Peripheral markers of membrane metabolism: characterization of individuals at high risk for psychosis

Author(s)

Alana Caroline Costa

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2023-06-21

Examining board members

Wagner Farid Gattaz; José Alexandre de Souza Crippa; Leandro da Costa Lane Valiengo; Marcus Vinicius Zanetti

• Advisor: Wagner Farid Gattaz; Leda Leme Talib

Abstract

Psychotic disorders can affect up to 3.5% of the general population and tend to be chronic and disabling. Even before developing frank psychosis, individuals display behavioral changes. Based on this, criteria were created for identifying patients referred to as Ultra-high risk (UHR) for psychosis. However, research demonstrates that conversion rates to frank psychosis vary widely, and significant efforts have been made to make these criteria more specific and accurate. Alterations in membrane metabolism and lipid composition have been widely described in psychotic disorders and may be an important tool for better characterizing these individuals. Phospholipases are responsible for remodeling the plasma membrane, an essential physiological process for maintaining the fluidity and conformation of this cellular structure. Studies with schizophrenia patients indicate an increase in phospholipase A2 (PLA2) activity, as well as reductions in membrane phospholipids, an increase in their metabolites, and alterations in membrane fluidity. PLA2 is the main enzyme responsible for membrane phospholipid metabolism and is a vast family of enzymes divided into three subgroups: iPLA2, cPLA2, and sPLA2. In addition, phospholipase D (PLD) is also involved in biological processes regulating the plasma membrane. Our research group has already described that PLA2, and plasma metabolite levels can discriminate among different neuropsychiatric disorders. In 2018, we suggested a panel of four plasma metabolites - PC aa C26:0, PC aa C38:4, PC aa C34:3, and C16-OH - based on the classification and regression model capable of predicting, among individuals in their first psychotic episode, which would evolve into schizophrenia or bipolar disorder with an accuracy of 87.1%. The main objective of the present work was to quantify these metabolites in UHR individuals and verify if the profile is like that of patients with schizophrenia, since UHR individuals would be in the prodromal phase of psychosis, in addition to quantifying platelet PLA2 and leukocyte PLD activity. Plasma metabolites were quantified by mass spectrometry, PLA2 activity by radioenzymatic assay, and PLD activity by fluorescence assay. We observed an increase in iPLA2, cPLA2, and PLD activity in UHR individuals versus healthy controls, but we did not observe differences in those who did not convert. This negative finding, although in a small sample, does not support the hypothesis that metabolites can be predictors of psychosis conversion. Plasma metabolites followed the profile established by the regression model proposed in 2018, however, when evaluated individually, the absolute quantification did not present the same magnitude established previously. The results are promising and in line with the hypothesis that there is an imbalance in metabolism and membrane composition that precedes clinical symptoms and can be visualized in peripheral biological matrices. It is hoped that these findings can complement clinical diagnosis by providing objective and standardized biomarkers to better characterize individuals at high risk for psychosis (AU)

• FAPESP's process: 17/26291-2 - Peripheral markers of membrane metabolism: characterization of individuals at ultra-high risk for psychosis
• Grantee: Alana Caroline Costa
• Support Opportunities: Scholarships in Brazil - Doctorate