Abstract
This study introduces a clinical lipidomics platform leveraging fragment-based quantification on parallel reaction monitoring (PRM)-parallel accumulation serial fragmentation (PASEF) for lipid quantification. An isomeric model, termed "SN regression model", built on specific PASEF-fragment ion patterns, was developed for the quantification of coeluting sn positional isomers without prior derivatization. This PASEF-isomeric lipidomics aids in the resolution and quantification of 176 lipid isomers coeluting in chromatography and/or ion mobility dimensions, expanding the lipidome quantitative coverage to 481 plasma lipids covering 14 lipid subclasses with CV <40% for 32 plasma replicates. We demonstrated the method's advantage for clinical research by detailed quantitative lipidomic phenotyping of patients with Parkinson's disease, enabling the delineation of new biochemical pathways affected by the disorder and stratification of patients. The method's amenability for high-throughput deep quantitative coverage of highly structurally resolved lipidome has implications for improving the diagnosis and understanding of the distinct metabolic alterations in Parkinson's disease subgroups and, generally, for disorders associated with lipid dysregulation.