Clinical Research in AD

Question 1

Transition from Normal Ageing To AD

Answer 1

Normal ageing -> MCI -> probable AD -> definite AD

Time taken from MCI to death is highly variable, averaging between 2-15 years

The only definitive diagnosis of AD is through post mortem analysis of the brain to identify amyloid plaques and neurofibrillary tangles

Question 2

Study Design in AD

Answer 2

AD may take 15 years to reach clinical threshold even though amyloid has been accumulating in this time

For many years the neuronal death can be compensated so no symptoms are presents

This means the length of study and application of biomarkers has to be carefully considered based on stage of disease and type of trial

Question 3

Primary Prevention

Answer 3

Aims to prevent onset of disease
Patients have normal cognitive function but evidence of some amyloid accumulation
Aims to stop progression to clinical symptoms

Question 4

Secondary Prevention

Answer 4

Clinical symptoms of disease have started but you want to stop the disease progressing any further

Typical stage used in many studies

Question 5

Tertiary Prevention

Answer 5

Symptomatic agents to help manage the disease

Makes no difference to course of disease

Question 6

Patient Severity

Answer 6

There is such variable progression in individuals which can result in very different rates of decline

If patients are slow decliners it can be difficult to tell if the slow progression is due to the drug intervention or is just the natural progression of the disease

Question 7

Patient Stratification

Answer 7

Aim to include patients who have mild disease before there is significant irreversible neuronal loss

May include different cutoff points for high/low drug responders

Question 8

Cognitive Measures

Answer 8

MMSE and ADL

ADAS-Cog

CIBIC-plus (clinician and caregiver input)

Question 9

Fluid Biomarkers

Answer 9

Blood and CSF biomarkers used to improve the probability of a correct diagnosis

BUT the levels of amyloid do not linearly correlate with clinical progression

Question 10

Volumetric MRI with Digital Corrections

Answer 10

Uses volumetric MRI but digitally corrects artefacts from any slight changes in position

This increase reproducibility of the data and allows differences to be seen in a shorter time period -> reduces the length of clinical trials

There is a very comparable brain volume loss in controls over time, but huge differences in AD

Question 11

EEG in AD

Answer 11

AD shows a general activity slowing
- increased delta and theta (BUT changes in many conditions and also with age)
- decreased beta and alpha

Many drugs have little effect on EEG outputs

Question 12

Event Related Potentials

Answer 12

Voltage wave occurs after presentation of an auditory stimulus

Reaction time gives an idea of speed of information processing

In AD there is reduced amplitude and increased latency of P300 wave
- may correlate with disease progression

Question 13

Mismatch Negativity

Answer 13

Response elicited by an infrequent change in a repetitive sound

Objective measure of auditory discrimination and sensory-memory processing

Decrease amplitude in AD (but also in other CNS disorders)

Question 14

MEG

Answer 14

Records the magnetic field generated by electrical activity in the brain

Few studies in AD but they do show consistent results with EEG
- increased low-frequency power
- decreases high-frequency power

Question 15

Considerations in Clinical Research

Answer 15

1. Reproducibility of results
2. Within and between subject test-retest validity
3. Marker validation in prospective studies
4. Learning effect in cognitive testing
5. Correlation of fluid biomarkers