CSF AD biomarkers in clinical practice Flashcards
What is the difference between Alzheimer’s disease and dementia?
Dementia is a general term that encompasses many brain specific diseases, Alzheimer’s disease is a specific brain disease.
What biomarkers/indications are there for Alzheimer’s?
- A-beta
- Tau-mediated neuronal injury and dysfunction
- Structural brain changes
- Memory loss
- Clinical function
Why are biomarkers important?
To know what’s happening in the brain for:
- diagnosis
- prognosis
- disease monitoring
What is currently going wrong in the diagnosis of Alzheimer’s Disease (AD) and what consequences does this have?
1 in 4 AD diagnosis are wrong and AD is often missed (especially in early stages), the consequences are:
- Misinformation and uncertainty
- Less optimal symptomatic treatment
What are characterstics of frontotemproal dementia?
- Loss of social cognition
- Behavioral abnormalities
- Language variants
What are characteristics of lewy body dementia?
- Extrapyramidal symptoms (i.e. most frequently involuntary movements)
- REM sleep behavioral disorder
- Autonomic dysfunction
- Hallucinations
- Fluctuations
What are characteristics of vascular dementia?
- Executive dysfunction
- Bradyphrenia (slow thinker)
- Focal neurological signs
What is important to take into consideration when developing a biomarker?
That you always need to interpret within the whole context of the patient (as part of a full clinical work-up). Thus, the biomarker needs to reflect the brain pathology.
What biomarkers reflect the core pathology of Alzheimer’s Disease?
- Amyloid plaques
- Tau tangles
- Neurodegeneration
Fill in if the biomarkers increase or decrease in the CSF of AD patients
- AB42
- p-tau
- t-tau
- AB42 → decreases
- p-tau → increases
- t-tau → increases
Biomarkers such as amyloid-beta are detected with the use of immunoassays such as ELISA. How does ELISA work?
- Coating → antibodies (primary antibody) are adhered to e.g. wells.
- Blocking → sample (with antigens) i.e. CSF is loaded onto the wells and antigens bind to their specific antibody
- Detection → enzyme conjugated detection antibody (secondary antibody) binds antigen
- Readout → substrate is catalyzed by enzyme to generate colored readout
A newer technique to ELISA is electrochemiluminescence. How does this technique work?
This technique uses two antibodies from the start on:
- the sample (e.g. CSF) is incubated with two antibodies. One is bound to a magnetic bead, the other antibody binds to the antigen.
- The two antibodies form a ‘sandwich’ with the antigen inbetween.
- The ‘sandwich’ is then moved to a measurement cell, where a magnetic force binds the beads to the surface of the cell
- The complexes with no antigen bound are washed off and the remaining complexes are analyzed.
So (CSF or blood) biomarkers can be measured with the use of ELISA or electrochemiluminescence. Another way to measure biomarkers is with PET scans, where amyloid depositions can be visualized.
- What is seen when comparing biomarker measurement via ELISA with biomarker measurement via PET scans?
- What is seen when comparing biomarker measurement via electrochemiluminescence with biomarker measurement via PET scans?
- When comparing ELISA to PET scans, it is seen that a large part of the samples measured via ELISA are PET negative. So this means that ELISA might be more sensitive to measure biomarkers like amyloid-beta. It can also be the case that ELISA is more prone to false-positives.
- When comparing electrochemiluminescence to PET scans, it is seen that a large part of the samples measured via electrochemiluminescence are PET positive. So this means that electrochemiluminescence might be less sensitive to amyloid-beta, but it’s also possible that electrochemiluminescence is more prone to false-negatives.
