Lecture Week Five: Huntington's Disease Flashcards
Huntington’s Disease was first described in ….
1872
What is the average age of onset for Huntington’s Disease?
42 years old
How many years do people with Huntington’s Disease live after diagnosis (on average)?
15 years
Which gender is most affected by Huntington’s Disease?
Females, Males, or both equally?
Both equally
Does juvenile-onset ever occur in Huntington’s Disease?
Yes, sometimes
What is the gene involved in Huntington’s Disease?
Gene IT15 on chromosome 4 codes for the protein ‘huntingtin’. Huntingtin produces glutamine in both neural and non-neural tissue. The gene is an unstable trinucleotide (CAG) repeat sequence. It is autosomal dominant with complete penetrance.
How many repeats of the Huntingtin nucleotide triplet (CAG) is considered normal? and how many are considered abnormal?
11-34 repeats of CAG are normal
35+ repeats of CAG are abnormal
(Huntington’s Disease in adults = 36-50, Juvenile onset = 60+)
What explains 50-60% of cases that onset in Juvenile years, not Adulthood?
The large length of Huntingtin (CAG) nucleotide repeats in the gene. 60+ repeats occur in juveniles and explain why their onset of symptoms is so much earlier.
How do extra repeats of the CAG nucleotide triplet cause a problem?
When the CAG nucleotide repeats become excessively large (e.g. 36x +) it causes the huntingtin protein to abnormally fold. Now, instead of performing its normal function, the misfolded protein instead performs toxic and harmful functions. This causes the symptoms of Huntington’s Disease.
In Huntington’s Disease, age of onset correlates with…. (3)
- CAG repeat length in huntingtin protein
- Mode of transmission (paternal)
- Rate of progression
Higher CAG repeats = ___ rate of atrophy & progression, _____ onset, and reflects ______ transmission.
Higher CAG repeats = faster rate of atrophy & progression, earlier onset, and reflects paternal transmission.
True or False: In Huntington’s disease, people who have earlier onset have the most severe symptoms
True
What is the rarest cause of Huntington’s Disease?
Spontaneous mutation of the huntingtin protein gene
True or False: The majority of current HD patients have descended from other HD cases
True
How can we detect the HD gene?
A single blood test
What is the neuropathology of HD like?
– Progressive and selective atrophy of the striatum (caudate and putamen)
– Head of caudate is affected earlier on in disease, followed by dorsal putamen and then tail of caudate
– The atrophy leads to marked dilation of the lateral ventricles, seen on CT early in disease
In HD, brain weight can reduce by __-__%
In HD, brain weight can reduce by 25-30%
Apart from atrophy of the striatum (caudate and putamen), what areas of the cortex and underlying white matter can also show atrophy? (5)
- primary and associative visual cortex,
- cingulate cortex,
- primary motor cortex,
- medial temporal cortex,
- posterior parietal areas.
In HD, there are two areas of the CNS where atrophy is controversial. What are these two areas?
- Spinal cord
- Cerebellum
What type of neuron is most affected by HD?
HD shows severe loss of medium spiny striatal neurons (form 80% of all striatal neurons)
How does HD affect dendrites? (3)
HD causes dendritic abnormalities like:
- recurved endings of distal segments,
- increased and decreased spine density
- changes in the size and shape of spines
What type of neurons are NOT affected by HD?
Striatal aspiny neurons
What are the 5 semi-independent and parallel cortico-striato-thalamo-cortical circuits?
- Motor
- Oculomotor
- Dorsolateral Prefrontal
- Anterior Cingulate (Limbic)
- Lateral Orbitofrontal
The striatum normally receives _______ _______ input from cortex
striatum normally receives excitatory glutamatergic input from cortex
In HD there is ________ excitatory glutamatergic input from _____ to _____
In HD there is excessive excitatory glutamatergic input from cortex to BG.
Excessive excitatory glutamatergic input from cortex to BG results in …….. leading to neurotoxicity.
results in overstimulation of glutamate receptors in the striatum and thus excessive calcium influx, leading to neurotoxicity.
Excessive calcium related neurotoxicity in the striatum causes loss of……. in the …..
causes loss of GABA neurones in the BG indirect pathway initially (later on in illness there is also under activity of the direct pathway).
Frontostritatal dysfunction caused by HD results in an imbalance in….. (3)
Imbalance in:
- DAergic system,
- GABAergic neurons,
- Cholinergic striatal neurons
In HD, under activity of the indirect BG pathway can lead to…
chorea and unwanted movements (hyperkinetic movements).
In HD, under activity of the direct BG pathway can lead to…
akinesia and rigidity (hypokinetic movements).
Damage to what area of the brain, and dysfunction of what circuits explain cognitive deficits in HD?
caudate damage as well as dysfunction of dorsolateral prefrontal and orbitofrontal circuits
Deficits in what circuit explains HD saccadic deficits?
Deficits in oculomotor circuitry
Deficits in what circuit explain personality and emotional alterations in HD?
Deficits in anterior cingulate circuitry
Deficits in what circuits explain motor dysfunction & chorea in HD?
Deficits in motor circuits
What does the majority of HD research look at finding?
Looks at finding biomarkers that show promise as being sensitive indicators in not only detecting HD related change early, but are also reliable in tracking change with HD disease progression
Does early intervention make a difference in people with HD?
Yes, significantly better outcomes the earlier treatment begins.
Are structural brain changes or cognitive changes first apparent for people with HD?
Structural changes can be seen before cognitive changes can be detected. Structural changes can be seen 25 years before HD onset. Cognitive decline can be seen 10-15 years before HD onset.
What are the four types of MRI used to look at HD, and what component do they look for?
- MRI: looks at structure
- fMRI: looks at function
- Diffusion Tensor Imaging: looks at connections
- Susceptibility Weighted Imaging: looks at trace metals (iron)
What research method has been mostly used to look at HD and PD?
Cross-sectional studies
How do BACK tests work?
BACK tests look at working memory.
0-BACK = requires no working memory
1-BACK = requires remembering 1 number at a time
2-BACK = requires remembering 2 numbers at a time
What did the results show for the pre-HD group in the 30 month 1-BACK study?
Pre-HD sig (p<0.05) increased activation
in left DLPFC and medial frontal cortex
(MFC), compared to controls
What did the results show for the pre-HD group in the 30 month 2-BACK study?
Pre-HD sig (p<0.05) increased activation in medial frontal (MFC), inferior parietal (IPL), posterior cingulate cortices (PCC), and caudate and putamen, compared to controls.
In the HD BACK studies, longitudinal reduction of functional connectivity was seen in only what group?
Seen only in Pre-HD, not symptomatic HD or controls
In HD BACK studies, the Prefrontal caudate connectivity decline may represent an early loss of….
Prefrontal caudate connectivity decline may represent an early loss of information transfer (or decoupling) between regions.
In HD BACK studies, pre HD ability to increase activation in prefrontal cortex may reflect…
re HD ability to increase activation in prefrontal cortex may reflect an early neural compensatory response.
are pre-HD pathological processes (seen in 30 month BACK study) considered Dynamic, or Static?
Dynamic, as there is increased activation and reduced connectivity in cortico striatal regions.
What type of medication is used to treat involuntary movements?
involuntary movements are treated with medications which block dopamine neurotransmission, such as:
Haloperidol, pimozide, fluphenazine, and thioridazine
Drugs / dietary supplements that improve intracellular metabolism & potentially provide neuroprotection, are: (5)
- Coenzyme Q,
- nicotinamide,
- ascorbic acid,
- riboflavin,
- carnitine
nonpharmacological non-invasive treatments for HD include… (4)
- physical therapy,
- speech therapy,
- counseling,
- stress management
These help the patient cope with the progression of the disease, they do not stop it.
How is HD often diagnosed?
HD is diagnosed by a neurologist or psychiatrist. It can be done through a neuroimaging scan or gene test. Family history is acknowledged in diagnosis. And, the motor component of the Unified Huntington’s Disease Rating Scale (UHDRS) can be used to make a diagnosis along with clinical judgement. It is also common to have other lab tests ti EXCLUDE other possible illnesses.
What are the 3 major consequences of HD?
- Movement disorder
- Cognitive deterioration
- Personality/emotional alterations
How are Huntington’s Disease and Dementia related? (similar deficits = 6)
HD = sub-cortical dementia Share similar deficits: - impaired memory retrieval - slowed thinking - apathy - depression - forgetfulness - inability to make decisions
What is the most visible clinical manifestation in Huntington’s Disease?
Chorea - involuntary, jerky, irregular, nonrhythmic, and unstained movements. At first, it can be confused with clumsiness and restlessness. As symptoms develop, it can progress into a full tick like twitching, grimacing, or “piano playing” finger movements.
Other than Cholera, what are some other motor symptoms of Huntington’s disease? (3)
- abnormal movement of the arms, legs, or head (patient is aware of these)
- difficulty in initiating saccades (rapid eye movement), decreased saccade velocity, smooth pursuit and corrective saccades
- end stages of HD, involuntary movements diminish and the patient becomes immobile and rigid
What types of difficulties do people with HD have with motor movements? (5)
- voluntary movements (akinesia and bradykinesia)
- re-programming movements
- acceleration and deceleration
- slower time-to-peak
- overshoot of targets
Movements for individuls with HD may improve when performing a ______ task
concurrent task; that is, multitasking
In the absence of visual cues, people with HD have problems with: (3)
absence of visual cues = problems with:
- sequencing movements
- motor programming
- planning
What does it mean when HD causes a person’s gait to become ‘cerebellar’? (6)
This means their gait shows the following characteristics:
- Wide base
- Ataxic (impaired coordination)
- Slow steps
- Irregular rhythm
- Poor balance
- Falls
What difficulties do HD patients face when their executive functioning is impaired? (4)
Difficulties with:
- Planning, organising, & scheduling
- Mental flexibility
- Switching tasks & inhibiting irrelevant information
- Learning motor, perceptual, and cognitive skills
What aspect of executive functioning is not impaired by HD?
Verbal learning
What aspect of executive functioning is impaired by HD early on in the disease?
- Planning, organising, and scheduling
Is attention affected early, middle, or late in the disease?
Early
What tests of attention are affected by HD? (7)
Difficulties and abnormalities on:
- serial events
- arithmetic
- digit span
- digit symbol
- picture arrangement
- stroop
- holding, shifting, & orienting attention to cues
How is memory affected by HD?
- retrieval of previously learned information = greatly impaired
- difficulty learning and retaining new information
- memory for past events = minimally affected (depends on the individual and how much time has lapsed)
How are HD patients affected in terms of attitude and personality?
- become apathetic and lack initiative
- social interaction decreases
- become withdrawn and uncommunicative, physically inactive
- become irritable, outbursts of anger, inappropriate/bizarre behaviour
Does HD cause aphasia?
No, unlike AD
How is speech affected by HD? (7)
- Impairment of speech planning, initiation, sequencing, & production
- speech output decreases over time
- length of sentences decreases
- long response latencies
- loss of volume
- speech becomes slow and slurred (dysarthric)
- speech has abnormal rhythm/rate
In HD, problems with speech are most likely attributed to…
problems may be due to uncoordinated control of preparatory, tongue, facial and pharyngeal musculature
What are 2 HD related issues for visuospatial abilities? (that are not caused by motor deficits)
- decreased accuracy and speed in copying geometric figures
- deficits in perceptual and mental manipulation of personal (egocentric) space
What are 5 major emotional and mental health issues caused by HD?
– affective disturbance (in the form of depression and manic depression)
– anxiety, apathy, irritability, aggression
– sexual disturbance
–“schizophrenic like” thought disorder
– psychosis (involving hallucinations and delusions)
HD suicide rate is about __% and _____ than all other neurodegenerative disorders
HD suicide rate is about 6% and higher than all other neurodegenerative disorders
What are 4 pre-symptomatic characteristics that are only shown in individuals who are HD gene-positive, not gene-negative individuals?
– subtle motor abnormalities (reduced reaction times & movement times)
– slower decision making
– slower on picture arrangement & digit symbol tests
– visual spatial problems
What are the 3 types of potential markers for HD?
- clinical
- neurobiological
- neurocognitive
HD is described as a ______ movement disorder with problems of ______ control
HD is described as a HYPERKINETIC movement disorder with problems of VOLUNTARY control
What kind of allele/gene inheritance is the huntingtin gene?
autosomal dominant inheritance
