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Precision Medicine in Neurodegenerative Disorders
Part II
1st Edition - February 16, 2023
Editor: Alberto J. Espay
Hardback ISBN:9780323855556
9 7 8 - 0 - 3 2 3 - 8 5 5 5 5 - 6
eBook ISBN:9780323900652
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
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