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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 121

INTRODUCTION
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The pathologic
hallmarks of PD are Lewy bodies, which consist of intraneuronal cytoplasmic depositions of pathological
[1]
a-synuclein . Thus, PD is considered a synucleinopathy. Clinical diagnosis of PD is straightforward in
typical cases. However, it can be problematic in patients with atypical clinical features. Accuracy of clinical
[2]
diagnosis of PD is suboptimal, since as many as 25% of patients can be misdiagnosed .
Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA)
and dementia with Lewy bodies (DLB) are the most common causes of atypical Parkinsonism. All of these
diseases manifest with Parkinsonism, which is poorly or only transiently responsive to dopaminergic
treatment.

MSA is a synucleinopathy, like PD. Its pathologic hallmark is glial cytoplasmic inclusions, which consist of
[3]
abnormal a-synuclein deposition in oligodendrocytes . DLB is also a synucleinopathy, characterized by
[4]
predominantly cortical Lewy bodies . PSP and CBD on the other hand are considered tauopathies, since
their main pathologic findings (tufted astrocytes and astrocytic plaques, respectively) consist of abnormal
[5,6]
tau protein aggregates in astrocytes .

Tau protein can present in six isoforms, depending on the alternate splicing of the microtubule associated
[7]
protein tau (MAPT) gene . This results in the variable expression of no, one or two oligonucleotides (N1
and N2) coded by exons 2 and 3 of the MAPT gene, as well as the presence of 3-repeat (3R) or 4-repeat
(4R) microtubule binding regions coded by exon 10. Depending on the predominance of 3R- or 4R-tau
isoforms, tauopathies are further divided into 4R- or 3R-tauopahies. PSP and CBD are considered 4-repeat
(4R) tauopathies, Alzheimer’s disease (AD) is a mixed 3R- and 4R-tauopathy, whereas Pick’s disease is a
3R-tauopathy.

), phosphorylated tau protein at threonine 181 (τ ) and amyloid beta with 42 amino
Total tau protein (τ T P-181
acids (Aβ ) are well-characterized cerebrospinal fluid (CSF) biomarkers of AD. These biomarkers have
42
been incorporated into the most recent AD diagnostic criteria and are the basis of the recently proposed
[8]
AT(N) taxonomy system, which introduces biomarkers (according to their molecular specificity) for the
in vivo pathological characterization of patients with AD .
[9]
The aim of this review is to present data on the utility of these three classical CSF biomarkers (τ , τ P-181
T
and Aβ ) in the differential diagnosis of atypical Parkinsonism from PD. To this end, only studies which
42
included patients with atypical Parkinsonism vs. PD or healthy controls are included.

This review includes representative studies which either have established our current knowledge on CSF
biomarkers in Parkinsonism or provide new insights on the subject [Table 1].

STUDIES IN PSP
Most studies do not report any differences in CSF Aβ between PSP and other causes of Parkinsonism
42
or controls [10-16] . Interestingly, however, some studies have reported lower Aβ values in PSP compared to
42
[19]
controls [17-19] . Moreover, a single study reported lower Aβ levels in PSP vs. PD . According to this study,
42
Aβ could differentiate PSP from PD with 83% sensitivity and 67% specificity.
42
Regarding CSF τ , several studies could not establish any differences between PSP patients and
T
controls [13-17] . Likewise, no difference in τ was evident between PSP and CBD [13,15-17] , MSA [13,15,16] or PD [15,16]
T
in most studies. Two studies have supported that PSP patients exhibit lower τ levels when compared to
T