Molecular Portraits of Aqueous Humor in Primary and Pseudoexfoliative Open-Angle Glaucoma

Glaucoma is a neurodegenerative disease that affects the optic nerve and retinal ganglion cells. The two most common forms, primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEG), are associated with ocular hypertension caused by impaired aqueous humor (AH) outflow but have specific ocular and systemic features that may determine their diagnosis and treatment. To identify these features, we compared AH composition in patients using a multiomics approach. Total reflection X-ray fluorescence analysis revealed an increase in zinc and calcium concentrations more pronounced in PEG. Nuclear magnetic resonance study identified common metabolomic changes involving amino acids (Ala, Glu, His, Lys, Tre) and tricarboxylic acid cycle components (citrate and succinate). Targeted liquid chromatography-tandem mass spectrometry data demonstrated shared elevation of oxidative stress-related oxylipins (9/13-HODE, 9-HOTrE) and POAG-specific changes in phospholipase A2 products (DHA, lyso-PAF) and inflammatory prostaglandins (PGE2 and 15d-PGJ2). POAG featured secretion of proteins controlling intraocular pressure (angiotensinogen) and trabecular meshwork outflow (myocilin and cystatin C) and altered levels of neurotrophic factors (PEDF, VGF). Our data highlight novel AH biomarkers distinguishing POAG from PEG (15d-PGJ2, VGF) and demonstrate that they have specific triggers and responses to ocular hypertension but share common mechanisms, such as oxidative stress, mitochondrial dysfunction, and zinc and calcium toxicity.