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Paraskevas. Neuroimmunol Neuroinflammation 2020;7:183-93 I http://dx.doi.org/10.20517/2347-8659.2019.008 Page 187

which depends on normal, border-zone or abnormal biomarker levels, has been suggested to determine the
[81]
[80]
level of neurochemical probability for (or against) AD in both dementia and pre-dementia stages .
In case of atypical, conflicting or inconclusive CSF biomarker results, other neurochemical and/or imaging
[50]
biomarkers, and/or later repetition of CSF sampling and analysis may be necessary .

VARIABILITY OF BIOMARKER RESULTS
Despite intensive research, there is still a significant inter- and intra-laboratory variability in the results
of biomarker level determination, as a result of pre-analytical, analytical, post-analytical and kit-related
factors, even between laboratories using the same methods [82-86] . During the last decade, various
international initiatives, quality control programs and international workshops have been organized to
reduce variability and harmonize the levels of biomarkers [67,82,83] , including the “Biomarkers for Alzheimer’s
disease and Parkinson’s disease” project of the Joint Programming Neurodegenerative Disease (JPND-
[87]
BIOMARKAPD) . As a result, recommendations have been published regarding lumbar puncture,
pre-analytical and analytical standardized operating procedures [82,88-90] , leading to improvement in diagnostic
[91]
performance and reduction of measurement errors . Although a measurement error of ± 20% in only one
of the three biomarkers may have a minimal effect on overall diagnostic performance in everyday practice
(variability ≤ 8%), errors of greater magnitude and/or affecting more than one biomarker, may lead to a
significant decrease in diagnostic accuracy . Newer methods for the determination of classical biomarkers
[92]
may show better repeatability and reproducibility and less inter-laboratory variability [66,93] .

NEW AND EMERGING BIOMARKERS FOR AD AND OTHER DISORDERS
Among many molecules studied in AD, neurogranin, neurofilament light (NFL), the ectodomain of
triggering receptor expressed on myeloid cells 2 (sTREM2) and visinin-like protein 1 (VILIP-1) may
serve as markers of synaptic loss, neuronal/axonal damage, microglial activation and neurodegeneration,
respectively [66-68] .

Recently, promising results have been published for CSF TDP-43 in patients with FTD and/or amyotrophic
lateral sclerosis (ALS) [94-96] . The τ P-181 /τ ratio has been suggested as another marker, which may prove
T
helpful in the identification of FTD pathology , but its combination with TDP-43 may increase its
[97]
[66]
[95]
diagnostic value even more . NFL may also have some value in patients with FTD and/or ALS . Further
studies are needed, and they are in progress, both for validation and standardization of TDP-43 methods
and for identifying the optimum combination of TDP-43 with other biomarkers for in vivo detection of the
FTD subtype.

Alpha-synuclein (α-syn) has been studied as a biomarker of Lewy body synucleinopathies, in the
differential diagnosis of cognitive and/or movement disorders [98,99] . Several studies have revealed that
in synucleinopathies such as DLB, CSF α-syn levels are reduced, as compared to controls or AD [100,101] .
However, increased levels in DLB vs. AD [102] or PDD [103] have also been reported, especially of oligomeric
α-syn [104] , while for PD or PDD, a non-significant reduction was too small to achieve diagnostic significance
[13]
vs. controls and other movement disorders or AD [103] . The above discrepancies indicate that, despite
intensive research, there are methodological problems in α-syn quantification. Determination of α-syn
needs strict pre-analytical control for confounding factors (especially bloody CSF), while assay parameters
such as antibodies used, and forms of α-syn detected, necessitate further studies before one or more robust
tests become widely acceptable [99,105] .

CONCLUDING REMARKS
Classical CSF biomarkers of AD are useful tools in the (differential) diagnosis of patients with cognitive
decline, especially in early or atypical cases [Table 1]. They are useful in differentiating AD from normal