Untargeted metabolomics and mendelian randomization analysis identify alpha-linolenic acid and linoleic acid as novel biomarkers of perioperative neurocognitive dysfunction.

Perioperative neurocognitive dysfunction (PND) occurs in elderly individuals undergoing
anesthesia and surgery. To explore the potential molecular mechanisms, we performed right-
sided cervical exploratory surgery under sevoflurane anesthesia in 18-month-old male Sprague-
Dawley rats. Anxiety-depression-like behaviors and learning memory abilities were assessed
using the Open Field Test (OFT) and Novel Object Recognition (NOR). Additionally, the
hippocampus was collected one day after surgery for inflammatory factor detection, TUNEL
staining, and metabolomics analysis. Mendelian randomization (MR) analyses were
subsequently conducted to validate the causal relationships by using a series of GWAS
datasets related to representative differential metabolites as exposures and cognitive
impairment as endpoints. The results indicated that rats exposed to anesthesia and surgery
exhibited poorer cognitive performance, significant elevations in hippocampal inflammatory
factors such as IL-1β and TNF-α, and extensive neuronal apoptosis. LC-MS/MS-based
untargeted metabolomics identified 19 up-regulated and 32 down-regulated metabolites in the
test group, with 6 differential metabolites involved in metabolic pathways enriched according to
the KEGG database. ROC analysis revealed a correlation between α-linolenic acid (ALA) and
linoleic acid (LA) and the development of PND. Further MR analysis confirmed that ALA was
significantly associated with cognitive performance and the risk of depression, while LA was
significantly associated with the risk of memory loss. Taken together, our results identified ALA
and LA as potentially powerful biomarkers for PND.