Identification and validation of novel fluid biomarkers for dementia

Question 1

What is the value of fluid biomarkers?

Answer 1

used for…
- Diagnosis –> increase diagnostic accuracy
- Prognosis –> predict what will happen
- Treatment –> monitoring/ treatment response
- Understanding diseases ethology

• eg. help discriminate between the different forms of dementia

Question 2

What is the process of developing and validating novel fluid biomarkers?

Answer 2

Phase 1: Biomarker Identification

Phase 2: Initial validation

Phase 3: Retrospective longitudinal studies

Phase 4: Prospective studies

Phase 5: Implementation

Question 3

What are biomarkers?

Answer 3

“a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.”

Question 4

What is the current state of blood-bases biomarkers?

Answer 4

The use of blood-based biomarkers for diagnosis and prognosis of Alzheimer’s disease is near clinical use

Question 5

What is Dementia? What does it entail?

Answer 5

• Progressive impairment of cognitive functions (reasoning, emotional control, memory)

Question 6

What are the different forms of dementia?

Answer 6

1. Alzheimer’s disease
   - cause: Neurofibrillary tangles (NFTs) + amyloid plagues
   - most common form among older adults
   - increased risk mutation: apolipoprotein E4 (APOE)
2. Vascular dementia
   - cause: damage to blood vessels in brain/ interruption of blood flow/oxygen to brain
   - symptoms: difficulties problem-solving. slow thinking, loss of focus and organisation
3. Lewy Body dementia
   - cause: abnormal alpha-synuclein (Lewy bodies) deposits
   - symptoms: visual hallucinations, problem focus and attention, slow movement, tremor, rigidity
4. Frontotemporal dementia
   - cause: abnormal Tau or TDP-43 protein
   - in people younger than 60
   - symptoms: personality, behaviour, language, movement

(5. Mixed dementia)

Question 7

What can make the distinction between different dementia types difficult?

Answer 7

• overlapping clinical features and co-pathologies

Question 8

Challenges and solution on phase 1 (biomarker identification)

Answer 8

Challenge:
- which biomarker to choose from dataset
- cross-technology translation

Solution:

Improve selection process
- disease evaluation
- biological evaluation
- feasibility check
- best practise
–> discussion among junior + senior researchers
–> shortlist 2-5 markers

novel technologies
- ie. mass spectrometry, immunoassay

Question 9

What Phases of the biomarker discovery are the clinical validation? And what do they entail?

Answer 9

• Phase 3 (Retrospective longitudinal studies) –> cross-sectional study (1 point in time)
• Phase 4 (prospective studies) –> longitudinal study (multiple points over time)

Question 10

Why is CSF as a medium for biomarkers interesting?

Answer 10

• easiest way to look at brain without biopsy of brain
• alternative is looking at brain after death - always looking at end stage
• fundamental research (not much known about CSF)
• excreted proteins seen here most