Spatial Lipidomics of the Human Prefrontal Cortex for Metabolic Insights in Schizophrenia
P. Enrico, C. Cabasino, G. Delvecchio, P. Brambilla, Y. Torrente, I. BongarzoneIntroduction
Schizophrenia (SCZ) is a severe psychiatric disorder with only partly understood biological mechanisms. Lipids, which account for more than half of the brain’s dry weight, play fundamental roles in myelination, neurotransmission, and immune-glial interactions. Increasing evidence has linked lipid dysregulation to psychiatric disorders, yet most studies rely on bulk lipidomics, which lacks anatomical resolution. Spatial approaches are needed to characterize lipid distribution in the human brain and to investigate disease-related alteration
Objectives
The aim of this study was to perform high-resolution spatial lipidomic mapping of the dorsolateral prefrontal cortex (DLPFC) in post-mortem human brains, and to conduct preliminary analyses of lipid alterations in SCZ compared with matched controls.
Methods
Post-mortem DLPFC tissue was obtained from the NIMH Human Brain Collection Core. Five non-diagnostic cases were analyzed to define the spatial distribution of individual lipid species, while an additional cohort of five SCZ and five matched controls was included for preliminary group comparisons. Sections were processed with a standardized matrix-assisted laser desorption ionization (MALDI) imaging workflow in negative-ion mode (Figure 1). Multivariate segmentation and dimensionality reduction were applied to identify regional molecular profiles. Region- and group-level differences were tested with ANOVA including false discovery rate correction. Lipid assignments were confirmed on tissue by MALDI-LIFT MS/MS and validated through curated database and literature matching of fragment ions.
Results
Spatial analyses revealed reproducible separation of white and grey matter subregions, with PCA showing that the first five components explained 87% of variance (Figure 2). Sulfatides were enriched in white matter, whereas N-acyl phosphatidylserines localized to upper cortical layers, with highly significant regional differences (pFDR < 10⁻¹⁰ for the most discriminant species). Preliminary SCZ versus control analyses based on Pearson’s correlation values and ROC curves stratified by white and grey matter identified phospholipid alterations suggesting possible links with compartment-specific neuroglial and metabolic processes (Figure 3).
Image 1: Long description.