells
- Other Genetic Risk Factors Converge at the Lysosome in Immune Cells
- Bridging the Gap Between Lysosomal Dysregulation and Immune Function in Parkinson’s
- Conclusion
- References
- Chapter 5: Disease mechanisms as Subtypes: Mitochondrial and bioenergetic dysfunction
- Abstract
- PD Risk Factors
- Selective Neuronal Vulnerability in PD
- Can Lowering Mitochondrial Stress Slow PD Progression?
- Personalized Medicine and the Path Forward
- References
- Chapter 6: Disease mechanisms as subtypes: Immune dysfunction in Parkinson's disease
- Abstract
- Introduction
- Autoantibodies and PD
- Central neuroinflammatory mechanisms in PD
- Peripheral immune system
- Gut–brain axis and inflammatory mechanisms
- Immunogenetic factors in PD
- Immune targets and potential therapeutic approaches
- Peripheral immunity and precision medicine
- Peripheral immunity and neurodegeneration: Beyond diseases
- Conclusions
- References
- Chapter 7: Disease mechanisms as subtypes: Inflammation in Parkinson disease and related disorders
- Abstract
- Neuroinflammation in PD and Related Disorders
- Mechanisms of Neuroinflammation in PD and Related Disorders
- Disease Modifying Therapies, and the Critical Roles of Subtypes
- Inflammation: Driving Force for Progression of PD and Related Disorders
- Inflammation in PD and Related Disorders: Subtypes
- Inflammation in PD and Related Disorders: Role of Disease Duration and Aging
- Sex as a Biological Variable
- Differential Biology and Immunology of Distinct Synuclein Diseases
- Co-Pathologies as a Complicating Factor in Synucleinopathies
- Concluding Remarks
- References
- Chapter 8: Disease mechanisms as subtypes: Microbiome
- Abstract
- Introduction
- Microbiota in Healthy Subjects
- Gut Microbiota in PD: Insights Into Disease Mechanisms
- Microbiota in PD From the Upper to the Lower GI Tract
- Is Gut Dysbiosis a Cause or a Consequence of PD?
- Treatment Approaches to Gut Dysbiosis: Present Consensus and Future Directions
- Conclusions
- References
- Chapter 9: LRRK2: Genetic mechanisms vs genetic subtypes
- Abstract
- Section A: Genetics
- Section B: Clinical and Pathologic Phenotypic Heterogeneity
- Section C: Functional Mechanism (Include Mouse Models)
- Section D: Targeted Clinical Trials and Therapeutics
- Section E: Overall Discussion/Conclusion
- Acknowledgments
- References
- Chapter 10: Genetic mechanism vs genetic subtypes: The example of GBA
- Abstract
- Introduction
- Potential Mechanisms Involved in GBA-Associated PD
- Genetic Subtyping of GBA Variant Carriers
- Other Potential Genetic Modifiers in GBA-Associated PD
- Will Different GBA Variants Require Different Therapies?
- Future Directions and Conclusions
- References
- Chapter 11: Subtyping monogenic disorders: Huntington disease
- Abstract
- Introduction
- Composition and function of Huntingtin
- Clinical manifestations and management
- Current treatment of HD: Away from subtyping
- CAG expansion: How does it lead to pathology?
- Modifiers affecting disease phenotype: The principles of subtyping
- Lower HTT levels increase toxicity
- Disease modification efforts beyond HTT
- Conclusions
- References
- Part 4: Clinical trials and therapeutic approaches
- Chapter 12: Disease-modifying vs symptomatic treatments: Splitting over lumping
- Abstract
- Introduction
- Lumping: Current Treatments and Past Trials
- Splitting, Not Lumping
- The Paradox of Epidemiologic Studies
- Disease Modification: Precision Medicine and Rescue Therapies
- Conclusions
- References
- Chapter 13: Restorative cell and gene therapies for Parkinson's disease
- Abstract
- Introduction
- Rescuing and Regrowing the Dopaminergic Nigrostriatal Pathway
- Replacing the Dopaminergic Nigrostriatal Pathway—Transplanting in New Dopamine Cells
- Replacing the Dopaminergic Nigrostriatal Pathway—Reprogramming the Host Brain to Make New Dopamine Cells
- Replacing Striatal Dopamine Through Gene Therapies
- Conclusions
- References
- Chapter 14: The promise and challenges of extracellular vesicles in the diagnosis of neurodegenerative diseases
- Abstract
- Introduction
- Extracellular Vesicles
- Promise of EVs in Diagnostics
- Challenges of EV-Based Diagnostics
- Conclusion and Future Direction
- References
- Chapter 15: Therapeutic potential of extracellular vesicles in neurodegenerative disorders
- Abstract
- Introduction
- EVs in Neurodegenerative Disorders
- Alzheimer's Disease
- Multiple sclerosis
- Parkinson Disease
- Amyotrophic Lateral Sclerosis
- Huntington Disease
- Acquired Brain and Spinal Cord Injury
- Conclusion
- References
- Chapter 16: Lessons from antiamyloid-β immunotherapies in Alzheimer's disease
- Abstract
- Introduction
- Development of Anti-Aβ Immunotherapies
- Passive Immunotherapy in Alzheimer's Disease
- Therapeutic Anti-Aβ Antibodies
- Amyloid-β Vaccines
- Impact and Perspectives of the Immunotherapies in Alzheimer's Disease and Related Dementia
- Acknowledgments
- References
- Chapter 17: Lessons from immunotherapies in multiple sclerosis
- Abstract
- Precision Medicine and Personalized Medicine in Multiple Sclerosis
- Tools for Precision Medicine in MS
- Personalized Therapeutic Approaches in MS
- Lessons From Clinical Trials for Personalization of Treatment in MS
- The Patient Perspective
- Personalized Medicine: Lessons From Clinical Rehabilitation and Studies in Recovery
- A View of the Future
- References
- Chapter 18: Adaptive clinical trials and master protocols
- Abstract
- Introduction
- General Considerations for Adaptive Design
- Use of Adaptive Principles Across the Drug Development Spectrum
- Seamless Adaptive Designs
- Master Protocols
- Future Directions
- References
- Chapter 19: Role of novel endpoints and evaluations of response in Parkinson disease
- Abstract
- Disease-Specific Considerations for Clinical Trial Endpoints in PD
- Traditional Endpoints Used in PD Clinical Trials
- Traditional Outcomes Used to Measure Effects of Symptomatic Therapies
- Traditional Outcomes Used to Measure Effects in Disease Modification Trials
- Potential Novel Surrogate Outcomes in PD Clinical Trials
- Digital Measures
- Biologic Biomarkers
- Imaging
- Conclusion
- References
- Chapter 20: Leveraging the regulatory framework to facilitate drug development in Parkinson's disease
- Abstract
- Parkinson's Disease: Current Challenges for Drug Development
- Therapeutic Targets in Parkinson Disease
- Providing the Tools for Drug Development
- Leveraging Regulatory Tools for PD Drug Development
- Conclusions
- References
- Index
- No. of pages: 392
- Language: English
- Published: February 16, 2023
- Imprint: Elsevier
- Hardback ISBN: 9780323855556
- eBook ISBN: 9780323900652
AE
Alberto J. Espay
Dr. Alberto Espay is Professor and Endowed Chair of the James J. and Joan A. Gardner Center for Parkinson’s disease at the University of Cincinnati. He has published over 300 peer-reviewed research articles and 8 books, including Common Movement Disorders Pitfalls, which received the Highly Commended BMA Medical Book Award in 2013 and Brain Fables, the Hidden History of Neurodegenerative Diseases and a Blueprint to Conquer them, coauthored with Parkinson patient and advocate Benjamin Stecher, selected by the Association of American Publishers for the PROSE Award honoring the best scholarly work in Neuroscience published in 2020. He has served as Chair of the Movement Disorders Section of the American Academy of Neurology, Associate Editor of the Movement Disorders journal, and on the Executive Committee of the Parkinson Study Group. Among other honors, he has received the Cincinnati Business Courier’s Health Care Hero award, the Spanish Society of Neurology’s Cotzias award, and honorary membership in the Mexican Academy of Neurology. He currently serves as President-Elect of the Pan-American Section of the International Parkinson and Movement Disorders Society. With colleagues at the University of Cincinnati, he launched the first biomarker study of aging (CCBPstudy.com), designed to match people with neurodegenerative disorders to available therapies from which they are most biologically suitable to benefit, regardless of their clinical diagnoses.
Affiliations and expertise
Professor of Neurology, Endowed Chair, James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, United States