UID:
edoccha_9961017511402883
Format:
1 online resource (290 pages)
ISBN:
9780323900645
Series Statement:
Handbook of Clinical Neurology ; v. 192
Content:
Precision Medicine in Neurodegenerative Disorders, Part One, Volume 192 in the Handbook of Clinical Neurology deals with the "Why" in the approach to slow the progression of accelerated brain aging. This volume is intended to provide a scholarly background on the framework, basic science and conceptual pitfalls related to disease-modifying efforts in Parkinson's, Alzheimer's and other neurodegenerative disorders. Among topics covered are different models of precision medicine, the lumping-versus-splitting tension in biomarker development and therapeutics, and the rationale for replacing the convergence of the prevailing autopsy-based nosology of neurodegenerative diseases with the divergence of a systems biology approach to human diseases. Specific chapters are dedicated to the promise of genetic subtypes and the lessons in disease modification offered by the fields of oncology and cystic fibrosis that can be adapted to the field of neurodegeneration. Matching a biology-correcting therapy with those biologically suitable to benefit from such therapy represents the vision and mission of precision medicine, the highest level of personalized medicine.
Note:
Intro -- Precision Medicine in Neurodegenerative Disorders, Part I -- Copyright -- Available titles -- Foreword -- In Memoriam-Michael Parkinson -- Preface -- Contributors -- Contents -- Part 1: Conceptual framework -- Chapter 1: The definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension -- Introduction -- Lessons from other fields -- Precision Medicine in the Fields of Oncology vs Neurodegeneration -- One Disease-Many Diseases Tension -- Why have we failed in disease modification? -- Disease heterogeneity -- Clinical heterogeneity -- Clinical subtypes -- Data-driven subtypes -- Challenges related to both approaches -- The ``brain-first´´/``body-first´´ hypothesis -- Genetic heterogeneity -- Environmental factors contributing to heterogeneity -- Pathologic heterogeneity -- Other concomitant proteinopathies/concurrent factors -- Pathogenic heterogeneity -- Heterogeneity and the One Disease-Many Diseases Tension -- Requirements for precision medicine -- Biomarkers -- Diagnostic accuracy -- The concept of prodromal stages of neurodegenerative diseases -- Moving From Heterogeneity to Precision Medicine and Successful DMT -- Conclusion -- References -- Chapter 2: Models of precision medicine for neurodegeneration -- From the Clinicopathologic Model to Individualized Biological Subtyping -- Is the Model for Symptomatic Treatments Also Helpful for Precision Medicine? -- The Big Picture -- Logistical Implications of the Clinicopathologic Model of Disease -- The false allure of a perfect trial -- If PD is not one disease, why dont we strategize as if we mean it? -- The epidemiology-therapy disconnect -- Toxic pathology? -- When do we reject a hypothesis? -- ``Lessons from failures´´ -- Why Is There Resistance to Change Away From the Clinicopathology Model?.
,
Genetic mutations predicting disease mean the corresponding proteins must be toxic -- Absolute values do not tell the story in the way ratios do -- Seeding aggregation assays mean pathology is pathogenic -- Toward a New Model of Precision Medicine -- Biomarker development efforts -- Biomarker-driven molecular subtyping -- Clinical trial efforts -- Conclusions -- Acknowledgment -- Declaration of competing interest -- Disclosures -- Funding -- References -- Chapter 3: Pathology vs pathogenesis: Rationale and pitfalls in the clinicopathology model of neurodegeneration -- Introduction -- Synucleinopathies vs Synucleinopenia -- Clinical phenotypes -- Neuropathology -- Pathological hallmarks -- The question of ``copathology´´ -- From immunohistochemical patterns to ``spread of pathology´´ -- The nonspecificity of Lewy pathology -- The nonpathogenicity of Lewy pathology -- Tau-Based Disorders: Tauopathies vs Tauopenia -- Clinical phenotypes -- Neuropathology -- Pathological hallmarks (Fig. 3.3B) -- On ``copathologies´´ -- Special tau-based cases -- Tau aggregation as consequence, not cause -- The Amyloidosis of Alzheimer's Disease -- Clinical phenotypes -- Neuropathology -- The biomarker-based classification of AD -- Clinicopathologic discrepancies -- Why has tau been considered a more accurate biomarker of AD? -- TDP-43 Proteinopathies and/or TDP-43 Proteinopenia -- Clinical phenotypes -- Neuropathology -- Loss of the soluble TDP-43 has been invisible in research -- Pathology Is Not Pathogenesis -- The biophysics of the transformation of normal protein into pathology -- Conclusions and Future Remarks -- References -- Chapter 4: Mixed pathology as a rule, not exception: Time to reconsider disease nosology -- Introduction -- Tau pathology in the PD brain -- Pathological tau spreading through a ``prion-like´´ mechanism in PD brain.
,
Interaction between α-synuclein and tau pathogens -- Amyloid plaques deposits in PD brain -- The interaction of amyloid precursor protein and Parkinson's disease associated proteins -- TDP-43 in PD -- Neuroinflammation in the PD Brain -- Pathological α-synuclein may induce neuroinflammation -- Neuroinflammation modulating α-synuclein pathology -- Neuroinflammation participates in α-synuclein propagation -- Possible mechanisms in neuroinflammation-induced PD pathology -- Conclusions -- Acknowledgment -- References -- Chapter 5: Neurodegenerative disorders: From clinicopathology convergence to systems biology divergence -- Introduction -- From GWAS to Disease Pathways -- Systems Medicine for Multifactorial Diseases -- Omics, Multiomics, and Functional Enrichment -- Complex Diseases and Disease Networks -- A Systems Biology View on Parkinson's Disease -- A Systems Biology View on Alzheimer's Disease -- Neurodegeneration Mechanisms From a Systems Biology Point of View -- Concluding Remarks and Perspectives -- References -- Chapter 6: The emergence of genotypic divergence and future precision medicine applications -- A History of Wrong Divergences and Convergences -- Descriptive and Convergent Use of Genetic Variation -- Oligo- and Digenic Genetic Inheritance Causal Quests: First Divergent Steps in Precision Medicine? -- Gain- and Loss-of-Function Genotypes: Truly Divergent Precision Medicine -- Layers of Genotypic Divergence, Penetrance Modifiers, and Somatic Mosaicism -- Penetrance modifiers -- Somatic mosaicism -- Are We Approaching the Limit? -- References -- Chapter 7: Lessons from other fields of medicine, Part 1: Breast cancer -- Introduction to Breast Cancer -- Molecular Subtypes and Evolution of Biomarkers -- Histology -- Endocrine therapy: Estrogen receptor (ER) and progesterone receptor (PR) -- Human epidermal growth factor receptor 2 (HER2).
,
Surgical Evolution and Multimodal Influences -- Genetics -- Single Gene Prognostic Markers -- Multigene Prognostic Markers -- Future Directions -- Conclusion -- Financial disclosure -- References -- Chapter 8: Lessons from other fields of medicine, Part 2: Cystic fibrosis -- Introduction -- Genetics, Pathophysiology, and Classification -- Novel Therapeutics and Transformation of CF Therapy -- CFTR potentiators -- CFTR correctors -- Turning Back the Clock: Pushing the Age Frontier for CFTR Modulator Therapy -- Translational Read-Through and CFTR mRNA Therapies -- CFTR Biomarkers -- Evolution of Cell-Based Assays and CFTR Modulator Theratyping -- Organizational Support -- Venture philanthropy -- Impact of quality improvement initiatives -- Future of CF Care and Challenges Ahead -- Conclusions -- References -- Chapter 9: Lessons learned from evolving frameworks in adult glioblastoma -- Introduction -- Medical Imaging of GBMs -- Histopathology -- Molecular subtyping -- Transcription-based subtyping -- Early exploration -- The new era -- DNA methylation-based classification -- Genetic alteration-based classification -- Genomic Testing, Diagnosis, and Standard of Care -- Diagnosis -- Prognosis and treatment -- MGMT promoter methylation status -- Surgical treatment -- Molecular subtype-specific therapy -- Clinical Trials and Future Perspectives -- PRMT5 inhibitors -- Therapies targeting CDK5 -- Immunotherapy -- Conclusions -- References -- Further reading -- Part 2: Pitfalls in definitions, cohorts, and measures of progression -- Chapter 10: Finding the falsification threshold of the toxic proteinopathy hypothesis in neurodegeneration -- Background -- Language and narrative -- Belief -- Where is the Threshold of Hypothesis Falsification? -- The foretold conclusion of an unfalsifiable hypothesis: Aducanumab.
,
The impossible threshold for hypothesis falsification -- Why and How to Falsify a Hypothesis -- It is an ethical imperative that an incorrect hypothesis is falsified -- Underdetermination: Failed hypothesis or failed trial? -- Four steps to falsifying a hypothesis -- Step 1: State the therapeutic hypothesis being tested -- Step 2: Design a simple test of the therapeutic hypothesis -- Step 3: Identify a surrogate marker to rule out background assumptions -- Step 4: Propose an alternative hypothesis (from refutation to rejection) -- An Alternative to the Toxic Proteinopathy Hypothesis -- Conclusions -- References -- Chapter 11: The theoretical problems of ``prodrome´´ and ``phenoconversion´´ in neurodegeneration -- Introduction -- Clinical prodrome -- Dream-enactment behaviors -- Dysautonomia -- Olfactory -- Cognition -- Protein ``propagation´´ as unifying theme between prodrome and disease -- Rationale of and support for the Braak hypothesis of protein propagation -- Lost in translation: ``synucleinopathies´´ -- Lost in translation: ``amyloidopathies´´ -- Lost in translation: ``tauopathies´´ -- Prodrome vs disease and phenoconversion -- Phenoconversion -- Pitfalls in prodromal subtyping -- Purpose of prodromal subtyping -- Suggestions for Future Research -- Conclusions -- Conflict of Interest Disclosures -- References -- Chapter 12: The dilemma between milestones of progression versus clinical scales in Parkinson´s disease -- Introduction -- The Natural History of Parkinson's Disease -- Clinical Scales -- Motor scales -- Motor scale subscores -- Functional and quality of life assessment -- Cognitive scales -- Nonmotor scales -- Wearable technology -- Milestones -- Postural instability -- Medication-related milestones -- Motor complications -- Dementia -- Death -- Discussion -- Conclusion -- Acknowledgments -- References.
,
Chapter 13: Biomarkers of diagnosis, prognosis, pathogenesis, response to therapy: Convergence or divergence? Lessons fro.
Additional Edition:
Print version: Espay, Alberto J. Precision Medicine in Neurodegenerative Disorders San Diego : Elsevier,c2023 ISBN 9780323855389
Language:
English
Bookmarklink
