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Brain PD > week 8 part 2 > Flashcards

week 8 part 2 Flashcards

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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

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2
Q

What is the hallmark of dementia?

A

memory loss

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3
Q

What do all the combined factors lead to?

A

Difficulty with day to day living

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4
Q

What is the incidence of dementia?

A

aprrox at 850,000

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5
Q

Who will suffer from dementia in their life time?

A

1 in 3 people born in UK

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6
Q

What is Mini mental state Examination and also Montreal Cognitive Assessment (MoCA)

A

widely used screening assessment for detecting cognitive impairment.

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7
Q

General Practitioner Assessment of Cognition (GPCOG) Score?

A

GP screening tool for dementia

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8
Q

What is Clock drawing test?

A

Tests visual-spatial skills which are often declined in Alzheimer’s patients and dementia sufferers

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9
Q

Alzheimer’s disease

A

60% of all dementia cases

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10
Q

What are different forms of Dementia?

A
  1. Frontotemporal dementia
  2. Parkinson’s dementia
  3. Dementia with other Lewy bodies
  4. Vascular dementia
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11
Q

What did Alzheimer’s notice?

A
  1. Impaired memory disorentiation

2. The inability to use language and psychosocial incompetence

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12
Q

What are the 2 pathological hallmark?

A
  1. Plaques (between neurons)

2. Tangles (within neurons)

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13
Q

what are amyloid plaques?

A

Extracellular accumulations composed of abnormally folded amyloid-beta with 40 or 42 amino acids

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14
Q

What are two by-products of amyloid precursor protein metabolism?

A
  1. AB40

2. AB42

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15
Q

What is found within plaques?

A

AB42
more abundant

higher rate of fibrillisation and insolubility

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16
Q

Where is there huge abundance of amyloid in?

A

Alzheimer’s disease patient brain

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17
Q

What is Tau?

A
  1. microtubule-associated protein
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18
Q

What does Tau have a role in?

A
  1. Microtubule stabilisation

2. Axonal transport

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19
Q

What is Tau-microtubule binding maintained by?

A

co-ordinated action of kinases and phosphatases

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20
Q

What does phosphorylation of tau regulate?

A

its activity to bind to microtubules

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21
Q

What does hyperphosphorylation of tau result in?

A

formation of neurofibrillary tangles

composed of paired helical filament of tau

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22
Q

What is Alzheimer’s disease neurodegeneration?

A
  1. Extreme shrinkage of the hippocampus
  2. Extreme shrinkage of the cerebral cortex
  3. Severely enlarged ventricles
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23
Q

Early onset Alzheimer’s disease

A
  1. age 30-50

2. mutation in APP = PSEN1/PSEN2

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24
Q

Late onset Alzheimer’s disease

A

develops over age of 60

driven by a complex interplay of genetic and environmental factors

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25
Q

What has been implicated as a strong genetic risk factor?

A

Apolipoprotein E gene (ApoE)

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26
Q

What is APP?

A

transmwmbrane protein

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27
Q

What are the roles of APP?

A
  1. Neural proliferation
  2. Migration
  3. Differentiation
  4. Plasticity and synaptogenesis
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28
Q

What is associated with familial forms of early-onset ALZHEIMER’S DISEASE AS WELL AS CEREBRAL AMYLOID ANGIOPAHTY?

A

mutations in APP

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29
Q

What do mutations in APP generally increase?

A

AB production

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30
Q

What decreases AB production and is protective of Alzheimer’s disease?

A

A673T mutation

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31
Q

What 3 secretases cleaves APP?

A
  1. alpha secretases
  2. Beta secretases
  3. Gamma secretases
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32
Q

Where is APP cleaved in?

A

non-amyloidogenic pathway and amyloidogenic pathway

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33
Q

What does Amyloidogenic pathway lead to/?

A

Production of AB 40-42 which form fibrillar insoluble plaques between neurons

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34
Q

What does alpha secretases generate?

A

P53

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35
Q

What does beta secretases generate?

A

amyloid-beta 40-42 fragments

36
Q

What are subunits of gamma-secretases?

A
  1. PSEN1

2. PSEN2

37
Q

What is responsible for AB generation?

A

Aspartyl protease

38
Q

What have been reported in PSEN1?

A

over 200 mutations

39
Q

What have been reported in PSEN2?

A

approx 40 mutations

40
Q

What is the most common cause of early-onset AD?

A

PSEN1

41
Q

What is the rare cause of early-onset AD?

A

PSEN2

42
Q

What have PSEN mutations been shown to impair?

A

Gamma-secretases function

Drive amyloidosis through changes in the AB42/AB40 ratio

43
Q

What is Apolipoprotein E (ApoE)?

A

A secreted lipoprotein involved in cholesterol metabolism

44
Q

What are 3 alleles of ApoE gene?

A
  1. ApoE2
  2. ApoE3
  3. ApoE4
45
Q

What is ApoE4?

A

A strong risk factor for late-onset AD

46
Q

What has ApoE4 shown to decrease?

A

clearance of extracellular AB

47
Q

What does amyloid hypothesis explain?

A

explains both early on set and late onset of AD contribution to Dementia

48
Q

What is ACH involved in?

A

Critical physiological process including within attention, learning and memory

49
Q

Where is ACH synthesised from?

A
  1. Choline

2. Aceytl- coenzyme A by choline acetyltransferase (ChAt)

50
Q

How is ACH transferred into synaptic vesicle?

A

Vesicular acetylcholine transporter (VaChT)

51
Q

What promotes ACH exocytosis?

A

Pre-synaptic neuron depolarisation

52
Q

Where does ACH bind to?

A

Nicotinic or muscarinic receptors leading to a stimulatory or inhibitory response

53
Q

Where is ACH rapidly hydroylsed by?

A

acetylcholinesterase (AChE)
releasing acetate and choline
recycled into pre-synaptic neuron by high-affinity choline transporter (CHT1)

54
Q

What are particularly affected in AD?

A

Cholinergic neurons

55
Q

What is a major correlate of cognitive impairment?

A

synaptic loss

56
Q

what can promote amyloid fibril formation?

A

AChE

57
Q

What can pharmacological intervention help?

A

Improve symptoms of AD

58
Q

who are prescribed acetylcholinesterase inhibitors?

A

A person with mild to moderate AD

59
Q

What do AChE inhibitors act to increase?

A

ACH levels

alleviate cognitive symtpoms - problems with memory, language, judgement

Allow a patient to continue with activities of daily living

60
Q

What are examples of AChE inhibitors?

A
  1. Donepezil
  2. Galantamine
  3. Rivastigmine
61
Q

What is a result of synaptic dysfunction and has been associated with a number of neurodegenerative disorder?

A

NMDAR overactivation

Subsequent glutamate mediated neurotoxicity

62
Q

What is excessive glutamate associated with?

A

Intense transient influx of Ca2+
impairment in mitochondrial function
ATP depletion
formation of reactive oxygen species

63
Q

What is Memantine?

A

Low affinity NMDA receptor antagonist that blocks excessively open NMDA receptor ion channel to reduce glutamate mediated neurotoxicity

64
Q

What does amyloid strategies include

A
  1. Inhibition of secretases involved in APP metabolism

2. Anti-amyloid immunotherapy

65
Q

What is anti-amyloid immunotherapy divided into?

A
  1. Active approaches (development of anti-AB42 vaccine)

2. Passive approaches (Administration of anti-AB42 antibodies)

66
Q

What does anti-tau strategies include?

A
  1. Tau phosphorylation inhibition

2. Anti-tau immunotherapy

67
Q

How can Tau hyperphosphorylation be reduced by?

A

Inhibiting GSK3 (lithium treatment)

68
Q

What is AAD-vac1?

A

Vaccine targeting structural determinants on disordered Tau

Crucial for pathological tau-tau interactions

69
Q

What is AAD-vac1 currently undergoing?

A

phase 2 clinical trials for AD

70
Q

What is MMSE?

A
  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
Q

What is Montreal cognitive assessment?

A
  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
Q

What is GPCOG?

A
  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
Q

What does CPCOG consist of?

A
  1. Time orientation
  2. Information
  3. Recall test
74
Q

What is the order of biomarker unravelling pathogenic cascade?

A
  1. AB
  2. Tau-mediated neuronal injury and dysfunction
  3. Brain structure
  4. Memory
  5. Clinical function
75
Q

In typical cases of Alzheimer’s disease where does AB deposition precede?

A
  1. Neurofibrillary and neurotransmission changes

2. Apparent origin in the frontal and temporal lobes, hippocampus and limbic system

76
Q

Where does the neurofibrillary tangle and neurotic regeneration start?

A
  1. Medial temporal lobe
  2. Hippocampus
  3. Progressively spread to other areas of the neocortex
77
Q

What is Alzheimer’s disease associated with?

A
  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
Q

What is AB derived by?

A
  1. Proteolytic cleavage of APP by complex family of enzymes (gamma secretases and Beta-secretases) which include PS1 and PS2
79
Q

What is ~70% of AD risk attributable to?

A

Genetic factors

80
Q

What genes are thought to influence amyloid precursor protein metabolism?

A
  1. APP
  2. PSEN2/PSEN1
  3. ADAM10
  4. PLD3
  5. SORL1
  6. ABCA7
  7. PICALM
  8. CLU
  9. INPP5 D
81
Q

What genes are thought to influence tau metabolism?

A
  1. CASS4
  2. FERMT 2
  3. BIN1
82
Q

GWAS have identified more than 20 genetic risk factors, what do these implicate in?

A
  1. Inflammatory metabolism
  2. Cholesterol metabolism
  3. Endosomal-vesicle recycling pathways
83
Q

What is now recognised to play a key role in AD pathogensesis?

A

Microglia activation in response to amyloid deposition

84
Q

What is now recognised to play a key role in AD pathogensesis?

A

Microglia activation in response to amyloid deposition

85
Q

A deeper cut

A
  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
Q

What is AB amyloid hypothesis’s?

A
  1. Amyloid plaque resulting from AB overproduction or reduced clearance
  2. AB-amyloid induced synaptic- and neurotoxicity
  3. Neurodegeneration
87
Q

Why has numerous clinical trials of anti-amyloid agents have not met their pre-specified endpoints?

A
  1. Inadequate preclinical data
  2. Poor brain penetration
  3. Little human biomarker change
  4. Low therapeutic index

Brain PD (15 decks)

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