Abstract
PURPOSE: Neovascular age-related macular degeneration (nAMD) is a major aetiology of vision loss characterized by lipid metabolism dysregulation. This study investigated the alterations in lipid profiles associated with wet AMD (wAMD) and its subtype, polypoidal choroidal vasculopathy (PCV). METHODS: A cross-sectional lipidomic analysis was derived from a prospective longitudinal study in China (2017-2019). Serum samples from 195 wAMD patients, 130 PCV patients and 119 controls were analysed using ultra-performance liquid chromatography‒tandem mass spectrometry (UPLC‒MS/MS), focusing on acylcarnitines, glycerophospholipids and sphingolipids. Training and test sets were randomly generated after sample size matching. Orthogonal partial least squares-discriminant (OPLS-DA), univariate and multivariate analyses were performed. The selection criteria for differential lipids were a variable importance in projection (VIP) > 1.0, a fold change (FC) > 1.2 or < 0.83, and a false discovery rate (FDR) < 0.05. Key lipids were refined using the Boruta algorithm and evaluated through Firth regression and receiver operating characteristic (ROC) analysis. Spearman's rank correlation analysis was used to assess the relationships between the differential lipids and ocular indicators, including central retinal thickness (CRT), central retinal volume (CRV) and best-corrected visual acuity (BCVA). RESULTS: No significant Lipid profile differences were detected between wAMD and PCV. Compared with the controls, wAMD patients had 53 differential lipids (52 upregulated, 1 downregulated), whereas PCV patients had 34 (31 upregulated, 3 downregulated). Upregulated PC ae C42:0 was consistently associated with ocular indicators in both groups. A 9-lipid panel for wAMD and a 6-lipid panel for PCV showed moderate diagnostic performance in the ROC models. Significant correlations with macular structure and BCVA were observed in PCV patients for 12 phosphatidylcholines, 3 sphingomyelins and 2 acylcarnitines and in wAMD patients for one phosphatidylcholine and one acylcarnitine. Downregulated lipids were negatively correlated with CRT or CRV, whereas upregulated lipids showed the opposite trend. Age-related lipid associations were found in wAMD but not in PCV patients. CONCLUSIONS: PCV and wAMD had shared and distinct lipidomic dysregulations, with stronger systemic-retinal associations in PCV, suggesting that subtype-specific metabolic reprogramming may affect nAMD pathology, offering new perspectives regarding early diagnosis and intervention strategies to mitigate disease burden. TRIAL REGISTRATION: NCT03128463 ( www. CLINICALTRIAL: gov ) was registered on 9 March 2017.