Chapter
Chapter 1: Genetics of Huntington disease
Definition of normal and abnormal CAG repeat lengths
Normal (10-26 CAG repeats)
Normal, mutable (27-35 CAG repeats)
Abnormal, incomplete penetrance (36-39 CAG repeats)
Abnormal, complete penetrance (40 and above)
Clinical genetics and epidemiology of HD
Compound heterozygosity for HD gene mutation
A Huntington disease chromosomal haplotype
Meiotic instability of the CAG repeat
Somatic mosaicism for CAG repeat length
Genetic modifiers of age of onset of HD
Chapter 2: Mechanisms underlying neurodegeneration in Huntington disease: applications to novel disease-modifying therapies
Genetic insights into huntington disease pathogenesis
Huntington disease and selective neuronal vulnerability
The normal function of Htt and loss-of-function toxicity
Transcription and knockdown of mutant Htt
Translation and clearance of mutant Htt
Conformation and aggregation of Htt
Cell-cell interaction mechanisms and Htt propagation
Posttranslational modifications of Htt
Proteolytic cleavage of Htt
Htt and gene transcription
Vesicular trafficking, cytoskeleton, and other cell signaling
Excitotoxicity and inflammation
Alternative mechanisms of pathogenesis
Conclusion and questions for future study
Section II: Clinical aspects
Chapter 3: Epidemiology of Huntington disease
Epidemiology before the genetic test
Genetic testing and ascertainment
Relationship to age of onset
Frequency of the mutation
Penetrance of the mutation
Factors influencing prevalence
Ethnic differences in prevalence
Australia and New Zealand
Other African populations
Haplotypes in the HTT gene region
Complete genetic ascertainment
Chapter 4: Statistical modeling of Huntington disease onset
Potential for uncertainty in age-at-onset
Regression Models for Age-At-Onset
Correlation analysis and linear regression
Logistic regression with binary phenoconversion status outcome
Survival Models for Age-At-Onset
Brief overview of survival analysis
Models with genetic mutation status known
Models with gene mutation status unknown
Extensions of Langbehn et al. (2004) Model
Chapter 5: The diagnosis and natural history of Huntington disease
Chapter 6: Cognitive and behavioral changes in Huntington disease before diagnosis
Introduction: the prodrome and diagnosis of huntington disease
The prodromal stages of HD
HD prodrome II: medium/mid
HD prodrome III: high/near
Cognitive changes in huntington disease individuals before diagnosis
Mild cognitive impairment (MCI)
Time estimation and production
Clinical trials for cognitive outcomes in huntington disease prodrome
Behavioral and personality changes in huntington disease individuals before diagnosis
Irritability and aggression
Obsessive-compulsive (O-C) traits
Chapter 7: Preclinical motor manifestations of Huntington disease
Efforts to identify preclinical motor changes in HD
Large prospective studies
Chapter 8: The highly anxious individual presenting for Huntington disease-predictive genetic testing: the psychiatrist' ...
Chapter 9: Preimplantation genetics and other reproductive options in Huntington disease
Chapter 10: Genetic testing for Huntington disease
Preparing for predictive testing: first do no harm
Preliminary results with linkage
The development of testing guidelines
Testing Persons At 25% Risk
The discovery of the HD gene
Intermediate alleles (IAs)
Preimplantation genetic diagnosis
Attitudes towards genetic testing
Adverse events after testing
Documenting trends through long-term follow-up
Section III: Treatment of Huntington disease
Chapter 11: Medical treatment of behavioral manifestations of Huntington disease
Obsessive-compulsive behaviors
Suicidal ideation and suicidal behavior
Chapter 12: Medical management of motor manifestations of Huntington disease
Assessing the motor disorder in huntington disease
What is/are the motor manifestations? Is there a predominant movement disorder? What are the other motor features?
Does the motor manifestation have an impact on the person with HD? Are the motor features transient or permanent, mild or disa
Is the intervention/medication appropriate for this person? Is there an impact on other manifestations of HD? Do nonmotor feat
What comorbidities are there and is there an impact on motor manifestations?
Will withdrawal of medications improve motor manifestations?
Practicalities of deciding on treatment: can this person manage medications? Is the person likely to drop tablets, choke on me
Are there ethical concerns? Is this person aware of the motor changes? Do they pose a risk for this person? Does the person wa
Management of specific motor features
Disorders of tone, e.g., clonus and extrapyramidal features
Disordered gait and unsteadiness and falls
Bulbar features of dysphagia and dysarthria
Chapter 13: The role of rehabilitation therapy in Huntington disease
Effects of cognitive, behavioral, and motor impairments on physical functioning in HD
Cognitive and behavioral impairments
Functional limitations in HD
Outcome measures to evaluate rehabilitation interventions
Rehabilitation interventions in HD
Motor training interventions
Multidisciplinary inpatient rehabilitation interventions
Management of falls and mobility problems
Aerobic exercise and physical activity
Barriers and facilitators to physical activity
Directions for future research
Chapter 14: Contemporary health care for Huntington disease
Stage of disease and care complexity
The financial and human cost of care in HD
Improving care delivery in HD
Multidisciplinary tertiary care model
Outreach shared-care models
Georgetown, United States
North Carolina, United States
Huntington Study Group/Griffin Foundation/HD Reach outreach to community providers and HD families
Standards of care and treatment guidelines
Improving outcomes in rare disease: the Cystic Fibrosis Foundation model
Chapter 15: The impact of Huntington disease on young people
Chapter 16: Making a measurable difference in advanced Huntington disease care
Problem solving requires ongoing assessments: my cat!
Common issues experienced by people with advanced HD
Advanced HD family concerns
Proposed pre-admission process to facilitate interagency communication
Template for cover letter
Patient-centered assessment
Current collaborating models of care
Outside the united states
Proposed approaches to care in advanced HD
Activities of daily living
How to enter a room, using a five-step approach
Nonverbal communication and body language
Approaches to imbalance, slips, near trips, trips, and falls
Comfortable breathing, safe eating, and less choking
Environmental modifications
Letters requesting exceptions to the rule
Nonpharmacologic approach
Problem solving requires ongoing assessments: spitting
Section IV: Experimental therapeutics
Chapter 17: New symptomatic therapies for Huntington disease
Phosphodiesterase 10 inhibitors
Nonpharmacologic intervention
Cognitive symptom treatment
Neuropsychiatric symptom treatment
Neuroprotective treatment
Chapter 18: Motor outcome measures in Huntington disease clinical trials
EHDN UHDRS-TMS online certification
UHDRS-TMS subscales: TMS-4, mMS, and others
Limitations and perspectives
Q-Motor: quantitative-motor assessments
Q-Motor in TRACK-HD: the structure-function correlation
Q-Motor in the AFQ056 clinical trial in HD - no placebo effect
Q-Motor in other trials - perspectives
Chapter 19: Cognitive assessment in Huntington disease clinical drug trials
Possible roles of cognitive assessment tools in clinical trials
Clarification of terminology
Cognitive measures in preclinical drug development
Cognitive assessment in HD clinical trials: a review
Cognitive assessment in schizophrenia and alzheimer disease trials
Guidance for the selection of cognitive outcome measures
Development of a purpose-built cognitive assessment battery for HD clinical trials: the HD-CAB
Criterion 1: appropriateness
Criterion 4: responsivity
Criterion 6: interpretability
Criteria 7 and 8: acceptability and feasibility
Chapter 20: Structural imaging in premanifest and manifest Huntington disease
Structural changes in premanifest huntington disease
Structural changes in manifest huntington disease
Influences on rates of disease progression
Effect of CAG repeat length
Correlations with clinical measures
Neuropsychiatric measures
Comparison with nonimaging biomarkers
Structural imaging for clinical trials
Chapter 21: Functional imaging in Huntington disease
Brief overview of radiotracer imaging
Longitudinal changes with disease progression
Other neurotransmitter and neuromodulator systems
Neuroinflammation and activated microglia
Cerebral metabolism and blood flow
Network analysis of regional metabolism
Cerebral blood flow and activation studies
Functional magnetic resonance imaging
Longitudinal changes of disease progression
Huntington Disease
( Volume 144 )
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