Alzheimer's Disease Flashcards Preview

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Flashcards in Alzheimer's Disease Deck (72):
1

What are the 4 characteristic brain hallmarks of alzheimer's disease?

Amyloid beta plaques
Neurofibrillary Tau tangles
Inflammation
Glycation

2

What part of the brain does AD start in?

Lateral enterorhinal cortex

3

What regions does AD spread to after the lateral enterorhinal cortex?

cortical regions like the parietal cortex

4

What happens to the brain in AD?

Shrinks and loses grey matter.
Shutdown in brain metabolism and loss of activity.
(brain atrophy)

5

How many amino acids long are Abeta plaques?

42

6

What is Tau part of?

the cytoskeleton- the microtubule stabilising protein

7

What are the microglia?

Resident brain macrophages. The immune cells in the brain

8

What do microglia do?

Clean up damaged neurones

9

Are advanced glycation end products intra or extra cellular?

Extracellular

10

What do advanced glycation end products reflect?

Sugar modification and oxidation through radical type damage of proteins in the brain

11

98% of AD cases are what?

Sporadic

12

Sporadic AD cases have an age of onset of what?

>65 years

13

Carrying one copy of ApoE4 allele increases your risk of AD by what?

4 times

14

ApoE2 allele increases your risk of AD or protects you?

Gives you protection

15

Genetic forms of AD account for what % of the population?

less than 1%

16

What types of neurones are lost in AD?

Cholinergic

17

Is the presynaptic or postsynaptic side of the neurone lost first?

Presynaptic

18

What is the therapeutic idea with regards to cholinergic neurones?

Maintain acetylcholine in the synapse

19

How is acetylcholine maintained in the synapse?

By blocking acetylcholinesterase

20

What are the three acetykcholinesterase inhibitors?

Aricept (donepezil hydrocholride)
Exelon (rivastigmine)
Reminyl (galantamine)

21

Acetylcholinesterase inhibitors are recommended for what form of AD?

Mild to moderate

22

what percentage of individuals show some benefit from acetylchilinesterase inhibitors for a limited amount of time?

50-60%

23

What is Ebixa (memantine)?

NMDA receptor antagonist

24

What type of AD is memantine recommended for?

Moderate to severe

25

What system does Ebixa (memantine) target?

Glutamate

26

What are glutamate ion channels important in?

Memorry

27

Over activation of glutamate ion channels is associated with what?

Brain damage

28

What does Ebixa (memantine) mimick?

Magnesium

29

What removes Ebixa (memantine) from the glutamate ion channel?

Action potential (not background activity)

30

Why is it important that Ebixa (memantine) doesn't permanently block glutamate channels?

They are needed for brain cognition and memory

31

What is the problem with MK-801?

It is not thrown out by synaptic activity so causes a global blockade. Side effects outweighed the benefits.

32

Os a combination of ChEI and Memantine prescribed routinely anywhere?

No

33

What do ChEI and Memantine do?

ChEI return signalling towards normal
Memantine reduces the background noise

34

What is the first step of the emyloid cascade hypothesis?

Changes in AB metabolism
-increase in total AB production
-increase in the Ab42/AB40 ratio
-reduced AB degradation/clearance

35

What happens after the initial changes in AB metabolism?

Oligomerisation of AB42 and initial AB42 deposits

36

What are the main steps of Amyloid cascade hypothesis?

Changes in AB metabolism
Oligomerisation and deposition of AB42 deposits
Inflammatory response
Neuronal injury
Oxidative injury
Oligomerisation and hyperphosphorylation of tau
Cell death associated with NT deficits

37

What happens if APP is cut by a-secretase?

No amyloid beta formation

38

What happens if APP is cut by b-secretase?

Leads to amyloid beta peptides

39

Where do almost all of the mutations in APP sit?

At or alongside the beta-secretase cleavage site

40

Where do all the familial mutations lie?

Gama-secretase

41

What is Semagacestat (LY450139)?

Y-secretase inhibitor

42

Why was the phase 3 trial for Semagacestat halted?

Failed to slow disease progression, made cognition worse and increased the risk of skin cancer

43

What is Verubecestat (MK-8931)?

B-Secretase inhibitor

44

What do initial phase 1 studies report for Verubecestat?

Reductions in AB40, !B42 and sAPPB in the CSF

45

What is the theory behind the use of anti-AB antibodies?

-Plaque breakdown
-Peripheral sink
-Aggregation inhibitor

46

How does plaque breakdown occur with anti-AB antibodies?

Plaques are destroyed through Fc-mediated phagocytosis by microglia

47

How does the peripheral sink occur with anti-AB antibodies?

The formation of antigen-antibody complexes in the periphery sequesters amyloid away from the brain

48

How does 'aggregation inhibition' occur with anti-AB antibodies?

Formation of antigen-antibody complexes prevents amyloid beta from accumulating in plaques.

49

What are the two forms of active immunisation?

Immunisation with intact AB42 peptide
Immunisation with AB fragments

50

What is passive immunisation?

Immunisation with anti-AB antibodies

51

What type of immunisationis AN1792?

Active

52

What is AN1792?

Aggregated synthetic human AB1-42

53

Why was the AN1792 trial halted?

18 patients developed meningoencephalitis

54

What was the AN1792 trial result?

Halted due to meningoencephalitis,
Clearance of cortical amyloid plaques
No clear evidence of clinical response

55

What type of immunisation is Bapineuzumab?

Passive

56

What is Bapineuzumab?

A monoclonal humanised antibody which recognises AB1-5

57

What was the outcome of Bapuneuzumab?

Reduction in cerebral AB load
Limited evidence of clinical benefit

58

What type of immunisation is Solanezumab?

Passive

59

What is Solanezumab?

A humanised monocloncal antibody which preferentially binds to soluble forms of AB (AB13-28)

60

What did the Solanezumab trial fail?

Failed to reach endpoints

61

What type of immunisation is Aducanumab?

Passive

62

What is Aducanumab?

A human monoclonal antibody

63

What do mutations in Tau lead to?

Fronto-Temporal Dementia

64

Why is Tau better for targeting than AB?

It correlates much better with the appearance of symptoms

65

What is Rember?

Tau aggregation inhibitor

66

What are two drugs which target tau pathology?

Rember
GSK3B inhibitors

67

What adverse effect did GSK3B inhibitors cause?

Liver toxicity

68

How do we reduce tau pathology?

Inhibit phosphorylation

69

What was the outcome of the trials for the first drug to target tau tangles?

Reduced brain shrinkage
Scores on cognition and performance significantly improved

70

What are the 6 targets for disease progression?

Amyloid beta
Tau
Unfolded protein response
Oxidative stress
Apoptosis
Inflammation

71

When do AB changes occur?

10/20 years before you see any symptoms

72

What evidence is there that we have the wrong target for drugs (AB)?

AB observed in non demented brains.
AB vaccination cleared plaques but no cognitive benefit.