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Applied Neuroanatomy > Huntingtons Disease > Flashcards

Huntingtons Disease Flashcards

1
Q

What do many HD patients show signs of before motor symptoms?

A

psychiatric disorders

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2
Q

What are some examples of motor symptoms associated with HD?

A 
Chorea
Dystonia
Poor Posture
Incoordination
Impaired Gait and Balance
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3
Q

What are the cognitive symptoms of HD?

A 
rigid, inflexible thoughts
difficulty in multitasking
poor concentration
poor insight
STM loss
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4
Q

What are some of the psychiatric disorders seen in HD?

A

depression, social isolations, delusions, hallucinations, paranoia

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5
Q

What can be seen in 100% of Juvenile HD cases?

A

rigidity
ataxia
bradykinesia
dysarthria

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6
Q

What are the most common signs in adult HD?

A

rigidity
chorea
atazia
pyramidal signs

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7
Q

What causes enlargement of the ventricles in HD?

A

the atrophy in the basal ganglia or striatum

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8
Q

What effect does the striatum have on the GPe?

A

inhibitory

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9
Q

What happens to the effect on the GPe in HD?

A

inhibitory effect is lost -> increases inhibition to STN

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10
Q

What effect does the GPe normally have on the STN?

A

inhibitory, but small inhibitory

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11
Q

What happens to the effect of the GPe on the STN in HD?

A

disinhibition of GPe leads to increased inhibition of STN

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12
Q

What effect does the STN have on the GPi?

A

an excitatory effect - diminished in HD

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13
Q

What happens to the effect of STN on the GPi in HD?

A

reduced excitatory effect due to increased inhibition from GPe

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14
Q

What effect does the GPi normally have on the Thalamus?

A

reasonable inhibition - reduced because the excitation from STN is lost

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15
Q

What is the normal effect of the Thalamus on the Motor Cortex?

A

Thalamus inhibited so reduced excitatory input to motor cortex

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16
Q

What happens to the effect of the Thalamus on the motor cortex in HD?

A

decreased inhibition from GPi causes extra excitation

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17
Q

What does the indirect pathway account for in the HD?

A

the increased involuntary movement from the chorea

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18
Q

What is the normal effect of the Striatum on the GPi in the direct pathway?

A

normally inhibitory which inhibits the GPi

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19
Q

What is the effect of the Striatum on the GPi in HD?

A

inhibition lost so GPi can send large inhibitory input to thalamus

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20
Q

What influence does the GPi normally have on the thalamus in the direct pathway?

A

slight inhibitory effect, normally disinhibited by striatum

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21
Q

What effect does the GPi normally have on the thalamus in HD?

A

large inhibitory effect as GPi is not inhibited in thalamus

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22
Q

What is the net result of the direct pathway in HD?

A

less stimulation to motor cortex - reason it is difficult to initiate voluntary movement

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23
Q

What accounts for the fact that chorea appears first?

A

The striatal cells that project to the GPe die before the ones that project to the GPi

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24
Q

When do neurons start to struggle in HD?

A

in the prodromal phase - symptoms are not totally noticeable

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25
Q

How is HD diagnosed?

A

neurological exam, family history and genetic testing

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26
Q

Why will patients younger than 18 not be tested?

A

there is no treatment for either the prodromal or the symptomatic phase

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27
Q

Why is indirect genetic testing of the fetus possible?

A

for parents who may have HD but wish to be undiagnosed

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28
Q

What can early motor symptoms such as chorea be treated with?

A

tetrabenazine -> reduces DA release

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29
Q

What sorts of therapies are in the pipeline for HD?

A

gene silencing, PDE inhibitors, Stem cells research

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30
Q

Where is the substantia nigra in comparison to the striatum?

A

upstream

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31
Q

What effect does the SN have on the striatum?

A

it inhibits it by releasing dopamine via D1 and D2 receptors

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32
Q

Which DA receptors are on the GPe?

A

D2

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33
Q

Which DA receptors are on the GPi?

A

D1

34
Q

What is the effect of tetrabenazine?

A

inhibits the SN by reducing DA production and inhibiting receptors so that the striatum is disinhibited and restores normal function for a while

35
Q

How is HD inherited?

A

autosomal dominant mutation on chromosome 4

36
Q

What is the penetrance of the HD gene?

A

100%

37
Q

What is the mutation in HD?

A

CAG repeats > 36 (>40 for testing)

38
Q

Which part of the gene is the mutation in (HD)?

A

exon 1 of the htt gene

39
Q

What does the length of the CAG repeat do?

A

determines severity and age of onset

40
Q

Why is Htt vital?

A

KO is embryonic lethal

41
Q

Where is the highest expression of Htt?

A

brain and testes

42
Q

What is the issue with targeting mutant Htt?

A

the difference between it and WT is the number of CAG repeats - how do you get something to target that

43
Q

What happens to mutant Htt?

A

very long protein so can be misfolded and start to aggregate

44
Q

Where within the neurons does Htt accumulate?

A

in the nuclei of neurons

45
Q

What does Htt aggregation lead to?

A

neuronal death

46
Q

What is involved with gene silencing?

A

using anti-sense oligonucleotides (similar to ALS)

47
Q

How do anti-sense oligonucleotides work in HD?

A

reduce the overall amount of Htt by blocking mRNA from producing the protein

48
Q

What was found in Animal studies of ASO in Htt?

A

Silencing of Htt lasted 4 months

49
Q

Who did the animal studies in Htt ASO?

A

Kordasiewicz et al 2012, Neuron

50
Q

What was found in the YAC128 HD mouse with ASO?

A

improvement of the motor phenotype correlated with reduction in mHtt levels

51
Q

Who conducted the YAC128 mouse study with ASO?

A

Stanek et al. 2013, J of HD

52
Q

How might patients be given ASO in future?

A

epidural injection of ASO tagged with a protein that can cross the BBB - ie brain shuttle

53
Q

What needs to be considered in terms of ASO distribution?

A

whether it reaches the striatum (rats and mice suggest it does not) - if it doesn’t will it make any difference

54
Q

What needs to be considered in terms of ASO and how it attacks the protein?

A

What is going on with WT?
are both turned off?
is WT Htt reduced anyway?
are there side-effects to switching off WT Htt?

55
Q

What considerations need to be taken into account when choosing the target of ASO?

A

where should the ASO target? SNPs or the CAG repeat?

56
Q

What are the considerations in terms of ASO and side-effects?

A

does it have off-target effects and other mRNA

what about immune responses?

57
Q

What are the potential models for studying HD?

A

cell lines
invertebrates
stem cell

58
Q

What are the advantages of using cell lines?

A
  • immortalised cells which can be human or non-human
  • easy to manipulate
  • used to dissect the molecular machinery involved
59
Q

What are the advantages of using invertebrates?

A
  • whole organism with quick reproduction
  • simpler genetic manipulation
  • quick to understand the pathways in the whole animal
60
Q

What are the advantages of using Stem cells?

A
  • can be derived from patient fibroblasts
  • induced pluripotency to generate neurons
  • directly test drug effects
61
Q

What are the options of mouse model in HD?

A

N-terminal transgenics
Full length transgenics
Knock Ins

62
Q

What are the limitations of mouse models of HD?

A
  • mice do not respond to HD the same way as humans - neuronal death occurs at end stages
63
Q

What is the advantages of using an N-terminal transgenic?

A

more severe symptoms more quickly so quicker research

64
Q

What is the advantage of using full length transgenics?

A

closer to human disease but milder symptoms that develop laters

65
Q

What is the YAC128 mouse?

A

full length transgenic that expresses full length human HTT with 100 and 126 CAG repeats but also has 9 interspersed CAA
expresses transgene at roughly same level as endogenous mouse Htt (75%)

66
Q

What needs to be considered in the YAC128 mouse?

A

whether the CAG-CAA combination alters the mRNA toxicity in HD

67
Q

What phenotypes can be seen in YAC128?

A 
motor impairement
procedural learning deficit
Impaired strategy shifting
depression like behaviour
anxiety like behaviour
increased body weight - Pouladi et al. 2013 Nat Rev Neurosci
68
Q

Review for all the YAC128 behaviour phenotypes?

A

Pouladi et al. 2013 Nat Rev Neursci

69
Q

What is the feature of the N-terminal transgenic?

A

carries small portion of 5’ end of human Htt gene - exon 1 the CAG repeat

70
Q

What is the phenotype of the N-terminal transgenic?

A

loss of coordination, tremors, hypokinesis, abnormal gait, neuropathology and premature death

71
Q

What are the potential models of N-terminal transgenics?

A

R6/2, R6/1

72
Q

What is the issue with CAG instability in the R6/2 transgenic?

A

CAG repeat length can vary from 40-600 although more stable if bred through female line

73
Q

What are the features of the Knock In?

A

can be heterozygous for Htt and WT - important as this is common in humans - can explore WT Htt contribution to HD

74
Q

What is the control for studies with Knock ins?

A

HdhQ82 - basically fine - no HD

75
Q

What is the issue with Knock INs?

A

need so many repeats - at least 100 to show signs of disease at old age

76
Q

What did studies show with Q111 locus?

A

in the striatum, pyramidal tracts of the CA1 neurons

77
Q

Where do Q111 phenotypes not have issues in cognition

A

novel object recognition is fine in homo, het at 2/13 months

78
Q

What issues does the Q111 phenotype have in cognition?

A
  • object place recognition in homo and het at 13 months not 2 months
  • object context recognition at 13 months in homo and het
  • object place context in homo and het at 2 and 13 months
79
Q

What was shown to happen to hippocampal LTP in Q111?

A

homo and hets only showed a small % increase of fEPSP

80
Q

What happens to Q111 mouse when a5IA applied?

A

improves fEPSP in homo and a little in het

translates into an improvement in episodic memory at 2months

Applied Neuroanatomy (11 decks)

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