Diseases of the Nervous System, 2nd Edition

Front Cover
Diseases of the Nervous System
Copyright
Dedication
Contents
About the Author
Acknowledgments
Introduction
Section I: Static nervous system diseases
Chapter 1 Cerebrovascular Infarct: Stroke
1 Case story
2 History
3 Clinical presentation/diagnosis/epidemiology
4 Disease mechanism/cause/basic science
4.1 Causes of Vessel Occlusions: the Thrombolytic Cascade
4.2 The Ischemic Cascade
4.3 The Ischemic Penumbra
4.4 The NMDA Receptor and Glutamate Excitotoxicity
4.5 Role of glutamate
4.6 NMDA Inhibitors to Treat Stroke
4.7 Effect of temperature
4.8 Stroke genetics
5 Treatment/standard of care/clinical management
5.1 Chemical thrombolysis using intravenous tPA
5.2 Mechanical thrombolysis by endovascular therapy for Ischemic stroke
5.3 Anticlotting factors to prevent recurrence
5.4 Treatment of hemorrhagic stroke
5.5 Rehabilitation
5.6 Stroke Prevention
6 Experimental Approaches/Clinical Trials
6.1 Neuroprotection
6.2 Hypothermia
6.3 Improved clot busters
6.4 Brain rewiring after stroke
6.5 Why Have so Many Promising Drugs Failed in Human Clinical Trials?
7 Challenges and opportunities
Acknowledgment
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Chapter 2 Central Nervous System Trauma
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 Traumatic Brain Injury
3.2 Spinal Cord Injury
3.3 Shaken Baby Syndrome—Abusive Head Trauma
3.4 Value of Imaging: Diffusion-Tensor Magnetic Resonance Imaging
4 Disease Mechanism/Cause/Basic Science
4.1 Anatomy of the CNS
4.2 How Does Trauma Cause Injury?
4.3 Amyloid and Tau Aggregates Following Trauma—Chronic Traumatic Encephalopathy (CTE)
4.4 How Are Brain and Spinal Cord Protected From Trauma?
4.5 Why Is the CNS Still So Vulnerable to Mechanical Injury?
4.6 Why Are Axonal Connections Not Restored After Injury?
4.7 Activity-Dependent Functional Recovery After Injury
4.8 Inflammation
4.9 Animal Models of Disease
Traumatic Brain Injury/Concussion
Spinal Cord Injury
5 Treatment/Standard of Care/Clinical Management
5.1 Clinical Management of Traumatic Brain Injury
5.2 Clinical Management of Spinal Cord Injury
6 Experimental Approaches/Clinical Trials
6.1 Limiting Excitotoxicity After TBI
6.2 Treatment of TBI by Hypothermia
6.3 Erythropoetin in TBI
6.4 Biomarkers for TBI
6.5 Rewiring the Spinal Cord After SCI
6.6 Stem Cells in SCI
6.7 Estrogen and Progesterone
6.8 Robotic Rehabilitation/Forced Walking
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Chapter 3 Seizure Disorders and Epilepsy
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 Epidemiology
3.2 Seizure Definition and Characterization
Focal Seizures
Generalized Seizures
Status Epilepticus
3.3 Epilepsy Classification
4 Disease Mechanism/Cause/Basic Science
4.1 Hyperexcitability, Network Excitability, and Synchronization
4.2 Emerging Unifying Hypothesis: Excitation–Inhibition Imbalance
4.3 Epileptogenesis
4.4 Laboratory Work/Animal Models 1
Chemical Induction
Kindling
Lesions
4.5 Transmitter Systems and Epilepsy
Astrocytes
4.6 Ion Channels
4.7 Genetics of Epilepsy
4.8 Emerging Targets and Mechanisms Suspected to Play a Role in Epilepsy
Kcc2/Nkcc1
Mammalian Target of Rapamycin
Synaptic Vesicle Protein 2A
Neurotrophins
Ca 2    + -Regulated Enzymes
Astrocytes
Stem Cells
Epigenetics
5 Treatment/Standard of Care/Clinical Management
5.1 Diagnosis
5.2 Pharmacological Treatment
5.3 Surgical Treatment
5.4 Neuromodulatory Epilepsy Therapy
5.5 Immunological Approaches, Diet, and Alternative Treatments
5.6 Comorbidities and Psychological Issues to Consider
6 Experimental Approaches/Clinical Trials
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Basic
Clinical
Section II: Progressive Neurodegenerative Diseases
Chapter 4 Aging, Dementia, and Alzheimer Disease *
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 Epidemiology
3.2 Patient Presentation and Diagnosis
3.3 Alzheimer Disease
3.4 Frontotemporal Dementia
3.5 Other Causes of Dementia
4 Disease Mechanism/Cause/Basic Science
4.1 Memory and Distribution in the Brain
4.2 Structural Changes Underlying Alzheimer Disease and Other Forms of Dementia
Anatomical Changes
Neurofibrillary Tangles
Amyloid
Secretases
Clearance of Deposits
Cell-to-Cell Transmission of Disease
4.3 Vascular Changes in Alzheimer Disease
4.4 The Genetics of Alzheimer Disease
4.5 Animal Models of Alzheimer Disease
4.6 Changes in Transmitter Systems in Alzheimer Disease
4.7 Alzheimer Disease and Inflammation
5 Treatment/Standard of Care/Clinical Management
5.1 Imaging, Diagnosis, and Disease Prediction
5.2 Drug Treatment
5.3 Disease Onset Delay and Prevention
6 Experimental Approaches/Clinical Trials
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Paper
Basic Science Paper
Chapter 5 Parkinson Disease *
1 Case Story
2 History
3 Clinical Presentation, Diagnosis, and Epidemiology
3.1 Epidemiology and Risk Factors
3.2 Disease Presentation and Diagnosis
3.3 Disease Stages
3.4 Related Movement Disorders
4 Disease Mechanism/Cause/Basic Science
4.1 Dopamine and the Control of Movement
4.2 The Basal Ganglia
4.3 Lewy Bodies Pathology and Progression of Disease
4.4 How Might α -Synuclein Aggregation in Lewy Bodies Contribute to Disease?
4.5 How Might We Explain the Progressive Neuronal Loss Primarily in the SN?
4.6 Why Does It Take 60 Years or Longer for PD to Develop?
4.7 Genetics of PD
4.8 Animal Models of PD
Chemically Induced Animal Models of PD
Drosophila as Model to Study PD
5 Treatment/Standard of Care/Clinical Management
5.1 Dopamine and Dopamine Replacement Therapy
5.2 Deep Brain Stimulation
5.3 Neuroprotection
5.4 Treatment of Nonmotor Symptoms
6 Experimental Approaches/Clinical Trials
6.1 Nicotine
6.2 Urate
6.3 Nonsteroidal Antiinflammatory Drugs (NSAIDs)
6.4 Ca 2    + Channel Blockers
6.5 Prevention of Lewy Body Formation
6.6 Cell-Based Therapies
7 Challenges and Opportunities
Acknowledgment
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Paper
Basic Paper
Chapter 6 Diseases of motor neurons and neuromuscular junctions
1 Case story
2 History
3 Clinical presentation/diagnosis/epidemiology
3.1 Amyotrophic Lateral Sclerosis
3.2 Progressive Muscular Atrophy
3.3 Spinal Muscular Atrophy
3.4 Kennedy Disease
3.5 Myasthenia Gravis
3.6 Lambert Eaton Myotonia
3.7 Guillain-Barré Syndrome
3.8 Differential Diagnoses for Motor Neuron Diseases
4 Disease mechanism/cause/basic science
4.1 Motor Pathways
4.2 ALS Pathology
4.3 Gene Mutations Associated with ALS and Heritability
4.4 Animal Models
4.5 When and How do Motor Neurons Die?
4.6 Cellular Mechanisms of Motor Neuron Death
4.7 Noncell-Autonomous Toxicity and Neurodegeneration in ALS
4.8 Inflammation and ALS
4.9 Mechanism(s) of Disease Spread
4.10 Putting It All Together: The “Perfect Storm”
5 Treatment/standard of care/clinical management
6 Experimental approaches/clinical trials
7 Challenges and opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Chapter 7 Huntington Disease *
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 The Diagnosis of HD
3.2 Brain Imaging
3.3 Epidemiology
3.4 Prognosis
4 Disease Mechanism/Cause/Basic Science
4.1 Neuropathology
4.2 Genetics of HD
4.3 Heritability and Anticipation
4.4 Animal Models
4.5 Normal Function of Huntingtin Protein (HTT)
4.6 Mutant Huntingtin
4.7 What Causes Disease: Mutated DNA, RNA, or Protein?
4.8 Are Intranuclear Protein Inclusions Toxic?
4.9 The Proteostasis Network
4.10 Glutamate, Excitotoxicity, and Synaptic Function
4.11 BDNF and Synaptic Function
4.12 Mitochondria and Metabolic Dysfunction
4.13 Role of Glia in HD
4.14 Related Glutamine Repeat Diseases
5 Treatment/Standard of Care/Clinical Management
5.1 Treatment
5.2 Genetic Testing
6 Experimental Approaches/Clinical Trials
6.1 Targeting Mutant HTT
6.2 Metabolism
6.3 Excitotoxicity
6.4 PDE10 Inhibition
6.5 Stem Cells
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Section III: Secondary progressive neurodegenerative diseases
Chapter 8 Multiple Sclerosis
1 Case story
2 History
3 Clinical presentation/diagnosis/epidemiology
3.1 Epidemiology and Risk Factors
3.2 Clinical Presentation
3.3 Diagnosis
4 Disease mechanism/cause/basic science
4.1 Histopathological Changes
4.2 Toxicity to Oligodendrocytes and Myelin
4.3 The Immune Attack in Multiple Sclerosis
4.4 Demyelination and Action Potential Block
4.5 Remyelination
4.6 White Matter Atrophy and Axonal Injury
4.7 Genetics
4.8 Environment
4.9 Animal Models of Disease
5 Treatment/standard of care/clinical management
5.1 Supportive Treatments
5.2 Disease-Modifying Drugs
6 Experimental approaches/clinical trials
6.1 Na + Channel Blockers
6.2 K + Channel Blockers
6.3 Hypothermia
6.4 Medical Marijuana
6.5 Vitamin D
6.6 Diet
6.7 Estriol to Induce a Pregnancy-Like State
6.8 Stem Cells
7 Challenges and opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Chapter 9 Brain Tumors
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 Metastatic CNS Tumors
3.2 Primary CNS Tumors
3.3 Patient Presentation and Diagnosis
4 Disease Mechanism/Cause/Basic Science
4.1 Cell(s) of Origin
4.2 Cancer Stem Cells
4.3 Glioma: A Genetic Disorder
4.4 Growth Control (Cell Proliferation and Evasion of Apoptosis)
4.5 Tumor Invasion/Intracranial Metastasis
4.6 Glioma Vascular Interactions/Angiogenesis
4.7 The Many Roles of Glu in Glioma Biology
4.8 Tumor Stromal Interactions
4.9 Glioma: A Neurodegenerative Disease?
5 Treatment/Standard of Care/Clinical Management
5.1 Surgery
5.2 Radiation
5.3 Chemotherapy
5.4 Palliative Therapy
6 Experimental Approaches/Clinical Trials
6.1 Glutamate Release
6.2 Ceftriaxone
6.3 Levetiracetam (Keppra)
6.4 Cilengitide
6.5 Chlorotoxin
6.6 Tumor-Treating Fields
6.7 Immunotherapy
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Paper
Basic
Chapter 10 Infectious Diseases of the Nervous System
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology/Disease Mechanism
3.1 Meningitis
3.2 Botulism
3.3 Tetanus
3.4 Neurosyphilis
3.5 Poliomyelitis
3.6 Rabies
3.7 HIV and Neuro-AIDS
3.8 Prion Diseases
3.9 Brain-Eating Amoeba ( Naegleria fowleri)
3.10 Neurocysticercosis
4 Beyond the Infection: Bona Fide Brain Disorders Involving Pathogens
4.1 Viral Etiology of Multiple Sclerosis: Epstein–Barr Virus
4.2 Viral Cause of Schizophrenia
4.3 Infection, Immunization, and Autism
4.4 Prions in AD
5 Experimental Approaches/Clinical Trials
5.1 Medical Use of Neurotoxins (Botox)
5.2 Viruses to Deliver Genes for Gene Therapy or Reprogramming of Endogenous Cells
5.3 Weapons and Bioterrorism
6 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Paper
Basic
Section IV: Developmental Neurological Conditions
Chapter 11 Neurodevelopmental Disorders
1 Case Study
2 History
3 Development of Synapses in the Human Cortex and Diseases Thereof
3.1 Phases of Normal Synaptic Development
4 Down Syndrome
4.1 Neurobiology of DS
4.2 Genes Affected by the Triplication of Chromosome 21 and Their Potential Link to DS Symptoms
4.3 Emerging Treatments
5 Fragile X Syndrome
5.1 Neurobiology of FXS
5.2 Emerging Treatments
6 Rett Syndrome
6.1 Neurobiology of RTT
Mouse Models of RTT
Role of Glia in RTT
6.2 Emerging Treatments
Other Conditions With MECP2 Mutations
7 Autism Spectrum Disorder (ASD)
7.1 Risk Factors
7.2 Neurobiology of ASD
Animal Models of Disease
7.3 Emerging Treatments
Prognosis
8 Common Disease Mechanism
9 Challenges and Opportunities
Acknowledgment
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Section V: Neuropsychiatric Illnesses
Chapter 12 Mood Disorders and Depression
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 Grieving
3.2 Secondary Depression
3.3 Clinical Depression
3.4 Bipolar Depression
4 Disease Mechanism/Cause/Basic Science
4.1 Structural Changes
4.2 Cellular and Network Changes
4.3 Neuroendocrine Changes
4.4 Genetics
4.5 Animal Models to Study Depression
4.6 The Environment and Depression Susceptibility
4.7 Depression and the Immune System
5 Treatment/Standard of Care/Clinical Management
5.1 Psychological Treatments for Clinical Depression (Psychotherapy)
5.2 Drugs to Treat Major Depression
5.3 Treatment of Bipolar Disorder
5.4 Placebo
5.5 Electroconvulsive Therapy
6 Experimental Approaches/Clinical Trials
7 Challenges and Opportunities
Acknowledgment
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Chapter 13 Schizophrenia
1 Case Story
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
4 Disease Mechanism/Cause/Basic Science
4.1 Imaging
4.2 Genetics
4.3 Neurotransmitters
4.4 The Dopamine Hypothesis
4.5 The Glutamate Hypothesis
4.6 The GABA Hypothesis, Network Changes, and Gamma Oscillations in Schizophrenia
4.7 Synaptic Changes in Schizophrenia
4.8 White Matter Changes in Schizophrenia
4.9 Schizophrenia as a Neurodevelopmental Disorder
4.10 Animal Models
5 Treatment/Standard of Care/Clinical Management
6 Experimental Approaches/Clinical Trials
6.1 Novel Allosteric Modulators of NMDA Signaling
6.2 Glutathione
6.3 Nicotine
6.4 Electroconvulsive Therapy
6.5 Transcranial Magnetic Stimulation Therapy
6.6 Vitamin D
6.7 Early Detection and Prevention
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Chapter 14 Pain
1 Case Study
2 History
3 Clinical Presentation/Diagnosis/Epidemiology
3.1 Diagnosis
3.2 Epidemiology
4 Disease Mechanism/Cause/Basic Science
4.1 How Do We Sense Pain? Neuroanatomy of Pain Sensation
4.2 Nociceptors
4.3 Sensory Neurons
4.4 From Nociception to Pain
4.5 How Is the Pain Signal Propagated? Sodium Channels in Pain
4.6 Regulation of Pain: Gate Theory
4.7 The Regulation of Pain: Pain Memory and Pain Sensitization
4.8 Glia and Pain
4.9 Animal Models to Study Pain
4.10 Endogenous Pain Control: Endorphins and Beyond
4.11 Placebo & Pain
5 Common Forms of Pain and Currently Approved Treatments
5.1 The Pain Management Ladder
5.2 Visceral Pain
5.3 Cancer Pain
5.4 Backache and Other Forms of Neuropathic Pain
5.5 Arthritis
5.6 Headaches and Migraine
5.7 Genetic Forms of Neuropathic Pain: Inherited Erythromelalgia and Congenital Pain Insensitivity
5.8 Diabetic Neuropathy
5.9 Fibromyalgia
5.10 Trigeminal Neuralgia
5.11 Phantom Limb Pain
5.12 Sunburn
5.13 Itch
5.14 Emotional Pain
5.15 Pain, Anxiety, and Depression
5.16 Pain for “Secondary Gain”
6 Experimental Approaches/Clinical Trials
6.1 Sodium Channel Inhibitors
6.2 Analgesics Targeting TRPs
6.3 Medical Marihuana
6.4 Acupuncture
6.5 Vagus Nerve Stimulation
6.6 Deep Brain Stimulation
6.7 Chiropractic Care
6.8 Spinal Nerve Block With Conotoxin
7 Challenges and Opportunities
Acknowledgments
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical
Basic
Chapter 15 Drug Addiction
1 Case Story
2 History of Drug Use and Addiction
3 Biology of Substance Use and Addiction
3.1 What is Addiction?
3.2 Biology of Reward and Pleasure
3.3 The Brain Circuits of Drug Reward and Addiction
3.4 Tolerance, Physical Dependence, and Withdrawal
3.5 Evolutionary Behavioral Origin of Addiction
3.6 Genetics and Epigenetics of Addiction
3.7 Sociocultural Aspects of Addiction
3.8 Regulation of Drug Use
3.9 Animal Models to Study Drug Addiction
4 Common Substance Use Disorders, Underlying Biology, Epidemiology, and Treatment
4.1 Nicotine
4.2 Alcohol
4.3 Cannabis
4.4 Cocaine
4.5 Opioids
4.6 Psychedelic Drugs (LSD, Mescaline, Psilocybin)
4.7 PCP and Ketamine
4.8 Amphetamines
5 Challenges and Opportunities
Acknowledgments
References
General Readings Used
Readings for Journal Club
Clinical
Basic
Section VI Common Concepts in Neurological and Neuropsychiatric Illnesses
Chapter 16 Shared Mechanisms of Disease
1 Introduction
2 Neuronal Death
3 Glutamate Toxicity
3.1 Why Is Glutamate Toxic?
3.2 Role of Ca2 +
3.3 Astrocytic Glutamate Transport
3.4 Extrasynaptic NMDA Receptors
4 Protein Aggregates and Prion-Like Spread of Disease
4.1 Proteostasis
4.2 Prion-Like Spread of Misfolded Protein
5 Mitochondrial Dysfunction
5.1 Genetic Mitochondrial Defects in Parkinson Disease
5.2 Mitochondrial Defects in Other Neurodegenerative Diseases
5.3 Impaired Redox Status
5.4 Improving Mitochondrial Function to Ameliorate Disease
6 Heritability of Disease With Elusive Genetic Causes
6.1 Gene–Environment Interactions
6.2 Monogenetic Diseases
6.3 Polygenetic Diseases and Genome-Wide Association Study
7 Epigenetics
7.1 Epigenetics and Rett Syndrome
7.2 Epigenetics and Brain Tumors
7.3 Epigenetics and Epilepsy
7.4 Epigenetic Role in Anxiety and Depression
8 Noncell Autonomous Mechanisms
8.1 Microglia and Disease
8.2 Astrocytes and Disease
9 Inflammation
9.1 Microglial Activation in Primary Neurodegenerative Disorders
9.2 Astrocytes and Inflammation
9.3 Blood-Derived Cells and CNS Inflammation
9.4 Peripheral/Systemic Inflammation
9.5 Brain–Gut Axis
9.6 Harnessing the Brain’s Immune Response to Treat Disease
10 Vascular Abnormalities
11 Brain-Derived Neurotrophic Factor
11.1 Normal Brain-Derived Neurotrophic Factor Signaling
11.2 Brain-Derived Neurotrophic Factor and Rett Syndrome
11.3 Brain-Derived Neurotrophic Factor in Huntington Disease
11.4 Brain-Derived Neurotrophic Factor in Parkinson Disease
11.5 Brain-Derived Neurotrophic Factor in Alzheimer Disease
11.6 Brain-Derived Neurotrophic Factor and Amyotrophic Lateral Sclerosis
11.7 Brain-Derived Neurotrophic Factor and Depression
11.8 Structural Effects
11.9 Feasibility of Brain-Derived Neurotrophic Factor Therapy
12 Challenges and Opportunities
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Clinical Papers
Basic Papers
Section VII: Bench-To-Bedside Translation
Chapter 17 Drug Discovery and Personalized Medicine
1 Introduction
2 How Did We Get to This Point? A Brief History
3 Drug Discovery: How Are Candidate Drugs Identified?
3.1 Drug Discovery by Chance
3.2 New Diseases for Old Drugs
3.3 Biological Drugs: Nature’s Helping Hand
3.4 Unbiased Screens of Chemical Libraries
4 What Are Clinical Trials and Why Do Them?
4.1 Preclinical Evaluation
4.2 Clinical Phases
4.3 Important Considerations
Enrollment
End Points
Sample Size
Patient Safety and Informed Consent
Reporting and Registration
Success and Cost
5 The Placebo Effect
6 Why Do Clinical Trials Fail?
6.1 Irreproducible Laboratory Data
6.2 Publication of Negative Data
6.3 The Truth Wears Off
6.4 Poor and Potentially Biased Trial Design
6.5 Interpretation Bias
6.6 Approval of Drugs Based on Only Two Positive Trials
7 Personalized Medicine
8 Challenges and Opportunities
References
General Readings Used as Source
Suggested Papers or Journal Club Assignments
Section VIII: Neuroscience Jargon
Chapter 18 “Neuro”-Dictionary
Index
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