Widely targeted metabolomics of Alzheimer's disease postmortem cerebrospinal fluid based on 9-fluorenylmethyl chloroformate derivatized ultra-high performance liquid chromatography tandem mass spectrometry.

ABSTRACT

Confirmed biomarkers of postmortem cerebrospinal fluid (pCSF) are used to differentiate between Alzheimer's disease (AD) patients and healthy seniors with high diagnostic accuracy. However, the extent to which the performance of specific metabolic profiling facilitates reliable estimations of the concentrations of the different pCSF biomarkers and their ratios remains unclear. The interpretation of the lower levels of molecules of metabolic profiling and their concentration ratios in pCSF related to brain disorders could facilitate an unchallenging detection of peripheral biomarkers of AD stages and other dementia types. In this study, we proposed the use of widely targeted metabolomics for pCSF metabolic profiling using 9-fluorenylmethyl chloroformate- (FMOC) derivatized ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to evaluate the diversity of 97 amine-mediated metabolic patterns and pathways from confirmed diagnosis based on AD brain pathology. Our results identified the metabolites that contributed toward and mutually influenced the principal component analysis plot with integrated analytes. Furthermore, the AD group showed a significant variation in several analyte concentration levels compared to those of control subjects. These trends of the concentration levels expressed by the amine metabolic pathways indicated the decreased activity of polyamine and tryptophan-kynurenine (Trp-Kyn) metabolisms. Moreover, increased metabolites such as methionine sulfoxide, 3-methoxy-anthranilate, cadaverine, guanine, and histamine were observed by widely targeted metabolomics of pCSF from the AD subjects. According to their metabolic pathway analysis using FMOC-derivatized UHPLC-MS/MS assay, we supposed that the involvement of polyamine and Trp-Kyn metabolisms was observed in the pCSF samples.