Parkinson's Disease E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1695

Veröffentlichungsjahr: 2011

Beschreibung

Parkinson's Disease has traditionally been seen as a movement disorder, and diagnosed by the development of tremor. However, we are beginning to understand that the disease manifests itself in many ways, and that earlier diagnosis might be possible through non-tremor symptoms. This textbook aims to tell the full story of non-motor and non-dopaminergic features of Parkinson's Disease.

Leseprobe

Contents

Cover

Title Page

Copyright

List of Contributors

Chapter 1: The Dopaminergic and Non-Dopaminergic Features of Parkinson's Disease

The dopamine story

Levodopa-induced motor complications

The non-motor and non-dopaminergic features of PD

Conclusions

Chapter 2: Neuropathologic Involvement of the Dopaminergic Neuronal Systems in Parkinson's Disease

Introduction: the neuroanatomy of the dopaminergic system

Anatomic/functional considerations

Morphometric quantitative studies of substantia nigra (A9) in normal aging

Involvement of various dopaminergic neuronal groups in Parkinson’s disease

Clinicopathologic correlations

Understanding selective vulnerability

Chapter 3: Non-Dopaminergic Pathology of Parkinson's Disease

Introduction

Lewy pathology

Selective vulnerability

α-Synuclein

Incidental Lewy disease

Progression of the pathologic process

Acknowledgments

Chapter 4: Functional Anatomy of the Motor and Non-Motor Circuitry of the Basal Ganglia

Introduction

Basal ganglia components and general circuitry

Striatum: main entrance of extrinsic information to the basal circuits

The corticostriatal system: the main source of extrinsic information to the basal ganglia

The dual thalamostriatal systems: two major extrinsic sources of striatal excitability

The striatal dopaminergic systems: major modulators of basal ganglia networks

The direct and indirect basal ganglia circuits: “a simplified model that brought us a long way”

The segregation of direct and indirect striatofugal pathway neurons: an ongoing dilemma?

The hyperdirect corticosubthalamic system: anatomic and functional significance

The pedunculopontine nucleus: an intricate component of the basal ganglia circuitry

Basal ganglia outflow to the thalamus and brainstem

Concluding remarks

Acknowledgments

Chapter 5: Functional Organization of the Basal Ganglia: Dopaminergic and Non-Dopaminergic Features

Introduction

Functional organization of the basal ganglia

The origin of sensory features in Parkinson's disease

Somatosensory projections to the basal ganglia

Pathophysiologic mechanisms and clinical relevance of sensory manifestations

Non-dopaminergic motor manifestations

Conclusions

Chapter 6: Anatomy and Physiology of Limbic System Dysfunction in Parkinson's Disease

Introduction

Anatomy of the dopamine system

Physiology of the dopamine system

Dopamine actions on postsynaptic targets

Alteration of limbic system circuitry in Parkinson's disease: potential disruption by L-DOPA

Other potential alterations within limbic circuits in Parkinson's disease

Parkinson's disease and impulse-control disorders

Conclusion

Chapter 7: Animal Models of Parkinson's Disease: the Non-Motor and Non-Dopaminergic Features

Parkinson's disease

Classic PD models

Use of animal models to assess the non-motor and non-dopaminergic features of PD

Therapy-induced non-motor features of PD

Conclusion

Chapter 8: The Emerging Entity of Pre-Motor Parkinson's Disease

Prologue

Introduction

REM sleep behavioral disorder (RBD) – the concept of pre-motor PD comes of age

Olfactory dysfunction

Constipation

Cardiac autonomic denervation

Pure autonomic failure

Depression

Dementia

Where do we go from here? The need for prospective cohorts

Conclusion

Epilogue

Chapter 9: Functional Imaging Studies in Parkinson's Disease: the Non-Dopaminergic Systems

Introduction

Changes in the DA system in PD

Changes in monoamine transmitters other than DA

Other neurotransmitters

Neurotransmitter expression in the peripheral nervous system

Network activity in Parkinson's disease

Clues from functional imaging into etiology of PD and pathogenesis of complications

Conclusion

Chapter 10: Assessment of Non-Motor Features of Parkinson's Disease: Scales and Rating Tools

Introduction: principles of scale development and usage

Global PD scales

Multi-dimensional assessment tools

Focal non-motor scales

Future perspectives: other specific scale critiques in development

Chapter 11: Clinical Trial Measures of the Non-Motor Features of Parkinson's Disease

Introduction

Parkinson's disease pathology and clinical features

Measures of impairment (see Table 11.1)

Measures of function and health-related quality-of-life

New Study Designs (see Table 11.2)

Conclusion

Chapter 12: Clinical Features of Dementia Associated with Parkinson's Disease and Dementia with Lewy Bodies

Introduction

The interface between PDD and DLB

Descriptive epidemiology

Predicting dementia in PD

Cognitive features

Neuropsychiatric features

Motor, sleep, and other neurologic features

Diagnosis of PDD and DLB

Natural history and determinants of prognosis

Future directions

Conclusion

Chapter 13: Neuropsychologic Features of Parkinson's Dementias

Introduction

Parkinson's disease dementia

Dementia with Lewy bodies

Chapter 14: Neuropathology of Dementia in Parkinson's Disease

Introduction

Neuropathology of PD

Distribution of Lewy-related pathology

Staging Lewy-related pathology

Neuropathologic correlates of dementia in PD: a historical perspective

Significance of cortical Lewy-related pathology in PDD

Significance of Alzheimer-type pathology in PDD

Subcortical pathology in PDD

Cortical synaptic pathology in PDD

Acknowledgment

Chapter 15: Treatment of Dementia Associated with Parkinson's Disease

Introduction

General considerations on the treatment of PDD

Conclusion

Chapter 16: Psychosis in Parkinson's Disease

Introduction

Definitions

Clinical syndrome of Parkinson's disease psychosis (PDP)

Delusions

Differential diagnosis of psychosis (Box 16.2)

Clinical course

Measuring psychosis

Risk factors

Pathophysiology

Treatment

Patients with primary psychosis and Parkinson's disease

Conclusions and treatment recommendations

Chapter 17: Depression in Parkinson's Disease

Introduction

Diagnosis

Phenomenology

Epidemiology

Etiology

Depression and deep brain stimulation

Management and prognosis

Conclusion

Chapter 18: Anxiety Syndromes and Panic Attacks

Introduction

Epidemiology

Correlates and risk factors

Presentation

Etiology and pathophysiology

Assessment and diagnosis

Treatment

Chapter 19: Dopamine Dysregulation Syndrome

Introduction

Phenomenology of DDS and associated behaviors

Epidemiology of the DDS and associated behaviors in PD

DDS as a substance dependence disorder or addiction

Risk factors for dopamine dysregulation

Chronic dopaminergic treatment subverts brain reward systems

Management of DDS

Conclusion

Acknowledgments

Chapter 20: Neurobiology of Impulse Control Disorders in Parkinson's Disease

Introduction

Definitions and classifications

ICDs in PD

Epidemiology of ICDs in PD

Conceptualizing the ICDs

Models of behavioral addiction: theory and neurobiology

Functional anatomic substrates of addiction

Potential roles for dopamine in ICDs and addiction

A role for non-dopaminergic neurotransmitter systems in ICDs

Pathophysiology of ICDs in PD: potential roles for individual susceptibility, Parkinson's disease, and dopamine agonists

Potential roles of dopaminergic medications in the development of ICDs

Preferential stimulation of the DA D3 receptor subtype

DA receptor stimulation altering the assignment of salience

Priming effects of dopaminergic agents associated with craving

Implications for management

Conclusion

Chapter 21: Sleep Disorders in Parkinson's Disease

Introduction

Pathophysiologic aspects

Clinical symptoms

Disorders of initiating and maintaining sleep

Nocturnal akinesia

Periodic leg movements in sleep (PLMS)

Sleep benefit

REM sleep behavior disorder (RBD)

Nocturnal respiratory disorders

Excessive daytime sleepiness (EDS)

Diagnostic work-up

Video-based polysomnography and multiple sleep latency (MSLT)

Treatment of sleep disorders

Conclusion

Chapter 22: Neuronal Mechanisms of REM Sleep and Their Role in REM Sleep Behavior Disorder

Introduction

Overall control of wake–sleep switching

REM sleep state switching

REM atonia systems

Pathologic conditions of the REM atonia system

Is the hypertonia and gait disorder of Parkinson's disease caused by disinhibiting the LPT?

Chapter 23: REM Sleep Behavior Disorder and Neurodegenerative Disorders

Introduction

Demographics

Clinical features

Case example: RBD and parkinsonism

Pathophysiology

Epidemiology and associated conditions

Diagnosis (clinical and laboratory evaluation)

Differential diagnosis

Treatment

RBD variations

Perspectives

Conclusion

Chapter 24: Gastrointestinal and Swallowing Disturbances in Parkinson's Disease

Introduction

Basic mechanisms of swallowing and GI function

Pathology of GI dysfunction in PD

Clinical features

Conclusion

Chapter 25: Bladder Dysfunction in Parkinson's Disease and Other Parkinsonism

Introduction

Symptoms and pathophysiology

Genetic and atypical parkinsonisms

Diagnosis: urological assessment

Treatment

Conclusion

Chapter 26: Orthostatic Hypotension in Parkinson's Disease

Introduction

Pathophysiologic basis of OH in PD

Definition of OH and clinical manifestations of OH

Investigation of OH

Associated factors to consider in OH associated with PD

Management of OH in PD

Conclusion

Acknowledgment

Chapter 27: Sexual Dysfunction

Introduction

Sexual dysfunction and PD

Hyposexual behaviors

Hypersexual behaviors

Conclusion

Chapter 28: Olfactory Dysfunction

Introduction

Assessing smell loss in PD

The development of olfactory dysfunction as a biomarker of early PD

The neuropathology of olfactory dysfunction in PD

The role of olfactory system pathology in PD pathophysiology

Conclusion

Chapter 29: Pain and Paresthesia in Parkinson's Disease

Introduction

Epidemiology of sensory symptoms in PD

Clinical features

Mechanisms of PD-related pain

Diagnosis and management

Acknowledgments

Chapter 30: Restless Legs Syndrome and Akathisia in Parkinson's Disease

The restless legs syndrome (RLS)

Akathisia

Chapter 31: Speech and Voice Disorders in Parkinson's Disease

Incidence and impact of speech and voice disorders in Parkinson's disease

Origin of speech and voice disorders in PD

Treatment of speech and voice disorders in PD

Behavioral speech and voice treatment for PD

Intensive voice treatment (LSVT LOUD) for PD

LSVT LOUD: target, mode, and calibration

Technology-enhanced accessibility

When to refer for speech treatment

Conclusion

Acknowledgment

Disclosure

Chapter 32: Gait, Postural Instability, and Freezing

Introduction

Clinical assessment of balance and gait

Falls

Cognitive deficits

Treatment

Conclusion

Acknowledgment

Chapter 33: Orthopedic Complications of Parkinson's Disease

Introduction

Primary orthopedic complications

Secondary orthopedic complications

Parkinsonism complicating orthopedic surgery

Conclusion

Chapter 34: Other Non-Motor Symptoms of Parkinson's Disease

Visual disturbances

Salivation

Fatigue

Sweating

Skin disorders

Chapter 35: Overview of the Medical Treatment of the Non-Motor and Non-Dopaminergic Features of Parkinson's Disease

Introduction

Neuropsychiatric disorders

Sleep disorders

Autonomic dysfunction

Sensory disturbances

Bulbar disorders

Respiratory disturbances

Orthopedic problems

Conclusion

Chapter 36: Surgery for Non-Dopaminergic and Non-Motor Features of Parkinson's Disease

Introduction

Challenges in the non-motor and non-dopaminergic aspects of PD

Psychiatric symptoms

Future therapy in psychiatric aspects of PD

Conclusion

Chapter 37: Effects of Exercise on Basal Ganglia Function in Parkinson's Disease and Its Animal Models

Introduction

Effects of exercise on the normal brain

Exercise in animal models of Parkinson's disease

Physical therapy and exercise in Parkinson's disease

Conclusion

Acknowledgments

Chapter 38: Non-Dopaminergic Approaches to the Treatment of Parkinson's Disease

Introduction

Anti-cholinergics

Adenosine A2A antagonists

Glutamate antagonists

Noradrenaline

Serotonin

Endocannabinoid system

Opioid system

Histamine

Conclusions

Chapter 39: Prospects for Neuroprotective Therapies That Can Modulate Non-Dopaminergic Features in Parkinson's Disease

Introduction

Etiopathogenesis of PD

Animal models of PD

Outcome measures and study designs to detect disease-modification

Optimal population to study in disease-modifying trials

Conclusions

Plate

Index

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Library of Congress Cataloging-in-Publication Data Parkinson’s disease : non-motor and non-dopaminergic features / edited by C. Warren Olanow, Fabrizio Stocchi, Anthony E. Lang. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-9185-2 (hardcover : alk. paper) 1. Parkinson’s disease–Diagnosis. 2. Parkinson’s disease–Pathophysiology. I. Olanow, C. W. (Charles Warren), 1941- II. Stocchi, F. III. Lang, Anthony E. [DNLM: 1. Parkinson Disease–complications. 2. Dopamine–physiology. 3. Parkinson Disease–physiopathology. WL 359] RC382.P2657 2011 616.8′33–dc22 2010047397

A catalogue record for this book is available from the British Library.

This book is published in the following electronic formats: ePDF 9781444397956; Wiley Online Library 9781444397970; ePub 9781444397963

List of Contributors

Garnik Akopian MD Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA

Karen Anderson MD Department of Neurology, University of Maryland Medical Center, Baltimore, MD, USA

Kailash P. Bhatia MD, FRCP Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London, UK

Bastiaan R. Bloem MD Department of Neurology and Parkinson Centre Nijmegen, Donders Institute for Brain Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Heiko Braak MD Clinical Neuroanatomy, Department of Neurology, Center for Clinical Research, University of Ulm, Ulm, Germany

Jonathan M. Brotchie PhD Toronto Western Research Institute, Toronto Western Hospital, Toronto, ON, Canada

David J. Burn FRCP, MD, MA Professor of Movement Disorders Neurology and Honorary Consultant Neurologist, Clinical Ageing Research Unit, Campus for Ageing and Vitality, Newcastle upon Tyne, UK

Antonio Carbone MD Institute of Urology, University “La Sapienza”, Rome, Italy

Cynthia L. Comella MD Professor, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Michel A. Cramer Bornemann MD Minnesota Regional Sleep Disorders Center and Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN, USA

Leonardo Cruz de Souza MD Department of Neurology, Salpêtrière University Hospital, Paris, France

Virginie Czernecki PhD Department of Neurology, Salpêtrière University Hospital, Paris, France

Kelly Del Tredici MD, PhD Clinical Neuroanatomy, Department of Neurology, Center for Clinical Research, University of Ulm, Ulm, Germany

Dennis W. Dickson MD Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

Bruno Dubois MD Professor of Neurology, Department of Neurology, Salpêtrière University Hospital, Paris, France

John E. Duda MD Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Philadelphia Veterans Affairs Medical Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Mark J. Edwards PhD Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London, UK

Murat Emre MD Professor of Neurology, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul University, Çapa Istanbul, Turkey

Andrew H. Evans MD, FRACP Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, and Department of Medicine, University of Melbourne, Australia

Beth E. Fisher MD Division of Biokinesiology and Physical Therapy, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Cynthia M. Fox PhD, CCC-SLP Research Associate, Department of Speech, Language and Hearing Science, University of Colorado–Boulder and the National Center for Voice and Speech–Denver, CO, USA

Susan H. Fox BSc, MB, ChB, MRCP (UK), PhD Assistant Professor of Neurology, Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, ON, Canada

Jospeh H. Friedman MD Movement Disorders Program, Butler Hospital and Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA

Christopher G. Goetz MD Professor of Neurological Sciences and Professor of Pharmacology, Rush University Medical Center, Chicago, IL, USA

Anthony A. Grace PhD Departments of Neuroscience, Psychiatry, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA

Yvette Grimbergen MD Department of Neurology, Leiden University Medical Centre, Leiden and Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands

Staci Hoops BA Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

Alex Iranzo MD Neurology Service, Hospital Clinic and Institut d’Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Michael Jakowec MD Department of Neurology, Keck School of Medicine and Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, USA

Joseph Jankovic MD Professor of Neurology, Director, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA

Carlos Juri MD Clinica Universitaria and Medical School, Neuroscience Division, CIMA and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Navarra, Pamplona, Spain

Karl Kieburtz MD, MPH Professor of Neurology and Community and Preventive Medicine, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA

Jeffrey H. Kordower PhD Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

J. William Langston MD Scientific Director and CEO, Parkinson’s Institute, Sunnyvale, CA, USA

Andrew J. Lees FRCP Director of Research, Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, UK

Shen-Yang Lim MD, FRACP Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Andres W. Lozano MD, PhD, FRCSC, FRS Professor and Dan Family Chairman of Neurosurgery, University of Toronto and Senior Scientist, Toronto Western Research Institute, Canada Research Chair in Neuroscience, Toronto, ON, Canada

Jun Lu MD, PhD Department of Neurology, Program in Neuroscience and Division of Sleep Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA

Mark W. Mahowald MD Director, Minnesota Regional Sleep Disorders Center and Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN, USA

Christopher J. Mathias DPhil, DSc, FRCP, FMedSci Autonomic and Neurovascular Medicine Unit, Imperial College London at St Mary’s Hospital and Autonomic Unit, National Hospital for Neurology and Neurosurgery, Queen Square and Institute of Neurology, University College London, London, UK

Charlie K. Meshul MD Department of Behavioral Neurosciences, Oregon Health Sciences University, Research Services, Portland VA Medical Center, Portland, OR, USA

Janis Miyasaki MD, FRCPC Toronto Western Hospital (Movement Disorders Centre), University Health Network (UHN), University of Toronto, Toronto, ON, Canada

Uday Muthane DM, FNASc Parkinson and Aging Research Foundation, Bangalore, India

Jose A. Obeso MD, PhD Clinica Universitaria and Medical School, Neuroscience Division, CIMA and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Navarra, Pamplona, Spain

Carolyn F. Orr FRACP, PhD Department of Neurology, Mayo Clinic, Rochester, NY, USA

Sean S. O’Sullivan MRCPI Clincial Research Fellow, Reta Lila Weston Institute of Neurolgical Studies, Institute of Neurology, University College London, London, UK

Giovanni Palleschi MD Institute of Urology, University “La Sapienza”, Rome, Italy

Kimberly Pargeon MD Department of Neurology, University of Maryland Medical Center, Baltimore, MD, USA

Daniel P. Perl MD Professor of Pathology (Neuropathology), Uniformed Services University of the Health Sciences, Bethesda, MD, USA

Giselle Petzinger MD Department of Neurology, Keck School of Medicine and Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, USA

Ronald F. Pfeiffer MD Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

Shilpa Ramaswamy PhD Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Lorraine Ramig PhD, CCC-SLP Professor, University of Colorado–Boulder, Senior Scientist, National Center for Voice and Speech–Denver, CO, and Adjunct Professor, Columbia University, New York, NY, USA

Irene Hegeman Richard MD Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

Maria C. Rodriquez-Oroz MD, PhD Clinica Universitaria and Medical School, Neuroscience Division, CIMA and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Navarra, Pamplona, Spain

Jospeh Rudolph MD Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA

Cristina Sampaio MD, PhD Professor of Clinical Pharmacology and Therapeutics, Laboratory of Clinical Pharmacology and Therapeutics, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisbon, Portugal

Clifford B. Saper MD, PhD Department of Neurology, Program in Neuroscience and Division of Sleep Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA

Shimon Sapir PhD, CCC-SLP Associate Professor, Communication Sciences and Disorders, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel

Carlos H. Schenck MD Minnesota Regional Sleep Disorders Center and Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN, USA

Yvonne Schoon MD Department of Geriatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Friederike Sixel-Döring MD Paracelsus-Elena-Klinik, Center for Parkinsonism and Movement Disorders, Kassel and Philipps University, Marburg, Germany

Yoland Smith PhD Professor of Neurology, Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA, USA

Brian J. Snyder MD Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada

Katherine E. Soderstrom BA Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Arlène D. Speelman MSc Department of Neurology and Parkinson Centre Nijmegen, Donders Institute for Brain Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Mark Stacy MD Division of Neurology, Duke University Medical School, Durham, NC, USA

Thomas D.L. Steeves MD, FRCPC Toronto Western Hospital (Movement Disorders Centre), University Health Network (UHN), University of Toronto, Toronto, ON, Canada

Matthew B. Stern MD Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Philadelphia Veterans Affairs Medical Center, and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

A. Jon Stoessl CM, MD, FRCPC Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, BC, Canada

Antonio P. Strafella MD, PhD, FRCPC Associate Professor, Department of Medicine/Neurology, Movement Disorders Centre, Toronto Western Hospital and Senior Scientist, Division of Brain, Imaging and Behaviour–Systems Neuroscience, Toronto Western Research Institute and Associate Scientist, PET Imaging Center, Center for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

Michele Tagliati MD, FAAN Vice Chairman, Department of Neurology, Director, Movement Disorders, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Margherita Torti MD Institute of Neurology, IRCCS San Raffaele Pisana, Rome, Italy

Claudia Trenkwalder MD Paracelsus-Elena-Klinik, Center for Parkinsonism and Movement Disorders, Kassel and University of Göttingen, Göttingen, Germany

Marjolein A. van der Marck MSc Department of Neurology and Parkinson Centre Nijmegen, Donders Institute for Brain Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Tiffini Voss MD Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

John P. Walsh MD Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA

William J. Weiner MD Professor and Department Chairman, Department of Neurology, University of Maryland Medical Center, Baltimore, MD, USA

Daniel Weintraub MD Assistant Professor of Psychiatry, University of Pennsylvania and Parkinson’s Disease Research, Education and Clinical Center (PADRECC) and Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Affairs Medical Center Philadelphia, PA, USA

Chapter 1

The Dopaminergic and Non-Dopaminergic Features of Parkinson's Disease

C. Warren Olanow1, Fabrizio Stocchi2, & Anthony E. Lang3

1Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

2Institute of Neurology, IRCCS San Raffaele Pisana, Rome, Italy

3Division of Neurology, University of Toronto, Toronto, ON, Canada

The dopamine story

Parkinson's disease (PD) is a common age-related neurodegenerative disorder, second only to Alzheimer's disease (AD). It is named in honor of James Parkinson, who provided a description of the disorder in his classic monograph written in 1817 [1]. Clinically, the disease is characterized by a series of cardinal motor features which include resting tremor, rigidity, bradykinesia, and gait impairment with postural instability. The hallmark pathologic features of the disease were described in the early twentieth century and are highlighted by degeneration of neurons in the substantia nigra pars compacta (SNc) coupled with proteinaceous Lewy bodies [2]. The presence of the brainstem dopaminergic system was first described by Dahlström and Fuxe [3]. The importance of dopamine depletion in the pathophysiology of PD was suggested in the late 1950s by Carlsson and colleagues, who showed that inhibition of dopamine uptake by reserpine led to a Parkinson-like syndrome in rabbits that could be reversed with the dopamine precursor levodopa [4]. Shortly afterwards, Ehringer and Hornykiewicz identified that there was a profound dopamine deficiency in the striatum of patients with PD [5]. It was subsequently established that dopamine is not simply a precursor in the norepinephrine pathway, but is itself a neurotransmitter that is manufactured in SNc neurons and transported to the striatum by way of the nigrostriatal tract.

Based on these observations, it was hypothesized that dopamine replacement might be an effective treatment strategy for PD. Dopamine itself does not cross the blood–brain barrier, so interest focused on the dopamine precursor levodopa, which can gain entry into the brain via the large neutral amino acid transport pathway and can then be decarboxylated to form dopamine. Initial studies in the early 1960s reported a dramatic benefit with small doses of levodopa [6], but these results were surprisingly difficult to confirm in early trials. It was not until the reports by Cotzias and co-workers in 1967 and 1969 that it was appreciated that consistent benefits could be obtained with relatively higher doses of levodopa [7,8]. These results were subsequently confirmed in double-blind trials [9], and the levodopa era had begun. Although levodopa provided benefit for the vast majority of PD patients, therapy was complicated by nausea and vomiting and could not be tolerated by as many as 50% of individuals. This problem was found to be due to the peripheral accumulation of dopamine and activation of dopamine receptors in the nausea and vomiting center of the brain (area postrema) that are not protected by the blood–brain barrier. This problem was resolved by administering levodopa in combination with a peripherally acting dopamine decarboxylase inhibitor [10], and levodopa today is routinely administered in combination with the decarboxylase inhibitor carbidopa (Sinemet) or benserazide (Madopar). Since its introduction, levodopa has been the standard of care for PD and has benefited millions of patients throughout the world. Virtually all patients improve, and benefits have been noted with respect to the classic motor features of the disease, quality of life, independence, employability, and mortality [11].