{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T09:09:20Z","timestamp":1779700160728,"version":"3.53.1"},"reference-count":31,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>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 \u00d7 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\u2014primary open-angle glaucoma (POAG, glaucoma simplex in our clinical nomenclature), n = 102; PXG (glaucoma capsulare), n = 68; NTG (glaucoma sine tensio), n = 28\u2014and 106 healthy controls. The Cirrus HD-OCT 5000 AngioPlex 3 \u00d7 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\u2013Wallis 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 \u00b1 3.33%; 0.31 \u00b1 0.05) than in POAG (18.73 \u00b1 3.41%; 0.34 \u00b1 0.05; both p &lt; 0.001); Perfusion Inner was also lower than in NTG (p &lt; 0.05). FAZ Area was largest in NTG (0.27 \u00b1 0.11 mm2) and greater than in PXG (0.19 \u00b1 0.08; p &lt; 0.01); FAZ Circularity differed across subtypes (p &lt; 0.001). Combined OCTA\u2013structural 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 &lt; 0.01); in PXG, coupling shifted nasally (r = 0.41 and r = 0.46; both p &lt; 0.001). The exploratory XGBoost classifier separated glaucoma from controls with an internal cross-validated AUC of 0.975 \u00b1 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 (\u03b2 = \u221232.78; 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\u2013structural 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.<\/jats:p>","DOI":"10.3390\/medicina62050941","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Subtype-Specific Macular Vascular Signatures in Primary Open-Angle, Pseudoexfoliative, and Normal-Tension Glaucoma: OCT Angiography Study"],"prefix":"10.3390","volume":"62","author":[{"given":"Maja L. J.","family":"\u017divkovi\u0107","sequence":"first","affiliation":[{"name":"Ophthalmology Clinic, University Clinical Center Ni\u0161, Bulevar dr Zorana \u0110in\u0111i\u0107a 48, 18000 Nis, Serbia"},{"name":"Department of Ophthalmology, Faculty of Medicine, University of Ni\u0161, Bulevar dr Zorana \u0110in\u0111i\u0107a 81, 18000 Nis, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Zlatanovi\u0107","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, University Clinical Center Ni\u0161, Bulevar dr Zorana \u0110in\u0111i\u0107a 48, 18000 Nis, Serbia"},{"name":"Department of Ophthalmology, Faculty of Medicine, University of Ni\u0161, Bulevar dr Zorana \u0110in\u0111i\u0107a 81, 18000 Nis, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2064-9520","authenticated-orcid":false,"given":"Nevena","family":"Zlatanovi\u0107","sequence":"additional","affiliation":[{"name":"Community Health Center Ni\u0161 in Ni\u0161, Vojvode Tankosi\u0107a 15, 18000 Nis, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mladen","family":"Brzakovi\u0107","sequence":"additional","affiliation":[{"name":"Special Hospital for Ophthalmology \u201cClinic Maja\u201d, Vizantijski Bulevar 8, 18000 Nis, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5315-8053","authenticated-orcid":false,"given":"Mihailo","family":"Jovanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Kragujevac, Svetozara Markovi\u0107a 69, 34000 Kragujevac, Serbia"},{"name":"Ophthalmology Clinic, University Clinical Center Kragujevac, Zmaj Jovina 30, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_2","unstructured":"GBD 2019 Blindness and Vision Impairment Collaborators, and Vision Loss Expert Group of the Global Burden of Disease Study (2021). Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: The Right to Sight: An analysis for the Global Burden of Disease Study. Lancet Glob. Health, 9, e144\u2013e160."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"\u0141ukasik, U., Wr\u00f3bel-Dudzi\u0144ska, D., Jarecki, J., Gasi\u0144ska, K., \u017barnowski, T., \u015awi\u0119ch, A., and Kosior-Jarecka, E. (2023). The differences in the pattern of OCT and OCTA examinations between early normal- and high-tension pseudoexfoliative glaucoma. J. Clin. Med., 12.","DOI":"10.3390\/jcm12154899"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s40123-022-00483-1","article-title":"The role of vessel density as measured by optical coherence tomography angiography in the evaluation of pseudoexfoliative glaucoma: A review of the literature","volume":"11","author":"Chatziralli","year":"2022","journal-title":"Ophthalmol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10792-020-01564-5","article-title":"Comparison of vessel density in macular and peripapillary regions between primary open-angle glaucoma and pseudoexfoliation glaucoma using OCTA","volume":"41","author":"Subasi","year":"2021","journal-title":"Int. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1136\/bjophthalmol-2020-317605","article-title":"Optic nerve head vessel density in different stages of pseudoexfoliation disease","volume":"106","author":"Safizadeh","year":"2022","journal-title":"Br. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1177\/1120672118805882","article-title":"A comparison of two optical coherence tomography-angiography devices in pseudoexfoliation glaucoma versus primary open-angle glaucoma and healthy subjects","volume":"29","author":"Rebolleda","year":"2019","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/IJG.0000000000001303","article-title":"Pseudoexfoliative glaucoma, endothelial dysfunction, and arterial stiffness: The role of circulating apoptotic endothelial microparticles","volume":"28","author":"Bourouki","year":"2019","journal-title":"J. Glaucoma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/s41433-018-0042-2","article-title":"A normal tension glaucoma:Review of current understanding and mechanisms of the pathognesis","volume":"32","author":"Pircher","year":"2018","journal-title":"Eye"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1055\/s-0034-1368239","article-title":"Frequency of symptoms and signs of primary vascular dysregulation in Swiss and Korean populations","volume":"231","author":"Konieczka","year":"2014","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3079141","DOI":"10.1155\/2017\/3079141","article-title":"Foveal avascular zone in normal tension glaucoma measured by optical coherence tomography angiography","volume":"2017","author":"Zivkovic","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/s41598-020-80080-z","article-title":"Macular vessel density, branching complexity and foveal avascular zone size in normal tension glaucoma","volume":"11","author":"Cheng","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1136\/bjophthalmol-2020-317038","article-title":"OCT angiography measured changes in the foveal avascular zone area after glaucoma surgery","volume":"106","author":"Shoji","year":"2022","journal-title":"Br. J. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1167\/iovs.16-21079","article-title":"Alterations of the foveal avascular zone measured by optical coherence tomography angiography in glaucoma patients with central visual field defects","volume":"58","author":"Kwon","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1159\/000442773","article-title":"ZEISS Angioplex\u2122 spectral domain optical coherence tomography angiography: Technical aspects","volume":"56","author":"Rosenfeld","year":"2016","journal-title":"Dev. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16009","DOI":"10.1038\/s41598-018-34417-4","article-title":"Effect of macular vascular density on central visual function and macular structure in glaucoma patients","volume":"8","author":"Jeon","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ajo.2021.12.009","article-title":"Ganglion cell complex: The optimal measure for detection of structural progression in the macula","volume":"237","author":"Mohammadzadeh","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s00417-021-05321-x","article-title":"Macular, papillary and peripapillary perfusion densities measured with optical coherence tomography angiography in primary open angle glaucoma and pseudoexfoliation glaucoma","volume":"260","author":"Cornelius","year":"2022","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1159\/000478052","article-title":"Ganglion cell-inner plexiform layer thickness in different glaucoma stages measured by optical coherence tomography","volume":"59","author":"Zivkovic","year":"2018","journal-title":"Ophthalmic Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102611","DOI":"10.1016\/j.pdpdt.2021.102611","article-title":"Comparison of peripapillary and macular vascular density in primary open-angle glaucoma, pseudoexfoliation glaucoma, and normal control eyes","volume":"37","author":"Imani","year":"2022","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.21037\/atm-20-2828","article-title":"Optical coherence tomography angiography in glaucoma","volume":"8","author":"Ritch","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1136\/bjo-2023-323970","article-title":"Association of foveal avascular zone change and glaucoma progression","volume":"108","author":"Nishida","year":"2024","journal-title":"Br. J. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"OCT511","DOI":"10.1167\/iovs.15-18929","article-title":"Structural change can be detected in advanced-glaucoma eyes","volume":"57","author":"Belghith","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Eslami, Y., Hosseinikhah-Manshadi, H., Gholamhoseinpour-Omran, S., Beikmarzehei, A., Fakhraie, G., Mohammadi, M., Zarei, R., Vahedian, Z., Tabatabaei, S.M., and Moghimi, S. (2025). Comparing structural and vascular parameters between advanced pseudoexfoliation glaucoma and primary open angle glaucoma using optical coherence tomography angiography. BMC Ophthalmol., 25.","DOI":"10.1186\/s12886-025-03883-6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11576","DOI":"10.1038\/s41598-025-95082-y","article-title":"Retinal neurodegeneration, neuroretinal rim analysis and choroid thickness in pseudoexfoliation syndrome with spectral domain optical coherence tomography","volume":"15","author":"Couceiro","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ajo.2021.10.005","article-title":"Relationship between macular microvasculature and visual acuity in advanced and severe glaucoma","volume":"236","author":"Hsia","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"363","DOI":"10.4103\/IJO.IJO_771_23","article-title":"Structure-function relationship and diagnostic value of macular ganglion cell complex measurement using Fourier-domain OCT in glaucoma","volume":"72","author":"Dhabarde","year":"2024","journal-title":"Indian J. Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ong, J., Zarnegar, A., Corradetti, G., Singh, S.R., and Chhablani, J. (2022). Advances in optical coherence tomography imaging technology and techniques for choroidal and retinal disorders. J. Clin. Med., 11.","DOI":"10.3390\/jcm11175139"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kim, S.J., Cho, K.J., and Oh, S. (2017). Development of machine learning models for diagnosis of glaucoma. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177726"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.1167\/iovs.15-16805","article-title":"Artificial neural network approach for differentiating open-angle glaucoma from glaucoma suspect without a visual field test","volume":"56","author":"Oh","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/5\/941\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:53:04Z","timestamp":1779699184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/5\/941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":31,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["medicina62050941"],"URL":"https:\/\/doi.org\/10.3390\/medicina62050941","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]}}}