Alzheimer's Disease Flashcards

1
Q

Cognitive impairment feature in a number of neurodevelopmental, neurological and psychiatric disorders, including:

A
  • Schizophrenia
  • Depression
  • ADHD
  • Alzheimer’s Disease
  • Dementia
  • Parkinson’s Disease
  • Mild Cognitive Impairment
  • Fragile X
  • Foetal Alcohol Spectrum Disorder
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2
Q

Cognitive impairment feature in a number of neurodevelopmental, neurological and psychiatric disorders, including:

A
  • Schizophrenia
  • Depression
  • ADHD
  • Alzheimer’s Disease
  • Dementia
  • Parkinson’s Disease
  • Mild Cognitive Impairment
  • Fragile X
  • Foetal Alcohol Spectrum Disorder
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3
Q

What is MCI?

A

Patient complains of problems wit memory and this is confirmed by an informant.
Patient shows poor performance on formal memory tests, relative age and education matched healthy people.
Daily living and activities remain largely intact.
Do not meet the diagnostic criteria for Dementia.
Have an increased risk of developing Alzheimers Disease.
Around 50% or more of patients develop dementia within 5 years of MCI diagnosis.

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4
Q

What does ADAS- Cog stand for and what does it measure?

A

Alzheimers Disease Assessment Scale Cognitive Subscale. It is a test battery that measures the severity of impairment. Tests include memory & new learning, language and praxis.

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5
Q

We cannot currently predict which individuals will show the transition from MCI to dementia. What are some indications that can possible differentiate from those who will transition and those who will not?

A
  • Imaging patterns of cortical thinning
  • Serial MRI scans showing rate of change in brain atrophy
  • APOE 4 genes can alter cholesterol transport and synaptic plasticity - carriers of gene may be more likely
  • Poor performance on delayed recall tests
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6
Q

Treatments used for AD and dementia have been proven largely ineffective for MCI due to:

What MAY help?
_______ _________ required due to the risk of developing dementia

A
  • heterogeneity of patients
  • spectrum of aetiology and disorders
  • multiple susceptibility genes linked to AD
  • cognitive training
    sensitive counselling
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7
Q

What are the risk factors for AD?

A
  • age
  • stroke
  • genetic factors
  • high BP
  • head injury
  • high cholesterol
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8
Q

Late onset AD occurs

A

> 65 years (most cases)

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9
Q

Early onset AD occurs

A

30-65 years (familial)

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10
Q

Alzheimers Disease: Clinical Picture - There is a progressive decline

A
  • initially forgetful, difficulty finding words, leave tasks unfinished
  • need help with basic activities, poor hygiene
  • unable to recognise relatives or own reflection in mirror
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11
Q

Alzheimers Disease: Mood and behavioural disturbances

A
  • irritable, emotional outbursts
  • agitated, delusions of persecution (memory-related), disorientated
  • inappropriate sexual advances towards strangers, use of coarse language, loss of impulse control
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12
Q

What is the diagnosis for AD? And what are the clinical problems with diagnosing?

A

Macroscopic examination of brain tissue after death

  • problems differentiating from delirium or geriatric depression
  • problems with referral due to fear or denial
  • primarily based on memory dysfunction
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13
Q

In AD, there is a cognitive decline in:

A
  • both implicit and explicit memory
  • recognition memory
  • STM including working memory
  • semantic memory
  • attention
  • episodic memory
  • anterograde amnesia
  • retrograde amnesia
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14
Q

What is the pathology of AD?

A
  • atrophy of the brain

- loss of cholinergic neurones from nucleus basalis of meynert

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15
Q

What does the nucleus basalis innervate?

A
  • amygdala - emotion

- hippocampus & cortex - cognition

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16
Q

Loss of cholinergic neurones results in:

A
  • widespread reduction in CHAT (choline acetyl transferase)

- depletion of nicotinic and presynaptic M2 muscarinic receptors (post synaptic receptors are usually preserved)

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17
Q

What is axonal transport?

A

The movement of mitochondria, lipids, synaptic vesicles, proteins and other organelles to and from the neurone’s cell body. This occurs along a microtubule network.
Axons have no ribosomes and so rely on axonal transport for all their protein needs

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18
Q

What is Tau normally?

A

A soluble, microtubule-associated protein (MAP) which binds to microtubules and stabilises them.

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19
Q

Axonal transport relies on

A

microtubules acting as tracts which are stabilised by tau proteins.

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20
Q

Phosphorylation at crucial sites causes tau to

A

detach from microtubules, leading to microtubule breakdown and the accumulate of tau aggregated into paired helical filaments (PHFs)

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21
Q

Aggregations of tau proteins causes disruption of microtubules and subsequently the

A

normal transport of amyloid precursor protein (APP)

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22
Q

When tau threads become knotted and tangled up with another, they form

A

neurofibrillary tangles.

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23
Q

When tau threads become knotted and tangled up with another, they form ________ _______. When this happens, the microtubules…

A

neurofibrillary tangles.

disintegrate, collapsing the neurones transport system

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24
Q

When tau threads become knotted and tangled up with another, they form ________ _______. When this happens, the microtubules…
This may first result in

A

neurofibrillary tangles.
disintegrate, collapsing the neurones transport system
- malfunctions in communication between neurones and later neurodegeneration and cell death

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25
What single gene is Tau encoded by? and on which chromosome?
MAPT | chromosome 17
26
____ protein isoforms are generated by alternative splicing of exons __, __ or ____
6 2 3 10
27
Tau isoforms can differ in
the number of tubulin binding domains (3 or 4 repeats located on C terminal half) and referred to 3R or 4R tau isoforms.
28
In AD, the tau isoforms involved are
3R and 4R
29
In frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) there are _____ isoforms
several
30
In AD, how many tau mutations are there? However in FTDP-17 patients.... THEREFORE, tau pathology must be downstream of ____ in the neurodegenerative cascade. There must be Amyloid beta _____ and ______ ways of.....
``` None Tau mutations alone can cause neurodegeneration. Amyloid beta dependent independent causes tau aggregation ```
31
What are two hallmarks of AD?
amyloid plaques | neurofibrillary tangles
32
What/ Where are amyloid plaques.
Formed by beta amyloid (snipped from APP) which accumulate and form hard, insoluble plaques. Found BETWEEN nerve cells
33
What/ Where are neurofibrillary tangles?
Aggregated Tau proteins tangled with other tau proteins to for insoluble paired helical filament (PHF). Found WITHIN neurones.
34
How is beta amyloid made?
Through abnormal processing of APP (amyloid precursor protein)
35
What enzymes are involved in the conversion of APP to amyloid beta?
beta secretase | gamma secretase
36
Amyloid plaques (brown) consists of deposits of insoluble beta amyloid peptides. What else do they contain?
- APOE - reduced metal ions e.g. Cu++ - components of the complement cascade
37
Greater Ca++ influx is associated with amyloid plaques through:
- NMDA receptors on ion channels | - VG Ca++ channels
38
An increase in intracellular Ca++ (in regards to amyloid plaques) will.... Amyloid deposits can also
trigger the complement cascades which destroy neurones trigger the production of free radicals
39
What is the tau tangle hypothesis?
The number of tau tangles better predicts disease severity than the abundance of amyloid plaques. Amyloid plaques can be found in healthy ageing brains
40
What is the amyloid hypothesis?
Amyloid beta is neurotoxic and causes the neurofibrillary tau tangles in the first place.
41
What enzymes are involved in the conversion of APP to amyloid beta?
beta secretase and then | gamma secretase
42
gamma secretase processes beta C terminal fragment into either
harmless amyloid beta 40 OR toxic amyloid beta 42
43
gamma secretase is a comple multi protein unit that forms a __________ pore. It has a wide range of _______ and is said to be involved in multiple....
proteinaceous targets cell signalling events
44
Familial forms of AD show mutations in genes related to
beta amyloid production
45
What are some mechanisms of Amyloid beta 42 toxicity?
- free radical production - Ca dysregulation - mitochondrial dysfunction - toxic peptide - protein misfolding procession - Inflammation - loss of synaptic function
46
For the following locus names, give the gene symbol and protein name: - AD1 - AD2 - AD3 - AD4
- APP - Amyloid precursor protein - ApoE - Apolipoprotein E - PSEN 1 - Presenilin 1 - PSEN2 - Presenilin 2
47
What proteins are essential for gamma secretase activity?
Presenilin 1 and 2
48
Which genes/proteins affect early onset AD?
APP - Amyloid precursor protein PSEN1 - Presenilin 1 PSEN2 - Presenilin 2
49
Which gene/protein affects late onset AD?
ApoE - Apolipoprotein E
50
Early onset mutations directly/indirectly affect beta amyloid production, and thus neurodegeneration
directly
51
Late onset mutations (ApoE) may affect _____ _______
several pathways
52
Early onset mutations directly/indirectly affect beta amyloid production (by altering it), and thus neurodegeneration
directly
53
Late onset mutations (e.g. mutated ApoE) may affect _____ _______
``` several pathways. Examples include: - increased amyloid beta aggregation - decreased amyloid beta clearance - altered amyloid beta production ```
54
Normal ApoE is involved in several functions:
- cholesterol transport - synaptic plasticity - clearance of beta amyloid peptides
55
Which enzyme hyperphosphorylates tau?
Tau kinase
56
What type of drugs can you give to stop beta and gamma secretase?
beta and gamma secretase inhibitors.
57
What is the treatment for neurofibrillary tangles?
Tau aggregation inhibitors
58
What is the treatment for abnormal tau hyperphosphorylation?
tau kinase inhibitors
59
What is the treatment for micoglia and astrocytic activation/ inflammatory response?
Anti inflammatory drugs
60
What is the treatment for failure of Abeta clearance mechanisms/ Abeta 42 overproduction?
b- and y-secretase inhibitors
61
What is the treatment for accumulation and oligomerisation of Ab42 in limbic and association cortices?
Anti-Ab immunisation aggregation inhibitors and b- and y-secretase inhibitors
62
What is the treatment for gradual deposition of Ab42 oligomers as diffuse plaques?
Anti Ab immunisation aggregation inhibitors
63
What are the two approaches for treating cognitive problems?
- cholinergic approach | - glutamatergic approach
64
What is the rationale for cholinergic approach?
- ACh is known to be involved in cognition | - Loss of cholinergic neurons results in neurodegeneration
65
Scopalamine is...
a competitive muscarinic ACh receptor antagonist
66
Scopalamine induces
cognitive deficits.
67
Scopalamine induces ______ _______
cognitive deficits.
68
What are the (three) stratageies of enhancing ACh function?
1 - AChE inhibitor 2 - modulate release of ACh 3 - mimic ACh (agonist)
69
What are the (three) stratageies of enhancing ACh function?
1 - cholinesterase inhibitor 2 - modulate release of ACh - drug acts on presynaptic 3 - mimic ACh (agonist) - drug acts on post synaptic
70
What are the two cholinesterases in the body?
- acetylcholinesterase (most prevalent in the CNS) | - butyrylcholinesterase (pseudocholine
71
What are the two cholinesterases in the body?
- acetylcholinesterase (most prevalent in the CNS) | - butyrylcholinesterase (pseudocholinesteras)
72
Which cholinesterase is most prevalent at CNS synapses?
acetylcholinesterases
73
What are the two cholinesterases in the body?
- acetylcholinesterase (most prevalent in the CNS) | - butyrylcholinesterase (pseudocholinesterase)
74
The efficacy and tolerability of cholinesterase inhibitors depends on
how selective they are for acetylcholinesterase
75
What was the first AChE-I?
Tacrine
76
What enzyme(s) does Tacrine inhibit?
Acetylcholinesterase | Pseudocholinesterase
77
How often does Tacrine need to be taken?
4 times a day - short acting
78
Side effects of Tacrine?
Nausea, abdominal cramps and hepatotoxic
79
Name three AChE-I that are better than Tacrine
Donepezil Rivastigmine Galanthamine
80
How often are Donepezil, Rivastigmine and Galanthamine taken and mention the selectivity and side effects
once a day selective to AChE mild GI effects
81
How often are Donepezil, Rivastigmine and Galanthamine taken and mention the selectivity and side effects
once a day selective to AChE mild GI side effects
82
Cholinesterase inhibitor efficacy...
only lasts when neurones remain intact. When neurones degenerate, AChE-I cannot retard decline
83
What drug acts on pre synaptic receptor? State the drug name, what type of drug it is, the receptor it acts on, and the outcome.
- SCH 7790 - selective M2 muscarinic receptor antagonist - M2 muscarinic receptor - prevents autoinhibition, thus increasing levels of ACh in synapse
84
Selective M2 muscarinic receptor antagonist efficacy depends on
integrity of neurones - efficacy will eventually be lost
85
Selective M2 muscarinic receptor antagonist efficacy depends on
integrity of neurones - efficacy will eventually be lost
86
What is another muscarinic receptor antagonist being researched?
BIBN-99
87
Which drug has been proven to improve cognition in AD patients? How?
Nicotine. | Increases effects of post synaptic receptors
88
Which of the three treatments is the most commonly used to treat AD?
- AChE-I: efficacy depends on neuronal integrit
89
Which of the three treatments is theoretically possible?
- M2 muscarinic receptor antagonist : efficacy depends on neuronal integrity
90
What receptor does the glutamatergic approach target?
NMDA
91
gamma secretase is a complex multi protein unit that forms a __________ pore. It has a wide range of _______ and is said to be involved in multiple ___-________ events
proteinaceous targets cell signalling
92
Rationale for NMDA receptor antagonist?
NMDA has a role in neurodegeneration . Excessive levels of glutamate in brain causes prolonged depolarisation. Subsequent Ca++ entry eventually leads to cell death.
93
What are the (three) strategies of enhancing ACh function?
1 - cholinesterase inhibitor 2 - modulate release of ACh - drug acts on presynaptic 3 - mimic ACh (agonist) - drug acts on post synaptic
94
Rationale for NMDA receptor antagonist?
NMDA has a role in neurodegeneration . Excessive levels of glutamate in brain causes prolonged depolarisation. Subsequent Ca++ entry eventually leads to cell death. NMDA antagonists can block the effects of excessive glutamate release.
95
What is the problem with using NMDA antagonists?
Cognitive impairment
96
What are undesirable effects of NMDA antagonists?
hallucinations psychosis dissociative effects harmful effects on blood pressure
97
Give an example of a NMDA antagonist
Memantine
98
How does Memantine work?
Prevents excessive stimulation of glutamate (prevents neurodegeneration) but spares normal glutamatergic neurotransmission (hence no memory impairment)
99
What are some low level side effects of memantine?
- hallucinations - headache - confusion - tiredness - dizziness
100
What are some 'non-cognition' problems associated with dementia?
- depression - delusion and hallucinations - physical or verbal aggression - agitation
101
For the 'non cognition' problems listed below, give one possible treatment for each: - depression - delusion and hallucinations - physical or verbal aggression - agitation
- SSRIs e.g citalopram - antipsychotic (not really efficient) - carbamazepine - benzodiazepine and busiprone