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PY353 > Alzheimer's Disease > Flashcards

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
Q

What single gene is Tau encoded by? and on which chromosome?

A

MAPT

chromosome 17

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26
Q

____ protein isoforms are generated by alternative splicing of exons __, __ or ____

A

6
2
3
10

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27
Q

Tau isoforms can differ in

A

the number of tubulin binding domains (3 or 4 repeats located on C terminal half) and referred to 3R or 4R tau isoforms.

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28
Q

In AD, the tau isoforms involved are

A

3R and 4R

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29
Q

In frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) there are _____ isoforms

A

several

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30
Q

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…..

A 
None
Tau mutations alone can cause neurodegeneration.
Amyloid beta
dependent 
independent
causes tau aggregation
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31
Q

What are two hallmarks of AD?

A

amyloid plaques

neurofibrillary tangles

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32
Q

What/ Where are amyloid plaques.

A

Formed by beta amyloid (snipped from APP) which accumulate and form hard, insoluble plaques.
Found BETWEEN nerve cells

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33
Q

What/ Where are neurofibrillary tangles?

A

Aggregated Tau proteins tangled with other tau proteins to for insoluble paired helical filament (PHF). Found WITHIN neurones.

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34
Q

How is beta amyloid made?

A

Through abnormal processing of APP (amyloid precursor protein)

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35
Q

What enzymes are involved in the conversion of APP to amyloid beta?

A

beta secretase

gamma secretase

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36
Q

Amyloid plaques (brown) consists of deposits of insoluble beta amyloid peptides. What else do they contain?

A
  • APOE
  • reduced metal ions e.g. Cu++
  • components of the complement cascade
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37
Q

Greater Ca++ influx is associated with amyloid plaques through:

A
  • NMDA receptors on ion channels

- VG Ca++ channels

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38
Q

An increase in intracellular Ca++ (in regards to amyloid plaques) will….
Amyloid deposits can also

A

trigger the complement cascades which destroy neurones

trigger the production of free radicals

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39
Q

What is the tau tangle hypothesis?

A

The number of tau tangles better predicts disease severity than the abundance of amyloid plaques.
Amyloid plaques can be found in healthy ageing brains

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40
Q

What is the amyloid hypothesis?

A

Amyloid beta is neurotoxic and causes the neurofibrillary tau tangles in the first place.

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41
Q

What enzymes are involved in the conversion of APP to amyloid beta?

A

beta secretase and then

gamma secretase

42
Q

gamma secretase processes beta C terminal fragment into either

A

harmless amyloid beta 40
OR
toxic amyloid beta 42

43
Q

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….

A

proteinaceous
targets
cell signalling events

44
Q

Familial forms of AD show mutations in genes related to

A

beta amyloid production

45
Q

What are some mechanisms of Amyloid beta 42 toxicity?

A
  • free radical production
  • Ca dysregulation
  • mitochondrial dysfunction
  • toxic peptide
  • protein misfolding procession
  • Inflammation
  • loss of synaptic function
46
Q

For the following locus names, give the gene symbol and protein name:

  • AD1
  • AD2
  • AD3
  • AD4
A
  • APP - Amyloid precursor protein
  • ApoE - Apolipoprotein E
  • PSEN 1 - Presenilin 1
  • PSEN2 - Presenilin 2
47
Q

What proteins are essential for gamma secretase activity?

A

Presenilin 1 and 2

48
Q

Which genes/proteins affect early onset AD?

A

APP - Amyloid precursor protein
PSEN1 - Presenilin 1
PSEN2 - Presenilin 2

49
Q

Which gene/protein affects late onset AD?

A

ApoE - Apolipoprotein E

50
Q

Early onset mutations directly/indirectly affect beta amyloid production, and thus neurodegeneration

A

directly

51
Q

Late onset mutations (ApoE) may affect _____ _______

A

several pathways

52
Q

Early onset mutations directly/indirectly affect beta amyloid production (by altering it), and thus neurodegeneration

A

directly

53
Q

Late onset mutations (e.g. mutated ApoE) may affect _____ _______

A 
several pathways. 
Examples include:
- increased amyloid beta aggregation
- decreased amyloid beta clearance
- altered amyloid beta production
54
Q

Normal ApoE is involved in several functions:

A
  • cholesterol transport
  • synaptic plasticity
  • clearance of beta amyloid peptides
55
Q

Which enzyme hyperphosphorylates tau?

A

Tau kinase

56
Q

What type of drugs can you give to stop beta and gamma secretase?

A

beta and gamma secretase inhibitors.

57
Q

What is the treatment for neurofibrillary tangles?

A

Tau aggregation inhibitors

58
Q

What is the treatment for abnormal tau hyperphosphorylation?

A

tau kinase inhibitors

59
Q

What is the treatment for micoglia and astrocytic activation/ inflammatory response?

A

Anti inflammatory drugs

60
Q

What is the treatment for failure of Abeta clearance mechanisms/ Abeta 42 overproduction?

A

b- and y-secretase inhibitors

61
Q

What is the treatment for accumulation and oligomerisation of Ab42 in limbic and association cortices?

A

Anti-Ab immunisation aggregation inhibitors and b- and y-secretase inhibitors

62
Q

What is the treatment for gradual deposition of Ab42 oligomers as diffuse plaques?

A

Anti Ab immunisation aggregation inhibitors

63
Q

What are the two approaches for treating cognitive problems?

A
  • cholinergic approach

- glutamatergic approach

64
Q

What is the rationale for cholinergic approach?

A
  • ACh is known to be involved in cognition

- Loss of cholinergic neurons results in neurodegeneration

65
Q

Scopalamine is…

A

a competitive muscarinic ACh receptor antagonist

66
Q

Scopalamine induces

A

cognitive deficits.

67
Q

Scopalamine induces ______ _______

A

cognitive deficits.

68
Q

What are the (three) stratageies of enhancing ACh function?

A

1 - AChE inhibitor
2 - modulate release of ACh
3 - mimic ACh (agonist)

69
Q

What are the (three) stratageies of enhancing ACh function?

A

1 - cholinesterase inhibitor
2 - modulate release of ACh - drug acts on presynaptic
3 - mimic ACh (agonist) - drug acts on post synaptic

70
Q

What are the two cholinesterases in the body?

A
  • acetylcholinesterase (most prevalent in the CNS)

- butyrylcholinesterase (pseudocholine

71
Q

What are the two cholinesterases in the body?

A
  • acetylcholinesterase (most prevalent in the CNS)

- butyrylcholinesterase (pseudocholinesteras)

72
Q

Which cholinesterase is most prevalent at CNS synapses?

A

acetylcholinesterases

73
Q

What are the two cholinesterases in the body?

A
  • acetylcholinesterase (most prevalent in the CNS)

- butyrylcholinesterase (pseudocholinesterase)

74
Q

The efficacy and tolerability of cholinesterase inhibitors depends on

A

how selective they are for acetylcholinesterase

75
Q

What was the first AChE-I?

A

Tacrine

76
Q

What enzyme(s) does Tacrine inhibit?

A

Acetylcholinesterase

Pseudocholinesterase

77
Q

How often does Tacrine need to be taken?

A

4 times a day - short acting

78
Q

Side effects of Tacrine?

A

Nausea, abdominal cramps and hepatotoxic

79
Q

Name three AChE-I that are better than Tacrine

A

Donepezil
Rivastigmine
Galanthamine

80
Q

How often are Donepezil, Rivastigmine and Galanthamine taken and mention the selectivity and side effects

A

once a day
selective to AChE
mild GI effects

81
Q

How often are Donepezil, Rivastigmine and Galanthamine taken and mention the selectivity and side effects

A

once a day
selective to AChE
mild GI side effects

82
Q

Cholinesterase inhibitor efficacy…

A

only lasts when neurones remain intact. When neurones degenerate, AChE-I cannot retard decline

83
Q

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.

A
  • SCH 7790
  • selective M2 muscarinic receptor antagonist
  • M2 muscarinic receptor
  • prevents autoinhibition, thus increasing levels of ACh in synapse
84
Q

Selective M2 muscarinic receptor antagonist efficacy depends on

A

integrity of neurones - efficacy will eventually be lost

85
Q

Selective M2 muscarinic receptor antagonist efficacy depends on

A

integrity of neurones - efficacy will eventually be lost

86
Q

What is another muscarinic receptor antagonist being researched?

A

BIBN-99

87
Q

Which drug has been proven to improve cognition in AD patients? How?

A

Nicotine.

Increases effects of post synaptic receptors

88
Q

Which of the three treatments is the most commonly used to treat AD?

A
  • AChE-I: efficacy depends on neuronal integrit
89
Q

Which of the three treatments is theoretically possible?

A
  • M2 muscarinic receptor antagonist : efficacy depends on neuronal integrity
90
Q

What receptor does the glutamatergic approach target?

A

NMDA

91
Q

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

A

proteinaceous
targets
cell signalling

92
Q

Rationale for NMDA receptor antagonist?

A

NMDA has a role in neurodegeneration .
Excessive levels of glutamate in brain causes prolonged depolarisation. Subsequent Ca++ entry eventually leads to cell death.

93
Q

What are the (three) strategies of enhancing ACh function?

A

1 - cholinesterase inhibitor
2 - modulate release of ACh - drug acts on presynaptic
3 - mimic ACh (agonist) - drug acts on post synaptic

94
Q

Rationale for NMDA receptor antagonist?

A

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
Q

What is the problem with using NMDA antagonists?

A

Cognitive impairment

96
Q

What are undesirable effects of NMDA antagonists?

A

hallucinations
psychosis
dissociative effects
harmful effects on blood pressure

97
Q

Give an example of a NMDA antagonist

A

Memantine

98
Q

How does Memantine work?

A

Prevents excessive stimulation of glutamate (prevents neurodegeneration) but spares normal glutamatergic neurotransmission (hence no memory impairment)

99
Q

What are some low level side effects of memantine?

A
  • hallucinations
  • headache
  • confusion
  • tiredness
  • dizziness
100
Q

What are some ‘non-cognition’ problems associated with dementia?

A
  • depression
  • delusion and hallucinations
  • physical or verbal aggression
  • agitation
101
Q

For the ‘non cognition’ problems listed below, give one possible treatment for each:

  • depression
  • delusion and hallucinations
  • physical or verbal aggression
  • agitation
A
  • SSRIs e.g citalopram
  • antipsychotic (not really efficient)
  • carbamazepine
  • benzodiazepine and busiprone

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