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Disease in the brain > Huntington's & basal ganglia (finished) > Flashcards

Huntington's & basal ganglia (finished) Flashcards

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1
Q

What sort of disease is Huntington’s?

A

Neurodegenerative

Autosomal dominant - complete penetrance

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2
Q

What is the prevalence of Huntington’s disease?

A

4-10 per 100,000

(But may be twice as common as previously thought)

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3
Q

When does Huntington’s disease onset?

A

Most commonly presents in mid-life

Peak onset 30-50 yrs

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4
Q

How does Huntington’s progress?

A

Slow progressive 20-30 years

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5
Q

What are the general symptoms of Huntington’s disease?

A

Cognitive, motor & psychiatric symptoms

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6
Q

What gene is Huntington’s disease (mutation) caused by?

A
  • Huntington gene (HTT) is located on short arm chr 4
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7
Q

What is the mutation that causes Huntington’s?

A
  • 5’ end CAG repeat repeat seq
  • Protein extended to poly glutamate tail
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8
Q

What are the expansion sizes of the Huntington gene causing disease vs normal?

A

Normal = 17-21

Disease range = >40

Reduced penetrance = 36 - 39

Intermediate allele = 27 - 35

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9
Q

What does the autosomal dominant inheritance of Huntington’s disease mean for family members?

A
  • Autosomal dominant = complete penetrance
  • Most individual have +ive family history
  • If parent has gene 50% chance of child having it
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10
Q

How is Huntington’s disease onset determined?

A
  • Onset determined by clinical clinical onset of major symptoms
  • Relationship between CAG repeat length & age of onset
  • Not predictive on individual basis
  • Other genes that modify onset & phenotype - estimated 50% of variability in onset
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11
Q

What chromosome is the Huntingtin gene found on?

A

Chromosome 4

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12
Q

What does the Huntingtin gene code for?

A

Huntingtin protein

It us ubiquitously expressed

It is essential for embryonic development

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13
Q

Where is the Huntingtin protein primarily found?

A

In the cytoplasm

Some reports of nuclear localisation

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14
Q

What is the Huntingtin gene involved in?

A
  • Intracellular transport
  • Intracellular signalling
  • Metabolism
  • Neurogenesis & formation of CNS
  • Synaptic activity
  • Transcription regulation
  • Anti-apoptotic
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15
Q

What is the aggregation process?

A
  • Monomer
  • Oligomers formation (possibly toxic)
  • Globular intermediates (likely toxic)
  • Profibrils (possibly toxic)
  • Amyloid like fibres - beta-sheets (??)
  • Aggregates or inclusions (Protective?)
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16
Q

Why is aggregation important in Huntington’s?

A

The Huntington gene mutation causes protein to form aggregates

Lumps of proteins aggregates found in affected patients

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17
Q

What are the 6 elements of cellular pathology in Huntington’s disease?

A

1 - Protein aggregation

2 - Mitochondrial dysfunction

3 - Disrupted calcium signalling

4 - Vesicle transport defects

5 - Reduced BDNF expression

6 - Abnormal protein-protein interactions

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18
Q

How does reduced BNDF contribute to Huntington’s?

A

Aggregates can’t be removed anymore as BDNF expression is reduced

BDNF is important for cell survival

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19
Q

How is mitochondria dysfunction caused in Huntington’s?

A

Mutant Huntington protein impairs mitochondria

= reduced energy production, further stressing the cell

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20
Q

How is disrupted calcium signalling caused & what does it lead to?

A

Cause = protein interferes w the calcium in the endoplasmic reticulum

Means = altered Ca2+ levels can trigger stress pathways & contribute to neuronal dysfunction

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21
Q

What is the effect of impaired vesicle transport in Huntington’s?

A

Mutant Huntington = disrupts transport of vesicles in neuron

Vesicles are essential for communication between cells = leads to impaired signalling

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22
Q

What are the overall effects of the mutant Huntington protein?

A

Toxic gain of function & loss of normal functions

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23
Q

How does the brain size change in Huntington’s disease?

A

There is a 10-20% reduction in brain weight

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24
Q

How do the brain areas change in Huntington’s disease?

A
  • Dec striatal (caudate nuc & putamen) volume & cell death
  • Dec cortical volume & cell death
  • Inc ventricle size
  • Proteins inclusions throughout brain
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25
Q

In the caudate nucleus & putamen (striatum), what is affected first in HD?

A

Selective loss of GABAergic medium spiny neurones (MSN)

Then MSN in this area are particularly susceptible

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26
Q

What are the 2 type of medium spiny neurons found in the striatum?

A

Enkephalin containing MNS

Substance P containing MSN

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27
Q

Which pathway do each of these belong to?

Enkephalin containing MNS

Substance P containing MSN?

A

Enkephalin containing MNS = Indirect pathway

Substance P containing MSN = direct pathway

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28
Q

In what order do GABAergic medium spiny neurons in the striatum die in HD?

A

The enkephalin containing MSN dies first (indirect pathway)

Then the substance P containing MSN die second (direct pathway)

29
Q

Which neurons in the striatum are spared?

A

(The MSN die in the stratum in HD)

Cholinergic interneurons of the straitum are spared

30
Q

What are the components of the Basal Ganglia?

A
  • Caudate nucleus
  • Putamen
  • Globus pallidus (internal & external)
  • Subthalamic nucleus (STN)
  • Substantia nigra –> pars reticula (SNr) & pars compacta (SNc)
31
Q

What are the 2 pathways in the Basal Ganglia?

A
  • Indirect pathway
  • Direct pathway
32
Q

Where do both of the pathways in the basal ganglia originate?

A

Cell bodies originate in the striatum

33
Q

Which sort of DA receptors are on each pathway of the basal ganglia

A

Indirect = D2 receptors

Direct = D1 receptors

34
Q

Where do the terminals of each of the pathways of the basal ganglia release onto?

A

(Both cell bodies originate in the striatum)

Indirect = terminals release GABA onto EXTERNAL Globus Pallidus

Direct = terminal release GABA onto INTERNAL Globus Pallidus

35
Q

What do both of the pathways of the basal ganglia release onto the globus pallidus?

A

GABA

36
Q

What sort of receptors are the D1 & D2 DA recpetors?

A

D1 = excitatory

D2 = inhibitory

37
Q

What is the loop of the direct pathway?

A
  1. Cerebral cortex sends glutamatergic (excitatory signals) to striatum (more specifically- the putamen)
  2. Striatum- medium spiny neurons (MSN) receives signals- contain D1 receptors + release GABA
  3. Globus pallidus internus + substantia nigra pars reticulata = reduces inhibitory output to thalamus
  4. Thalamus - becomes more active and sends excitatory signals back to motor cortex
  5. Motor cortex- facilitates voluntary movements
38
Q

What is the loop of the indirect pathway?

A
  1. Cerebral cortex- excitatory input which sends glutamatergic signals to striatum
  2. Striatum- MSNs contain D2 receptors and GABA is released
  3. GABA sent to globus pallidus externus = results in reduced inhibition
  4. STN- reduction of inhibtion allows this to become more active = sends glutamatergic signals to ….
  5. Globus pallidus internas and substantia nigra pars reticulata = excitatory input increases inhibitory output to thalamus
  6. Thalamus = activity supressed
  7. Motor cortex = reduced excitatory input = inhibit movement
39
Q

Describe the role of dopamine in direct and indirect pathways of the basal ganglia

A

Direct- Dopamine released from substantia nigra pars compacta and binds to D1 receptors in striatum = enhancing activity of pathway + promoting movement

Indirect pathway = SNc binds to D2 receptors in striatum = decreases activity of pathway = reduced inhibitory output to thalamus = more excitatory signals to motor cortex = promotes movement

40
Q

Where do both he indirect & direct pathway meet?

A

At the Globus pallidus internal

(inderect passes thru the GPe first)

41
Q

Where in the basal ganglia is it decided if moment is created & why?

A

The globus pallidus internal

(This is where both direct & indirect pathways meet)

42
Q

What causes the over movement in Huntington’s disease?

A

1 - MSNs on indirect pathway begin to degenerate

2 - GPe is not excited = less inhibition of thalamus

3 - More glutamate is released onto the cortex

43
Q

Which pathway switches movement on?

A

Direct

44
Q

Which pathway switches movement off?

A

Indirect

45
Q

What is involved in the psychiatric symptoms of Huntington’s?

A

The medio orbito-frontal cortex

(Thru the basal ganglia circuitries)

46
Q

What is involved in the cognitive symptoms of Huntington’s disease?

A

The dorsolateral prefrontal cortex & lateral orbito frontal-cortex

47
Q

What are the early motor signs of Huntington’s?

A
  • Abnormal eye movements
  • Inappropriate hand & toe movements
  • General restlessness
48
Q

What are the midcourse motor symptoms of Huntington’s?

A
  • Onset of involuntary movements (chorea)
  • Hypertonic rigidity & dystonia (slow abnormal movements w inc muscle tone)
49
Q

What are the late stage motor symptoms of Huntington’s?

A

Impaired voluntary movements
- Rigidity
- Bradykinesia
- Dystonia
- Convulsions
- Weight loss

50
Q

How can the late stage motor symptoms of HD lead to death?

A

Death from:
- Pneumonia
- Choking
- Chronic skin ulcers
- Nutritional deficits

51
Q

What happens if both pathways are lost?

A

DA initiating movement via the striatum can no longer initiate movement as there is a break in circuitry

52
Q

How does the onset of the cognitive symptoms of HD vary from the motor symptoms?

A

They may precede the motor onset by a decade or more

53
Q

What are the cognitive symptoms of HD?

A

Dysexecutive syndrome:

  • Attention deficits, difficulty switching attention from one task to another
  • Impaired insight & judgement
  • Forgetfulness
  • Language deficits
54
Q

What test can be used to diagnose HD & why?

A

The Stroop test –> where the colour is written in a different colour to what it is

In HD you see a lot of errors in this test

55
Q

How does the onset of psychiatric symptoms vary from the onset of motor?

A

These, like cognitive, may precede motor symptoms by a decade or more

They are also highly variable between patients

56
Q

What are the features of the psychiatric symptoms of HD?

A

CORE:
- Irritability
- Apathy
- Depression

ALSO:
- Anxiety
- Disinhibition
- Obsessive/compulsive

LESS COMMON:
- Hallucinations & delusions

57
Q

What are the other significant symptoms of HD (not motor, cognitive or psychiatric)?

A
  • Weight loss
  • Sleep disturbance
  • Muscle weakness
58
Q

How does HD cause weight loss?

A
  • Involuntary movements
  • Loss appetite & motivation
  • Dysphagia
  • Metabolic dysfunctionH
59
Q

How does HD cause sleep disturbance?

A
  • Circadian rhythm disturbance
  • Depression
  • Loss of routine
  • ‘Break-through’ involuntary movements
  • Caffeine intake
60
Q

How does HD cause muscle weakness?

A
  • Primary muscle involvement (inclusion, mitochondrial dysfunction)
  • Disuse atrophy
  • Nutritional deficiencies
61
Q

How can HD be treated?

A

There are no disease modifying treatments atm

INSTEAD chorea can be managed by some drugs

62
Q

What are the drugs used to treat chorea (in HD)?

A
  • Antipsychotic medication - such as olanzapine (DA antagonist)
  • Tetrabenazine (Depletes DA & other monamines)
  • Benzodiazepines - such as clonazepam (enhances GABA)
63
Q

What do the drugs used to treat chorea target?

A

Reducing dopamine

OR

Enhancing GABA

64
Q

Why does GABA & DA being a target for the drugs to treat chorea work?

A
  • Dopamine antagonists = stop the DA acting on the direct pathway –> can revive the cells left in the indirect pathway
  • GABAergric = mimic function of GABA on the thalamus = inhibit output on the cerebral cortex
65
Q

What are the current management techniques for the psychiatric symptoms of HD?

A

Mostly standard pharmacological agents

Citalopram (SSRI) is useful for irritability

66
Q

What are the current management techniques for the cognitive symptoms of HD?

A

No treatments

67
Q

What are the current management techniques for the motor symptoms of HD?

A
  • Speech therapy - assessment of dysphagia/advice
  • Dietician/PEG
  • Physiotherapy
  • Late stage disease = palliative care, PEG
  • Family support
68
Q

Can HD be treated?

A

There are no disease-modifying treatments currently availble

Break through steps made recently - some promising trials in gene therapy etc

Disease in the brain (22 decks)

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