Neuordegenerative disorders 2: Alzheimer's and Huntington's Flashcards
1
Q
What is Huntington’s Disease also known as?
A
Huntington’s Chorea
2
Q
Which brain region dysfunction is involved in Huntington’s Disease?
A
Basal ganglia
similar to PD
3
Q
How does Huntington’s Disease relate to Parkinson’s Disease?
A
HD can be regarded as the opposite of Parkinson’s Disease
4
Q
What movement issue do patients with late-stage Huntington’s Disease suffer from?
A
Paucity of movement
similar to PD
5
Q
What treatment is sometimes used in late-stage Huntington’s Disease for hypokinesia?
A
L-DOPA
same as PD
6
Q
What are the observed brain changes in Huntington’s Disease patients?
A
Enlargement of the ventricles, shrinkage of the cerebral cortex, atrophy of the basal ganglia
7
Q
Fill in the blank: Huntington’s Disease involves dysfunction of the _______.
A
basal ganglia
8
Q
What is another name for Huntington’s disease?
A
Huntington’s chorea
9
Q
what does the term ‘chorea’ refer to ?
A
the involuntary writhing movements characteristic of the disease.
10
Q
What type of genetic inheritance pattern does Huntington’s disease follow?
A
Autosomal dominant
progressive loss of neurons across the brain
11
Q
What is the approximate prevalence of Huntington’s disease?
compared to AD and PD?
A
5 - 10 per 100,000
most common inherited neurodegenerative condition
fewer than alzheimer’s and PD- these are mostly idiopathic (not genetic)
12
Q
How does the onset of Huntington’s disease compare to Alzheimer’s and Parkinson’s disease?
A
Huntington’s tends to start much younger, often in middle life
PD and AD much later
13
Q
What are the main symptoms of Huntington’s disease?
A
Motor dysfunction, cognitive problems, psychiatric issues
14
Q
what are the symptoms of motor dysfunction in HD?
A
- involuntary writhing movement
- later stages: immobility
include bradykinesia and hyperkinesia
15
Q
what can cognitive problems of HD lead to ?
A
dementia
16
Q
What does the term ‘chorea’ literally mean?
A
Dance
17
Q
What are some early psychiatric symptoms experienced by patients with Huntington’s disease?
A
Depression, anxiety, aggression, compulsive behaviors
18
Q
What is the average time until death after the onset of Huntington’s symptoms?
A
Usually occurs within 20 years of onset of symptoms
30% by suicide
19
Q
What genetic feature characterizes Huntington’s disease?
A
Trinucleotide repeat disorder
20
Q
what does CAG code for in the Huntingtin protein?
A
glutamine (Q)
21
Q
What is the normal number of CAG repeats in the huntingtin gene?
gene/ protein
A
27 repeats or fewer
22
Q
What happens if the number of CAG repeats in the huntingtin gene is around 27-35?
gene/protein
A
extra phenotype, but normal
- risk elevated for next generation/children
23
Q
What happens if the number of CAG repeats in the huntingtin gene is around 36-39?
A
increased risk of developing HD
- tends to have later onset and slower progression
- increased risk of 50% inheritance for children
24
Q
What is the risk of developing Huntington’s disease with 40 or more CAG repeats?
A
You will get Huntington’s disease
- more you have the earlier the onset and faster progression
- 50% risk for inheritance
25
Huntingin protein
- ubiquitous (expressed in all cells)
- function unclear
- toxic to cells when mutated... mitochondrial dysfunction
26
What type of neurons are primarily lost in the early stages of Huntington's disease?
Medium spiny neurons from the indirect pathway
27
What type of movement occurs in the early stages of Huntington's disease?
Hyperkinesia/ chorea
## Footnote
excessive movement
28
why do we get hyperkinesia/chorea in early stages of HD?
loss of inhibitory neurons from indirect pathway, so we have excessive drive from thalamus to cortex
29
what does indirect pathway do ?
inhibits movement
30
why do we get later motor symptoms of HD?
loss of neurons form indirect and direct pathway
- reduces thalamacortical drive and so lower movement/ paucity of movement
- causes bradykinesia and hyperkinesia
31
what neurons are specifically lost from indirect and direct pathway ?
MSN's from striatum into GP
32
what do we know about dopamine and movement ?
facilitates/ promotes movement whether in indirect or direct pathway
33
What is a common pharmacological treatment for the early stages of Huntington's disease?
Tetrabenazine
34
what is tetrabenazine and what does it do?
- VMAT inhibitor
- decreases dopamine levels
35
What is the function of VMAT in relation to Huntington's disease treatment?
Packages dopamine into vesicles
## Footnote
VAMT - vesicular monoamine uptake
36
Which antipsychotic drug is commonly used to treat symptoms of Huntington's disease?
Chlorpromazine
37
what is chlorpromazine ?
dopamine competitive antagonist at receptors
38
what is the affinity of chlorpromazine ?
higher at D2 than D1
## Footnote
includes Haloperidol, olanzapine, risperidone and quetiapine
39
What is the role of genetic counseling in managing Huntington's disease?
Helps inform decisions about having children
40
True or False: The onset of Huntington's disease is typically in late adulthood.
False
41
What is the consequence of losing neurons from both the direct and indirect pathways in later stages of Huntington's disease?
Reduced thalamo-cortical drive leading to bradykinesia and hypokinesia
42
What is the central pathology in Huntington's Disease (HD)?
Protein misfolding
43
What is the mutant protein associated with Huntington's Disease?
Mutant huntingtin (mHTT)
44
How does mutant huntingtin (mHTT) differ from the normal protein?
It is broken down differently, resulting in fragments with extra glutamine repeats
45
What do the fragments of mutant huntingtin (mHTT) have a propensity to do?
Misfold
46
What can misfolded mHTT molecules aggregate to form?
Inclusion bodies
## Footnote
orange dot in micrograph
47
What is unclear about the inclusion bodies in Huntington's Disease?
Whether they are toxic to cells or represent an attempt to detoxify mHTT
48
What dysfunction does the presence of mHTT cause?
Mitochondrial dysfunction
49
What may be triggered by the presence of mutant huntingtin (mHTT)?
Neuroinflammation
50
At what age do most people develop HD symptoms?
Mid-later life
51
What percentage of people develop HD much earlier than the typical age?
About 10%
52
What is Juvenile onset HD?
HD that occurs before age 21
53
What genetic factor is associated with Juvenile onset HD?
A large number of CAG repeats in Huntingtin (>50)
54
What movement symptoms do individuals with Juvenile onset HD tend to lack?
Writhing movements
55
What symptoms do individuals with Juvenile onset HD develop very early?
Immobility symptoms
56
The loss of which neurons produces the chorea in early stage Huntington's Disease?
Striatal neurons projecting to the globus pallidus externus
## Footnote
AS INDIRECT PATHWAY IS EARLY STAGE - INDRECT IS GPe
57
what is the biggest single risk factor for AD?
Age
58
What is the initial cognitive symptom of Alzheimer's disease?
Gradual loss of the ability to use declarative memory (facts. etc)
59
What cognitive functions are affected as Alzheimer's disease progresses?
Difficulties in reasoning, language use, and calculations
60
What psychiatric problems can develop in the later stages of Alzheimer's disease?
psychosis with hallucinations and delusions
61
final stage presentation of AD ?
- mute
- incontinent
- bed-ridden
62
What are the most frequent causes of death in Alzheimer's patients?
* Pneumonia
* Cardiovascular disease
* Wasting
* Dehydration
63
What significant structural changes occur in the brains of Alzheimer's patients?
Shrunken brain, loss of cortical material, reduced hippocampus size, enlarged ventricles
64
What are the two characteristic types of lesions seen in Alzheimer's disease?
* Beta amyloid plaques (extracellular)
* Neurofibrillary tangles (intracellular)
65
What protein aggregates form beta amyloid plaques?
Beta-amyloid
66
What protein aggregates form neurofibrillary tangles?
Tau
67
Where does the initial loss of neurons occur in early Alzheimer's?
Basal forebrain
68
What areas of the brain are affected in mild and moderate Alzheimer's?
More diffuse areas across the brain
69
In severe Alzheimer's, where is neuronal loss observed?
Most brain areas
70
Risk factors of AD
- age
- genetics
- donw's syndrome
- obesity
- smoking
- high alcohol intake
- ethnicity
- female gender
- poor cardiovascular health
- head trauma
- poor sleep patterns
71
protective factors for AD
- physical exercuse
- cognitive activity
- social engagement
- mediterranean diet
- male gender
- NSAID use
72
what are the two subtypes of AD?
- early onset
- late onset
73
What is the role of amyloid precursor protein (APP) in Alzheimer's Disease?
APP is the precursor protein for amyloid β (Aβ), which is responsible for forming amyloid plaques.
74
What are the two forms of amyloid β (Aβ) involved in Alzheimer's Disease?
* Aβ40
* Aβ42
## Footnote
Aβ42 is thought to be more toxic.
75
What effect do mutations in APP have on the formation of Aβ?
form Aβ42 and Aβ40
76
what do the presence of Aβ mutations do ?
- alters breakdown of APP
- so formation of more toxic Aβ42 is favoured
77
What proteins form part of the protease (γ-secretase) that cleaves APP?
Presenilin 1 & 2
78
what does the cleavage of APP by presenilin proteins yeild ?
Aβ
79
what do mutations in the presenilins favour ?
formation of Aβ42
80
What gene is particularly important in late onset Alzheimer's Disease?
APOE
## Footnote
important in both sporadic and familial cases
81
what does the APOE gene code for ?
apolipoprotein E, a protein 'address marker' found in lipoprotein complexes (such as LDL).
82
How many different alleles of the APOE gene exist?
Three alleles: ε2, ε3, ε4
83
what is the ε4 allele associated with ?
higher risk for several disorders such as AD and atherosclerosis etc.
84
is APOE-ε4 a causative factor in AD?
no.
only increases risk of develoing it
85
What is the risk increase for heterozygotes of the APOE-ε4 allele for developing Alzheimer's?
About 3-fold
## Footnote
Homozygotes have a 15-20 fold higher risk.
86
What genetic condition is associated with early onset Alzheimer's Disease?
Down's Syndrome
## Footnote
People with Down's Syndrome usually develop symptoms by age 40.
87
What genetic anomaly causes Down's Syndrome?
Trisomy of chromosome 21
## Footnote
This results in a broad spectrum of physical and learning difficulties.
88
Why do people with Down's Syndrome likely produce higher amounts of Aβ protein?
They have an extra copy of the gene for amyloid precursor protein and are likely to produce higher amounts of the Aβ protein
89
What is the main challenge in treating Alzheimer's disease?
There aren't many current effective treatments
90
What brain region is associated with early neuron loss in Alzheimer's?
Basal forebrain
91
what is impotrant about the basal forebrain ?
contains cholinergic neuron cell bodies
92
cholinergic distribution / pathways
## Footnote
remember for revision - practice drawing and labelling on diagram
1. nucleus basalis into cortex
2. septohippocampal pathway
LABELS:
- PPT/LD
- septohippocampal
- striatal internuerons
- nucleus basalis
- Hip
- Hyp
- Th
- Str
- Sep
- C
## Footnote
note where red lines go
93
What are the two main cell groups in cholinegic pathways ?
1. Peduncluopontine (PPT)/ laterdorsal tegmentum (LD)
2. Magnocellular forebrain (NbM and septohippocampal)
94
What type of neurons are lost early in Alzheimer's disease?
Cholinergic neurons from basal forebrain
95
What is the therapeutic target identified in Alzheimer's research?
Restoring cholinergic neurons to address cholinergic deficit
96
What class of drugs is primarily used to treat Alzheimer's symptoms?
Cholinesterase inhibitors
## Footnote
main stays of AD therapy
97
What is the function of cholinesterase inhibitors?
Inhibit acetylcholine esterase to increase acetylcholine availability
98
Name one cholinesterase inhibitor that is no longer used and why
Tacrine
- hypatotoxic + cholinergic side effects (abdominal pain, nausea)
- not CNS selective (affects both AChE and BuCHE)
## Footnote
the first anticholinesteras shown to be efficacious in AD
99
List the three newer cholinesterase inhibitors recommended for mild to moderate Alzheimer's.
* Donepezil
* Rivastigmine
* Galantamine
100
Which cholinesterase inhibitor is taken once a day ?
Donepezil
101
what type of inhibition does donepezil have and what are the side effects ?
- CNS: AChE selective
- cholinergic
102
what type of inhibition does rivastigmine have and what are the side effects ?
- CNS selective
- cholinergic but subside with continued treatment
103
what are the inhibitory mechanisms of galantamine and what are the side effects ?
- CNS slective
- enhances nicotinic ACh receptor activation
- slight cholinegic side effects
104
What additional mechanism does galantamine have?
Enhances nicotinic acetylcholine receptors through an allosteric mechanism
105
What drug is considered for moderate to severe Alzheimer's or when cholinesterase inhibitors are not tolerated or for moderate to sever AD?
Memantine
106
What is the mechanism of action for memantine and what are the side effects?
NMDA receptor antagonist
- constipation, hypertension, dysponea, headache, dizziness, drowsiness
107
True or False: The drugs for Alzheimer's significantly improve cognitive function.
False
## Footnote
only marginal effects but NICE approves them
108
What is the French Healthcare System's stance on the use of Alzheimer's drugs?
They have delisted all drugs due to minimal beneficial effects and severe side effects
109
What type of drugs are used to manage behavioral problems in Alzheimer's patients?
Antipsychotics
110
Name two antipsychotics that are licensed for use in Alzheimer's disease.
* Risperidone
* Haloperidol
## Footnote
used as tranquilizers to reduce unwanted behaviours
111
What is a significant risk associated with antipsychotics in elderly patients?
Premature death primarily through stroke
112
How should antipsychotics suhc as risperidone and haloperidol be used in Alzheimer's patients?
For short-term and low dose to target specific behaviors
113
What are the two different kinds of brain lesions in Alzheimer's disease?
Amyloid-beta plaques and neurofibrillary tangles
114
how are amyloid-beta plaques formed ?
by the aggregation of amyloid beta protein outside the cell
115
how are neurofibrillary tangels formed ?
by the aggregation of hyper phosphorylated tau protein inside the cell.
116
What is the role of tau protein in healthy neurons?
Stabilizes microtubules
## Footnote
Tau protein is normally associated with microtubules and helps maintain their stability.
117
What happens to tau protein when it becomes hyper phosphorylated?
It self-aggregates and dissociates from microtubules
## Footnote
This leads to the formation of neurofibrillary tangles and destabilization of microtubules.
118
formation of amyloid-beta
- amyloid precursor protein is a membane protein
- acted on by 3 proteases (secreatases): alpha, beta, gamma
119
when does the non-amyloidogenic pathway occur?
if APP is cleaved by alpha and gamma secreatase
## Footnote
does not lead to fomration of amyloid-beta
120
when does the amyloidogenic pathway occur?
when APP cleaved with beta and gamma secreatase
## Footnote
produces amyloid-beta monomers
121
What are the two forms of amyloid-beta protein that are involved in Alzheimer's disease?
40 amino acid and 42 amino acid forms
## Footnote
The 42 amino acid form is thought to be the more toxic of the two.
122
what happens when amyloid beta misfolds in unhealthy neurons ?
forms oligomers which then form plaques
123
what happens in familial forms of AD that involves APP or presenilin mutations ?
- more likely to have more toxic 42 amino acid form
124
what is presenilin a component of ?
gamma secretase
125
what do amyloid-beta plaques do in AD?
- damage neurons and induce neuroinflammation
126
what do oligomers do in AD?
- thought to be more toxic form of amyloid-beta than plaques
- can be found in intracellular forms which can damage organelles like mitochondria
127
What role do neurofibrillary tangles play in neuronal health?
They are intracellular so can damage organelles like mitochondria and disrupt axonal transport
128
how tau lead to impaired axonal transport ?
can lead to disintegration of microtubules
129
What has been a major focus of drug development in Alzheimer's disease?
Disrupting the production of amyloid-beta plaques
## Footnote
This includes immunotherapies aimed at plaques and aggregation inhibitors such as antigen therapy or aggregation inhibitorss
130
What has been the outcome of many drug trials aimed at amyloid-beta?
They have not worked or caused toxicity or futhered congitive decline
131
How can the development of amyloid beta plaques and neurofibrillary tangles be monitored in patients?
Using PET scanning
| present as red and yellow / normal levels is green/blue
## Footnote
This technique allows researchers to track the accumulation of these proteins in living patients. NOT A DIAGNOSITIC TOOL.
132
What correlation has been found between cognitive decline in Alzheimer's and protein accumulation?
It correlates better with the development of neurofibrillary tangles than plaques
## Footnote
This finding challenges the amyloid-beta hypothesis.
133
What potential future research avenue is suggested for Alzheimer's drug development?
Investigating tau in more detail maybe by immunotherapies
## Footnote
This includes studies on inhibiting tau aggregation and phosphorylation.
134
How is type 2 diabetes related to Alzheimer's disease risk?
Involves insulin resistance which may compromise neuronal repair
## Footnote
This connection is being explored in relation to drug development.
135
What is liragultide and its relevance to Alzheimer's disease?
- anti-diabetes drug
- GLP1 agonist that has shown promise in animal models for AD
## Footnote
It is currently in clinical trials for its effects on Alzheimer's.
136
NSAID drugs and AD
use lowers risk of AD
137
What has been the effect of NSAIDs in clinical trials for Alzheimer's disease?
Very little effect or more harm than good
## Footnote
Despite epidemiological studies suggesting they lower Alzheimer's risk, clinical trials have not confirmed this benefit.
138
Which drug is an allosteric potentiator of nicotinic acetylcholine receptors?
Galantamine
139
Mutations in which protein are thought to explain a lot of the genetic risk in late onset sporadic Alzheimer's Disease?
APOPE
140
accumulating protein summary table in disorders for:
- AD
- PD
- HD
- ALS
- CJD
141
what is CJD ?
creutxfeld-Jakob DIsease
- prion disease
## Footnote
abnormal prion accumulation
142
what is a prion disease ?
- the infectious agent is a protein (prion protein, PrP) that folds abnoramlly
143
what does misfolding of the prion protein do and how does it affect cells ?
- causes other copies of prion proteins to form the same misfoleded pattern
- has more beta-sheet structure so greater tendency to stick together and form aggregates, leading to cell death
144
what is BSE
- bovine spongiform ecephalopathy
- mad cow disease
- neurodegenerative disease of cattle
- prion disease
- as a result of feeding cattle with products from other cattle that are contaminated
145
what happens if BSE prion agent is transmitted to humans ?
results in vCJD
## Footnote
v = variant
146
what are the symptoms of CJD ?
- psychiatric problems
- rapid progression of movement disorders and dementia
- thought to be transmitted primarily from contaminated meat
147
how can CJD occur ?
sporadic or inherited
- from organ donation or contaminated surgical instruments or cannibalism
## Footnote
inherited due to mutations in prion protein making it more likely to misfold
