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Week 2 Flashcards

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1
Q

What did George Huntington in 1873 describe?

A

A neurological disorder that lager came to bear his name

  • Huntington chorea
  • Huntington disease
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2
Q

What are the main characteristics of HD?

A
  1. Distinct clinical profile
  2. Involuntary movements
  3. Behavioural and psychiatric disturbances of cognitive dysfunction leading to dementia
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3
Q

What is the mean age at onset of HD?

A

35-50

More common in males than in females

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4
Q

What is HD?

A

A neurodegenerative disorder which affects people emotionally, mentally and physically

Autosomal dominant inheritance pattern

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5
Q

What is mean duration of HD?

A

17-20 years

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6
Q

What is the disease presentation of HD?

A
  1. Motor dysfunction
  2. Mild motor abnormalities at first
  3. Hyperkinetic stage develops chorea
  4. Motor skills continue to deteriorate
  5. Patient suffer dramatic weight loss and muscle wasting
  6. Choric movements are replaced by bradykinesia and rigidity
  7. Cognitive deficit
  8. Can be seen many years before any overt motor signs and follow a subcortical pattern
  9. Simple psychomotor task are particularly sensitivity 5-10 years before motor symptoms onset
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7
Q

What are the cognitive diagnosis of HD?

A
  1. Stroop word test

2. Stroop colour test

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8
Q

What is the stroop colour and word test (SCWT)?

A

Neuropsychological test of executive function that looks at selective attention and interference susceptibility and cognitive functions such as:

  1. Attention
  2. Processing speed
  3. Cognitive flexibility
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9
Q

What does SCWT assess?

A

The ability to inhibit cognitive interferences which occurs when the processing of a stimulus feature affects simultaneous processing of another attribute of the same stimulus

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10
Q

What is the common version of SCWT?

A

Subjects are required to read three different tables as fast as possible

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11
Q

What does two of them represent?

A

Congruous conditions

Participants are required to read names of colours and name different colour patches

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12
Q

What is the colour-word (CW) condition?

A

Colour-words are printed in an inconsistent colour ink

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13
Q

What is the incongruent condition?

A

Participants are required to name the colour of the ink instead of reading the word

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14
Q

What is the stroop effect?

A

The difficulty in inhibiting the more automated process

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15
Q

What is the aim of study of cognitive deficit (disease presentation)?

A

Evaluate the progression of cognitive decline in HD throughout the disease stages

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16
Q

What is the second aim of cognitive deficit (disease presentation)?

A

Assess whether the individual cognitive tasks are effective for measuring cognitive decline across all disease stages

Or if the task sensitivity is disease stage specific

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17
Q

What did the registry cognitive battery consist of?

A

UHDRD’ cognitive task

  1. Phonemic Verbal fluency (total number correct in 3 mins)
  2. The three conditions of stroop-colour-word interference task (total number correct within 45 seconds for each condition)
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18
Q

What was added to the cognitive battery?

A

The categorical fluency task (total number correct in 1 min)

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19
Q

What are the 3 conditions of stroop-colour- word inference task?

A
  1. Word reading
  2. Colour naming
  3. Inference condition
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20
Q

On each task, what does a higher numerical score indicate?

A

Higher cognitive performance

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21
Q

What was the raw cognitive scores at each visit used for?

A

Statistical analysis

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22
Q

Where did the performance of all cognitive task decline?

A

Throughout the different groups

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23
Q

When did the cognitive performance of stroop word test decline most rapidly?

A

When participants progressed from preA to stage 5

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24
Q

When does performance on task on executive function and memory appear to decline?

A

Around time of clinical disease onset

Become more severe as the disorder evolves

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25
Q

Retrieval-based memory deficit

A

Become obvious with time

Suggestive of fronts-striatal dysfunction

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26
Q

What are frontostriatal circuits?

A

Neural pathways that connect frontal lobe regions with basal ganglia that mediate motor, cognitive and behavioural functions within brain

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27
Q

The disease will progress towards a subcortical dementia syndrome

A
  1. Slowing of information processing
  2. Decreased motivation
  3. Depression
  4. Apathy personality changes (language is relatively spared)
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28
Q

Disease presentation: mood and psychiatric disturbances

A

Common many years before symptom onset
Apathy most common (70%) of patients
Depression - 33-69% people with a motor diagnosis of HD
Rate of suicidal ideation and suicide attempts are high

  1. Aggressive behaviour (22-66%)
  2. Irritability (38- 73%)
  3. Obsessive compulsive symptoms (20-50%)
  4. Anxiety (13-70%)
  5. Eating/body image disorder
  6. Sexual disorder
  7. Sleep disorder
  8. Substance abuse
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29
Q

What is the word chores taken from?

A

Greek word meaning “dance”
Used to describe an involuntary movement disorder
Sufferers arms and legs move in an unpredictable fashion comparable to dancing

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30
Q

The Maracaibo story

A

Americo Negrette arrives as local physician in village of San Luis

  1. Shocked to see many of villagers staggering around as if drunk with illness known locally as ‘El Mal de San Vito’
  2. Negrette concludes that he was dealing with a remarkable concentration of cases of HD
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31
Q

What was the area around Venezuela’s lake Maracaibo found to have?

A

Largest population of Huntington disease sufferers in the world

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32
Q

What did Milton Wexler - Los Angeles Psychoanalyst create?

A

Hereditary disease foundation (HDF) after his ex-wife was diagnosed with HD

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33
Q

What did Nancy Wexler create in 1979?

A

U.S. Venezuela Collaborative Research project

Leading scientists and physicians

(Neurologists, geneticists, anthropologists And historians) to Maracaibo

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34
Q

Over 20 years, what did they collect?

A

Over 4,000 blood samples and documented 18,000 different individuals in order to work out a common pedigree

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35
Q

What did James Gusella and Nancy Wexler identify in 1983?

A

Linkage analysis

Genetic locus for HD was in the short arm of chromosome 4

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36
Q

What did Anita Harding in 1993 identify?

A

The number of cytosine-adenine-guanine (CAG) trinucleotide repeats had a direct relationship with extent of the severity of disease

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37
Q

What did the HD collaborative Research Group do in 1993?

A

Isolate the HD disease (at 4p 16.3 position)

Called HTT or HD gene

It is the IT-5 (Interesting Transcript 15) gene coding for protein Huntington

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38
Q

Where is the pathological expansion of CAG triplet repeat?

A

Within exon 1 of the Huntington gene

39
Q

What is Polyglutamine disease?

A

A group of neurodegenerative disorder caused by expansion of trinucleotide repeat CAG which encodes the amino acid glutamine

40
Q

What does the disease caused by CAG-polyglutamine repeat expansion include?

A

Spinal and bulbar muscular atrophy
Huntington disease
Various spinocerebellar ataxias

41
Q

When does the progressive, fatal disorders occur?

A

When the length of the repeat exceeds a threshold number ( from around 20-50 CAGS)

42
Q

What do majority of patients show?

A

40-50 CAG repeats

43
Q

What do individuals with longer CAG repeats have?

A

More severe symptoms, and their disease onset occurs earlier in life

44
Q

What are the resulting mutant proteins?

A

Toxic and prone to aggregation

Brain nuclear and cytoplasmic inclusions

45
Q

What does expansion of >50 CAG repeats result in?

A

Juvenile or even infantile HD

46
Q

What is Juvenile HD?

A

A form of Huntington disease that affects children and teenagers

Hereditary in nature

47
Q

What is the domain structure of HD protein?

A
  1. PolyQ, polyglutamine tract
  2. PR - proline Rich domain responsible for protein-protein interactions
  3. HEAT repeats
  4. Protease cleavage region
  5. NES, nuclear export signal
48
Q

What is Huntington?

A

A protein with a molecular weight of about 350kDA and a polyglutamine tract at N terminus

49
Q

In the cell, what does Huntingtin function as?

A

Scaffold protein - it provides colocalization of the proteins interacting with it, helping them perform their functions

50
Q

What does Huntington (especially it’s N-terminal region) interact with?

A
  1. Numerous proteins
  2. Perform a wide variety of functions
    E.g. vesicular transport and endocytosis , regulation of transcription and apoptosis
51
Q

What does huntingtin molecule look like?

A

Solenoid with a hydrophobic core composed of docked HEAT repeats

52
Q

What participates in a protein-protein interaction?

A

Docked heat repeats and proline-rich regions

53
Q

What is HEAT?

A
  1. Acronym
  2. Four proteins in which repeat structure was first identified
  3. Huntingtin, Elongation factor 3, PR65/A, lipid kinase TOR)
54
Q

What is HD believed to be associated with?

A

Cleavage of N-terminal fragment from mutant Huntingtin

Encoded by first exon and contains polyQ tract

55
Q

Where is mutant HTT widely expressed?

A

Brain and body

56
Q

Where does primary neuropathology occur?

A

Caudate and putamen and cerebral cortex

57
Q

Features of primary neuropathology

A
  1. Decreased striatal and cortical volume
  2. Enlarge lateral ventricles
  3. Reduced brain weight
58
Q

What is the pathological hallmark of HD?

A

Degeneration and atrophy of stratium

As the disease progresses there is involvement of cerebral cortex and other subcortical structures

59
Q

Where are basal Ganglia located?

A

Deep in the grey matter

60
Q

What does the forebrain comprise

A

Basal Ganglia aping with cerebral cortex and diencephalon

61
Q

Where does basal Ganglia connect to?

A

Cortex and thalamus
Organise muscle-driven “motor” movements of the body

Mostly affected by HD

62
Q

What are the major divisions of the basal Ganglia?

A
  1. Caudate Nucleus
  2. Putamen
  3. Globes Pallidus
63
Q

What is caudate nucleus?

A

A collection of neuronal bodies that connect to many parts of the brain

64
Q

What is the role of caudate nucleus?

A

Organises and filters information that is sent to frontal lobes e.g. information from the limbic system

65
Q

Caudate nucleus + putamen

A

Comprises neostratium
Neurons are most affected by HD
Deterioration of its connections results in behavioural changes and inability to control emotions, impulses, thoughts or voluntary movements

66
Q

Globes pallidus

A

Relays information from caudate and putamen to the thalamus
Part of stratium
In HD, both it’s external and internal regions suffer neuronal loss

67
Q

Gliosis (excessive growth of cells - support and protect neurons)

A

In globus pallidus

Implicated in juvenile HD

68
Q

Damage to globus pallidus

A

Individuals who experience rigidity rather than chorea

69
Q

What is macroscopic pathology

A
  1. Striatal atrophy

2. Cortical atrophy

70
Q

Stratium atrophy

A

Loss of medium spiny neurons

Which account for >90% of the stratium neuronal population

71
Q

Cortical atrophy

A

Loss of cortical pyramidal neurons in motor and premotor areas

72
Q

Dysregulation of the corticostrarial pathways

A
  1. Direct pathway

2. Indirect pathway

73
Q

Direct pathway

A
  1. facilitate movement
  2. Striatonigral MSN in stratium receive excitatory, glutamatergic projections from the cortex and thalamus
  3. Excitation of stratus GABAergic MSNs / inhibits GABAergic projection in the GPi/SNr
  4. Less inhibition on the thalamus glutamatergic neurons
  5. Excitation of motor cortex and initiation of voluntary movement
  6. Result in rigidity and bradykinesia
74
Q

Indirect pathway

A
  1. Inhibits movement
  2. Striatopallidal MSN inhibit GABAergic neurons in the GPe
  3. Less inhibition on glutamatergic projection in STN
  4. The glutamatergic projection from STN excite the GABAergic neurons in the GPi/SNr which results in greater inhibition to thalamus and decreased signalling to motor cortex
  5. Results in uncontrollable voluntary movement such as chorea and tremor
75
Q

What plays a modulatory role?

A

DA projections from substantial nigra pars compacta (SNc)

76
Q

D1-like receptor

A

facilitates glutamatergic signalling in direct pathway, striatonigral MSNs

77
Q

D2-like receptor activation

A

Inhibits MSNs in the indirect pathway

78
Q

Dysrefulatiob of Glu or DA

A

Uncontrolled involuntary movements or bradykinesia

79
Q

What is motor function shaped by?

A

CPN projecting to stratial MSN in corticostrarial pathway

80
Q

Which are the most affected brain areas in HD?

A
  1. Cerebral cortex
  2. Stratium
    Massive MSN loss in stratium
81
Q

The preferential loss of MSN in the indirect pathway can result in

A

Inability to control voluntary movement resulting in a hyperkinetic phenotype (chorea)

82
Q

Dysregulation of direct pathway in the later stages of disease

A

Result in inability to facilitate movement

Result in a rigidity and bradykinesia

83
Q

Increase in NMDA response as well as enhancement of intracellular calcium

A

Changes in NMDA receptor signalling could result in excitotoxicity and neuronal death

84
Q

Fragment model

The R6/2 mouse model

A

Transgenic fragment model that displays many signs reminiscent of human HD

On a variety of tasks used to assess their locomotor phenotype

85
Q

What do R6/2 nude have?

A

Measurable and progressive motor deficit
Includes:
Irregular gait impairments in coordination and balance

86
Q

What does the R6/2 model express?

A

The mutant HTT gene exon 1
With 150 CAG repeat
Under control of human HTT promoter
A variety of cognitive impairment similar to those observed in patients

Motor disturbances detectable as early as 4.5 weeks of age

87
Q

What are the motor disturbances?

A
  1. Chorea-like shuddering movements
  2. Involuntary hindlimb movements
  3. Impaired coordination and gait
  4. Tremor
  5. Hypoactivity
88
Q

Moderate neurodegeneration

A

12 weeks of age

89
Q

What is the task that is most widely used to assess motor?

A

Rotarod

90
Q

What are the two different versions of rotarod?

A
  1. The rod can be rotated at multiple fixed speeds

2. The rod rotated in accelerating node

91
Q

What can performance on the task be influenced by?

A
  1. Motor learning
  2. Sensorimotor deficits
  3. Executive dysfunction
  4. Stress
92
Q

What is the Beam Walking task?

A

Cleaner alternative to rotarod

Assess motor coordination and balance in rodents

93
Q

What was Beam Walking used to compare?

A

Fine motor coordination and balance capabilities of R6/2 transgenic and control animals

Different level of task difficulty were achieved by varying shape and cross-sections of beams

94
Q

What is Footprint?

A
  1. Record footprint of animals by putting ink in fore paw and hind paw

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