Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression

Abstract

Objective: There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity.

Methods: Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ(1-42)), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and α-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally.

Results: The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ(1-42) that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples.

Interpretation: We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression.

Figure 1. Receiver operating characteristic (ROC) analysis of cerebrospinal fluid biomarkers

(A) For Parkinson disease (PD) patients versus controls, the combination of DJ-1 and Flt3 ligand (solid) and the combination of phosphorylated tau (p-tau), total tau (t-tau) and amyloid beta peptide 1-42 (Aβ_1-42) (dot-dash) were the best discriminating parameters along with DJ-1 (dot) and α-synuclein (not shown) alone (see also Table 2). (B) For PD versus multiple system atrophy (MSA), Flt3 ligand (solid) and the combination of α-synuclein and p-tau% (p-tau/t-tau) (dot) were the best discriminating parameters. (C) For MSA patients versus controls, Flt3 ligand (solid) along with the combination of DJ-1 and p-tau% (dot) were the best discriminating parameters.

Figure 2. Correlation of CSF fractalkine/Aβ_1-42 with Parkinson disease severity and rate of progression

(A) CSF fractalkine and Aβ_1-42 levels in cross-sectional CSF samples were measured by Luminex and the fractalkine/Aβ_1-42 ratio correlated with disease severity as measured by UPDRS motor scores (r=0.252, P<0.01) using linear regression analysis with Pearson’s correlation. (B) A similar trend was observed between the fractalkine/Aβ_1-42 ratio and Hoehn and Yahr (H&Y) stages in a small independent PD cohort (UPDRS not available); however, the correlation was not statistically significant (r=0.216, P>0.05). (C) In an independent longitudinally collected sample set, the fold change of fractalkine/Aβ_1-42 (endpoint/baseline) was also well correlated with the annual rate of UPDRS (motor) progression (r=0.325, P<0.05, Pearson’s correlation).