week 8 part 2 Flashcards
1
Q
What is dementia?
A
A clinical syndrome characterised by a cluster of symptoms manifested by difficulties in memory, language, behavioural, psychological changes and impairment in daily living
2
Q
What is the hallmark of dementia?
A
memory loss
3
Q
What do all the combined factors lead to?
A
Difficulty with day to day living
4
Q
What is the incidence of dementia?
A
aprrox at 850,000
5
Q
Who will suffer from dementia in their life time?
A
1 in 3 people born in UK
6
Q
What is Mini mental state Examination and also Montreal Cognitive Assessment (MoCA)
A
widely used screening assessment for detecting cognitive impairment.
7
Q
General Practitioner Assessment of Cognition (GPCOG) Score?
A
GP screening tool for dementia
8
Q
What is Clock drawing test?
A
Tests visual-spatial skills which are often declined in Alzheimer’s patients and dementia sufferers
9
Q
Alzheimer’s disease
A
60% of all dementia cases
10
Q
What are different forms of Dementia?
A
- Frontotemporal dementia
- Parkinson’s dementia
- Dementia with other Lewy bodies
- Vascular dementia
11
Q
What did Alzheimer’s notice?
A
- Impaired memory disorentiation
2. The inability to use language and psychosocial incompetence
12
Q
What are the 2 pathological hallmark?
A
- Plaques (between neurons)
2. Tangles (within neurons)
13
Q
what are amyloid plaques?
A
Extracellular accumulations composed of abnormally folded amyloid-beta with 40 or 42 amino acids
14
Q
What are two by-products of amyloid precursor protein metabolism?
A
- AB40
2. AB42
15
Q
What is found within plaques?
A
AB42
more abundant
higher rate of fibrillisation and insolubility
16
Q
Where is there huge abundance of amyloid in?
A
Alzheimer’s disease patient brain
17
Q
What is Tau?
A
- microtubule-associated protein
18
Q
What does Tau have a role in?
A
- Microtubule stabilisation
2. Axonal transport
19
Q
What is Tau-microtubule binding maintained by?
A
co-ordinated action of kinases and phosphatases
20
Q
What does phosphorylation of tau regulate?
A
its activity to bind to microtubules
21
Q
What does hyperphosphorylation of tau result in?
A
formation of neurofibrillary tangles
composed of paired helical filament of tau
22
Q
What is Alzheimer’s disease neurodegeneration?
A
- Extreme shrinkage of the hippocampus
- Extreme shrinkage of the cerebral cortex
- Severely enlarged ventricles
23
Q
Early onset Alzheimer’s disease
A
- age 30-50
2. mutation in APP = PSEN1/PSEN2
24
Q
Late onset Alzheimer’s disease
A
develops over age of 60
driven by a complex interplay of genetic and environmental factors
25
What has been implicated as a strong genetic risk factor?
Apolipoprotein E gene (ApoE)
26
What is APP?
transmwmbrane protein
27
What are the roles of APP?
1. Neural proliferation
2. Migration
3. Differentiation
4. Plasticity and synaptogenesis
28
What is associated with familial forms of early-onset ALZHEIMER'S DISEASE AS WELL AS CEREBRAL AMYLOID ANGIOPAHTY?
mutations in APP
29
What do mutations in APP generally increase?
AB production
30
What decreases AB production and is protective of Alzheimer's disease?
A673T mutation
31
What 3 secretases cleaves APP?
1. alpha secretases
2. Beta secretases
3. Gamma secretases
32
Where is APP cleaved in?
non-amyloidogenic pathway and amyloidogenic pathway
33
What does Amyloidogenic pathway lead to/?
Production of AB 40-42 which form fibrillar insoluble plaques between neurons
34
What does alpha secretases generate?
P53
35
What does beta secretases generate?
amyloid-beta 40-42 fragments
36
What are subunits of gamma-secretases?
1. PSEN1
| 2. PSEN2
37
What is responsible for AB generation?
Aspartyl protease
38
What have been reported in PSEN1?
over 200 mutations
39
What have been reported in PSEN2?
approx 40 mutations
40
What is the most common cause of early-onset AD?
PSEN1
41
What is the rare cause of early-onset AD?
PSEN2
42
What have PSEN mutations been shown to impair?
Gamma-secretases function
Drive amyloidosis through changes in the AB42/AB40 ratio
43
What is Apolipoprotein E (ApoE)?
A secreted lipoprotein involved in cholesterol metabolism
44
What are 3 alleles of ApoE gene?
1. ApoE2
2. ApoE3
3. ApoE4
45
What is ApoE4?
A strong risk factor for late-onset AD
46
What has ApoE4 shown to decrease?
clearance of extracellular AB
47
What does amyloid hypothesis explain?
explains both early on set and late onset of AD contribution to Dementia
48
What is ACH involved in?
Critical physiological process including within attention, learning and memory
49
Where is ACH synthesised from?
1. Choline
| 2. Aceytl- coenzyme A by choline acetyltransferase (ChAt)
50
How is ACH transferred into synaptic vesicle?
Vesicular acetylcholine transporter (VaChT)
51
What promotes ACH exocytosis?
Pre-synaptic neuron depolarisation
52
Where does ACH bind to?
Nicotinic or muscarinic receptors leading to a stimulatory or inhibitory response
53
Where is ACH rapidly hydroylsed by?
acetylcholinesterase (AChE)
releasing acetate and choline
recycled into pre-synaptic neuron by high-affinity choline transporter (CHT1)
54
What are particularly affected in AD?
Cholinergic neurons
55
What is a major correlate of cognitive impairment?
synaptic loss
56
what can promote amyloid fibril formation?
AChE
57
What can pharmacological intervention help?
Improve symptoms of AD
58
who are prescribed acetylcholinesterase inhibitors?
A person with mild to moderate AD
59
What do AChE inhibitors act to increase?
ACH levels
alleviate cognitive symtpoms - problems with memory, language, judgement
Allow a patient to continue with activities of daily living
60
What are examples of AChE inhibitors?
1. Donepezil
2. Galantamine
3. Rivastigmine
61
What is a result of synaptic dysfunction and has been associated with a number of neurodegenerative disorder?
NMDAR overactivation
| Subsequent glutamate mediated neurotoxicity
62
What is excessive glutamate associated with?
Intense transient influx of Ca2+
impairment in mitochondrial function
ATP depletion
formation of reactive oxygen species
63
What is Memantine?
Low affinity NMDA receptor antagonist that blocks excessively open NMDA receptor ion channel to reduce glutamate mediated neurotoxicity
64
What does amyloid strategies include
1. Inhibition of secretases involved in APP metabolism
| 2. Anti-amyloid immunotherapy
65
What is anti-amyloid immunotherapy divided into?
1. Active approaches (development of anti-AB42 vaccine)
| 2. Passive approaches (Administration of anti-AB42 antibodies)
66
What does anti-tau strategies include?
1. Tau phosphorylation inhibition
| 2. Anti-tau immunotherapy
67
How can Tau hyperphosphorylation be reduced by?
Inhibiting GSK3 (lithium treatment)
68
What is AAD-vac1?
Vaccine targeting structural determinants on disordered Tau
Crucial for pathological tau-tau interactions
69
What is AAD-vac1 currently undergoing?
phase 2 clinical trials for AD
70
What is MMSE?
1. Used by clinicians to help diagnose dementia and to help assess its progression and severity
2. Series of questions and tests, each of which scores points if answered correctly
3. Tests a number of mental abilities including a person’s memory, attention and language
4. The clinicians will consider a person’s MMSE alongside their history, symptoms, a physical exam and the results of other tests (e.g. a brain scan)
71
What is Montreal cognitive assessment?
1. Rapid screening instrument for mild cognitive dysfunction.
2. Assessment different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking and orientation
72
What is GPCOG?
1. Consists of both cognitive test of patient and an informant interview to increase its predictive power
2. Both parts can scored separately, together or sequentially
3. The cognitive test includes 9 items
- time orientation, clock drawing
- numbering and spacing
- placing hands correctly
- awareness of a current news event and recall of a name an address
- first name
- last name
- number
- street
- suburb
4. Each correct answer is valid one point leading to a maximum score of 9 (fewer points indicate more impairment)
73
What does CPCOG consist of?
1. Time orientation
2. Information
3. Recall test
74
What is the order of biomarker unravelling pathogenic cascade?
1. AB
2. Tau-mediated neuronal injury and dysfunction
3. Brain structure
4. Memory
5. Clinical function
75
In typical cases of Alzheimer’s disease where does AB deposition precede?
1. Neurofibrillary and neurotransmission changes
| 2. Apparent origin in the frontal and temporal lobes, hippocampus and limbic system
76
Where does the neurofibrillary tangle and neurotic regeneration start?
1. Medial temporal lobe
2. Hippocampus
3. Progressively spread to other areas of the neocortex
77
What is Alzheimer’s disease associated with?
1. Accumulation of insoluble forms of AB in plaques in extracellular spaces as well as in the walls of blood vessels
2. Aggregation of the microtubule protein tau in the neurofibrillary tangles in neurons
78
What is AB derived by?
1. Proteolytic cleavage of APP by complex family of enzymes (gamma secretases and Beta-secretases) which include PS1 and PS2
79
What is ~70% of AD risk attributable to?
Genetic factors
80
What genes are thought to influence amyloid precursor protein metabolism?
1. APP
2. PSEN2/PSEN1
3. ADAM10
4. PLD3
5. SORL1
6. ABCA7
7. PICALM
8. CLU
9. INPP5 D
81
What genes are thought to influence tau metabolism?
1. CASS4
2. FERMT 2
3. BIN1
82
GWAS have identified more than 20 genetic risk factors, what do these implicate in?
1. Inflammatory metabolism
2. Cholesterol metabolism
3. Endosomal-vesicle recycling pathways
83
What is now recognised to play a key role in AD pathogensesis?
Microglia activation in response to amyloid deposition
84
What is now recognised to play a key role in AD pathogensesis?
Microglia activation in response to amyloid deposition
85
A deeper cut
1. APP spans the membrane
2. Beta-secretases cleaves APP
3. Gamma secretase cleaves the remaining membrane bound portion.
4. Amyloid-bets is released from the cell
- the length of peptide reflects the site at which gamma secretases makes its cut
5. All forms of amyloid beta aggregate into oligomers, fibrils and then plaque. However, linger fragments are thought flat aggregate more readily
86
What is AB amyloid hypothesis’s?
1. Amyloid plaque resulting from AB overproduction or reduced clearance
2. AB-amyloid induced synaptic- and neurotoxicity
3. Neurodegeneration
87
Why has numerous clinical trials of anti-amyloid agents have not met their pre-specified endpoints?
1. Inadequate preclinical data
2. Poor brain penetration
3. Little human biomarker change
4. Low therapeutic index
