Biomarkers for neurodegenerative diseases Flashcards
General things about neurodegenerative diseases
Overlap in symptoms: dementia, motor
function
Long prodromal stage
Also classified as proteinopathies (proteins aggregate)
Pathogenesis not known
Are becoming more prevalent
100% sure diagnosis only at autopsy (looking at brain after death is still gold standard)
What is a biomarker?
Parameter that can be easily measured Underlies the disease pathology Helps diagnose disease Helps monitor disease progression/response to therapy Is not too unpleasant for the patient
E.g. bloodsugar for diabetes
Sensitivity
ability to correctly identify all those with disease (might lead to false positives)
Specificity
only identify those with the disease (will lead to false negatives)
AD prevalence
10-20% in population in over 65.
Most common type of AD
most patients (99%) have sporadic (non-genetic) form
Duration of AD
8-10 yrs, but can be 20-30 yrs
Length of prodromal AD phase
10-20 years
Protein aggregation in AD
beta-amyloid & phosphorylated tau
dominant theory on AD pathology
dominant theory: tau + beta-amyloid aggregation are toxic and lead to the other changes
Clinical diagnosis based on:
- Typical clinical features (dementia, in particular memory loss)
- Absence of alternative explanation (i.g. infection, metabolic)
- Progressive nature (can’t be too progressive –> might be another disorder)
The 3 biomarkers of AD
A - β amyloid deposition
T - pathologic tau
N - neurodegeneration
2 methods to access biomarkers of AD
imaging and through fluids (CSF)
Imaging methods to see markers of AD
β amyloid: Aβ positron emission tomography (PET)
pathologic tau: tau PET
neurodegeneration: MRI atrophy or FDG-PET
First biomarker of AD in prodromal phase
β amyloid
issues with FDG PET
accuracy of FDG PET decreases in older patients. In 60’s it’s almost 100% sensitivity, but in older it drops with 20%
Tau/β amyloid tracer trade off?
Tau tracer is highly specific for AD, however less sensitive than amyloid
CSF beta-Amyloid - 2 isoforms?
Aβ 42/40 ratio
placks are of the 42 type, but the total concentration is determined by 40 (more common)
in AD: 42 goes lower than in controls (ratio is senitive to that) - couterintuitive, but perhaps it’s becuase the aggragated version is stuck in the brain (but nobody knows why)
Measuring Tau in CFS?
Total vs phosphorylated Tau
Total Tau is marker of neuronal degeneration, phosphorylated tau is more for the clinical tool (diagnostic marker)
combination gives highest diagnostic certainty and is used in unclear clinical cases
In what other fluid than CSF can we measure protein aggregation?
In the blood
phosphorylated tau in blood-plasma correlated with which 2 things?
phosphorylated tau in CSF samples and disease progression
What are the “new” AD diagnostic criteria?
ONLY using biomarkers: beta-amyloid: pathological change beta-amyloid + tau: AD amyloid + tau + neurodegeneration: AD no beta-amyloid = no AD
Glial-types elevated in AD?
Astroglia and microglia
Possible future marker to see if MCI will progress to AD or not?
A metabolomic called 2,4-dihydroxybutanoic acid, which is up-regulated in those who progress
How/when is 2,4-dihydroxybutanoic acid up-regulated?
2,4-dihydroxybutanoic acid is up-regulated when we have cell stress and the Crebs cycle is disturbed
3 types of miRNA that are changed in AD?
hsa-miRNA 135a, 125b & 146a –> their pattern is opposite in cancer
The future of AD treatment
We hope to be able to treat individually based on biomarkers present (personalized treatment like we see with cancer patients)
How do we currently diagnose PD?
clinical signs - you need bradykinesia, tremor and rigidity
prodromal symptoms for PD
loss of smell, constipation and sleep problems.
RBD as a sleep disorder is a big one
What is RBD?
A sleep disorder - patients act out their dreams (moving legs while running) - 90% of those with RBD will get PD
Brain scan to diagnose PD
SPECT with ioflupane (I123-FP-CIT, or DaTSCAN)
Difference in SPECT and PET
PET it sends out a positron and SPECT a gamma ray
Issues with using SPECT to diagnose PD?
Slow specificity - reduced tracer uptake is also seen in those with MSA as well as PD
Non-brain imaging to diagnose PD?
MIBG-SPECT (measures sympathetic activation of the heart). This method don’t respond to MSA patients and is therefore more specific than SPECT with ioflupane
Which protein is phosphorylated and aggregated in PD?
alpha-synuclein
Why is it hard to measure alpha-synuclein in CSF?
Because of how little alpha-synuclein there is in the CSF
Is Oligomeric synuclein a good marker for PD?
No, not specific enough
real-time quaking induced conversion (RT-QuIC)
Similar to PMCA - method where you amplify the aggregated alpha-synuclein by feeding the seed with “healthy/cellular” alpha-synuclein
Why is CSF not a good tool in diagnosis?
It’s painful to extract
alpha-synuclein can be found in the PNS. Which types of PNS biopsies do we take?
Submandibular gland biopsy
Colonic biopsy
Skin biopsy
Effectiveness of a submandibular biopsy in PD diagnosis?
Not good - painful procedure and 50% of the time we don’t get the right tissue
Effectiveness of a colonic biopsy in PD diagnosis?
A bit better than the submandibular biopsy - the specificity/sensitivity is supposed to be better, but it’s still unclear. Again, the biopsy is painful
Effectiveness of a skin biopsy in PD diagnosis?
Highly specific (100%), about 80% sensitive - easier to obtain than the other biopsies
How can we improve the specificity/sensitivity of a skin biopsy for PD diagnosis?
Combining the tissue with real-time quaking induced conversion to amplify the protein
A PD marker other than alpha-synuclein?
Oxidised DJ-1 - the gene is a causative gene of a familial form of Parkinson’s disease (PARK7), but the oxidised protein is not very specific
Current biomarkers of PD used in diagnosis?
Loss of smell and cardiac sympathetic denervation (as support to the clinical symptoms)
Does protein pathology define PD?
the protein levels are a correlation and it’s not proven what causes what - in older individuals we see people with high protein deposits and they had no clinical symptoms
it’s also been found that those with more protein aggregation lives longer
Take-home messages
- AD is associated with beta-amyloid and tau pathology
- PD is associated with alpha-synuclein pathology
- Association ≠ causation
- Protein deposits are very helpful biomarkers
- As of now AD and PD are diagnosed clinically based on expert opinion (that can be a supported by biomarkers)
- Diagnosis is shifting from clinical towards protein-based diagnostic tests
- A combination of diagnostic tests will likely be required for early detection and monitoring of progression
