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NEUR0010 > Biomarkers in Early Phase Clinical Trials: Alzheimer's Disease > Flashcards

Biomarkers in Early Phase Clinical Trials: Alzheimer's Disease Flashcards

1
Q

What are the approaches taken to prevent neurogeneration in AD?

A 
Inhibit AB synthesis
Increase AB clearance
Decrease inflammation
Inhibit tau tangle formation
Modulate neurotransmission (increase ACh)
Decrease excitotoxicty
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2
Q

What are the causes of decreased synaptic efficacy early in the neurodegeneration cascade?

A

Inflammation
Mito dysfunction
Protein misfolding and trafficking
Decreased neurogenesis

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3
Q

Name 5 key pathologies of AD

A 
Gradual accumulation of neurofibrillary tangles and AB plaques
Synapse loss
Neuronal loss
Dendritic pruning
Grey matter atrophy
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4
Q

When can AD diagnosis be certain rather than probabilistic?

A

Post-mortem

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5
Q

Which feature of AD affects drug trial randomisation and can affect the apparent trial outcome?

A

Variable rates of decline between different AD patients

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6
Q

What are the 2 prognosis biomarker types for AD?

A

Prospective - need clinically - predict who will develop AD

Retrospective - which participants developed AD at end of study - correlate with measured features

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7
Q

How can biomarkers be used in drug trials?

A

Measure effects of drugs

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8
Q

What are the 3 levels of disease treatment?

A

Tertiary - treat symptoms
Secondary - cure disease
Primary - prevent disease

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9
Q

Which test is widely used to measure cognitive enhancement in AD drug trials?

A

ADAS-Cog

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10
Q

Name 2 AChesterase inhibitors used to treat AD

A

Aricept

Phenserine

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11
Q

How has the placebo effect changed in recent AD drug trials and what is the effect of this?

A

Lasts longer

Need longer study times to see drug effect

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12
Q

What are the 2 main parameters which must be decided in an AD drug trial?

A

Slow/fast decliners

Point in disease to give drug - mild/moderate/severe patients

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13
Q

Which AD patient type is usually best to test and why?

A

Slow severe
Large margin of intervention
Easier to detect effect - large difference between normal and disease

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14
Q

What is a weakness of testing severe AD patients in drug trials?

A

May have already crossed line for disease being irreversible

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15
Q

How can PET imaging be used as an AD biomarker?

A

Detect if drug getting to brain

Detect AB accumulation

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16
Q

What is a weakness of amyloid PET imaging and what is the effect of this?

A

Amyloid signal strength does not predict disease severity - non-linear relationship
Cannot use as selectivity criteria for trials/to test effect of drug

17
Q

How can structural MRI be used as an AD biomarker?

A

Measure brain volume

18
Q

What is a strength of brain structural MRI?

A

Linear correlation between brain atrophy and cognitive performance

19
Q

What is a weakness of brain structural MRI?

A

Long time needed to see changes - low sensitivity

20
Q

Name 3 types of potential CSF AD biomarkers

A

Phospho-tau
Total tau
AB42

21
Q

How can PET be used as an AD biomarker?

A

Quantitative measure of brain metabolism

Measure binding densities of ligands to receptors - after giving drug

22
Q

Name the 2 types of functional PET

A

FDG-PET

rCBF-PET

23
Q

What is the function of FDG-PET?

A

FDG is sugar

More absorbed by fast-growing cells

24
Q

What is the function of rCBF-PET?

A

Measures cerebral bloodflow

Shows areas with increased metabolic demand - increased activity

25
Q

How can fMRI be used as an AD biomarker?

A

Shows areas with increased activity

Correlate brain activity changes with blood drug concentration/receptor occupancy

26
Q

How can EEG be used as an AD biomarker?

A

Record event-related potentials

27
Q

How is EEG activity altered in AD?

A

General slowing
Increased delta and theta (low frequency) power
Decreased alpha and beta power

28
Q

What is a weakness of EEG as a biomarker of AD?

A

Delta and theta (low frequency) activity can be abnormal in healthy elderly and multiple diseases

29
Q

Name the 2 event-related potentials recorded with EEG

A

P300

Mismatch negativity

30
Q

What is P300 and when does it occur?

A

Large positive voltage wave

~300ms after rare auditory stimulus embedded within sequence of standard stimuli

31
Q

What is P300 a measure of?

A

Reaction time - info processing speed

32
Q

How is P300 altered in AD?

A

Decreased amplitude

Increased latency

33
Q

How do AChesterase inhibitors affect P300 in AD patients?

A

Decrease latency

Increase amplitude

34
Q

What is a weakness of P300 as an AD biomarker?

A

Large EEG variability between individuals - hard to determine drug effect

35
Q

What is mismatch negativity and what causes it?

A

Part of auditory ERP

Caused by infrequent change in repetitive sound

36
Q

What is mismatch negativity a measure of?

A

Auditory discrimination

37
Q

How is mismatch negativity altered in AD?

A

Decreased amplitude

38
Q

How do AChesterase inhibitors affect mismatch negativity in AD patients?

A

Increase amplitude

NEUR0010 (9 decks)

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