Exploration of novel biomarkers for neurodegenerative diseases using ligand-binding assays

Abstract

Background

Neurodegeneration is a complex area involving multiple pathways and often has a long prodromal phase. Reliable biomarkers are needed to allow earlier diagnosis, monitoring of the disease progression, and studying the impact of therapeutic approaches.

Method

Therefore, a screening was performed by Sciomics GmbH to identify potential protein biomarkers. The most promising analytes were selected, including cluster of differentiation 14 (CD14), osteopontin (OPN), vascular endothelial growth factor A (VEGF-A), cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Using quantitative ligand-binding assays based on fluorescence or electrochemiluminescence these analytes were investigated regarding up- or downregulation in the presence of Alzheimer´s disease (AD), Parkinson´s disease (PD), Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS) compared to healthy patients.

Result

The quantitative assays confirmed the screening in that CD14 levels were elevated in cerebrospinal fluid (CSF) of AD patients and that OPN levels were increased in CSF of PD patients. In addition, the following significant changes were observed: OPN was elevated in plasma of PD and MS patients, while it was decreased in CSF of MS patients. VEGF-A levels were increased in the plasma of ALS patients and decreased in CSF of MS patients.

Conclusion

Increased CD14 levels in AD CSF are in agreement with studies suggesting that CD14, a co-receptor of toll like receptor 4 (TLR4) expressed on the surface of e.g. microglia, might mediate the interaction of fibrillar Aβ to TLR4 and thus induce inflammation. OPN has already been shown to be increased in CSF and blood of PD patients previously and it is suggested to be involved in PD pathogenesis due to its role in oxidative stress, apoptosis, mitochondrial dysfunction, and cytokine regulation. Other studies have shown increased levels of OPN in plasma of MS patients potentially due to its expression in activated T-cells. However, some studies also show increased MS CSF levels in contrast to our findings, where OPN levels are lower in MS CSF. Literature data for VEGF-A is more conflicting possibly due to different assays detecting different isoforms. To further solidify these findings, large-scale analyses using well characterized samples should be done in the future.