Biomarkers in Early Phase Clinical Trials: Alzheimer's Disease Flashcards
What are the approaches taken to prevent neurogeneration in AD?
Inhibit AB synthesis Increase AB clearance Decrease inflammation Inhibit tau tangle formation Modulate neurotransmission (increase ACh) Decrease excitotoxicty
What are the causes of decreased synaptic efficacy early in the neurodegeneration cascade?
Inflammation
Mito dysfunction
Protein misfolding and trafficking
Decreased neurogenesis
Name 5 key pathologies of AD
Gradual accumulation of neurofibrillary tangles and AB plaques Synapse loss Neuronal loss Dendritic pruning Grey matter atrophy
When can AD diagnosis be certain rather than probabilistic?
Post-mortem
Which feature of AD affects drug trial randomisation and can affect the apparent trial outcome?
Variable rates of decline between different AD patients
What are the 2 prognosis biomarker types for AD?
Prospective - need clinically - predict who will develop AD
Retrospective - which participants developed AD at end of study - correlate with measured features
How can biomarkers be used in drug trials?
Measure effects of drugs
What are the 3 levels of disease treatment?
Tertiary - treat symptoms
Secondary - cure disease
Primary - prevent disease
Which test is widely used to measure cognitive enhancement in AD drug trials?
ADAS-Cog
Name 2 AChesterase inhibitors used to treat AD
Aricept
Phenserine
How has the placebo effect changed in recent AD drug trials and what is the effect of this?
Lasts longer
Need longer study times to see drug effect
What are the 2 main parameters which must be decided in an AD drug trial?
Slow/fast decliners
Point in disease to give drug - mild/moderate/severe patients
Which AD patient type is usually best to test and why?
Slow severe
Large margin of intervention
Easier to detect effect - large difference between normal and disease
What is a weakness of testing severe AD patients in drug trials?
May have already crossed line for disease being irreversible
How can PET imaging be used as an AD biomarker?
Detect if drug getting to brain
Detect AB accumulation
What is a weakness of amyloid PET imaging and what is the effect of this?
Amyloid signal strength does not predict disease severity - non-linear relationship
Cannot use as selectivity criteria for trials/to test effect of drug
How can structural MRI be used as an AD biomarker?
Measure brain volume
What is a strength of brain structural MRI?
Linear correlation between brain atrophy and cognitive performance
What is a weakness of brain structural MRI?
Long time needed to see changes - low sensitivity
Name 3 types of potential CSF AD biomarkers
Phospho-tau
Total tau
AB42
How can PET be used as an AD biomarker?
Quantitative measure of brain metabolism
Measure binding densities of ligands to receptors - after giving drug
Name the 2 types of functional PET
FDG-PET
rCBF-PET
What is the function of FDG-PET?
FDG is sugar
More absorbed by fast-growing cells
What is the function of rCBF-PET?
Measures cerebral bloodflow
Shows areas with increased metabolic demand - increased activity
How can fMRI be used as an AD biomarker?
Shows areas with increased activity
Correlate brain activity changes with blood drug concentration/receptor occupancy
How can EEG be used as an AD biomarker?
Record event-related potentials
How is EEG activity altered in AD?
General slowing
Increased delta and theta (low frequency) power
Decreased alpha and beta power
What is a weakness of EEG as a biomarker of AD?
Delta and theta (low frequency) activity can be abnormal in healthy elderly and multiple diseases
Name the 2 event-related potentials recorded with EEG
P300
Mismatch negativity
What is P300 and when does it occur?
Large positive voltage wave
~300ms after rare auditory stimulus embedded within sequence of standard stimuli
What is P300 a measure of?
Reaction time - info processing speed
How is P300 altered in AD?
Decreased amplitude
Increased latency
How do AChesterase inhibitors affect P300 in AD patients?
Decrease latency
Increase amplitude
What is a weakness of P300 as an AD biomarker?
Large EEG variability between individuals - hard to determine drug effect
What is mismatch negativity and what causes it?
Part of auditory ERP
Caused by infrequent change in repetitive sound
What is mismatch negativity a measure of?
Auditory discrimination
How is mismatch negativity altered in AD?
Decreased amplitude
How do AChesterase inhibitors affect mismatch negativity in AD patients?
Increase amplitude
