Mass spectrometry imaging of two neocortical areas reveals the histological selectivity of schizophrenia-associated lipid alterations

Abstract

BACKGROUND: Schizophrenia is a psychiatric disorder known to affect brain structure and functionality. Structural changes in the brain at the level of gross anatomical structures have been fairly well studied, while microstructural changes, especially those associated with changes in the molecular composition of the brain, are still being investigated. Of special interest are lipids and metabolites, for which some previous studies have shown association with schizophrenia. AIM: To utilize a spatially resolved analysis of the brain lipidome composition to investigate the degree and nature of schizophrenia-associated lipidome alterations in the gray and white matter structures of two neocortical regions — the dorsolateral prefrontal cortex (Brodmann area 9, BA9) and the posterior part of the superior temporal gyrus (Brodmann area 22, posterior part, BA22p), as well compare the distribution of the changes between the two regions and tissue types. METHODS: We employed Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Imaging (MALDI-MSI), supplemented by a statistical analysis, to examine the lipid composition of brain sections. A total of 24 neocortical sections from schizophrenia patients (n=2) and a healthy control group (n=2), representing the two aforementioned neocortical areas, were studied, yielding data for 131 lipid compounds measured across more than a million MALDI-MSI pixels. RESULTS: Our findings revealed an uneven distribution of schizophrenia-related lipid alterations across the two neocortical regions. The BA22p showed double the differences in its subcortical white matter structures compared to BA9, while less bias was detected in the gray matter layers. While the schizophrenia-associated lipid differences generally showed good agreement between brain regions at the lipid class level for both gray and white matter, there were consistently more discrepancies for white matter structures. CONCLUSION: Our study found a consistent yet differential association of schizophrenia with the brain lipidome composition of distinct neocortical areas, particularly subcortical white matter. These findings highlight the need for broader brain coverage in future schizophrenia research and underscore the potential of spatially resolved molecular analysis methods in identifying structure-specific effects.