α-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies

Abstract

Background: The objective of this study was to investigate the discriminating value of a range of CSF α-synuclein species for dementia with Lewy bodies compared with Alzheimer's disease, PD, and cognitively normal controls.

Methods: We applied our recently published enzyme-linked immunosorbent assays to measure the CSF levels of total α-synuclein, oligomeric α-synuclein, and phosphorylated α-synuclein in dementia with Lewy bodies (n = 42), Alzheimer's disease (n = 39), PD (n = 46), and controls (n = 78). General linear models corrected for age and sex were performed to assess differences in α-synuclein levels between groups. We used backward-elimination logistic regression analysis to investigate the combined discriminating value of the different CSF α-synuclein species and Alzheimer's disease biomarkers.

Results: CSF levels of total α-synuclein were lower in dementia with Lewy bodies and PD compared with Alzheimer's disease as well as controls (P < 0.001). In contrast, CSF levels of oligomeric α-synuclein were higher in dementia with Lewy bodies and PD compared with Alzheimer's disease (P < 0.05) and controls (P < 0.001). No group differences were found for phosphorylated α-synuclein. In dementia with Lewy bodies and PD, CSF total α-synuclein levels positively correlated with tau and phosphorylated tau (both r > 0.40, P < 0.01), but not with amyloid-β_1-42 . The optimal combination to differentiate dementia with Lewy bodies from controls consisted of amyloid-β_1-42 , tau, total α-synuclein, oligomeric α-synuclein, age, and sex (AUC, 0.90). To differentiate dementia with Lewy bodies from Alzheimer's disease, the combination of tau and oligomeric α-synuclein resulted in an AUC of 0.83. CSF α-synuclein species do not contribute to the differentiation of dementia with Lewy bodies from PD.

Conclusions: CSF α-synuclein species could be useful as part of a biomarker panel for dementia with Lewy bodies. Evaluating both oligomeric α-synuclein and total α-synuclein in CSF helps in the diagnosis of dementia with Lewy bodies. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: CSF; biomarkers; dementia with Lewy bodies; α-synuclein.

Figure 1

Box‐and‐whiskers plots of CSF levels of α‐syn species in DLB, PD, AD, and controls. (A) CSF levels of t‐α‐syn, (B) CSF levels of o‐α‐syn, (C) CSF levels of pSer129‐α‐syn. The line through the middle of the boxes corresponds to the median and the lower and the upper lines to the 25th and 75th percentiles, respectively. The whiskers extend from the 5th percentile on the bottom to the 95th percentile on top. Differences between groups were assessed with the GLM, adjusted for age and sex. *P < 0.05, **P < 0.01, ***P < 0.001. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Correlations (Pearson) between CSF biomarkers in the diagnostic groups. Pearson correlation coefficients are depicted by the numbers within the plots. The colors represent the P value of the association. Darker colors represent lower P values, and lighter colors represent higher P values. Aβ_1‐42, amyloid‐β_1‐42; AD, Alzheimer's disease; DLB, dementia with Lewy bodies; PD, Parkinson's disease; pS129‐α‐syn, phosphorylated α‐synuclein protein at serine 129; p‐tau, tau phosphorylated at threonine 181; o‐αsyn, α‐synuclein oligomer; t‐α‐syn, total α‐synuclein; t‐tau, total tau protein. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Discriminant function plot of canonical discriminant functions for discrimination of DLB, PD, AD, and controls. Red circles indicate individual data of DLB patients, purple circles indicate individual data of Parkinson's disease patients, blue circles indicate individual data of Alzheimer's disease patients, and green circles indicate individual data of controls. The diamonds represent the group centroids. [Color figure can be viewed at wileyonlinelibrary.com]