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[63]
in vitro, alterations in CSF Aβ levels in a synucleinopathy are difficult to explain . In a transgenic
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mouse model with expression of both β-amyloid peptides and synuclein, β-amyloid peptides promoted
[50]
aggregation of a-synuclein . Likewise, pathological data from PD and DLB patients support the
accumulation of tau oligomers in these brains. Moreover, oligomeric tau forms may co-exist in the same
[51]
aggregates with a-synuclein, forming hybrid oligomers . Along the same lines, a-synuclein may induce
specific toxic tau oligomers in cell cultures .
[52]
DLB patients exhibit significantly lower CSF Aβ values compared to other Parkinsonian disorders.
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Moreover, studies support that τ in DLB may be elevated. However, AD can be differentiated from DLB
T
by means of a significant increase in τ and τ P-181 in AD compared to DLB. A significant percentage of
T
DLB patients harbor a CSF-AD profile, which indicates the frequent co-occurrence of Lewy body and AD
pathologies, especially in older patients.

CONCLUSIONS AND FUTURE DIRECTIONS
Classical CSF biomarkers in atypical Parkinsonism are important, particularly for the diagnostic work-
up of CBS and DLB patients. A CSF-AD profile in a CBS patient indicates an underlying AD pathology.
Conversely, in DLB patients, the presence of a CSF-AD profile indicates the co-occurrence of AD and Lewy
body pathologies, which usually correlates with poorer prognosis. Although some differences have been
reported in classical CSF biomarkers in both PSP and MSA, the results are inconsistent and require further
research.

The disparity of results on classical biomarkers in atypical Parkinsonism can be largely attributed to the
great heterogeneity of studies. This heterogeneity refers to diagnostic criteria, cohort synthesis, statistical
analysis and pre-analytical and analytical factors. Standardization of these pre-analytical and analytical
[64]
confounders, as established in recent recommendations, is paramount for more robust results . Moreover,
large cohorts of Parkinsonian disorders with CSF biomarker data and pathology-confirmed diagnoses are
lacking. These studies would reliably inform us on the interplay between CSF biomarkers and pathological
findings. This disparity in results also illustrates the limitations of classical biomarkers in the differential
diagnosis of patients with Parkinsonism, and emphasizes the need for novel approaches.

To this end, differences in isoforms of these known proteins (e.g., 3R- vs. 4R-tau protein), differences in
proteolytic products and quantification of specific peptides of these proteins are promising new approaches.
Moreover, better characterization of other proteins which may serve as biomarkers (such as a-synuclein or
TDP-43) is of great importance.

DECLARATIONS
Authors’ contributions
Conception of the study, drafting of the manuscript, literature review: Constantinides VC
Conception of the study, critical appraisal of manuscript: Paraskevas GP, Boufidou F
Conception of the study, critical appraisal of manuscript, literature review: Bourbouli M, Paraskevas PG
Conception of the study, critical appraisal of manuscript: Stefanis L, Kapaki E

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.