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Constantinides et al. Neuroimmunol Neuroinflammation 2020;7:120-31 I http://dx.doi.org/10.20517/2347-8659.2019.22 Page 127

(33 kDa) of tau protein were determined in CSF. The tau 33 kDa/55 kDa ratio was significantly lower in
PSP patients, compared to patients with AD, FTD, CBD, PD and DLB and emerged as a possible biomarker
[54]
[53]
for PSP . The same study group replicated these results in a larger cohort . However, these promising
[55]
results were not be replicated by another study group .
In another study, immuno-PCR essays were developed to measure 3R- and 4R-tau isoforms in CSF. These
essays were tested in four different cohorts, which included PSP, CBD, PDD and PDD patients. The study
we are referring to included four cohorts, in which the 3R and 4R-tau isoform levels varied considerably
among the four cohorts (mean values in control groups ranging for both 3R- and 4R-tau from < 5 pg/mL
to ~50 pg/mL). Analysis of tau isoforms in all cohorts combined indicated lower 4R-tau levels in PSP and
and 3R-tau/τ ratios were decreased in AD
AD. 3R-tau did not differ among study groups. The 3R-tau/τ T P-181
compared to PDD. The 4R-tau/τ was lower in PSP and AD compared to controls and the 4R-tau/τ P-181 ratio
T
[56]
was higher in PDD compared to PSP, CBD and AD .
[18]
Wagshal et al. developed a multitude of novel ELISAs, which target different epitopes of tau proteins, in
order to examine differences in the concentration of diverse tau protein fragments in CSF. These ELISAs
were applied in patients with AD, PSP and controls. Interestingly, PSP patients had lower concentrations of
most tau fragments compared to controls.

Another study group implemented mass spectrometry to quantify tau-specific peptides in the entire
sequence of tau protein in a cohort of PSP, AD and DLB. This novel approach yielded data for 18 tau
peptides. By use of these peptides, the authors determined that the 1N and 3R-tau isoforms were mostly
represented in CSF. Levels of tau peptides were intra-correlated and significantly increased in AD patients.
Interestingly, AD patients had relatively decreased levels of peptides in the central core region of tau
[57]
protein. This region contains phosphorylation sites, which may explain this finding .
[58]
Along the same lines, Cicognola et al. developed novel antibodies against tau fragments at amino acid
123 and 224 (tau-123 and tau-224, respectively), after having identified endogenous tau fragments ending
at these amino acids. They concluded that anti-tau-224, but not anti-tau-123, was present in neurofibrillary
tangles and neuropil threads of AD patients, whereas tau-224 levels were elevated in CSF of these patients
and correlated with conversion from mild cognitive impairment to AD. The authors concluded that only
tau-224 is neuron-specific, whereas tau-123 may represent a general non-specific marker of tau metabolism.

DISCUSSION
There has been extensive research on classical CSF biomarkers in patients with Parkinsonism, as
illustrated in this review of the literature. Most studies agree that PSP patients do not exhibit a specific CSF
biochemical profile. Few studies have reported decreased Aβ levels. A CSF-AD profile has rarely been
42
described in PSP patients.

An elevation in CSF τ levels has been systematically reported in CBS. Moreover, few studies have also
T
documented a decrease in Aβ and an increase in τ P-181 in these patients. Interestingly, a significant
42
percentage (< 40%) of CBS patients can harbor a CSF-AD profile [14,16,24] . This is in agreement with clinical-
pathological studies of CBS [59-62] , where AD is a relatively common underlying pathology of CBS. A study
emphasized that the frequently reported elevation in CSF τ and reduction in Aβ in CBS might not
42
T
represent an inherent biochemical characteristic of CBS and could be attributed to the inclusion of AD
[16]
patients presenting with CBS . Thus, classical CSF biomarkers are particularly important in CBS cohorts,
since they can indicate an underlying AD pathology.
Regarding MSA, most studies report an elevation in CSF τ protein, whereas a decrease in Aβ levels in
42
T
MSA has been rarely reported. Although an interplay between a-synuclein and Aβ has been established
42