Clinical Correlates Identify ProBDNF and Thrombo-Inflammatory Markers as Key Predictors of Circulating p75NTR Extracellular Domain Levels in Older Adults

Abstract

The p75^NTR receptor binds all neurotrophins and is mostly known for its role in neuronal survival and apoptosis. Recently, the extracellular domain (ECD) of p75^NTR has been reported in plasma, its levels being dysregulated in numerous neurological diseases. However, the factors associated with p75^NTR ECD levels remain unknown. We investigated clinical correlates of plasma p75^NTR ECD levels in older adults without clinically manifested neurological disorders. Circulating p75^NTR levels were measured by enzyme-linked immunosorbent assay in plasma obtained from participants in the BEL-AGE cohort (n = 1,280). Determinants of plasma p75^NTR ECD levels were explored using linear and non-linear statistical models. Plasma p75^NTR ECD levels were higher in male participants; were positively correlated with circulating concentrations of pro-brain-derived neurotrophic factor, and inflammatory markers interleukin-6 and CD40 Ligand; and were negatively correlated with the platelet activation marker P-selectin. While most individuals had p75^NTR levels ranging from 43 to 358 pg/ml, high p75^NTR levels reaching up to 9,000 pg/ml were detectable in a subgroup representing 15% of the individuals studied. In this cohort of older adults without clinically manifested neurological disorders, there was no association between plasma p75^NTR ECD levels and cognitive performance, as assessed by the Montreal Cognitive Assessment score. The physiological relevance of high p75^NTR ECD levels in plasma warrants further investigation. Further research assessing the source of circulating p75^NTR is needed for a deeper understanding of the direction of effect, and to investigate whether high p75^NTR ECD levels are predictive biomarkers or consequences of neuropathology.

Keywords: inflammation; neurotrophhic factors; p75NTR receptor; plasma; proBDNF.