CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers

Abstract

Background: Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson's disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers.

Methods: We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aβ-40), amyloid-beta-42 (Aβ-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD.

Results: Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated.

Conclusions: The current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.

Keywords: Alpha-synuclein oligomers; Biomarkers; Inflammatory markers; LRRK2 mutation carriers; Parkinson’s disease.

Fig. 1

Box-and-whiskers plots of CSF levels of α-syn forms in sPD, symptomatic and asymptomatic LRRK2 mutation carriers, and Ctrl. Box-and-whiskers plots of CSF levels of α-syn species in sPD, asymptomatic LRRK2 carriers, symptomatic LRRK2 carriers and Ctrls. a CSF levels of t-α-syn, b CSF levels of o-α-syn, c CSF levels of pSer129-α-syn, d ratio of o-α-syn/ t-α-syn %, e ratio of pSer129-α-syn/ t-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 compared to Ctrl group and adjusted for age and gender. *P < 0.05, **P < 0.01, ***P < 0.001

Fig. 2

Discriminant function plot of canonical discriminant functions. CSF biomarkers were z-transformed before analyses. Discriminant function plot of canonical discriminant functions for discrimination of asymptomatic LRRK2 mutation carriers, PD and controls. Yellow dots indicate individual data of control subjects, green dots indicate individual data of Parkinson’s disease patients (sporadic and symptomatic LRRK2 mutation carriers) and red dots indicate individual data of LRRK2 asymptomatic carriers. The golden stars represent the group centroids

Fig. 3

Receiver operating characteristic curves (ROC) showing the diagnostic accuracy of the final logistic regression models. Asymptomatic LRRK2 mutation carriers vs Ctrl subjects, (B) PD patients vs Ctrl subjects