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Page 126 Constantinides et al. Neuroimmunol Neuroinflammation 2020;7:120-31 I http://dx.doi.org/10.20517/2347-8659.2019.22

There is consensus among studies that CSF τ is increased in AD compared to DLB [14,32,33,37,40,41] . DLB
T
patients have been reported to harbor elevated τ levels compared to controls [14,33] , although several studies
T
could not establish any difference between DLB and controls [32,34,40] . Regarding other synucleinopathies (PD,
PDD and MSA), studies have produced mixed results, reporting either an increase in τ in DLB compared
T
[35]
to PD/PDD [35,37-39] and MSA or no difference among patient groups [34,43] .
Few studies have included τ P-181 in analyses of DLB cohorts. According to these limited studies, τ P-181 is
elevated in AD compared to DLB [14,37] , although one study could not establish a difference between AD and
DLB . Comparison between DLB and controls regarding τ P-181 has produced mixed results, with some
[33]
studies reporting an increase in τ P-181 in DLB [14,32,41] , whereas other studies could not establish any difference
[34]
between groups . PD/PDD patients do not differ from DLB in their τ P-181 profile [34,44] .

Lower CSF Aβ levels in DLB correlate with a worse outcome, according to several studies [14,40,42,45] .
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Likewise, elevated τ levels correlate with a poorer prognosis in DLB [37-39,41] .
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Several studies in DLB, which contain longitudinal data regarding CSF biomarker level alterations over
time, provide conflicting results. Two studies have reported stable Aβ over time in cohorts of DLB
42
[46]
patients [39,46] . According to these studies, CSF τ and τ P-181 levels either increase or decrease over time .
[39]
T
Conversely, two other studies have provided a different profile, with unaltered τ and τ P-181 levels over time,
T
combined with a decrease in Aβ during the transition from prodromal to demented stage of DLB [47,48] .
42
A CSF-AD profile (as defined by a decrease in Aβ and an increase in τ and/or τ P-181 ) is common in
T
42
DLB patients, presenting in 25%-50% of patients [14,42,45,49] . This profile invariably correlates with poorer
prognosis [42,45] . According to a recent study, as many as 85% of DLB patients have decreased Aβ in CSF,
42
[49]
either isolated (45%) or in the context of a CSF-AD profile (40%) .
A single study has provided insight into the relationship between pathological finding and CSF biochemical
[44]
profile . In this cohort, 72% of DLB patients had senile plaques and 50% had neurofibrillary tangles.
Interestingly, there was a correlation between the presence of senile plaques and CSF Aβ levels. The co-
42
occurrence of neurofibrillary tangles did not affect τ and τ P-181 levels in DLB patients.
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In conclusion, there is a general agreement that Aβ levels are decreased in DLB, either alone or
42
accompanied by increased τ or τ P-181 levels. The decrease of Aβ levels have been shown to correlate with
42
T
faster disease progression. Decreased CSF Aβ levels and increased τ and τ P-181 in DLB could be attributed
42
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to the frequent co-occurrence of AD pathology in patients with Lewy body disease. This hypothesis would
explain the correlation of a CSF-AD profile with worse outcomes in DLB patients. Intriguingly, multiple
lines of evidence suggest an interplay between a-synuclein and tau/amyloid beta aggregation, which may
explain the frequent co-occurrence of AD pathology and Lewy body disease [50-52] .

METHODOLOGICAL CONSIDERATIONS
Most studies on classical biomarkers in atypical Parkinsonism implemented enzyme-linked
immunosorbent assays (ELISAs). Advantages of ELISAs include relatively low cost, high reproducibility
and high availability, since commercial ELISAs of classical CSF biomarkers are readily available. There
have been efforts, however, to implement novel techniques and to target different proteins in search of new
biomarkers in neurodegenerative diseases.

To this end, a study examined differences in tau isoforms in CSF, which may reflect differences in post-
translational processing of tau protein. More specifically, differences in tau proteolytic products in CSF
were the main study endpoint. By means of immunoprecipitation, extended (55 kDa) and truncated forms