University of Groningen
Biomarkers in the differential diagnosis of dementia Reesink, Fransje Elisabeth
DOI:
10.33612/diss.96360985
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Publication date: 2019
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Reesink, F. E. (2019). Biomarkers in the differential diagnosis of dementia: cerebrospinal fluid compounds-and nuclear molecular imaging tracers. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.96360985
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12
Part 1: Cerebrospinal fluid (CSF) biomarkers in dementia
Chapter 2:
Perspectives of CSF biomarkers in dementia in the past,
present and future
13 Valid diagnostic biomarkers are linked to neuropathology, be able to detect the disease early in its course and be able to distinguish it from other dementias, as well as being non-invasive and simple to use, inexpensive and not influenced by symptomatic drug treatment, with a sensitivity and specificity of more than 85%1.
The first Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers were described more than two decades ago, using the ELISA methods,-the INNOTEST assays- for
quantification of total-tau (T-tau), phosphorylated tau (P-tau) and amyloid-β (Aβ42)2,3.
In AD, increased levels of T-Tau and P-tau are found, together with a decreased Aβ42, what reflects the key elements of AD pathophysiology. This AD CSF profile has been validated in numerous subsequent papers with very consistent findings4. High
performance of the core AD CSF biomarkers for the diagnosis of prodromal AD is verified in several large multicentre studies such as the DESCRIPA study5, the ADNI
study6, and the Swedish Brain Power study7. The National Institute on Aging and
Alzheimer’s Association (NIA-AA) working group has embedded the AD CSF biomarkers in their guidelines and clinical criteria of AD8. Recently, the NIA-AA working group has
defined AD as a pathological process, identified primarily by biomarkers grouped into amyloid-β deposition, tau pathology and neurodegeneration(A/T/N classification)9.
CSF, with its matrix in proximity to the brain parenchyma and proteins secreted from the brain extracellular space, is accessible by lumbar puncture. The hypothesis of a decreased CSF Aβ42 with disease progression, is that the hydrophobic peptide
aggregates and become sequestered in plaques, resulting in lower amounts remaining to be secreted to the extracellular space and CSF10. CSF Aβ1-42 and amyloid PET have been
shown to be valuable measures of amyloid plaque pathology11 in inverse relation with
lower CSF Aβ42 and higher positron emission tomography (PET) ligands binding to fibrillary Aβ in the brain12. Although they are regarded as equal measures of amyloid
plaques, they still show a mismatch in 6-21% of MCI and dementia patients and in 17-21% of cognitively healthy subjects13,14. Is has been suggested this is due to different Aβ
isoforms15. Aβ isoforms present in CSF are Aβ1-37, Aβ1-38 and Aβ40. Aβ40 is found
around 10 times higher16 and is less diagnostic than Aβ424, although the CSF ratio
Aβ42/Aβ40 has a higher performance to identify AD than single CSF Aβ4217. CSF Aβ1-37
and Aβ1-38 were found to improve differentiation between AD and Fronto-temporal
dementia (FTD) or dementia with Lewy bodies(DLB)18. CSF T-Tau seems to reflect the
intensity of neurodegeneration or severity of acute neuronal damage and is proposed as a non-specific ‘state marker’ of disease19, predicting more rapid clinical disease
progression20. CSF p-Tau probably reflects the phosphorylation state of tau and is
specific for AD21. Recently, PET Tau-ligands has been developed to visualize Tau
pathology, but the correlation with CSF Tau is still weak22.
One limitation of the ‘core’ CSF biomarkers is the uncertainty how to interpret untypical biomarker patterns. Also, in late-onset AD the severity of neuropathological changes
14 varies and in higher ages, the level of changes overlaps with those found in cognitively unimpaired elderly23. Another limitation of CSF biomarkers is the between-laboratory
variability of 15-25%, most pronounced for CSF Aβ42, according to the Alzheimer’s Association quality control (QC) programme for CFS biomarkers24. These differences
may be caused by pre-analytical procedures (e.g. type of test tube for CSF collection or freeze-thaw schedule) or discrepancies in analytical- and/or manufacturing procedures between laboratories25. Future developments for AD CSF biomarkers will be focus on
fully automated laboratory analyser assays with stable and precise results between laboratories and the establishment of uniform cut-off values26.
Another limitation is that a lumbar puncture is more invasive and CSF is less accessible than serologic markers. Blood brain biomarkers are a far more challenging matrix than CSF. This is caused by the facts that only a fraction of brain proteins enter the
bloodstream. In addition, they may be degraded by proteases in the liver or cleared by the kidneys, and their measurement may be hampered by high levels of plasmaprotein27.
The recent technical developments of novel ultrasensitive immunoassays and mass spectrometry methods are promising for the development of new blood biomarkers 26.
The technique is based on a single-molecule array (Simoa), with high analytical sensitivity (fg/ml) and reduced matrix interference28.
Novel biomarkers focussing on additional aspects of AD pathology, such as synaptic dysfunction and degeneration, are called presynaptic biomarkers. Loss of synapses in grey matter regions of AD is correlated with the degree of cognitive impairement29.
Synaptic proteins in CSF are Synaptotagmin, rab3a, the presynaptic membrane protein SNAP-25 and the dendritic protein neurogranin30. CSF Neurogranin, synaptotagmin-1
(SYT1) and SNAP-25 show promising results, but need validation in future studies31.
Neurofilament light (NF-L) is a Tau-independent CSF marker of non-specific general neuroaxonal degeneration32 and its increase is an inherent feature of AD, which predicts
a more rapid disease progression33. TREM2 (triggering receptor expressed on myeloid
cells 2) is a CSF biomarker of microglial activation34 , recently reported in both dementia
and MCI stages of AD and CSF TREM2 correlate with CSF Tau but not CSF Ab42 concentrations, suggesting that microglial activation occurs in close connection with onset of neurodegeneration35. The association of CSF sTREM2 with protective versus
harmful microglial activation is presently unknown; longitudinal studies with repeated CSF samplings over time are needed to determine this36.
Although CSF biomarkers can differentiate between AD pathology and other pathologies, there is still an absence of a specific CSF biomarker for other dementias. In case of FTD37,
neurofilament light has been identified as a promising biomarker candidate38. For DLB,
α-Synuclein was detected in cerebrospinal fluid (CSF)39 as potential biochemical
biomarker for DLB, with conflicting results; Most studies showed lower CSF levels of total- α-Synuclein in PD and DLB compared to healthy controls and Alzheimer’s disease (AD), but other showed increased levels or no difference at all43. The majority of the
15 pathologically unproven subjects41,42. Complicating methodological factors are the use of
different antibodies and standard proteins in the immunoassays, patient selection, variation in pre-analytical processing and blood contamination from traumatic lumbar puncture40. Synuclein has different species in CSF and immunoassays for total
α-Synuclein (t-α-syn) does not take into account its conformation or aggregation state. Early aggregated or solubable α-Syn oligomers (o-α-Syn) seems to be more neurotoxic and associated with PD and DLB neurodegeneration44. Immunoassays for CSF o-α-Syn is
described to be a promising biomarker for the diagnosis band to monitor disease severity45. Increased levels of soluble o-α-syn are found in PD/ PDD and DLB patients,
compared with other neurodegenerative diseases and healthy controls46.
Phosphorylated α-Syn at serine 129(pSer129-α-Syn) is described as dominant
pathological species of α-syn in post mortem DLB43, although pSer129-α-Syn was not
discriminative as CSF biomarker43. α-Synuclein in blood and saliva is investigated as
potential biomarker , but did not differ between PD and healthy controls, neither correlate with CSF α-Synuclein47,48. Various research groups focus to identify ligands
that have high Synuclein potency and specificity as PET/SPECT ligands for imaging α-Synuclein in vivo, but no suitable PET tracer has been reported yet49.
The next two chapters are published articles (2010 and 2012) about CSF biomarkers (T-tau, P-tau and Aβ42, α-Synuclein)and the potential to differentiate between AD and DLB.
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