CSF alpha-Synuclein Does Not Discriminate Dementia with Lewy Bodies from Alzheimer's Disease

Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 22(1):87-95. DOI: 10.3233/JAD-2010-100186
Source: PubMed


In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker α-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinson's disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of α-synuclein, amyloid-β 1-42 (Aβ1-42), total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF α-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Aβ1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower α-synuclein was related to lower MMSE-scores (β (SE) = 6(2) and p< 0.05) and fluency (β (SE) = 4(2), p< 0.05). Ultimately, CSF α-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (α-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF α-synuclein levels are related to worse cognitive performance.

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    • "The degree of change of CSF aSyn in Parkinson's disease is only minor, with aSyn being in the range of 80%e90% of the level in matched controls. Discrepant findings showing no change or elevated levels have been reported by other groups (Aerts et al., 2012; Lee et al., 2011; Noguchi-Shinohara et al., 2009; Ohrfelt et al., 2009; Park et al., 2011; Reesink et al., 2010; Spies et al., 2009; Wang et al., 2012). Several factors could explain these discrepancies , including the use of different assay formats and antibodies as well as differences in sample handling (Mollenhauer et al., 2010). "
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    ABSTRACT: Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program - Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 05/2015; 36(9). DOI:10.1016/j.neurobiolaging.2015.05.003 · 5.01 Impact Factor
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    • "In particular, detection of d-α-syn in body fluids may precede clinical symptoms or abnormalities in classical neuroimaging. To date, the analysis of total α-synuclein (t-α-syn) in cerebrospinal fluid (CSF) has been described in several publications [4, 5, 6, 7, 8, 9, 10, 11, 12] (see [13] for a review), while only single studies have dealt with the detection of disease-associated forms, including oligomers, in human plasma or CSF [7, 14]. However, there is no commercially available kit for the detection of d-α-syn in body fluids. "
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    ABSTRACT: With the aim to evaluate the significance and reliability of detecting disease-specific α-synuclein in the cerebrospinal fluid (CSF) we developed an ELISA and bead-assay. We used a commercial antibody (5G4) that does not bind to the physiological monomeric form of α-synuclein, but is highly specific for the disease-associated forms, including high molecular weight fraction of β-sheet rich oligomers. We applied both tests in CSF from a series of neuropathologically confirmed αsynucleinopathy cases, including Parkinson' disease dementia (PDD) and dementia with Lewy bodies (DLB) (n = 7), as well as Alzheimer' disease (n = 6), and control patients without neurodegenerative pathologies (n = 9). Disease-specific α-synuclein was detectable in the CSF in a subset of patients with α-synuclein pathology in the brain. When combined with the analysis of total α-synuclein, the bead-assay for disease-specific α-synuclein was highly specific for PDD/DLB. Detection of disease-associated αsynuclein combined with the total levels of α-synuclein is a promising tool for the in-vivo diagnosis of αsynucleinopathies, including PDD and LBD.
    Clinical neuropathology 09/2014; 33(5):329-34. DOI:10.5414/NP300796 · 1.53 Impact Factor
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    • "This wide variation (100-fold difference) probably reflects technical/methodological differences and/or different species of α-Syn measured, rather than an actual biological cause. In the majority of the studies, the control group comprised of patients suffering from other neurological diseases and only a few studies [19,21,27,28] have included a healthy control group. Other studies included no control group [11,16]. "
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    ABSTRACT: The detection of α-synuclein (α-syn) in the cerebrospinal fluid (CSF) of patients with synucleinopathy has yielded promising but inconclusive results. The aim of the present study was to determine the diagnostic value of α-syn as a biological marker for Dementia with Lewy bodies (DLB) vs. normal subjects and patients with Alzheimer's disease (AD), after strict control of several recognized confounders. Sixteen patients with DLB, 18 patients with AD and 22 age- and sex-matched normal controls (CTRL) were recruited. The levels of total α-syn in CSF were measured using a novel enzyme-linked immunosorbent assay. There was a significant increase of CSF α-syn levels in DLB patients as compared to the CTRL and AD groups (P= 0.049 and 0.01 respectively). ROC analysis revealed that increased α-syn was 81.8% specific for the discrimination of DLB vs. CTRL and 90% vs. AD. However, sensitivity was lower (56.2 % and 50% respectively). These findings provide evidence for a possible diagnostic role of α-syn as a surrogate biomarker for DLB.
    PLoS ONE 11/2013; 8(11):e81654. DOI:10.1371/journal.pone.0081654 · 3.23 Impact Factor
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