A metabolomics study in aqueous humor discloses altered arginine metabolism in Parkinson’s disease

Abstract

Background The lack of accessible and informative biomarkers results in a delayed diagnosis of Parkinson’s disease (PD), whose symptoms appear when a significant number of dopaminergic neurons have already disappeared. The retina, a historically overlooked part of the central nervous system (CNS), has gained recent attention. It has been discovered that the composition of cerebrospinal fluid influences the aqueous humor composition through microfluidic circulation. In addition, alterations found in the brain of patients with PD have a correlate in the retina. This new paradigm highlights the potential of the aqueous humor as a sample for identifying differentially concentrated metabolites that could, eventually, become biomarkers if also found altered in blood or CSF of patients. In this research we aim at analyzing the composition of the aqueous humor from healthy controls and PD patients. Methods A targeted metabolomics approach with concentration determination by mass spectrometry was used. Statistical methods including principal component analysis and linear discriminants were used to select differentially concentrated metabolites that allow distinguishing patients from controls. Results In this first metabolomics study in the aqueous humor of PD patients, elevated levels of 16 compounds were found; molecules differentially concentrated grouped into biogenic amines, amino acids, and acylcarnitines. A biogenic amine, putrescine, alone could be a metabolite capable of differentiating between PD and control samples. The altered levels of the metabolites were correlated, suggesting that the elevations stem from a common mechanism involving arginine metabolism. Conclusions A combination of three metabolites, putrescine, tyrosine, and carnitine was able to correctly classify healthy participants from PD patients. Altered metabolite levels suggest altered arginine metabolism. The pattern of metabolomic disturbances was not due to the levodopa-based dopamine replacement medication because one of the patients was not yet taking levodopa but a dopamine receptor agonist.

Advancing Personalized Medicine by Analytical Means: Selection of Three Metabolites That Allows Discrimination between Glaucoma, Diabetes, and Controls

“…The altered concentration of some metabolites found in the AH of patients in comparison to healthy individuals is providing valuable insights into the pathophysiological mechanisms of multiple diseases, including, but not limited to, open-angle glaucoma and type 2 diabetes [ 5 , 14 ], but a diagnostic tool is missing. Our laboratory has recently provided metabolomics-based evidence of altered arginine metabolism as a principal factor in Parkinson’s disease [ 20 ]. Usually, the studies give insight into the pathophysiological mechanisms while being unable to propose useful/promising biomarkers.…”

“…In our previous publications concerning the composition of AH, we were interested in looking for differentially concentrated metabolites and why they could give insight into disease mechanism. We discovered that glutamine, kynurenine, acyl-carnitine and lysophosphatidylcholine levels are altered in the AH of glaucoma patients [ 14 ], that biogenic amines are differentially concentrated in the AH of type 2 diabetes patients [ 5 ] and that the metabolism of arginine is altered as deduced from the composition of the AH of Parkinson’s disease patients [ 20 ]. In the present study, we use the data from previous studies to develop a novel methodology for disease diagnosis and management considering the perspective of personalized medicine.…”

“…Data Availability Statement: Data and resources may be provided by the corresponding (RF) or the first (DBC) authors upon reasonable request. All raw data used in this study are available as Supplementary Materials of previously published papers [5,14,20].…”