Tau protein, beta-amyloid1–42 and clusterin CSF levels in the differential diagnosis of Parkinsonian syndrome with dementia
Introduction
Parkinson's disease (PD) and Alzheimer disease (AD) are the two most common neurodegenerative disorders. Early in the course of PD, the most obvious symptoms are movement-related, while AD is the most common form of dementia.
Longitudinal studies of PD have confirmed that cognitive and behavioral problems may arise later and their severity can meet the diagnostic criteria for dementia [1]. At this point PD is referred to as Parkinson's disease with dementia (PDD) [2]. Patients with Parkinsonism who develop dementia during the first year are classified as dementia with Lewy bodies (DLB).
The clinical manifestation of DLB is similar to PDD, with the main difference being the temporal ordering of extrapyramidal symptoms and dementia onset. Distinguishing between these two disorders based on established clinical criteria is often difficult. Even the neuropsychological profiles of PDD and DLB are too close for differentiation [3]. A definitive diagnosis of both disorders is confirmed by autopsy. However, the neuropathology of both also share many similarities and exhibit only a few differences [4]. The histopathological hallmark of both PDD and DLB is alpha synuclein, which is the major component of Lewy bodies and Lewy neuritis. In a recently published study, the severity of cortical Lewy body pathology was positively associated with dementia in PD [5]. One of the differences between PDD and DLB is beta-amyloid deposition, which seems to be more frequent and widespread in DLB compared to PDD [6], [7]. Since cerebrospinal fluid (CSF) has close contact with brain tissue, it is therefore a potential source of these neurodegenerative markers in living patients. The most studied markers are beta-amyloid1–42 and tau protein. CSF beta-amyloid1–42 levels appear to be inversely related to the deposition of amyloid plaques, while the elevation of tau protein CSF levels is an indicator of neuronal cell destruction [8], [9]. In Parkinsonian syndrome with dementia, studies of these CSF markers have not shown unambiguous results yet. For better and earlier diagnosis and also to improve our understanding of pathogenesis, it is desirable to find another marker or a combination of markers.
Clusterin is becoming a new laboratory marker in neurodegenerative diseases [10], [11].
Clusterin, a heterodimeric glycoprotein, is thought to be involved in many cellular physiologic functions, including cell–cell interaction, cell survival and apoptosis. The increase of clusterin in brain tissue is thought to reflect a regenerative response process [12].
Immunohistochemical analysis has shown that clusterin colocalizes with α-synuclein in Lewy bodies. In these lesions, a strong clusterin staining correlated with a weaker α-synuclein staining, suggesting that clusterin may protect against α-synuclein aggregation [13]. In a recent study, higher ventricular CSF levels of clusterin were found postmortem in histologically verified PD patients compared to control subjects [14].
The aim of this study was to examine tau protein, beta-amyloid1–42 and clusterin in the CSF of patients with probable PD, PDD, DLB and AD, diagnosed using the current clinical criteria, and in the control group, and to search for a relationship between neurodegenerative CSF markers and the probable clinical diagnosis in order to highlight the potential of CSF analysis in vivo as a surrogate of postmortem pathology.
Section snippets
Methods
The study was approved by the Institutional Ethics Committee, and all patients signed an informed consent. PD was diagnosed using the United Kingdom Parkinson's Disease Society Brain Bank criteria [15]. PDD was diagnosed according to the Movement Disorders Society Task Force from 2007 [2]. DLB was diagnosed according to revised clinical diagnostic criteria for DLB from McKeith et al. [16]. AD was diagnosed using the National Institute of Neurological and Communicative Diseases and
Laboratory analysis and CSF sampling technique
The CSF samples were obtained by lumbar puncture performed under standard sterile conditions. During each puncture, a total of 10 ml of CSF was collected in a sterile test tube.
Subsequently, the CSF was morphologically assessed and centrifuged at 1100 g for 10 min at 4 °C. Each sample was frozen to − 80 °C, and the concentrations of total tau protein, betaamyloid1–42 and clusterin were measured with the Biorobot DSX analyser (Dynex, USA) for all subjects in the series within 10 weeks of freezing. At
Statistical analysis
SPSS software version 15 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. To determine differences among study groups, Fisher's exact test for qualitative parameters and Mann–Whitney U test for quantitative parameters were used. The level of significance was adjusted using Bonferroni correction for multiple comparisons so that the type I error did not exceed 0.05. The Shapiro–Wilk test was used to confirm the normal distribution of the data.
The p value < 0.05 was considered to be
Results
CSF levels of ND markers were assessed in 27 patients with PD, 14 patients with PDD, 14 patients with DLB and 17 patients with AD. The control group without signs of neurodegenerative disease (CG) comprised 24 patients, 14 patients had vertebrogenic disease and 8 patients had psychogenic syndrome with conversion signs. None of them were referred to our department for a cognitive complaint, and a cognitive deficit was ruled out (Table 1.)
A comparison of demographic data in the five subgroups
Discussion
Significantly higher CSF levels of clusterin were found in PD patients and PDD patients compared to the CG. Across the patient groups, beta-amyloid1–42 levels decreased in the order PD > PDD > DLB > AD, whereas tau protein and the tau protein/beta-amyloid1–42 index were increasing in the same order (PD < PDD < AD), except for DLB. Postmortem, pathological changes typical for Alzheimer dementia were found relatively often in patients with PD [6], [20], especially in patients with PDD and DLB. However, AD
Conclusions
The results of the present study support the role of clusterin in PD pathogenesis.
The present study shows that CSF of PDD and DLB patients manifests changes similar to those in AD patients, but some of these changes did not reach statistical significance. The decreasing CSF beta-amyloid1–42 levels in the order PDD, DLB and AD may relate to the increasing presence of AD pathology in these disorders.
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgments
The study was supported by the IGA MHCR NT12221-5/2010 grant.
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