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Page 124 Constantinides et al. Neuroimmunol Neuroinflammation 2020;7:120-31 I http://dx.doi.org/10.20517/2347-8659.2019.22

As a general conclusion, there are no significant abnormalities in the classical CSF biomarkers in PSP.
Despite being a 4R-tauopathy, CSF tau proteins do not seem to differ between PSP and other Parkinsonian
disorders. CSF total tau protein, which is considered a non-specific marker of neurodegeneration, would be
expected to increase in PSP, as is the case in AD. A plausible explanation would be that tau protein in PSP
is concentrated intracellularly (in astrocytic plaques, tufted astrocytes and neurofibrillary tangles), and for
this reason it does not enter the cerebrospinal fluid.

Additionally, no obvious clinical-biochemical correlation has been observed, while an AD biomarker
profile in PSP (indicating an AD co-occurrence or possibly a PSP-like phenotype of AD) is a rarity.
The presence of a CSF-AD profile in PSP patients is more likely to be indicative of the presence of dual
underlying pathologies (AD and PSP), since pathological studies have not established a correlation of AD
pathology and Richardson syndrome (the most common phenotype of PSP).

STUDIES IN CBD
Most studies have focused on CSF tau proteins in CBD, since CBD is a tauopathy. Several of these
studies have reported elevated levels of τ in CBD, compared to controls [12,16,21-23] , PSP [12,22,23] and PD [12,13] .
T
[23]
Interestingly, τ could differentiate CBD from PSP with 80% specificity and sensitivity in one study .
T
Likewise, CSF τ provided 75% sensitivity and 90% specificity in the discrimination of CBD from PD in
T
[12]
another study . However, no difference in τ between CBD and controls [14,15,17] , PSP [13,15,16,20] , MSA [15,16] and
T
PD [15,16] has also been reported.
Regarding CSF τ P-181 , most studies did not establish any meaningful difference between CBD patients and
other Parkinsonian disorders or controls [13-17] . A single study has reported elevated CSF τ P-181 levels in CBD
[13]
[12]
compared to PD , and another study in CBD patients compared to MSA patients .
CSF Aβ levels do not differ in CBD compared to other Parkinsonian disorders, according to several
42
studies [12,13,15,17] . However, lower Aβ has been described in CBD patients compared to controls [14,17] and
42
[16]
PD .
Regarding CSF biomarker indices, few studies have included relevant data in CBD. One study reported
decreased Aβ /τ ratio in CBS compared to PD and controls, whereas τ P-181 /τ ratio in CBS was decreased
T
42
T
[12]
compared to controls . According to this study, τ P-181 /τ was optimal for PSP vs. CBD discrimination (86%
T
sensitivity and 75% specificity). Another study posited that CBD patients have elevated τ /Aβ and τ P-181 /
T
42
[16]
Aβ compared to PD .
42
Clinical and demographic data do not correlate with levels of classical CSF biomarkers in CBD, according
to most relevant studies [13-15] . A single study reported that cognitive status, as measured by MMSE,
[12]
correlated with both τ and τ P-181 levels and was inversely correlated with Aβ levels . Intriguingly,
T
42
τ levels in CBD and PSP were dependent on disease severity in a single study, with maximal levels in
T
[23]
medium-stage disease .
Few studies have focused on the presence of a CSF-AD profile in cohorts of Parkinsonian disorders.
According to this approach, patients are divided in those harboring a CSF-AD profile and those who do
not harbor such a profile. An initial study concluded that 20% of CBS patients harbored a CSF-AD profile
> 400 pg/mL, Aβ < 400 pg/mL and τ /Aβ ratio > 1) . In another cohort, 38% of CBS
[24]
(as defined by τ T 42 T 42
patients had a CSF-AD profile, based on an index which included τ P-181 and Aβ values . Along the same
[14]
42
lines, a third study posited that ~30% of CBS patients had a typical CSF-AD profile (elevated τ and τ P-181
T
[16]
combined with decreased Aβ ) . Interestingly, when patients with a CSF-AD profile were excluded from
42
analyses, an initially reported elevated τ and decreased Aβ protein in CBS disappeared, and CBS patients
42
T