Subtype-Specific Macular Vascular Signatures in Primary Open-Angle, Pseudoexfoliative, and Normal-Tension Glaucoma:...

Background and Objectives: Open-angle glaucoma subtypes share a structural phenotype but differ in pathophysiology: pseudoexfoliative glaucoma (PXG) involves vascular endothelial dysfunction associated with deposition of exfoliative material, whereas normal-tension glaucoma (NTG) reflects primary vascular dysregulation in the absence of elevated intraocular pressure. We characterized subtype-specific OCT angiography (OCTA) profiles obtained from a 3 × 3 mm macular scan and evaluated their discriminatory power for pairwise subtype classification. Materials and Methods: This was a single-center, cross-sectional study of 304 eyes: 198 glaucomatous eyes-primary open-angle glaucoma (POAG, glaucoma simplex in our clinical nomenclature), n = 102; PXG (glaucoma capsulare), n = 68; NTG (glaucoma sine tensio), n = 28-and 106 healthy controls. The Cirrus HD-OCT 5000 AngioPlex 3 × 3 mm OCTA protocol was used to assess vessel density (VD), perfusion density, foveal avascular zone (FAZ) morphology, ganglion cell complex (GCC), and retinal nerve fiber layer (RNFL) thickness. Analyses included Kruskal-Wallis tests with Bonferroni post hoc correction, ROC analysis with DeLong comparison of combined versus structural-only models, multivariate regression, and an exploratory XGBoost classifier with SHAP-based interpretation. Results: VD Inner and Perfusion Inner were lower in PXG (16.37 ± 3.33%; 0.31 ± 0.05) than in POAG (18.73 ± 3.41%; 0.34 ± 0.05; both p < 0.001); Perfusion Inner was also lower than in NTG (p < 0.05). FAZ Area was largest in NTG (0.27 ± 0.11 mm²) and greater than in PXG (0.19 ± 0.08; p < 0.01); FAZ Circularity differed across subtypes (p < 0.001). Combined OCTA-structural models outperformed structural-only models for POAG vs. PXG (DeLong p = 0.002) and for PXG vs. NTG (AUC = 0.770; p = 0.010). Sector-resolved Spearman analysis revealed subtype-specific coupling: in NTG, VD Inner and Perfusion Inner correlated with the inferior RNFL (r = 0.53 and r = 0.52; both p < 0.01); in PXG, coupling shifted nasally (r = 0.41 and r = 0.46; both p < 0.001). The exploratory XGBoost classifier separated glaucoma from controls with an internal cross-validated AUC of 0.975 ± 0.008 (5-fold CV; not externally validated); FAZ Circularity (mean |SHAP| = 0.418) and FAZ Area (0.411) were the top inter-subtype features, supported by case-level SHAP. RNFL avg and average GCC independently predicted MD across subtypes; in PXG, Perfusion Inner also predicted MD (β = -32.78; p = 0.032). Conclusions: In this single-center, cross-sectional cohort, OCTA revealed subtype-associated macular microvascular profiles that are complementary to structural OCT. Reduced vessel and perfusion density characterized PXG, whereas FAZ enlargement and reduced circularity distinguished NTG and PXG. Vascular-structural coupling was nasal-predominant in PXG and inferior-predominant in NTG. Combined multimodal models outperformed structural-only approaches. Macular perfusion additionally predicted MD in PXG. The XGBoost/SHAP analysis is exploratory; prospective and externally validated studies are required before clinical deployment.