Corroborated evidence on change of metabolome after ischemic stroke due to large vessel occlusion.

Introduction: Metabolomic studies which search for acute ischemic stroke (AIS) biomarkers commonly have contradictory findings. Robust methodology is required to understand true metabolome changes after AIS.

Methods: To improve validity, we obtained corroborative evidence on change of serum metabolome after AIS by: (1) focusing on patients with large vessel occlusion (LVO), (2) combining cross-sectional and longitudinal study designs, and (3) performing analysis using different metabolome platforms: Nuclear Magnetic Resonance (NMR) and Liquid Chromatography-Mass Spectrometry (LC-MS). In the cross-sectional part we compared serum metabolome of 84 AIS patients and 82 controls using NMR at 48-72 h, while in the longitudinal part we prospectively analyzed serum metabolome using LC-MS on 15 AIS patients at < 24 h, 48-72 h, 5-7 days, 80-120 days. We hypothesized that serum metabolites elevated in cross-sectional part would show rising trajectory in longitudinal part, and vice versa.

Results: We found that glycerol, phosphatidylethanolamine (PE), ceramide, phenylalanine and their derivatives had consistent increases, while other key metabolites including histidine, tyrosine, valine, glutamine, phosphatidylcholine (PC), sphingomyelin, fatty acids (FA) had consistent decreases after AIS.

Conclusion: We identified corroborated changes in metabolome after AIS across different technologies and study designs. These changes correspond to loss of nerve cell membrane integrity and activation of alternative metabolic pathways in the setting of blood brain barrier (BBB) disruption. If proven on a larger sample, our findings may improve prediction of mortality, and functional outcomes after AIS.