Inflammation biomarker discovery in Parkinson's disease and atypical parkinsonisms

Abstract

Background: Parkinson's disease (PD) and atypical parkinsonisms (APD) have overlapping symptoms challenging an early diagnosis. Diagnostic accuracy is important because PD and APD have different prognosis and response to treatment. We aimed to identify diagnostic inflammatory biomarkers of PD and APD in cerebrospinal fluid (CSF) using the multiplex proximity extension assay (PEA) technology and to study possible correlations of biomarkers with disease progression.

Methods: CSF from a longitudinal cohort study consisting of PD and APD patients (PD, n = 44; multiple system atrophy (MSA), n = 14; vascular parkinsonism (VaP), n = 9; and PD with VaP, n = 7) and controls (n = 25) were analyzed.

Results: Concentrations of CCL28 were elevated in PD compared to controls (p = 0.0001). Five other biomarkers differentiated both MSA and PD from controls (p < 0.05) and 10 biomarkers differentiated MSA from controls, of which two proteins, i.e. beta nerve growth factor (β-NGF) and Delta and Notch like epidermal growth factor-related receptor (DNER), were also present at lower levels in MSA compared to PD (both p = 0.032). Two biomarkers (MCP-1 and MMP-10) positively correlated with PD progression (rho > 0.650; p < 0.01).

Conclusions: PEA technique identified potential new CSF biomarkers to help to predict the prognosis of PD. Also, we identified new candidate biomarkers to distinguish MSA from PD.

Keywords: Biomarkers; Inflammation; Multiple system atrophy; Parkinson’s disease.

Fig. 1

Receiver operating characteristic (ROC) curve analysis of PD versus MSA. The combination of NFL levels with DNER and β-NGF in cerebrospinal fluid (solid black) does not yield better diagnosis accuracy than NFL alone (dashed dark grey) (AUC = 0.88 and 0.87 respectively, p value < 0.0001). Reference line in solid clear grey

Fig. 2

Correlation of biomarkers with Parkinson’s disease (PD) progression. a. Correlation between MCP-1 and Hoehn and Yahr (HY) progression score; b. Correlation between MMP-10 and unified Parkinson’s Disease rating scale (UPDRS) progression score. Data were analyzed using Spearman correlation. Biomarker values are expressed as normalized protein expression. Right whisker plots represent median, interquartile range, minimum, maximum and outliers of disease score progression. Upper whisker plots represent median, interquartile range, minimum, maximum and outliers of the protein marker levels in cerebrospinal fluid of PD patients. Rho was > 0.600 and p value < 0.01 for both correlations