Comparative Analysis of Optical Coherence Tomography Angiography Metrics in Primary Open- Angle Glaucoma and Ocular Hypertension

Comparative Analysis of Optical Coherence Tomography Angiography Metrics in Primary Open- Angle Glaucoma and Ocular Hypertension | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Analysis of Optical Coherence Tomography Angiography Metrics in Primary Open- Angle Glaucoma and Ocular Hypertension Büşra Karadağ, Belgin İzgi, Şerife BAYRAKTAR This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8281184/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Purpose: To investigate the diagnostic and follow-up utility of optical coherence tomography angiography (OCT-A) in glaucoma by evaluating macular ganglion cell complex (GCC) thickness and parafoveal vessel density (pfVD) in patients with ocular hypertension (OHT) and various stages of primary open-angle glaucoma (POAG). Material and Methods: This cross-sectional study included 150 eyes from 56 patients with POAG and 32 with OHT, all under regular follow-up at the Glaucoma Unit of the Istanbul Faculty of Medicine, Department of Ophthalmology. Evaluations were conducted between November and December 2022.Additionally,50 eyes from 25 healthy individuals without ocular or systemic pathology were included as a control group. OCT-A images were obtained using the Topcon DRI OCT Triton (Topcon Corporation, Japan). Macular GCC thickness and pfVD in the superficial and deep capillary plexuses were measured and compared among the groups. Results: A total of 113 participants (74 females,39 males) were enrolled. No statistically significant differences in macular GCC thickness or pfVD were found between the control and OHT groups. In contrast, both parameters were significantly reduced in the POAG group, with a progressive decline corresponding to disease severity. The decrease in pfVD was more pronounced in the superficial plexus compared to the deep plexus. In early-stage POAG, GCC thinning was more prominent than pfVD reduction. Conclusıon: Our findings suggest that assessment of macular GCC thickness and pfVD via OCT-A can be utilized alongside structural and functional tests in the diagnosis and follow-up of glaucoma. In our study, macular GCC measurements were significantly lower in the glaucoma group compared to other groups, with more pronounced thinning observed in advanced stages. Notably, in early-stage glaucoma, the reduction in macular GCC was more prominent than that in pfVD. These findings indicate that structural damage in macular GCC may occur earlier than vascular changes in pfVD and may be particularly useful in the early monitoring of glaucoma progression. Ganglion Cell Complex Glaucoma OCT-A Parafoveal Vessel Density Ocular Hypertension Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Glaucoma is a chronic and progressive optic neuropathy characterized by the gradual loss of visual function and visual field, primarily due to irreversible damage to the optic nerve, which may ultimately lead to blindness 1 – 5 . It encompasses a heterogeneous group of disorders, and despite numerous proposed mechanisms, its precise etiopathogenesis remains incompletely elucidated. Although elevated intraocular pressure (IOP) is recognized as the most prominent risk factor for both the onset and progression of the disease, it is now well established that glaucoma is a multifactorial condition, with vascular dysregulation emerging as a key element potentially contributing to its development and advancement. Glaucoma is among the leading causes of preventable yet irreversible vision loss worldwide. Consequently, early diagnosis and effective monitoring of disease progression are critical for preserving visual function. Currently, standard clinical practice involves the use of visual field testing, which assesses functional impairment, and optical coherence tomography (OCT), which provides detailed structural analysis 6 – 11 . Notably, functional deficits such as visual field loss typically become detectable only after approximately 30% of retinal ganglion cells (RGCs) have already degenerated, underscoring the necessity of identifying structural alterations at earlier stages 12 , 13 . Given that nearly half of all RGCs and their axons are concentrated within the macular region, macular ganglion cell complex (GCC) analysis has gained increasing relevance in glaucoma evaluation 14 – 18 . Historically, several techniques—including fluorescein angiography, color Doppler ultrasonography, laser Doppler flowmetry, and Heidelberg retinal flowmetry—have been employed to investigate optic nerve head (ONH) perfusion in glaucomatous eyes. Although these methods have demonstrated altered blood flow in glaucomatous optic neuropathy, their clinical adoption has been limited due to invasiveness, potential adverse effects, low reproducibility, and operational constraints. Optical coherence tomography angiography (OCT-A), a recent advancement in retinal imaging, enables high-resolution, dye-free visualization of retinal and choroidal microvasculature. OCT-A allows for the quantitative assessment of perfusion and vessel density parameters, offering valuable insights into the vascular component of glaucoma pathophysiology 7 . Furthermore, it facilitates three-dimensional analysis of the GCC, thereby enhancing the potential for early structural detection prior to functional decline. OCT-A has been increasingly recognized as a noninvasive and reproducible method for evaluating retinal microcirculation and its alterations in glaucoma 19 – 21 . In this study, OCT-A was utilized to quantify macular vessel density as well as GCC thickness in individuals with ocular hypertension (OHT) and primary open-angle glaucoma (POAG) at various stages of disease. These parameters were compared with those of a healthy control group to investigate the diagnostic and monitoring potential of OCT-A in glaucoma management. MATERIALS AND METHODS Ethical Approval The study was approved by the Ethics Committee of Istanbul University Faculty of Medicine (Approval Date and Number: 25.11.2022–1381233). All procedures involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Informed consent, both written and verbal, was obtained from all participants prior to their inclusion in the study. The methodology adopted for the study is detailed below: As described in the abstract, this study aimed to evaluate macular GCC thickness and parafoveal vessel density (pfVD) in patients with POAG and OHT using OCT-A. The following section details the imaging protocol and quantitative analysis methodology. The study included 150 eyes of 56 patients diagnosed with POAG and 32 patients diagnosed with OHT who were under regular follow-up at the Glaucoma Unit of the Department of Ophthalmology, Istanbul Faculty of Medicine, and presented for examination between November and December 2022. Additionally, 50 eyes of 25 healthy individuals with no systemic or ophthalmological pathology were included as a control group. OCT-A images were obtained using the Topcon ImageNet 6 system (DRI OCT Triton, Topcon Corporation, Japan) available in our clinic. Measurements of macular GCC thickness and both superficial and deep parafoveal vessel density (pfVD) were compared across diagnostic groups. Statistical analyses were conducted with a 95% confidence interval, and significance was defined as p < 0.05. Inclusion Criteria Participants were between 40 and 65 years of age, free of systemic diseases, and had a confirmed diagnosis of POAG or OHT based on comprehensive ophthalmic evaluation, including biomicroscopy, gonioscopy, intraocular pressure (IOP) measurements, optical coherence tomography (OCT), and visual field testing. To ensure optimal image quality for OCT-A and visual field analysis, eligible participants were required to have a best-corrected visual acuity (BCVA) of 0.7 or better, spherical and cylindrical refractive errors within the range of +3.00 to –3.00 diopters, and clear ocular media without significant opacities. The control group consisted of age-matched individuals (40–65 years) who were both ophthalmologically and systemically healthy, with no history of ocular surgery other than uncomplicated cataract extraction. Control subjects also met the visual and refractive criteria stated above and exhibited clear ocular media. Ophthalmological Evaluation All participants underwent a comprehensive ophthalmic examination, including refraction assessment, BCVA determination, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry for IOP measurement, and detailed fundus examination using a 90 D lens. Peripapillary retinal nerve fiber layer (RNFL) thickness was assessed using spectral-domain OCT (HRA+OCT Spectralis, Heidelberg Engineering). Visual field testing was performed with the Humphrey Field Analyzer II (Model 750) using the 24-2 Swedish Interactive Threshold Algorithm. Mean deviation (MD) values were used to stage glaucoma severity: MD 21 mmHg without any glaucomatous structural or functional changes on OCT or visual field testing. POAG was diagnosed based on open angles on gonioscopy, characteristic glaucomatous optic nerve damage, and reproducible visual field defects consistent with glaucoma. OCT-A Imaging and Analysis Optical coherence tomography angiography (OCT-A) scans were acquired using the Topcon ImageNet 6 system (DRI OCT Triton, Topcon Corporation, Japan). To ensure image quality and analytic reliability, scans with a signal strength below 6/10 were excluded from further evaluation. A 6 × 6 mm scan area was employed for quantitative assessment of macular vessel density, while a broader 7 × 7 mm scan area was utilized to evaluate parameters of the macular ganglion cell complex (GCC). The foveal avascular zone (FAZ) was automatically delineated by the device software, and the vessel density within a 300-μm radius surrounding the FAZ was defined as the foveal vessel density. Vessel density in the superficial capillary plexus (SCP)—encompassing the retinal slab from 2.6 μm below the internal limiting membrane (ILM) to 15.6 μm below the inner plexiform layer (IPL)—was calculated automatically. In contrast, deep capillary plexus (DCP) measurements, which span from 15.6 µm to 70.2 µm below the IPL, were manually delineated due to segmentation limitations of the automated algorithm. The detailed layer segmentation and anatomical boundaries of SCP and DCP regions are illustrated in Figure 1. GCC thickness parameters were extracted from OCT-A scans centered on the foveal region. Quantitative analysis was performed using the six-sector map of the Early Treatment Diabetic Retinopathy Study (ETDRS), which was automatically overlaid by the software to ensure standardized regional comparisons. The spatial distribution of GCC thickness, aligned with the ETDRS grid, is presented in Figure 2, providing a comprehensive overview of the structural integrity of the macular ganglion cell layer. Statistical Analysis Statistical analyses were conducted using the NCSS 2020 Statistical Software (NCSS LLC, Kaysville, Utah, USA). Quantitative variables were expressed as mean ± standard deviation, median, minimum, and maximum values, while categorical variables were summarized as frequencies and percentages. The distribution of continuous variables was assessed for normality using the Shapiro-Wilk test and supported by visual inspection of Box Plot graphics. For comparisons involving more than two independent groups with non-normally distributed variables, the Kruskal–Wallis test was employed, followed by the Dunn post hoc test to determine pairwise group differences. The Fisher–Freeman–Halton test was used for evaluating associations between categorical variables. All statistical tests were performed within a 95% confidence interval, and a p-value of <0.05 was considered indicative of statistical significance. Correlation Analyses Spearman correlation analyses were conducted to explore the relationships among OCT-A metrics in each diagnostic group. In controls and OHT, superficial and deep macular vessel densities (sfVD–dVD) were strongly correlated (Control: r = 0.612, p = 2.31×10⁻⁶; OHT: r = 0.703, p = 1.91×10⁻¹⁰) (Table 1). This strong coupling persisted in early POAG (r = 0.703, p = 1.38×10⁻¹⁰) but weakened in mid-stage POAG (r = 0.243, p = 0.383) and disappeared in advanced POAG (r = –0.049, p = 0.828), indicating increasing layer-specific dissociation with disease progression (illustrated in Figure 3). In contrast, the association between sfVD and macular GCC thickness was not significant in OHT (r = –0.077, p = 0.550) or early POAG (r = –0.141, p = 0.269), became borderline in mid-stage (r = 0.527, p = 0.064), and reached a moderate, significant level in advanced POAG (r = 0.541, p = 0.011) (Figure 4). This pattern suggests that structural macular damage (GCC thinning) may precede microvascular reduction in parafoveal vessel density, especially in early disease, while both parameters converge as glaucoma advances. Pooled POAG analyses confirmed significant positive associations for sfVD–dVD (r = 0.600, p = 4.14×10⁻¹¹) and sfVD–GCC (r = 0.535, p = 1.65×10⁻⁸) as summarized in Table S (Supplementary Data). RESULTS A total of 113 participants were included in the study, comprising 32 individuals diagnosed with ocular hypertension (OHT), 56 individuals with primary open-angle glaucoma (POAG), and 25 healthy individuals who constituted the control group. The mean age of the study cohort was 59.3 ± 4.81 years, while the control group had a mean age of 49.32 ± 5.75 years. The demographic characteristics of the participants are summarized in Table 2. Macular vessel density within both the superficial and deep capillary plexuses was also assessed using OCT-A and compared across groups (Table 3). Statistically significant differences were detected in all quadrants (superior, inferior, temporal, and nasal). A progressive decline in macular vessel density was observed in correlation with the severity of glaucoma. No statistically significant differences were found between the control and OHT groups across any of the macular parameters. However, the intermediate-stage POAG group showed significantly reduced vessel density in all quadrants, except the nasal quadrant of the deep capillary plexus (p = 0.001; p < 0.01). The comparison of average vessel density values in the macular superficial and deep capillary plexuses among groups did not reveal statistically significant differences (Table 4). While the control group demonstrated higher mean values in the superficial capillary plexus compared to both early- and intermediate-stage POAG groups, no significant difference was found between the OHT and early-stage POAG groups. In contrast, vessel density in the deep capillary plexus was significantly lower in the intermediate-stage POAG group compared to all other groups. Ganglion cell complex (GCC) thickness measurements obtained via OCT-A are presented in Table 5. Statistically significant differences were identified among groups in all quadrants, including superior, inferior, superonasal (SN), superotemporal (ST), inferonasal (IN), and inferotemporal (IT) regions. GCC thickness showed a progressive decline in conjunction with advancing disease severity. Subgroup analyses indicated significantly reduced GCC measurements in both early- and intermediate-stage POAG groups compared to the control and OHT groups. Furthermore, the intermediate-stage group exhibited significantly lower GCC values than the early-stage POAG group. DISCUSSION In this study, we evaluated macular vessel density, alongside ganglion cell complex (GCC) thickness, using optical coherence tomography angiography (OCT-A) in patients diagnosed with early- and intermediate-stage primary open-angle glaucoma (POAG) and ocular hypertension (OHT). These parameters were then compared with those obtained from healthy eyes to assess their potential utility in the diagnosis and monitoring of glaucoma. A total of 200 eyes from 113 patients were analyzed, comprising 32 eyes with OHT, 56 eyes with POAG (34 early-stage, 22 intermediate-stage), and 50 eyes from 25 healthy controls. Statistically significant differences were observed among the groups in terms of age, intraocular pressure (IOP), and best-corrected visual acuity (BCVA), while gender distribution did not differ significantly. We compared parafoveal vessel density (pfVD) in both the superficial and deep capillary plexuses across four macular quadrants (superior, inferior, nasal, and temporal), as well as their mean values. All parameters were reduced in glaucomatous eyes, with more severe reductions in advanced stages. Notably, no significant differences were observed between the OHT and control groups across pfVD measurements. Similarly, early-stage POAG eyes did not differ significantly from OHT and control eyes, except for select quadrants of the superficial plexus (temporal, nasal) and the superior quadrant of the deep plexus. The reduction in superficial pfVD was more prominent than in the deep plexus 22 . El-Nimri et al. similarly reported lower superficial pfVD in glaucomatous eyes, without significant differences in deep pfVD across groups. Lommatzsch et al. found decreased superficial and deep pfVD in glaucoma patients relative to controls but did not observe differences between disease stages 23 . In contrast, our findings demonstrate stage-dependent changes, particularly in superficial pfVD. Traditionally, structural retinal ganglion cell (RGC) damage in glaucoma is assessed via circumpapillary RNFL thickness using OCT 24–27 . However, this method only evaluates the axons of RGCs, omitting the somas and dendritic structures in the ganglion cell layer (GCL) and inner plexiform layer (IPL), which are also compromised in glaucoma 28 . Experimental data suggest that RGC soma and dendrite damage precedes axonal degeneration, highlighting the potential superiority of macular GCC assessment over RNFL measurements for early glaucoma detection 29,30 . Several studies have established the diagnostic advantage of GCC thickness over total macular thickness 28 . While most prior investigations have utilized OCT for GCC evaluation, Wang et al. uniquely employed OCT-A, reporting significantly reduced macular vessel density and GCC thickness in glaucomatous eyes, with progressive deterioration associated with disease severity 31 . Our findings are consistent with this literature, showing decreased GCC thickness in glaucomatous eyes, with more pronounced reductions in intermediate-stage POAG 30,32,33 . Several limitations should be acknowledged. First, the study sample had a higher proportion of female participants (65.5%), although gender distribution did not differ significantly among groups and was not found to influence vascular density. Second, the intermediate-stage POAG group had a higher mean age compared to other groups. Since age is known to affect vessel density and GCC thickness, this could be a confounding factor; however, the age distribution within the glaucoma groups was not statistically different. Additionally, some patients were on topical anti-glaucomatous therapy during the study. While these medications could potentially affect vascular density, discontinuing treatment would not have been ethically or clinically feasible. The impact of such therapies on vessel density remains underexplored in the literature, and our study did not control for this variable. Moreover, the control group was composed of younger participants to ensure systemic and ocular health, which may account for the slightly lower mean age compared to the glaucoma groups. Despite this, age ranges across all groups remained relatively narrow and balanced. Interpretation of Correlation Findings The loss of coupling between superficial and deep vessel densities from early to advanced POAG suggests that the superficial capillary plexus is the earlier and predominantly affected layer. Moreover, the lack of sfVD–GCC association in early POAG, contrasted with the significant correlation in advanced disease, is consistent with structural macular damage occurring prior to microvascular changes. These results reinforce the clinical utility of macular GCC as an early indicator of glaucomatous neurodegeneration and support the hypothesis that GCC thinning may precede measurable reductions in parafoveal vessel density. However, these findings should be interpreted with caution, as the cross-sectional design of the present study does not allow definitive conclusions regarding the temporal sequence of structural and vascular changes. Longitudinal studies are required to further elucidate whether macular GCC thinning consistently precedes microvascular alterations during the early stages of glaucoma. In conclusion, despite its limitations, our study provides important contributions to the understanding of vascular and structural changes in glaucomatous eyes, reinforcing the potential of OCT-A in glaucoma evaluation. Further research with larger and demographically balanced cohorts is warranted to validate and expand upon these findings. CONCLUSION Our findings suggest that assessment of macular ganglion cell complex (GCC) thickness and parafoveal vessel density (pfVD) using optical coherence tomography angiography (OCT-A) can be utilized alongside established structural and functional tests in the diagnosis and follow-up of glaucoma. Experimental evidence has demonstrated that retinal ganglion cell damage may occur prior to axonal loss; accordingly, macular GCC evaluation may theoretically provide earlier structural information compared with peripapillary retinal nerve fiber layer (RNFL) analysis. In the present study, macular GCC measurements were significantly lower in glaucomatous eyes compared with other groups, with more pronounced thinning observed in advanced disease stages. Notably, in early-stage glaucoma, the reduction in macular GCC thickness was more prominent than the corresponding decrease in pfVD. While OCT-A–derived macular vessel density and GCC thickness both provide valuable insights into glaucomatous changes, our findings suggest that structural alterations in macular GCC may precede detectable microvascular changes in early disease stages. Therefore, macular GCC assessment may serve as a complementary parameter in the early monitoring of glaucoma progression, rather than as a standalone tool. Further longitudinal studies with larger and more diverse cohorts are warranted to confirm these observations and to clarify the temporal relationship between structural and vascular changes in glaucoma. Abbreviations OCT-A : Optical Coherence Tomography Angiography POAG : Primary Open-Angle Glaucoma OHT : Ocular Hypertension GCC : Ganglion Cell Complex pfVD : Parafoveal Vessel Density IOP : Intraocular Pressure Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Istanbul University Faculty of Medicine (Approval date and number: 25.11.2022–1381233). All procedures were conducted in accordance with the principles of the Declaration of Helsinki and relevant institutional guidelines. Written and verbal informed consent was obtained from all participants prior to enrollment. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ contributions BK : Study conception and design, data acquisition, analysis and interpretation, manuscript drafting. BI: Study supervision, critical revision of the manuscript for important intellectual content. SB : Data interpretation and manuscript review. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank the staff of the Glaucoma Unit, Department of Ophthalmology, Istanbul University Faculty of Medicine, for their support during data collection. References Chung, J.K., Hwang, Y.H., Wi, J.W., et al., Glaucoma Diagnostic Ability of the Optical Coherence Tomography Angiography Vessel Density Parameters. Curr Eye Res , 2017. 42(11): p. 1458-1467. doi: 10.1080/02713683.2017.1337157. Weinreb, R.N., Aung, T., Medeiros, F.A. The pathophysiology and treatment of glaucoma: A review. 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Invest Ophthalmol Vis Sci , 2010. 51(9): p. 4646-51. doi: 10.1167/iovs.09-5053. Wang, Y., Xin, C., Li, M., et al., Macular vessel density versus ganglion cell complex thickness for detection of early primary open-angle glaucoma. BMC Ophthalmol , 2020. 8;20(1): p. 17. doi: 10.1186/s12886-020-1304-x. Penteado, R.C., Zangwill, L.M., Daga, F.B., et al., Optical Coherence Tomography Angiography Macular Vascular Density Measurements and the Central 10-2 Visual Field in Glaucoma. J Glaucoma , 2018. 27(6): p. 481-489. doi: 10.1097/IJG.0000000000000964. Hou, H., Moghimi, S., Zangwill, L.M., et al., Macula Vessel Density and Thickness in Early Primary Open-Angle Glaucoma. Am J Ophthalmol , 2019. 199: p. 120-132. doi: 10.1016/j.ajo.2018.11.012. Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Karadağ","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYBACAzB5AEQkMD4Akjx8pGhhBnF42EjRwiYBoghqMZdIf/bhxxm7fP729GuVX3PsZNgYmB8+uoFHi+WMHOOZPTeSLWeceVN2W3ZbMtBhbMbGOfgcdiOHmYHnA9AbN3LSbktuYwZq4WGTxq8l/THjnw/1BvJALcWS2+qJ0ZJgzMxz47ABUO8xxo/bDhPWYtnzxphZ5sxxA8Mzb5ilGbcd52FjJuAXc3agw94cqzaQO57+8OPPbdX2/OzNDx/j04IEeAyYeUA0M3HKQYD9AeMP4lWPglEwCkbBCAIAYItJ7v0hu0AAAAAASUVORK5CYII=","orcid":"","institution":"Istanbul University","correspondingAuthor":true,"prefix":"","firstName":"Büşra","middleName":"","lastName":"Karadağ","suffix":""},{"id":561357474,"identity":"f3e81756-4c0f-494e-8a8a-26b775265f5a","order_by":1,"name":"Belgin İzgi","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"prefix":"","firstName":"Belgin","middleName":"","lastName":"İzgi","suffix":""},{"id":561357479,"identity":"8e35a23e-ee63-4f32-a7dc-5fc843d5e000","order_by":2,"name":"Şerife BAYRAKTAR","email":"","orcid":"","institution":"Istanbul University Medicine Faculty","correspondingAuthor":false,"prefix":"","firstName":"Şerife","middleName":"","lastName":"BAYRAKTAR","suffix":""}],"badges":[],"createdAt":"2025-12-04 16:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8281184/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8281184/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98779198,"identity":"57c699e3-e642-4d6c-b131-76b3864b0418","added_by":"auto","created_at":"2025-12-22 12:30:04","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1588078,"visible":true,"origin":"","legend":"","description":"","filename":"FinalManuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/0afca293a38f3dc7f43bb92d.docx"},{"id":98779014,"identity":"f4329d5c-a9da-46ab-be26-eebfe8bd124e","added_by":"auto","created_at":"2025-12-22 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12:29:59","extension":"xml","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":95486,"visible":true,"origin":"","legend":"","description":"","filename":"615192a4957b4fb39fb92b06fdf443121structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/8e66af9738be7db9a54bcfa5.xml"},{"id":98759528,"identity":"13ea2fec-b28e-4f4f-abc5-81fb316013c6","added_by":"auto","created_at":"2025-12-22 09:49:08","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":107725,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/a2193a3bb6e29d1a3cc046d4.html"},{"id":98759510,"identity":"5d5baab9-e6cc-4e14-8030-a71759de9c3a","added_by":"auto","created_at":"2025-12-22 09:49:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":202930,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative 6×6 mm macular scan showing superficial capillary plexus vessel density measurement obtained by OCT-A in a patient with primary open-angle glaucoma\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/3f7de25016c857736ece4c59.jpg"},{"id":98759508,"identity":"1b025b21-a0ec-4b11-81ae-3fa62b52f2fa","added_by":"auto","created_at":"2025-12-22 09:49:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":147846,"visible":true,"origin":"","legend":"\u003cp\u003eIllustrative 7×7 mm scan demonstrating ganglion cell complex (GCC) thickness measurement in a patient with ocular hypertension (OHT), acquired using OCT-A\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/2cbfa9cc6c7d61ced54c7aa2.jpg"},{"id":98759507,"identity":"41b33a63-e8b7-4130-895b-69853adc3705","added_by":"auto","created_at":"2025-12-22 09:49:07","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":65598,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plots of superficial vs deep parafoveal vessel density (sfVD–dVD) across diagnostic groups. Strong coupling in Control/OHT/Early POAG attenuates with stage and vanishes in advanced disease, indicating layer-specific dissociation\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/6f0264fff87927585208abdd.jpg"},{"id":98778116,"identity":"1767a766-aa7d-49b1-9d52-96daee915524","added_by":"auto","created_at":"2025-12-22 12:28:55","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":78069,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plots of superficial vessel density vs macular GCC (sfVD–GCC). The association is absent in early POAG but emerges in mid/advanced disease, suggesting earlier structural macular damage relative to microvascular change\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/258d86651463c7e6a3f712cc.jpg"},{"id":98797649,"identity":"492715e8-2229-4f3a-b5a3-420f982e7641","added_by":"auto","created_at":"2025-12-22 13:39:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1117120,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/55ea2f23-476f-4b3d-bf8b-43ecf4ce816a.pdf"},{"id":98759505,"identity":"9a5b5124-8aa9-4237-8c55-5b4f276051ad","added_by":"auto","created_at":"2025-12-22 09:49:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":53651,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8281184/v1/b2f9a1d29968cdd04c281827.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Analysis of Optical Coherence Tomography Angiography Metrics in Primary Open- Angle Glaucoma and Ocular Hypertension","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eGlaucoma is a chronic and progressive optic neuropathy characterized by the gradual loss of visual function and visual field, primarily due to irreversible damage to the optic nerve, which may ultimately lead to blindness\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. It encompasses a heterogeneous group of disorders, and despite numerous proposed mechanisms, its precise etiopathogenesis remains incompletely elucidated. Although elevated intraocular pressure (IOP) is recognized as the most prominent risk factor for both the onset and progression of the disease, it is now well established that glaucoma is a multifactorial condition, with vascular dysregulation emerging as a key element potentially contributing to its development and advancement.\u003c/p\u003e \u003cp\u003eGlaucoma is among the leading causes of preventable yet irreversible vision loss worldwide. Consequently, early diagnosis and effective monitoring of disease progression are critical for preserving visual function. Currently, standard clinical practice involves the use of visual field testing, which assesses functional impairment, and optical coherence tomography (OCT), which provides detailed structural analysis\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Notably, functional deficits such as visual field loss typically become detectable only after approximately 30% of retinal ganglion cells (RGCs) have already degenerated, underscoring the necessity of identifying structural alterations at earlier stages\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Given that nearly half of all RGCs and their axons are concentrated within the macular region, macular ganglion cell complex (GCC) analysis has gained increasing relevance in glaucoma evaluation\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHistorically, several techniques\u0026mdash;including fluorescein angiography, color Doppler ultrasonography, laser Doppler flowmetry, and Heidelberg retinal flowmetry\u0026mdash;have been employed to investigate optic nerve head (ONH) perfusion in glaucomatous eyes. Although these methods have demonstrated altered blood flow in glaucomatous optic neuropathy, their clinical adoption has been limited due to invasiveness, potential adverse effects, low reproducibility, and operational constraints.\u003c/p\u003e \u003cp\u003eOptical coherence tomography angiography (OCT-A), a recent advancement in retinal imaging, enables high-resolution, dye-free visualization of retinal and choroidal microvasculature. OCT-A allows for the quantitative assessment of perfusion and vessel density parameters, offering valuable insights into the vascular component of glaucoma pathophysiology\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Furthermore, it facilitates three-dimensional analysis of the GCC, thereby enhancing the potential for early structural detection prior to functional decline. OCT-A has been increasingly recognized as a noninvasive and reproducible method for evaluating retinal microcirculation and its alterations in glaucoma\u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, OCT-A was utilized to quantify macular vessel density as well as GCC thickness in individuals with ocular hypertension (OHT) and primary open-angle glaucoma (POAG) at various stages of disease. These parameters were compared with those of a healthy control group to investigate the diagnostic and monitoring potential of OCT-A in glaucoma management.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cem\u003eEthical Approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Istanbul University Faculty of Medicine (Approval Date and Number: 25.11.2022–1381233). All procedures involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Informed consent, both written and verbal, was obtained from all participants prior to their inclusion in the study.\u003c/p\u003e\n\u003cp\u003eThe methodology adopted for the study is detailed below:\u003c/p\u003e\n\u003cp\u003eAs described in the abstract, this study aimed to evaluate macular GCC thickness and parafoveal vessel density (pfVD) in patients with POAG and OHT using OCT-A. The following section details the imaging protocol and quantitative analysis methodology.\u003c/p\u003e\n\u003cp\u003eThe study included 150 eyes of 56 patients diagnosed with POAG and 32 patients diagnosed with OHT who were under regular follow-up at the Glaucoma Unit of the Department of Ophthalmology, Istanbul Faculty of Medicine, and presented for examination between November and December 2022. Additionally, 50 eyes of 25 healthy individuals with no systemic or ophthalmological pathology were included as a control group. OCT-A images were obtained using the Topcon ImageNet 6 system (DRI OCT Triton, Topcon Corporation, Japan) available in our clinic. Measurements of macular GCC thickness and both superficial and deep parafoveal vessel density (pfVD) were compared across diagnostic groups. Statistical analyses were conducted with a 95% confidence interval, and significance was defined as p \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInclusion Criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were between 40 and 65 years of age, free of systemic diseases, and had a confirmed diagnosis of POAG or OHT based on comprehensive ophthalmic evaluation, including biomicroscopy, gonioscopy, intraocular pressure (IOP) measurements, optical coherence tomography (OCT), and visual field testing. To ensure optimal image quality for OCT-A and visual field analysis, eligible participants were required to have a best-corrected visual acuity (BCVA) of 0.7 or better, spherical and cylindrical refractive errors within the range of +3.00 to –3.00 diopters, and clear ocular media without significant opacities.\u003c/p\u003e\n\u003cp\u003eThe control group consisted of age-matched individuals (40–65 years) who were both ophthalmologically and systemically healthy, with no history of ocular surgery other than uncomplicated cataract extraction. Control subjects also met the visual and refractive criteria stated above and exhibited clear ocular media.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOphthalmological Evaluation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants underwent a comprehensive ophthalmic examination, including refraction assessment, BCVA determination, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry for IOP measurement, and detailed fundus examination using a 90 D lens. Peripapillary retinal nerve fiber layer (RNFL) thickness was assessed using spectral-domain OCT (HRA+OCT Spectralis, Heidelberg Engineering). Visual field testing was performed with the Humphrey Field Analyzer II (Model 750) using the 24-2 Swedish Interactive Threshold Algorithm. Mean deviation (MD) values were used to stage glaucoma severity: MD \u0026lt; –6.0 dB defined early-stage glaucoma, while MD between –6.0 and –12.0 dB indicated moderate-stage disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDiagnostic Criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOHT was diagnosed in the presence of an IOP \u0026gt; 21 mmHg without any glaucomatous structural or functional changes on OCT or visual field testing. POAG was diagnosed based on open angles on gonioscopy, characteristic glaucomatous optic nerve damage, and reproducible visual field defects consistent with glaucoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOCT-A Imaging and Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOptical coherence tomography angiography (OCT-A) scans were acquired using the Topcon ImageNet 6 system (DRI OCT Triton, Topcon Corporation, Japan). To ensure image quality and analytic reliability, scans with a signal strength below 6/10 were excluded from further evaluation.\u003c/p\u003e\n\u003cp\u003eA 6 × 6 mm scan area was employed for quantitative assessment of macular vessel density, while a broader 7 × 7 mm scan area was utilized to evaluate parameters of the macular ganglion cell complex (GCC). The foveal avascular zone (FAZ) was automatically delineated by the device software, and the vessel density within a 300-μm radius surrounding the FAZ was defined as the foveal vessel density.\u003c/p\u003e\n\u003cp\u003eVessel density in the superficial capillary plexus (SCP)—encompassing the retinal slab from 2.6 μm below the internal limiting membrane (ILM) to 15.6 μm below the inner plexiform layer (IPL)—was calculated automatically. In contrast, deep capillary plexus (DCP) measurements, which span from 15.6 µm to 70.2 µm below the IPL, were manually delineated due to segmentation limitations of the automated algorithm. The detailed layer segmentation and anatomical boundaries of SCP and DCP regions are illustrated in Figure 1.\u003c/p\u003e\n\u003cp\u003eGCC thickness parameters were extracted from OCT-A scans centered on the foveal region. Quantitative analysis was performed using the six-sector map of the Early Treatment Diabetic Retinopathy Study (ETDRS), which was automatically overlaid by the software to ensure standardized regional comparisons. The spatial distribution of GCC thickness, aligned with the ETDRS grid, is presented in Figure 2, providing a comprehensive overview of the structural integrity of the macular ganglion cell layer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using the NCSS 2020 Statistical Software (NCSS LLC, Kaysville, Utah, USA). Quantitative variables were expressed as mean ± standard deviation, median, minimum, and maximum values, while categorical variables were summarized as frequencies and percentages. The distribution of continuous variables was assessed for normality using the Shapiro-Wilk test and supported by visual inspection of Box Plot graphics.\u003c/p\u003e\n\u003cp\u003eFor comparisons involving more than two independent groups with non-normally distributed variables, the Kruskal–Wallis test was employed, followed by the Dunn post hoc test to determine pairwise group differences. The Fisher–Freeman–Halton test was used for evaluating associations between categorical variables. All statistical tests were performed within a 95% confidence interval, and a p-value of \u0026lt;0.05 was considered indicative of statistical significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCorrelation Analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpearman correlation analyses were conducted to explore the relationships among OCT-A metrics in each diagnostic group. In controls and OHT, superficial and deep macular vessel densities (sfVD–dVD) were strongly correlated (Control: r = 0.612, p = 2.31×10⁻⁶; OHT: r = 0.703, p = 1.91×10⁻¹⁰) (Table 1). This strong coupling persisted in early POAG (r = 0.703, p = 1.38×10⁻¹⁰) but weakened in mid-stage POAG (r = 0.243, p = 0.383) and disappeared in advanced POAG (r = –0.049, p = 0.828), indicating increasing layer-specific dissociation with disease progression (illustrated in Figure 3).\u003c/p\u003e\n\u003cp\u003eIn contrast, the association between sfVD and macular GCC thickness was not significant in OHT (r = –0.077, p = 0.550) or early POAG (r = –0.141, p = 0.269), became borderline in mid-stage (r = 0.527, p = 0.064), and reached a moderate, significant level in advanced POAG (r = 0.541, p = 0.011) (Figure 4). This pattern suggests that structural macular damage (GCC thinning) may precede microvascular reduction in parafoveal vessel density, especially in early disease, while both parameters converge as glaucoma advances. Pooled POAG analyses confirmed significant positive associations for sfVD–dVD (r = 0.600, p = 4.14×10⁻¹¹) and sfVD–GCC (r = 0.535, p = 1.65×10⁻⁸) as summarized in Table S (Supplementary Data).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 113 participants were included in the study, comprising 32 individuals diagnosed with ocular hypertension (OHT), 56 individuals with primary open-angle glaucoma (POAG), and 25 healthy individuals who constituted the control group. The mean age of the study cohort was 59.3 ± 4.81 years, while the control group had a mean age of 49.32 ± 5.75 years. The demographic characteristics of the participants are summarized in Table 2.\u003c/p\u003e\n\u003cp\u003eMacular vessel density within both the superficial and deep capillary plexuses was also assessed using OCT-A and compared across groups (Table 3). Statistically significant differences were detected in all quadrants (superior, inferior, temporal, and nasal). A progressive decline in macular vessel density was observed in correlation with the severity of glaucoma. No statistically significant differences were found between the control and OHT groups across any of the macular parameters. However, the intermediate-stage POAG group showed significantly reduced vessel density in all quadrants, except the nasal quadrant of the deep capillary plexus (p = 0.001; p \u0026lt; 0.01).\u003c/p\u003e\n\u003cp\u003eThe comparison of average vessel density values in the macular superficial and deep capillary plexuses among groups did not reveal statistically significant differences (Table 4). While the control group demonstrated higher mean values in the superficial capillary plexus compared to both early- and intermediate-stage POAG groups, no significant difference was found between the OHT and early-stage POAG groups. In contrast, vessel density in the deep capillary plexus was significantly lower in the intermediate-stage POAG group compared to all other groups.\u003c/p\u003e\n\u003cp\u003eGanglion cell complex (GCC) thickness measurements obtained via OCT-A are presented in Table 5. Statistically significant differences were identified among groups in all quadrants, including superior, inferior, superonasal (SN), superotemporal (ST), inferonasal (IN), and inferotemporal (IT) regions. GCC thickness showed a progressive decline in conjunction with advancing disease severity. Subgroup analyses indicated significantly reduced GCC measurements in both early- and intermediate-stage POAG groups compared to the control and OHT groups. Furthermore, the intermediate-stage group exhibited significantly lower GCC values than the early-stage POAG group.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we evaluated macular vessel density, alongside ganglion cell complex (GCC) thickness, using optical coherence tomography angiography (OCT-A) in patients diagnosed with early- and intermediate-stage primary open-angle glaucoma (POAG) and ocular hypertension (OHT). These parameters were then compared with those obtained from healthy eyes to assess their potential utility in the diagnosis and monitoring of glaucoma.\u003c/p\u003e\n\u003cp\u003eA total of 200 eyes from 113 patients were analyzed, comprising 32 eyes with OHT, 56 eyes with POAG (34 early-stage, 22 intermediate-stage), and 50 eyes from 25 healthy controls. Statistically significant differences were observed among the groups in terms of age, intraocular pressure (IOP), and best-corrected visual acuity (BCVA), while gender distribution did not differ significantly.\u003c/p\u003e\n\u003cp\u003eWe compared parafoveal vessel density (pfVD) in both the superficial and deep capillary plexuses across four macular quadrants (superior, inferior, nasal, and temporal), as well as their mean values. All parameters were reduced in glaucomatous eyes, with more severe reductions in advanced stages. Notably, no significant differences were observed between the OHT and control groups across pfVD measurements. Similarly, early-stage POAG eyes did not differ significantly from OHT and control eyes, except for select quadrants of the superficial plexus (temporal, nasal) and the superior quadrant of the deep plexus. The reduction in superficial pfVD was more prominent than in the deep plexus\u003csup\u003e22\u003c/sup\u003e. El-Nimri et al. similarly reported lower superficial pfVD in glaucomatous eyes, without significant differences in deep pfVD across groups. Lommatzsch et al. found decreased superficial and deep pfVD in glaucoma patients relative to controls but did not observe differences between disease stages\u003csup\u003e23\u003c/sup\u003e. In contrast, our findings demonstrate stage-dependent changes, particularly in superficial pfVD.\u003c/p\u003e\n\u003cp\u003eTraditionally, structural retinal ganglion cell (RGC) damage in glaucoma is assessed via circumpapillary RNFL thickness using OCT\u003csup\u003e24–27\u003c/sup\u003e. However, this method only evaluates the axons of RGCs, omitting the somas and dendritic structures in the ganglion cell layer (GCL) and inner plexiform layer (IPL), which are also compromised in glaucoma\u003csup\u003e28\u003c/sup\u003e. Experimental data suggest that RGC soma and dendrite damage precedes axonal degeneration, highlighting the potential superiority of macular GCC assessment over RNFL measurements for early glaucoma detection\u003csup\u003e29,30\u003c/sup\u003e. Several studies have established the diagnostic advantage of GCC thickness over total macular thickness\u003csup\u003e28\u003c/sup\u003e. While most prior investigations have utilized OCT for GCC evaluation, Wang et al. uniquely employed OCT-A, reporting significantly reduced macular vessel density and GCC thickness in glaucomatous eyes, with progressive deterioration associated with disease severity\u003csup\u003e31\u003c/sup\u003e. Our findings are consistent with this literature, showing decreased GCC thickness in glaucomatous eyes, with more pronounced reductions in intermediate-stage POAG\u003csup\u003e30,32,33\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSeveral limitations should be acknowledged. First, the study sample had a higher proportion of female participants (65.5%), although gender distribution did not differ significantly among groups and was not found to influence vascular density. Second, the intermediate-stage POAG group had a higher mean age compared to other groups. Since age is known to affect vessel density and GCC thickness, this could be a confounding factor; however, the age distribution within the glaucoma groups was not statistically different. Additionally, some patients were on topical anti-glaucomatous therapy during the study. While these medications could potentially affect vascular density, discontinuing treatment would not have been ethically or clinically feasible. The impact of such therapies on vessel density remains underexplored in the literature, and our study did not control for this variable.\u003c/p\u003e\n\u003cp\u003eMoreover, the control group was composed of younger participants to ensure systemic and ocular health, which may account for the slightly lower mean age compared to the glaucoma groups. Despite this, age ranges across all groups remained relatively narrow and balanced.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInterpretation of Correlation Findings\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe loss of coupling between superficial and deep vessel densities from early to advanced POAG suggests that the superficial capillary plexus is the earlier and predominantly affected layer. Moreover, the lack of sfVD–GCC association in early POAG, contrasted with the significant correlation in advanced disease, is consistent with structural macular damage occurring prior to microvascular changes. These results reinforce the clinical utility of macular GCC as an early indicator of glaucomatous neurodegeneration and support the hypothesis that GCC thinning may precede measurable reductions in parafoveal vessel density.\u003c/p\u003e\n\u003cp\u003eHowever, these findings should be interpreted with caution, as the cross-sectional design of the present study does not allow definitive conclusions regarding the temporal sequence of structural and vascular changes. Longitudinal studies are required to further elucidate whether macular GCC thinning consistently precedes microvascular alterations during the early stages of glaucoma.\u003c/p\u003e\n\u003cp\u003eIn conclusion, despite its limitations, our study provides important contributions to the understanding of vascular and structural changes in glaucomatous eyes, reinforcing the potential of OCT-A in glaucoma evaluation. Further research with larger and demographically balanced cohorts is warranted to validate and expand upon these findings.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur findings suggest that assessment of macular ganglion cell complex (GCC) thickness and parafoveal vessel density (pfVD) using optical coherence tomography angiography (OCT-A) can be utilized \u003cstrong\u003ealongside established structural and functional tests\u003c/strong\u003e in the diagnosis and follow-up of glaucoma. Experimental evidence has demonstrated that retinal ganglion cell damage may occur prior to axonal loss; accordingly, macular GCC evaluation may theoretically provide earlier structural information compared with peripapillary retinal nerve fiber layer (RNFL) analysis.\u003c/p\u003e\n\u003cp\u003eIn the present study, macular GCC measurements were significantly lower in glaucomatous eyes compared with other groups, with more pronounced thinning observed in advanced disease stages. Notably, in early-stage glaucoma, the reduction in macular GCC thickness was more prominent than the corresponding decrease in pfVD.\u003c/p\u003e\n\u003cp\u003eWhile OCT-A–derived macular vessel density and GCC thickness both provide valuable insights into glaucomatous changes, our findings suggest that \u003cstrong\u003estructural alterations in macular GCC may precede detectable microvascular\u003c/strong\u003e \u003cstrong\u003echanges\u003c/strong\u003e in early disease stages. Therefore, macular GCC assessment may serve as a complementary parameter in the early monitoring of glaucoma progression, rather than as a standalone tool. Further longitudinal studies with larger and more diverse cohorts are warranted to confirm these observations and to clarify the temporal relationship between structural and vascular changes in glaucoma.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eOCT-A\u003c/strong\u003e: Optical Coherence Tomography Angiography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePOAG\u003c/strong\u003e: Primary Open-Angle Glaucoma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOHT\u003c/strong\u003e: Ocular Hypertension\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGCC\u003c/strong\u003e: Ganglion Cell Complex\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003epfVD\u003c/strong\u003e: Parafoveal Vessel Density\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIOP\u003c/strong\u003e: Intraocular Pressure\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Istanbul University Faculty of Medicine (Approval date and number: 25.11.2022–1381233). All procedures were conducted in accordance with the principles of the Declaration of Helsinki and relevant institutional guidelines. Written and verbal informed consent was obtained from all participants prior to enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBK\u003c/strong\u003e: Study conception and design, data acquisition, analysis and interpretation, manuscript drafting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBI:\u003c/strong\u003e Study supervision, critical revision of the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSB\u003c/strong\u003e: Data interpretation and manuscript review.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the staff of the Glaucoma Unit, Department of Ophthalmology, Istanbul University Faculty of Medicine, for their support during data collection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChung, J.K., Hwang, Y.H., Wi, J.W., et al., Glaucoma Diagnostic Ability of the Optical Coherence Tomography Angiography Vessel Density Parameters. \u003cem\u003eCurr Eye Res\u003c/em\u003e, 2017. 42(11): p. 1458-1467. doi: 10.1080/02713683.2017.1337157.\u003c/li\u003e\n\u003cli\u003eWeinreb, R.N., Aung, T., Medeiros, F.A. 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Comparison of the ganglion cell complex and retinal nerve fiber layer thickness in pseudoexfoliation syndrome, pseudoexfoliation glaucoma and healthy subjects. \u003cem\u003eNew Front Ophthalmol\u003c/em\u003e, 2017. 3: p. 173. doi: 10.15761/NFO.1000173\u003c/li\u003e\n\u003cli\u003eBalıkoğlu Yılmaz M, Kumcu ND, Daldal H, Sarıtepe İmre S, Aydın E, \u0026Ouml;zg\u0026uuml;l S, et al. May ganglion cell complex analysis be a marker for glaucoma susceptibility in unilateral Fuchs\u0026rsquo; uveitis syndrome?\u003cbr\u003e\u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e, 2021. 259: p. 1975\u0026ndash;1983. doi: 10.1007/s00417-021-05182-4\u003c/li\u003e\n\u003cli\u003eYılmaz, H., Optıcal Coherence Tomography Angıography in Glaucoma, in Multidisciplinary Research in Health Sciences. 2020. p. 231-244.\u003c/li\u003e\n\u003cli\u003eLiu L, Jia Y, Takusagawa HL, Barnum MJ, Chiang RK, Hwang TS, et al. Optical coherence tomography angiography of the peripapillary retina in glaucoma. \u003cem\u003eJAMA Ophthalmol\u003c/em\u003e, 2015. 133(9): p. 1045\u0026ndash;1052. doi: doi:10.1001/jamaophthalmol.2015.2225\u003c/li\u003e\n\u003cli\u003eYarmohammadi A, Zangwill LM, Diniz-Filho A, Suh MH, Manalastas PIC, Fatehee N, et al.\u003cbr\u003eOptical coherence tomography angiography vessel density in healthy, glaucoma suspect, and glaucoma eyes. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e, 2016. 57(9): p. OCT451\u0026ndash;OCT459. doi: 10.1167/iovs.15-18944.\u003c/li\u003e\n\u003cli\u003eEl-Nimri, N.W., Manalastas, P.I., Zangwill, L.M., et al., Superficial and Deep Macula Vessel Density in Healthy, Glaucoma Suspect, and Glaucoma Eyes. \u003cem\u003eJ Glaucoma\u003c/em\u003e, 2021. 30(6): p. e276-e284. doi: 10.1097/IJG.0000000000001860.\u003c/li\u003e\n\u003cli\u003eLommatzsch, C., Rothaus, K., Koch, J.M., et al., OCTA vessel density changes in the macular zone in glaucomatous eyes. \u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e, 2018. 256(8): p. 1499-1508. doi: 10.1007/s00417-018-3965-1.\u003c/li\u003e\n\u003cli\u003eLeung, C.K., Chan, W., Yung, W., et al., Comparison of macular and peripapillary measurements for the detection of glaucoma: an optical coherence tomography study. \u003cem\u003eOphthalmology,\u003c/em\u003e 2005. 112(3): p. 391-400. doi: 10.1016/j.ophtha.2004.10.020.\u003c/li\u003e\n\u003cli\u003eLeung, C.K., Liu, S., Weinreb, R.N., et al., Evaluation of retinal nerve fiber layer progression in glaucoma a prospective analysis with neuroretinal rim and visual field progression. \u003cem\u003eOphthalmology\u003c/em\u003e, 2011. 118(8): p. 1551-7. doi: 10.1016/j.ophtha.2010.12.035.\u003c/li\u003e\n\u003cli\u003eDi Staso, S., Agnifili, L., Di Staso, F., et al., Diagnostic capability of optic nerve head rim width and retinal nerve fiber thickness in open-angle glaucoma. \u003cem\u003eEur J Ophthalmol\u003c/em\u003e, 2018. 28(4): p. 459-464. doi: 10.1177/1120672117750057.\u003c/li\u003e\n\u003cli\u003eMedeiros, F.A., Zangwill, L.M., Bowd, C., et al., Evaluation of retinal nerve fiber layer, optic nerve head, and macular thickness measurements for glaucoma detection using optical coherence tomography. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e, 2005. 139(1): p. 44-55. doi: 10.1016/j.ajo.2004.08.069.\u003c/li\u003e\n\u003cli\u003eTan, O., Chopra, V., Lu, A.T., et al., Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. \u003cem\u003eOphthalmology\u003c/em\u003e, 2009. 116(12): p. 2305-14 e1-2. doi: 10.1016/j.ophtha.2009.05.025.\u003c/li\u003e\n\u003cli\u003eFortune, B., G.A. Cull, and C.F. Burgoyne, Relative course of retinal nerve fiber layer birefringence and thickness and retinal function changes after optic nerve transection. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e, 2008. 49(10): p. 4444-52. doi: 10.1167/iovs.08-2255.\u003c/li\u003e\n\u003cli\u003eKim, N.R., Lee, E.S., Seong, G.J., et al., Structure-function relationship and diagnostic value of macular ganglion cell complex measurement using Fourier-domain OCT in glaucoma. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e, 2010. 51(9): p. 4646-51. doi: 10.1167/iovs.09-5053.\u003c/li\u003e\n\u003cli\u003eWang, Y., Xin, C., Li, M., et al., Macular vessel density versus ganglion cell complex thickness for detection of early primary open-angle glaucoma. \u003cem\u003eBMC Ophthalmol\u003c/em\u003e, 2020. 8;20(1): p. 17. doi: 10.1186/s12886-020-1304-x.\u003c/li\u003e\n\u003cli\u003ePenteado, R.C., Zangwill, L.M., Daga, F.B., et al., Optical Coherence Tomography Angiography Macular Vascular Density Measurements and the Central 10-2 Visual Field in Glaucoma. \u003cem\u003eJ Glaucoma\u003c/em\u003e, 2018. 27(6): p. 481-489. doi: 10.1097/IJG.0000000000000964.\u003c/li\u003e\n\u003cli\u003eHou, H., Moghimi, S., Zangwill, L.M., et al., Macula Vessel Density and Thickness in Early Primary Open-Angle Glaucoma. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e, 2019. 199: p. 120-132. doi: 10.1016/j.ajo.2018.11.012.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ganglion Cell Complex, Glaucoma, OCT-A, Parafoveal Vessel Density, Ocular Hypertension","lastPublishedDoi":"10.21203/rs.3.rs-8281184/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8281184/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo investigate the diagnostic and follow-up utility of optical coherence tomography angiography (OCT-A) in glaucoma by evaluating macular ganglion cell complex (GCC) thickness and parafoveal vessel density (pfVD) in patients with ocular hypertension (OHT) and various stages of primary open-angle glaucoma (POAG).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and Methods: \u003c/strong\u003eThis cross-sectional study included 150 eyes from 56 patients with POAG and 32 with OHT, all under regular follow-up at the Glaucoma Unit of the Istanbul Faculty of Medicine, Department of Ophthalmology. Evaluations were conducted between November and December 2022.Additionally,50 eyes from 25 healthy individuals without ocular or systemic pathology were included as a control group. OCT-A images were obtained using the Topcon DRI OCT Triton (Topcon Corporation, Japan). Macular GCC thickness and pfVD in the superficial and deep capillary plexuses were measured and compared among the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 113 participants (74 females,39 males) were enrolled. No statistically significant differences in macular GCC thickness or pfVD were found between the control and OHT groups. In contrast, both parameters were significantly reduced in the POAG group, with a progressive decline corresponding to disease severity. The decrease in pfVD was more pronounced in the superficial plexus compared to the deep plexus. In early-stage POAG, GCC thinning was more prominent than pfVD reduction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusıon: \u003c/strong\u003eOur findings suggest that assessment of macular GCC thickness and pfVD via OCT-A can be utilized alongside structural and functional tests in the diagnosis and follow-up of glaucoma. In our study, macular GCC measurements were significantly lower in the glaucoma group compared to other groups, with more pronounced thinning observed in advanced stages. Notably, in early-stage glaucoma, the reduction in macular GCC was more prominent than that in pfVD. These findings indicate that structural damage in macular GCC may occur earlier than vascular changes in pfVD and may be particularly useful in the early monitoring of glaucoma progression.\u003c/p\u003e","manuscriptTitle":"Comparative Analysis of Optical Coherence Tomography Angiography Metrics in Primary Open- Angle Glaucoma and Ocular Hypertension","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:49:01","doi":"10.21203/rs.3.rs-8281184/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-04T06:46:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-28T21:50:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59287221676279245145627839549751332142","date":"2026-04-11T15:38:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-06T16:05:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196783366508451496376074391483066585313","date":"2026-01-04T06:05:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-16T12:52:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-16T12:49:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-15T07:57:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-14T17:53:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-12-14T17:47:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"62fdefbc-ed32-4c6f-abce-1879fc712d60","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-21T05:54:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:49:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8281184","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8281184","identity":"rs-8281184","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}