Phosphorylated α-synuclein in Parkinson's disease: correlation depends on disease severity

Abstract

Introduction: α-Synuclein (α-syn) is a key protein in Parkinson's disease (PD), and one of its phosphorylated forms, pS129, is higher in PD patients than healthy controls. However, few studies have examined its levels in longitudinally collected cerebrospinal fluid (CSF) or in preclinical cases. In this study, CSF and clinical data were contributed by >300 subjects from three cohorts (the longitudinal DATATOP cohort, a large cross-sectional cohort, and a cohort of LRRK2 mutation carriers).

Results: Consistent with our previous observation that CSF pS129 positively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) scores, CSF pS129 in the DATATOP cohort increased over approximately two years of disease progression (mean change 5.60 pg/ml, p = 0.050). Intriguingly, in the DATATOP cohort, pS129 negatively correlated with UPDRS scores at the baseline (R = -0.244, p = 0.017), but not final point, suggesting that this association may depend on disease stage. Reanalysis of our previous cohort with stratification by PD stage, and addition of a cohort of LRRK2 mutation carriers with very early/preclinical PD, supported the idea that the relationship between CSF pS129 and disease severity over a wider range of PD stages might be represented with a U-shaped curve, in which lower pS129 levels correlated with worse clinical condition at early stages, but better condition at later stages.

Conclusion: The observation of a negative-to-positive transition of correlation of pS129 to disease severity as PD progresses could have profound impact on how pS129 is used as a biomarker clinically as well as in modeling PD experimentally.

Figure 1

Longitudinal changes in pS129 and relationship with total α-syn. A) Change in pS129 by baseline level. Triangles: subjects that did not reach endpoint. Squares: subjects that reached endpoint. Solid line: regression line generated from all subjects combined. B) Association between total α-syn and pS129 levels by time point. Circles: baseline time point. Squares: final time point. Lines represent correlation between total α-syn and pS129 for each time point.

Figure 2

The relationship between pS129 and motor symptoms changes with disease severity. pS129 and UPDRS motor scores by disease duration A) Relationship between CSF pS129 and UPDRS motor scores in subjects in DATATOP and cross-sectional cohorts. Line is Loess curve for combined datasets including multi-center collaborative cohort and DATATOP baseline and final time points. B)-E) Relationship between pS129 and UPDRS in cohort subsets divided by disease stage. B) DATATOP DD less than 2 years. C) DATATOP DD greater than 2 years. D) Cross-sectional DD less than 2 years. D) Cross-sectional DD greater than 2 years. MC: Multi-center collaborative cohort. DD: Disease duration, time since diagnosis in years. DB: DATATOP baseline time point. DF: DATATOP final time point. Diamonds: multi-center collaborative cohort. Black circles: DATATOP baseline. Gray circles: DATATOP final.

Figure 3

LRRK2 subjects with greater brain pathology have lower CSF pS129. A) Significant decrease in TBZ scores in subjects with PD diagnoses. B. Relationship between TBZ scores and pS129 in LRRK2 mutation carriers. Note that x-axis is inverted to facilitate comparison with UPDRS measurements in Figure 2. Dotted regression lines represent whole cohort; solid lines represent cohort excluding subjects with TBZ scores ≥1. Black triangles: Subjects without PD diagnosis and TBZ < 1. Open triangles: Subjects with no diagnosis and TBZ > 1. Circles: Subjects with PD diagnosis and UPDRS motor scores < 20.