Week 2 Flashcards
1
Q
What did George Huntington in 1873 describe?
A
A neurological disorder that lager came to bear his name
- Huntington chorea
- Huntington disease
2
Q
What are the main characteristics of HD?
A
- Distinct clinical profile
- Involuntary movements
- Behavioural and psychiatric disturbances of cognitive dysfunction leading to dementia
3
Q
What is the mean age at onset of HD?
A
35-50
More common in males than in females
4
Q
What is HD?
A
A neurodegenerative disorder which affects people emotionally, mentally and physically
Autosomal dominant inheritance pattern
5
Q
What is mean duration of HD?
A
17-20 years
6
Q
What is the disease presentation of HD?
A
- Motor dysfunction
- Mild motor abnormalities at first
- Hyperkinetic stage develops chorea
- Motor skills continue to deteriorate
- Patient suffer dramatic weight loss and muscle wasting
- Choric movements are replaced by bradykinesia and rigidity
- Cognitive deficit
- Can be seen many years before any overt motor signs and follow a subcortical pattern
- Simple psychomotor task are particularly sensitivity 5-10 years before motor symptoms onset
7
Q
What are the cognitive diagnosis of HD?
A
- Stroop word test
2. Stroop colour test
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:
- Attention
- Processing speed
- Cognitive flexibility
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
10
Q
What is the common version of SCWT?
A
Subjects are required to read three different tables as fast as possible
11
Q
What does two of them represent?
A
Congruous conditions
Participants are required to read names of colours and name different colour patches
12
Q
What is the colour-word (CW) condition?
A
Colour-words are printed in an inconsistent colour ink
13
Q
What is the incongruent condition?
A
Participants are required to name the colour of the ink instead of reading the word
14
Q
What is the stroop effect?
A
The difficulty in inhibiting the more automated process
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
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
17
Q
What did the registry cognitive battery consist of?
A
UHDRD’ cognitive task
- Phonemic Verbal fluency (total number correct in 3 mins)
- The three conditions of stroop-colour-word interference task (total number correct within 45 seconds for each condition)
18
Q
What was added to the cognitive battery?
A
The categorical fluency task (total number correct in 1 min)
19
Q
What are the 3 conditions of stroop-colour- word inference task?
A
- Word reading
- Colour naming
- Inference condition
20
Q
On each task, what does a higher numerical score indicate?
A
Higher cognitive performance
21
Q
What was the raw cognitive scores at each visit used for?
A
Statistical analysis
22
Q
Where did the performance of all cognitive task decline?
A
Throughout the different groups
23
Q
When did the cognitive performance of stroop word test decline most rapidly?
A
When participants progressed from preA to stage 5
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
25
Retrieval-based memory deficit
Become obvious with time
| Suggestive of fronts-striatal dysfunction
26
What are frontostriatal circuits?
Neural pathways that connect frontal lobe regions with basal ganglia that mediate motor, cognitive and behavioural functions within brain
27
The disease will progress towards a subcortical dementia syndrome
1. Slowing of information processing
2. Decreased motivation
3. Depression
4. Apathy personality changes (language is relatively spared)
28
Disease presentation: mood and psychiatric disturbances
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%)
4. Eating/body image disorder
5. Sexual disorder
6. Sleep disorder
7. Substance abuse
29
What is the word chores taken from?
Greek word meaning “dance”
Used to describe an involuntary movement disorder
Sufferers arms and legs move in an unpredictable fashion comparable to dancing
30
The Maracaibo story
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
31
What was the area around Venezuela’s lake Maracaibo found to have?
Largest population of Huntington disease sufferers in the world
32
What did Milton Wexler - Los Angeles Psychoanalyst create?
Hereditary disease foundation (HDF) after his ex-wife was diagnosed with HD
33
What did Nancy Wexler create in 1979?
U.S. Venezuela Collaborative Research project
Leading scientists and physicians
(Neurologists, geneticists, anthropologists And historians) to Maracaibo
34
Over 20 years, what did they collect?
Over 4,000 blood samples and documented 18,000 different individuals in order to work out a common pedigree
35
What did James Gusella and Nancy Wexler identify in 1983?
Linkage analysis
| Genetic locus for HD was in the short arm of chromosome 4
36
What did Anita Harding in 1993 identify?
The number of cytosine-adenine-guanine (CAG) trinucleotide repeats had a direct relationship with extent of the severity of disease
37
What did the HD collaborative Research Group do in 1993?
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
38
Where is the pathological expansion of CAG triplet repeat?
Within exon 1 of the Huntington gene
39
What is Polyglutamine disease?
A group of neurodegenerative disorder caused by expansion of trinucleotide repeat CAG which encodes the amino acid glutamine
40
What does the disease caused by CAG-polyglutamine repeat expansion include?
Spinal and bulbar muscular atrophy
Huntington disease
Various spinocerebellar ataxias
41
When does the progressive, fatal disorders occur?
When the length of the repeat exceeds a threshold number ( from around 20-50 CAGS)
42
What do majority of patients show?
40-50 CAG repeats
43
What do individuals with longer CAG repeats have?
More severe symptoms, and their disease onset occurs earlier in life
44
What are the resulting mutant proteins?
Toxic and prone to aggregation
| Brain nuclear and cytoplasmic inclusions
45
What does expansion of >50 CAG repeats result in?
Juvenile or even infantile HD
46
What is Juvenile HD?
A form of Huntington disease that affects children and teenagers
Hereditary in nature
47
What is the domain structure of HD protein?
1. PolyQ, polyglutamine tract
2. PR - proline Rich domain responsible for protein-protein interactions
2. HEAT repeats
4. Protease cleavage region
5. NES, nuclear export signal
48
What is Huntington?
A protein with a molecular weight of about 350kDA and a polyglutamine tract at N terminus
49
In the cell, what does Huntingtin function as?
Scaffold protein - it provides colocalization of the proteins interacting with it, helping them perform their functions
50
What does Huntington (especially it’s N-terminal region) interact with?
1. Numerous proteins
2. Perform a wide variety of functions
E.g. vesicular transport and endocytosis , regulation of transcription and apoptosis
51
What does huntingtin molecule look like?
Solenoid with a hydrophobic core composed of docked HEAT repeats
52
What participates in a protein-protein interaction?
Docked heat repeats and proline-rich regions
53
What is HEAT?
1. Acronym
2. Four proteins in which repeat structure was first identified
3. Huntingtin, Elongation factor 3, PR65/A, lipid kinase TOR)
54
What is HD believed to be associated with?
Cleavage of N-terminal fragment from mutant Huntingtin
| Encoded by first exon and contains polyQ tract
55
Where is mutant HTT widely expressed?
Brain and body
56
Where does primary neuropathology occur?
Caudate and putamen and cerebral cortex
57
Features of primary neuropathology
1. Decreased striatal and cortical volume
2. Enlarge lateral ventricles
3. Reduced brain weight
58
What is the pathological hallmark of HD?
Degeneration and atrophy of stratium
| As the disease progresses there is involvement of cerebral cortex and other subcortical structures
59
Where are basal Ganglia located?
Deep in the grey matter
60
What does the forebrain comprise
Basal Ganglia aping with cerebral cortex and diencephalon
61
Where does basal Ganglia connect to?
Cortex and thalamus
Organise muscle-driven “motor” movements of the body
Mostly affected by HD
62
What are the major divisions of the basal Ganglia?
1. Caudate Nucleus
2. Putamen
3. Globes Pallidus
63
What is caudate nucleus?
A collection of neuronal bodies that connect to many parts of the brain
64
What is the role of caudate nucleus?
Organises and filters information that is sent to frontal lobes e.g. information from the limbic system
65
Caudate nucleus + putamen
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
Globes pallidus
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
Gliosis (excessive growth of cells - support and protect neurons)
In globus pallidus
| Implicated in juvenile HD
68
Damage to globus pallidus
Individuals who experience rigidity rather than chorea
69
What is macroscopic pathology
1. Striatal atrophy
| 2. Cortical atrophy
70
Stratium atrophy
Loss of medium spiny neurons
| Which account for >90% of the stratium neuronal population
71
Cortical atrophy
Loss of cortical pyramidal neurons in motor and premotor areas
72
Dysregulation of the corticostrarial pathways
1. Direct pathway
| 2. Indirect pathway
73
Direct pathway
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
Indirect pathway
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
What plays a modulatory role?
DA projections from substantial nigra pars compacta (SNc)
76
D1-like receptor
facilitates glutamatergic signalling in direct pathway, striatonigral MSNs
77
D2-like receptor activation
Inhibits MSNs in the indirect pathway
78
Dysrefulatiob of Glu or DA
Uncontrolled involuntary movements or bradykinesia
79
What is motor function shaped by?
CPN projecting to stratial MSN in corticostrarial pathway
80
Which are the most affected brain areas in HD?
1. Cerebral cortex
2. Stratium
Massive MSN loss in stratium
81
The preferential loss of MSN in the indirect pathway can result in
Inability to control voluntary movement resulting in a hyperkinetic phenotype (chorea)
82
Dysregulation of direct pathway in the later stages of disease
Result in inability to facilitate movement
| Result in a rigidity and bradykinesia
83
Increase in NMDA response as well as enhancement of intracellular calcium
Changes in NMDA receptor signalling could result in excitotoxicity and neuronal death
84
Fragment model
| The R6/2 mouse model
Transgenic fragment model that displays many signs reminiscent of human HD
On a variety of tasks used to assess their locomotor phenotype
85
What do R6/2 nude have?
Measurable and progressive motor deficit
Includes:
Irregular gait impairments in coordination and balance
86
What does the R6/2 model express?
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
What are the motor disturbances?
1. Chorea-like shuddering movements
2. Involuntary hindlimb movements
3. Impaired coordination and gait
4. Tremor
5. Hypoactivity
88
Moderate neurodegeneration
12 weeks of age
89
What is the task that is most widely used to assess motor?
Rotarod
90
What are the two different versions of rotarod?
1. The rod can be rotated at multiple fixed speeds
| 2. The rod rotated in accelerating node
91
What can performance on the task be influenced by?
1. Motor learning
2. Sensorimotor deficits
3. Executive dysfunction
4. Stress
92
What is the Beam Walking task?
Cleaner alternative to rotarod
| Assess motor coordination and balance in rodents
93
What was Beam Walking used to compare?
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
What is Footprint?
1. Record footprint of animals by putting ink in fore paw and hind paw
