Evaluation of foveal microvasculature changes by optical coherence tomography angiography in eyes of pacientes with type 2 diabetes diagnosed more than 5 years ago without clinical signs of diabetic retinopathy versus patients without diabetes

Evaluation of foveal microvasculature changes by optical coherence tomography angiography in eyes of pacientes with type 2 diabetes diagnosed more than 5 years ago without clinical signs of diabetic retinopathy versus patients without diabetes | 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 Evaluation of foveal microvasculature changes by optical coherence tomography angiography in eyes of pacientes with type 2 diabetes diagnosed more than 5 years ago without clinical signs of diabetic retinopathy versus patients without diabetes Alexandre Caiado Ferreira Pires, Jamil Miguel Neto, Heitor Amaral Simões, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6256471/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The aim of this study was to compare vascular density (VD) and foveal avascular zone (FAZ) using optical coherence tomography angiography (OCTA) in patients with type 2 diabetes mellitus (DM) without signs of diabetic retinopathy (DR) with non-diabetic patients. Methods: A total of 26 type 2 DM and 17 non-diabetic subjects were included in a case-control study. All subjects underwent OCTA (DRI OCT-1 SS TRITON PLUS; Topcon, Tokyo, Japan). Average vessel density (VD) in superficial capillary plexus (SCP), deep capillary plexus (DCP), FAZ area (mm2) in SCP, and FAZ area (mm2) in DCP were included in the analysis. The comparisons were evaluated using the analysis of variance (ANOVA) and Tukey’s post hoc test. Results: Parafoveal vessel density in both SCP and DCP decreased in eyes without clinical DR compared to non-diabetic controls (p < 0.001). Statistical significance was also observed when comparing controls with patients diagnosed with type 2 DM 5-10 years ago (p < 0.001), controls with patients diagnosed with type 2 DM more than 10 years ago (p < 0.001), and patients diagnosed with type 2 DM 5-10 years ago with those diagnosed more than 10 years ago (p < 0.001). In addition, the FAZ area in both plexuses increased in case eyes compared to controls (p < 0.001). However, there was no significance of FAZ area in SCP when comparing cases diagnosed between 5-10 years ago to those diagnosed more than 10 years ago (p = 0.06). Conclusion : It was demonstrated that OCTA can detect preclinical DR before the manifestation of clinically apparent retinopathy in diabetic eyes, especially in long-term diagnosed disease. In type 2 DM patients without DR, SCP and DCP were affected, and the changes were progressive and significant with increasing time to diagnosis. Our results suggest that OCTA may be a promising tool for regular screening of diabetic eyes for DR. optical coherence tomography angiography foveal avascular zone vascular density diabetic retinopathy type 2 diabetes Figures Figure 1 Figure 2 Figure 3 Figure 4 BACKGROUND The global prevalence of diabetes mellitus (DM) is increasing exponentially each year due to increased life expectancy and changes in dietary habits. In 2010, it affected approximately 285 million people (6.4% of the world's population), and it is estimated that by 2030, approximately 439 million people (7.7% of the world's population) will have the disease. [ 1 ] Diabetic retinopathy (DR) is a specific microangiopathy secondary to DM [ 2 ] characterized by peripheral and central capillary ischemia, macular hyperpermeability, and a secondary increase in angiogenic factors. Diabetic macular edema (DME) is the result of impairment of the internal blood-retinal barrier, consisting of the capillary endothelium, leading to extravasation of fluid from the retinal vessels into the retina. The diagnosis of DME is made when there is retinal thickening involving the macula by imaging or fundoscopic evaluation. [ 3 ] With the development of OCT angiography (OCTA), which is performed without intravenous contrast, it is possible to evaluate the superficial and deep retinal vascular plexuses as well as the choroidal vessels through the flow of red blood cells by means of multiple slices (scans). In combination with OCTA, En Face OCT allows the segmentation of the retinal layers and provides a frontal scan to determine the affected area among the different planes of the retina. [ 4 ] The purpose of this study was to investigate the retinal microvascular differences between diabetic eyes with no evidence of DR on fundoscopy and control eyes of patients without DM using swept-source (SS) scanning technology with the A-OCT DRI OCT-1 SS TRITON PLUS (Topcon, Tokyo, Japan). Materials and Methods Research Project This was a cross-sectional comparative case-control study (unpaired), carried out at the Ophthalmology Reference Center of the University of Goiás (CEROF-UFG) and OCTA and structural OCT examinations at the Eye Hospital of Aparecida (HOA), from January 10th to June 30th, 2022. This study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review boards of the participating institutions. All subjects voluntarily agreed to participate by signing the informed consent form. Initially, 96 eyes were considered for inclusion, of which 10 were excluded after meeting the exclusion criteria. A total of 86 eyes of 43 patients were included in the study. The case group included 52 eyes of 26 patients with type 2 diabetes mellitus (DM2), 30 eyes of 15 patients diagnosed between five and ten years ago and showing no signs of DR on fundus examination, and 22 eyes of 11 patients diagnosed with type 2 DM for more than ten years and showing no signs of DR. The control group consisted of 34 eyes of 17 patients with no previous diagnosis of type 2 DM. Inclusion Criteria Inclusion criteria for the case group were patients over 18 years of age, diagnosed with DM2 more than 5 years ago, and without DR findings on fundus examination. The inclusion criteria for the control group were patients over 18 years of age, with no previous diagnosis of DM, no other ocular pathology, and (corrigida ou não) visual acuity ou best corrected visual better than 20/30. The date of diagnosis of type 2 DM was obtained from the patients' medical records or by self-report of how long they had known about the disease. Exclusion Criteria Exclusion criteria were patients with fundus changes of DR (such as microaneurysms, microhemorrhages, exudates, intraretinal microvascular abnormalities - IRMAs, neovascularization); any pathology that could interfere with the test results, such as cataract (lens opacity); corneal opacity (such as leukoma, ulcers, keratopathies); ocular trauma; myopia with spherical equivalent greater than 6 diopters, best corrected visual acuity ≤ 20/40; Previous macular pathology (such as macular hole, epiretinal membrane, age-related macular disease, vascular occlusions, retinal dystrophies); patients without laboratory tests to assess DM in the last six months, OCTA scans of unsatisfactory quality, such as those that produced images of inadequate quality with an index of less than 40, patients who underwent cataract surgery in the last three months, and patients who did not know how long they had been diagnosed with the disease. Ophthalmic evaluation The patients included in the study were examined by two ophthalmologists, specialists in ophthalmology of the Brazilian Council of Ophthalmology, and underwent a complete questionnaire, anamnesis, past pathological history, ophthalmological history, dynamic refraction to obtain the best visual correction, using a manual refractor and Snellen chart at a distance of six meters, and a manual photopter (BR07 Shin-Nippon), with subsequent conversion to a logarithmic scale with the smallest angle of resolution (logMAR). Ophthalmic examinations were performed in the following order: anterior segment biomicroscopy with a slit lamp (Topcon SL-D2); applanation tonometry with a calibrated Goldmann tonometer (CT210, Reichert Inc, Depew, USA) two minutes after instillation of one drop of anesthetic eye drops (0. 4% benoxinate hydrochloride) and one drop of 1% sodium fluorescein; retinal mapping (RM) with an indirect binocular ophthalmoscope (Keeler Vantage Plus LED, Keeler Optical, Windsor, UK) and a 20D lens (Volk Optical Inc, Mentor, USA) 30 minutes after instillation of the last drop of 1% tropicamide eye drops, three times, five minutes apart. After RM, patients were referred for color retinography, which was performed by a single trained, masked technician using the Canon cx-1 retinograph (Canon Medical System, USA). After the examination at CEROF-UFG, patients who were eligible for structural OCT and OCTA according to the inclusion and exclusion criteria were scheduled to undergo the examinations at another hospital (maximum interval of 15 days from the first examination). At the HOA, patients underwent OCT and OCTA in a dark room without the need for eye drops for pupil dilation by an experienced and masked technician using the DRI OCT-1 SS TRITON PLUS device (Topcon, Tokyo, Japan). The travel expenses of the volunteers were paid by the investigator. Assessment of foveal avascular zone and vascular density Vascular density (VD) and the foveal avascular zone (FAZ) area were assessed with OCTA (Triton) using a 3 x 3 mm slice with four repeated scans centered on the fovea. Good image quality, according to the manufacturer of the OCT used in this study, is greater than 40. The automatic segmentation of the Triton device extends in the superficial capillary plexus (SCP) from 2.6 µm below the internal limiting membrane and the lower limit of 15.6 µm below the internal plexiform layer (IPL)/internal nuclear layer (INS) interface; in the deep capillary plexus (DCP), the upper limit of 15.6 µm below the IPL/INS interface and the lower limit of 70.2 µm below the IPL/INS interface. After the examinations, the images were quantified, evaluated, and compared with the VD and FAZ area of the superficial and deep retinal plexuses using ImageJ. The analysis of VD and FAZ area at the SCP and DCP levels was performed with the en face image and image quality greater than 40 points (0-100) of the OCTA. Images were exported from OCTA in PDF format. The projections were opened using the ImageJ image analysis program, version 1.49, which is in the public domain and available from the US National Institute of Health (Bethesda, USA. Available at: https://imagej.nih.gov/ij/ ). The 3 x 3 mm scans were converted to pixelated and binarized images. To assess the area of the superficial and deep plexus FAZ, the points of the avascular area were manually marked by two unmasked examiners at different times. The area contained within the geometric shape was automatically calculated by ImageJ in mm² according to the total number of pixels within the region, with the final value calculated as the average of the two measurements obtained. (Fig. 1 and Fig. 2) VD was expressed as a ratio by taking the total area of the vessel divided by the total area of the region analyzed over the entire 3 x 3 mm scan. After extracting the original images from the visualization software, the images were imported into ImageJ. A binarized image with thresholding, as implemented in the software, was used to measure VD. The application assumes that the image contains two classes of pixels that follow a bimodal distribution. It calculates the optimal threshold by minimizing the intra-class variance and maximizing the inter-class variance. The total number of pixels occupied by vessels was then divided by the total number of pixels in the entire image and the value was expressed as a ratio. Statistical Analysis The profile of patients in the control and type 2 DM groups was characterized using absolute frequency, relative frequency for categorical variables, and mean and standard deviation for continuous variables. The distribution of the profile between groups was tested using Pearson's chi-squared test. The normality of the data was tested using the Kolmogorov-Smirnov test, while the comparison of FAZ area and VD values between groups was performed using analysis of variance (ANOVA) followed by Tukey's post hoc test. Data were analyzed using the Statistical Package for Social Science (IBM Corporation, Armonk, USA) version 26.0, with a significance level of 5% (p < 0.05). Main Results Initially, 96 eyes were considered for inclusion, 10 of which were excluded after meeting the exclusion criteria. A total of 86 eyes of 43 patients were included in the study. The case group consisted of 52 eyes of 26 patients with type 2DM, 30 eyes of 15 patients diagnosed between five and ten years ago and showing no signs of DR on fundus examination and 22 eyes of 11 patients diagnosed with DM2 for more than ten years and showing no signs of DR. The control group consisted of 34 eyes of 17 patients with no previous diagnosis of type 2 DM. Discussion DR is one of the leading causes of irreversible blindness in the working population. [ 5 ]. Currently, the disease is screened using fundoscopy and angiofluoresceinography, which have some limitations, the main one being their ability to detect changes only when DR is already present. The aim of this study was to use optical coherence tomography angiography as the method of choice for screening preclinical retinal changes in patients with type 2 diabetes mellitus, in order to develop preventive strategies to avoid future complications. One of the characteristics of DR is the progressive nature of the changes, always from deep to superficial areas, although the literature has not been able to validate a single pathophysiological mechanism that explains the chronology of the changes. Although Choi et al . initially showed a reduction in VD in SCP [ 6 ] the vast majority of studies suggest that changes in the retinal circulation first originate in the outer layers, only to manifest later with the funduscopic findings of DR [ 7 , 8 , 9 , 10 , 11 ]. The findings of Iwase et al . (2016) support this reasoning, as they showed a higher oxygen demand in the deeper retinal plexuses, justifying the onset of changes in this region [ 12 ]. As this was a cross-sectional analysis of the data, it was not possible to assess the chronology of VD changes, as both plexuses showed a reduction in patients in the case group (DM with more than 5 years of disease diagnosis). There are some inconsistencies in the literature regarding the changes found in the FAZ. A study by Carnevali et al using OCTA with ED technology (CIRRUS HD-OCT model 5000, Carl Zeiss Meditec, Dublin, CA) compared 25 patients diagnosed with type 1 DM with more than five years of disease and no DR findings on fundus examination with 25 patients in the control group without DM. It showed that there was no increase in the FAZ in the superficial and deep plexuses in the different groups [ 13 ], contrary to the findings of the present study, which showed an increase in the FAZ area in patients in the case group (type 2 DM > 5 years of diagnosis without signs of DR) compared to the control group. A likely explanation is that this study evaluated patients withtype 2 DM, which is known to be a silent disease in its early stages, and therefore it is difficult to determine the time of exposure to the disease [ 14 ]. Another factor that may have contributed to these findings is the lower sensitivity of the spectrum domain technology compared to the scanning source used in this study [ 15 ]. Another point to emphasize when interpreting the results is the fact that not finding an increase in FAZ area does not mean a complete absence of changes. For example, the study by Inanc et al . showed that the irregularity of the FAZ is part of the pathophysiological mechanism of the disease and that it occurs before the increase in its área [ 16 ], unlike the present study, which used a cross-sectional approach and evaluated only the area of the FAZ. Cao et al . used a methodology similar to the present study, but with limitations that should be considered. Although they also evaluated patients with type 2 DM and no signs of DR on fundus examination, they found no difference in SCP FAZ area between the groups analyzed (type 2 DM vs. control without DM) [ 17 ]. However, the study was not randomized by disease duration and the section size used was 6 x 6 mm. In the present study, the section used was 3 x 3 mm, which has important limitations that may directly affect the outcome. For example, Ho et al . showed that the 3 x 3 mm slice was superior to the 6 x 6 mm OCTA scan, justifying a higher diagnostic accuracy due to the better image quality of the foveal area, which optimizes the ability to assess retinal vessels [ 18 ]. Other studies have shown increased FAZ in people with DM without signs of DR [ 19 , 20 ]. In a study of 55 DM2 patients without signs of DR and 48 non-diabetics with an average disease duration of 17.9 years, significant differences in FAZ area of the SCP were found. The FAZ area of the DCP in the DM2 group was (0.37 ± 0.13 mm2) compared to the control group (0.29 ± 0.11 mm2; P = 0.012) [ 6 ]. Another study showed that in DM patients without evidence of DR, DV decreased in the superficial and deep vascular plexus, while ZAF increased in the superficial vascular plexus, suggesting that retinal vascular changes precede retinal structural changes [ 21 ], which is consistent with the hypothesis of the present study, although the patients were not followed longitudinally. Even in the present study, although the aim was not to follow patients longitudinally, when comparing groups with different exposure times (type 2 DM 5–10 years vs. type 2 DM > 10 years), an increase in FAZ was seen only in the deep plexus (p = 0.04), highlighting the importance of exposure time to the disease and that the involvement really begins in the deep layers. Therefore, longitudinal studies with longer exposure to type 2 DM are needed to better understand the progression of changes to the more superficial layers. However, it seems clear from this study that patients with longer duration of disease (type 2 DM > 10 years) tend to have a smaller VD and a larger FAZ than patients with type 2 DM 5–10 years, and these in turn have a larger FAZ and a smaller VD than patients without diagnosed DM and without retinal disease. In the present study, type 2 DM patients without signs of DR showed an increase in the area of the FAZ in the superficial and deep plexus. In addition, other studies have shown an increased FAZ in individuals without signs of DR (preclinical changes), demonstrating that there may be changes in type 2 DM [ 19 , 20 , 21 ]. These studies support the findings of the present study, which showed an increase in FAZ in diabetic patients without evidence of DR. In this context, we can conclude the importance of OCTA in the evaluation of diabetic patients, as it is a non-invasive test and can show changes that cannot be detected by clinical examination. However, this study has several limitations. First, fluorescein angiography (FA) was not performed on the eyes with preclinical DR and the control group. Patient evaluation and screening for inclusion were determined by clinical examination by two unmasked examiners, which may have introduced some error and bias. Another factor that may have affected the results was the size of the sample analyzed: 52 eyes in the case group and 34 eyes in the control group. In addition, OCTA scans performed with a 3 x 3 mm slice may include a small area of analysis in the posterior pole, which may limit the understanding of microvascular changes in the peripheral retina in eyes without evidence of DR on fundoscopic examination. Still from the same perspective of limitation, this is a cross-sectional study with images taken at a single point in time, making it clear that a follow-up with longitudinal data from patients with DR could be even more useful to determine the role of OCTA in the assessment of VD and FAZ in patients with DM. Another source of bias was the assessment of the case and control groups using only the questionnaire to obtain information on disease duration and exclusion of DM diagnosis. Many patients did not have glycated hemoglobin or fasting glucose tests at the time of assessment. In addition, time since diagnosis of type 2 DM is a difficult factor to assess, as patients may have had type 2 DM for longer than reported. Finally, artifacts may affect the assessment of VD and FAZ, especially with DCP. In the present study, we emphasized the presence of preclinical changes detected by OCTA in relation to FAZ area and VD in SCP and DCP, which precede any apparent abnormalities on clinical examination of the retina. These findings are relevant because they identify retinal microvascular changes in diabetic eyes before fundoscopic signs, using a non-invasive and rapid test. Therefore, OCTA may become an important tool not only in ophthalmology, allowing the observation of preclinical lesions of diabetic retinopathy, but also in internal medicine, allowing the early detection of target organ damage and the possibility of clinical-medical adjustments of glycemic control to prevent further damage. In the future, as the cost of the technology decreases and access to the population increases, OCTA may become a more widely used method for risk stratification of patients with DM. The relevance of these findings is that OCTA can detect early changes in the retinal vasculature of diabetic eyes before they are visible on fundoscopy. Screening of DM patients by dilated pupil fundoscopy is important and will not replace this assessment. In fact, by using OCTA, one could better assess VD and FAZ and detect the onset of DR even if the patient has normal visual acuity and no symptoms. Individuals with DM with "preclinical" changes may be more likely to develop retinopathy and therefore could be examined more frequently than those without changes. In conclusion, OCTA may in the near future become a screening test in the ophthalmologic routine of patients with DM, thus contributing to the early diagnosis of DR and consequently reducing late diagnosis and major complications such as blindness. However, longitudinal studies are needed to determine the real value of using this type of technology to establish the relationship between foveal microvascular findings of VD and FAZ area and the onset of clinically detectableDR. Conclusions In patients with DM for more than 5 years without signs of DR on fundoscopy, we observed a decrease in the vascular density of the superficial and deep plexuses and an increase in the foveal avascular zone of the superficial and deep plexuses compared to the group of healthy patients. Considering patients with DM between 5 and 10 years of disease without signs of DR, we observed a decrease in vascular density in the superficial and deep plexuses and an increase in the foveal avascular zone in the superficial and deep plexuses compared to the group of healthy patients. Abbreviations ANOVA Analysis of Variance CBO Brazilian Council of Ophthalmology CEROF-UFG Ophthalmology Reference Center DCP Deep Capillary Plexus DM Diabetes mellitus DM Diabetes mellitus DME Diabetic Macular Edema DR Diabetic retinopathy FA Fluorescein angiography FAZ Foveal Avascular Zone HOA Eye Hospital of Aparecida IPL Inner Plexiform Layer IRMAs Intraretinal Microvascular Abnormalities mm Millimeters NPDR Non Proliferative Diabetic Retinopathy (você não utilizou eu acho) NV Neovascularization (você não utilizou eu acho) OCT Optical Coherence Tomography OCTA Optical Coherence Tomography Angiography PDR Proliferative Diabetic Retinopathy (você não utilizou eu acho) PFC Panphotocoagulation (você não utilizou eu acho) SBD Brazilian Diabetes Society (você não utilizou eu acho) SCP Superficial Capillary Plexus SS Swept Source TD Temporal Domain (você não utilizou eu acho) UFG Federal University of Goiás VD Vascular Density Declarations Ethics approval and consent to participate This research was approved by the Ethics Research Committee of the Federal University of Goiás (number 51283221.2.0000.5078). Informed consent was obtained from all participants included. The procedures used were in accordance with the tenets of the Declaration of Helsinki for research involving human beings. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests MA is a reviewer in this journal. The authors declare no other potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding This study was funded by the author himself. Authors' contributions ACFP, JMN, HSA, KFI, LLN, RTR, LPF,ACT, DLCI and MPA participated in the design, interpretation of the studies and analysis of the data; ACFP, LLN JMN and DLCI reviewed the manuscript; ACFP and HSA performed ophthalmological examination in the patients included in the study; ACFP, JMN and DLCI Isaac wrote the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. 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Am J Ophthalmol. 2021;222:226-237. Dimitrova G, Chihara E, Takahashi H, Amano H, Okazaki K. Quantitative Retinal Optical Coherence Tomography Angiography in Patients With Diabetes Without Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2017;58(1):190-196. doi: 10.1167/iovs.16-20531. PMID: 28114579. Tables Table 1. Profile characterization of patients in control and diabetes Groups Groups Total p-value Control DM 5 to 10 years DM > 10 years Age (years) Mean value ± SD 65.7 ± 10.6 62.5 ± 10.1 65.4 ± 10.9 64.5 ± 10.5 0.43** Age group n (%) 43 to 59 years 10 (29.4) 10 (33.3) 8 (36.4) 28 (32.6) 0.85* 60 to 83 years 24 (70.6) 20 (66.7) 14 (63.6) 58 (67.4) Eye n (%) Right 17 (50.0) 15 (50.0) 11 (50.0) 43 (50.0) 1.00* Left 17 (50.0) 15 (50.0) 11 (50.0) 43 (50.0) *Chi-square; **ANOVA; n, absolute frequency; %, relative frequency; SD, standard deviation Table 2. Results of comparison of FAZ and VD in the control and DM groups without DR. Control DM > 5 years p-value FAZ SCP (mm 2 ) 0.24 ± 0.04 0.37 ± 0.64 <0.001 VD SCP (%) 62.38 ± 0.87 56.52 ± 3.99 <0.001 FAZ DCP (mm 2 ) 0.36 ± 0.03 0.47 ± 0.75 <0.001 VD DCP (%) 73.67 ± 1.12 65.32 ± 5.19 <0.001 ANOVA* FAZ: foveal avascular zone; SCP: superficial capillary plexus; DCP: deep capillary plexus VD: vascular density Table 3. Results of FAZ and VD comparisons all groups. Groups p a p b p c Control DM 5 to 10 years DM > 10 years FAZ/ SCP (mm 2 ) 0.24 ± 0.04 0.36 ± 0.06 0.38 ± 0.07 <0.001 <0.001 0.06 VD/ SCP (%) 62.38 ± 0.87 59.03 ± 1.48 53.73 ± 1.20 <0.001 <0.001 <0.001 FAZ/ DCP (mm 2 ) 0.36 ± 0.03 0.45 ± 0.06 0.49 ± 0.09 <0.001 <0.001 0.04 VD/ DCP (%) 73.67 ± 1.12 68.98 ± 1.54 61.67 ± 1.31 <0.001 <0.001 10 years; c DM 5 to 10 years vs DM > 10 years FAZ: foveal avascular zone; SCP: superficial capillary plexus; DCP: deep capillary plexus VD: vascular density; DM: diabetes mellitus Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6256471","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":434539318,"identity":"6e51f81e-264f-4dbb-bc24-b59472edcdd2","order_by":0,"name":"Alexandre Caiado Ferreira Pires","email":"data:image/png;base64,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","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":true,"prefix":"","firstName":"Alexandre","middleName":"Caiado Ferreira","lastName":"Pires","suffix":""},{"id":434539319,"identity":"c5ad8a2d-a793-41b0-8c67-d602f10f0198","order_by":1,"name":"Jamil Miguel Neto","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Jamil","middleName":"Miguel","lastName":"Neto","suffix":""},{"id":434539320,"identity":"61c4d153-98ee-4a81-8d93-f013f48cc0ca","order_by":2,"name":"Heitor Amaral Simões","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Heitor","middleName":"Amaral","lastName":"Simões","suffix":""},{"id":434539321,"identity":"24cf6640-2612-43ad-8342-18ce39f9f9bd","order_by":3,"name":"Karime Fugihara Iwamoto","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Karime","middleName":"Fugihara","lastName":"Iwamoto","suffix":""},{"id":434539322,"identity":"6c647187-a5e7-4d94-ad3c-0f637cfe23c6","order_by":4,"name":"Raphael Toledo Remiggi","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Raphael","middleName":"Toledo","lastName":"Remiggi","suffix":""},{"id":434539323,"identity":"e51960ca-bacd-4585-bd66-cb1ab213ffc0","order_by":5,"name":"Leticia Pinheiro Freitas","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Leticia","middleName":"Pinheiro","lastName":"Freitas","suffix":""},{"id":434539324,"identity":"8985288b-3c05-4e14-8cf0-753f74bd9d79","order_by":6,"name":"Laís Lauria Neves","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Laís","middleName":"Lauria","lastName":"Neves","suffix":""},{"id":434539325,"identity":"341ac633-d3bd-4646-9ea3-cbb146af6d0a","order_by":7,"name":"Alexandre Chater Taleb","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Alexandre","middleName":"Chater","lastName":"Taleb","suffix":""},{"id":434539326,"identity":"490b7a32-71e2-4f94-9c1f-9ccb25dd5b7f","order_by":8,"name":"David Leonardo Cruvinel Isaac","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"Leonardo Cruvinel","lastName":"Isaac","suffix":""},{"id":434539327,"identity":"da4233c6-263c-40b8-bd57-07abea699dea","order_by":9,"name":"Marcos Ávila","email":"","orcid":"","institution":"Federal University of Goiás Goiânia","correspondingAuthor":false,"prefix":"","firstName":"Marcos","middleName":"","lastName":"Ávila","suffix":""}],"badges":[],"createdAt":"2025-03-18 22:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6256471/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6256471/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79563509,"identity":"c57c4e77-8e56-47a3-bd1d-498db042c6c0","added_by":"auto","created_at":"2025-03-31 09:07:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":209576,"visible":true,"origin":"","legend":"\u003cp\u003ePoints to define the area of the SCP of the FAZ in the ImageJ\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6256471/v1/b80e998b341c558c859baefd.png"},{"id":79562900,"identity":"0482320c-f6d0-4962-8f19-7011db5c1fd7","added_by":"auto","created_at":"2025-03-31 08:59:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":407734,"visible":true,"origin":"","legend":"\u003cp\u003ePoints to define the area of the DCP of the FAZ in the ImageJ.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6256471/v1/ced433061c126ffeb7e81945.png"},{"id":79563511,"identity":"b5d83102-0db9-49da-beb0-a9cf553824b4","added_by":"auto","created_at":"2025-03-31 09:07:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":156599,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplot graph showing the central tendency, symmetry and dispersion of the FAZ values in mm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6256471/v1/cb6df45c3bab1c8d314dccd4.png"},{"id":79564431,"identity":"1b474124-a94f-4103-88ae-22f414668f56","added_by":"auto","created_at":"2025-03-31 09:15:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":114187,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplot graph showing the central tendency, symmetry and dispersion of VD values in %\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6256471/v1/f0a72025c313f4ab6b68b200.png"},{"id":79989424,"identity":"b304be62-4e8b-4efc-bc4d-5e1fb177c2a7","added_by":"auto","created_at":"2025-04-06 09:46:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1649428,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6256471/v1/5b03472f-e616-4b7c-8caa-ac30eddc2baf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of foveal microvasculature changes by optical coherence tomography angiography in eyes of pacientes with type 2 diabetes diagnosed more than 5 years ago without clinical signs of diabetic retinopathy versus patients without diabetes","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eThe global prevalence of diabetes mellitus (DM) is increasing exponentially each year due to increased life expectancy and changes in dietary habits. In 2010, it affected approximately 285\u0026nbsp;million people (6.4% of the world's population), and it is estimated that by 2030, approximately 439\u0026nbsp;million people (7.7% of the world's population) will have the disease. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eDiabetic retinopathy (DR) is a specific microangiopathy secondary to DM [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] characterized by peripheral and central capillary ischemia, macular hyperpermeability, and a secondary increase in angiogenic factors. Diabetic macular edema (DME) is the result of impairment of the internal blood-retinal barrier, consisting of the capillary endothelium, leading to extravasation of fluid from the retinal vessels into the retina. The diagnosis of DME is made when there is retinal thickening involving the macula by imaging or fundoscopic evaluation. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eWith the development of OCT angiography (OCTA), which is performed without intravenous contrast, it is possible to evaluate the superficial and deep retinal vascular plexuses as well as the choroidal vessels through the flow of red blood cells by means of multiple slices (scans). In combination with OCTA, En Face OCT allows the segmentation of the retinal layers and provides a frontal scan to determine the affected area among the different planes of the retina. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe purpose of this study was to investigate the retinal microvascular differences between diabetic eyes with no evidence of DR on fundoscopy and control eyes of patients without DM using swept-source (SS) scanning technology with the A-OCT DRI OCT-1 SS TRITON PLUS (Topcon, Tokyo, Japan).\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eResearch Project\u003c/h2\u003e \u003cp\u003eThis was a cross-sectional comparative case-control study (unpaired), carried out at the Ophthalmology Reference Center of the University of Goi\u0026aacute;s (CEROF-UFG) and OCTA and structural OCT examinations at the Eye Hospital of Aparecida (HOA), from January 10th to June 30th, 2022. This study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review boards of the participating institutions. All subjects voluntarily agreed to participate by signing the informed consent form.\u003c/p\u003e \u003cp\u003eInitially, 96 eyes were considered for inclusion, of which 10 were excluded after meeting the exclusion criteria. A total of 86 eyes of 43 patients were included in the study. The case group included 52 eyes of 26 patients with type 2 diabetes mellitus (DM2), 30 eyes of 15 patients diagnosed between five and ten years ago and showing no signs of DR on fundus examination, and 22 eyes of 11 patients diagnosed with type 2 DM for more than ten years and showing no signs of DR. The control group consisted of 34 eyes of 17 patients with no previous diagnosis of type 2 DM.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria for the case group were patients over 18 years of age, diagnosed with DM2 more than 5 years ago, and without DR findings on fundus examination. The inclusion criteria for the control group were patients over 18 years of age, with no previous diagnosis of DM, no other ocular pathology, and (corrigida ou n\u0026atilde;o) visual acuity ou best corrected visual better than 20/30. The date of diagnosis of type 2 DM was obtained from the patients' medical records or by self-report of how long they had known about the disease.\u003c/p\u003e\n\u003ch3\u003eExclusion Criteria\u003c/h3\u003e\n\u003cp\u003eExclusion criteria were patients with fundus changes of DR (such as microaneurysms, microhemorrhages, exudates, intraretinal microvascular abnormalities - IRMAs, neovascularization); any pathology that could interfere with the test results, such as cataract (lens opacity); corneal opacity (such as leukoma, ulcers, keratopathies); ocular trauma; myopia with spherical equivalent greater than 6 diopters, best corrected visual acuity\u0026thinsp;\u0026le;\u0026thinsp;20/40; Previous macular pathology (such as macular hole, epiretinal membrane, age-related macular disease, vascular occlusions, retinal dystrophies); patients without laboratory tests to assess DM in the last six months, OCTA scans of unsatisfactory quality, such as those that produced images of inadequate quality with an index of less than 40, patients who underwent cataract surgery in the last three months, and patients who did not know how long they had been diagnosed with the disease.\u003c/p\u003e\n\u003ch3\u003eOphthalmic evaluation\u003c/h3\u003e\n\u003cp\u003eThe patients included in the study were examined by two ophthalmologists, specialists in ophthalmology of the Brazilian Council of Ophthalmology, and underwent a complete questionnaire, anamnesis, past pathological history, ophthalmological history, dynamic refraction to obtain the best visual correction, using a manual refractor and Snellen chart at a distance of six meters, and a manual photopter (BR07 Shin-Nippon), with subsequent conversion to a logarithmic scale with the smallest angle of resolution (logMAR). Ophthalmic examinations were performed in the following order: anterior segment biomicroscopy with a slit lamp (Topcon SL-D2); applanation tonometry with a calibrated Goldmann tonometer (CT210, Reichert Inc, Depew, USA) two minutes after instillation of one drop of anesthetic eye drops (0. 4% benoxinate hydrochloride) and one drop of 1% sodium fluorescein; retinal mapping (RM) with an indirect binocular ophthalmoscope (Keeler Vantage Plus LED, Keeler Optical, Windsor, UK) and a 20D lens (Volk Optical Inc, Mentor, USA) 30 minutes after instillation of the last drop of 1% tropicamide eye drops, three times, five minutes apart. After RM, patients were referred for color retinography, which was performed by a single trained, masked technician using the Canon cx-1 retinograph (Canon Medical System, USA).\u003c/p\u003e \u003cp\u003eAfter the examination at CEROF-UFG, patients who were eligible for structural OCT and OCTA according to the inclusion and exclusion criteria were scheduled to undergo the examinations at another hospital (maximum interval of 15 days from the first examination). At the HOA, patients underwent OCT and OCTA in a dark room without the need for eye drops for pupil dilation by an experienced and masked technician using the DRI OCT-1 SS TRITON PLUS device (Topcon, Tokyo, Japan). The travel expenses of the volunteers were paid by the investigator.\u003c/p\u003e\n\u003ch3\u003eAssessment of foveal avascular zone and vascular density\u003c/h3\u003e\n\u003cp\u003eVascular density (VD) and the foveal avascular zone (FAZ) area were assessed with OCTA (Triton) using a 3 x 3 mm slice with four repeated scans centered on the fovea. Good image quality, according to the manufacturer of the OCT used in this study, is greater than 40. The automatic segmentation of the Triton device extends in the superficial capillary plexus (SCP) from 2.6 \u0026micro;m below the internal limiting membrane and the lower limit of 15.6 \u0026micro;m below the internal plexiform layer (IPL)/internal nuclear layer (INS) interface; in the deep capillary plexus (DCP), the upper limit of 15.6 \u0026micro;m below the IPL/INS interface and the lower limit of 70.2 \u0026micro;m below the IPL/INS interface.\u003c/p\u003e \u003cp\u003eAfter the examinations, the images were quantified, evaluated, and compared with the VD and FAZ area of the superficial and deep retinal plexuses using ImageJ. The analysis of VD and FAZ area at the SCP and DCP levels was performed with the en face image and image quality greater than 40 points (0-100) of the OCTA.\u003c/p\u003e \u003cp\u003eImages were exported from OCTA in PDF format. The projections were opened using the ImageJ image analysis program, version 1.49, which is in the public domain and available from the US National Institute of Health (Bethesda, USA. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://imagej.nih.gov/ij/\u003c/span\u003e\u003cspan address=\"https://imagej.nih.gov/ij/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e).\u003c/span\u003e The 3 x 3 mm scans were converted to pixelated and binarized images. To assess the area of the superficial and deep plexus FAZ, the points of the avascular area were manually marked by two unmasked examiners at different times. The area contained within the geometric shape was automatically calculated by ImageJ in mm\u0026sup2; according to the total number of pixels within the region, with the final value calculated as the average of the two measurements obtained. (Fig.\u0026nbsp;1 and Fig.\u0026nbsp;2)\u003c/p\u003e \u003cp\u003eVD was expressed as a ratio by taking the total area of the vessel divided by the total area of the region analyzed over the entire 3 x 3 mm scan. After extracting the original images from the visualization software, the images were imported into ImageJ. A binarized image with thresholding, as implemented in the software, was used to measure VD. The application assumes that the image contains two classes of pixels that follow a bimodal distribution. It calculates the optimal threshold by minimizing the intra-class variance and maximizing the inter-class variance. The total number of pixels occupied by vessels was then divided by the total number of pixels in the entire image and the value was expressed as a ratio.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe profile of patients in the control and type 2 DM groups was characterized using absolute frequency, relative frequency for categorical variables, and mean and standard deviation for continuous variables. The distribution of the profile between groups was tested using Pearson's chi-squared test. The normality of the data was tested using the Kolmogorov-Smirnov test, while the comparison of FAZ area and VD values between groups was performed using analysis of variance (ANOVA) followed by Tukey's post hoc test. Data were analyzed using the Statistical Package for Social Science (IBM Corporation, Armonk, USA) version 26.0, with a significance level of 5% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e"},{"header":"Main Results","content":"\u003cp\u003eInitially, 96 eyes were considered for inclusion, 10 of which were excluded after meeting the exclusion criteria. A total of 86 eyes of 43 patients were included in the study. The case group consisted of 52 eyes of 26 patients with type 2DM, 30 eyes of 15 patients diagnosed between five and ten years ago and showing no signs of DR on fundus examination and 22 eyes of 11 patients diagnosed with DM2 for more than ten years and showing no signs of DR. The control group consisted of 34 eyes of 17 patients with no previous diagnosis of type 2 DM.\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eDR is one of the leading causes of irreversible blindness in the working population. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Currently, the disease is screened using fundoscopy and angiofluoresceinography, which have some limitations, the main one being their ability to detect changes only when DR is already present.\u003c/p\u003e \u003cp\u003eThe aim of this study was to use optical coherence tomography angiography as the method of choice for screening preclinical retinal changes in patients with type 2 diabetes mellitus, in order to develop preventive strategies to avoid future complications.\u003c/p\u003e \u003cp\u003eOne of the characteristics of DR is the progressive nature of the changes, always from deep to superficial areas, although the literature has not been able to validate a single pathophysiological mechanism that explains the chronology of the changes. Although Choi \u003cem\u003eet al\u003c/em\u003e. initially showed a reduction in VD in SCP [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] the vast majority of studies suggest that changes in the retinal circulation first originate in the outer layers, only to manifest later with the funduscopic findings of DR [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The findings of Iwase \u003cem\u003eet al\u003c/em\u003e. (2016) support this reasoning, as they showed a higher oxygen demand in the deeper retinal plexuses, justifying the onset of changes in this region [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As this was a cross-sectional analysis of the data, it was not possible to assess the chronology of VD changes, as both plexuses showed a reduction in patients in the case group (DM with more than 5 years of disease diagnosis).\u003c/p\u003e \u003cp\u003eThere are some inconsistencies in the literature regarding the changes found in the FAZ. A study by Carnevali \u003cem\u003eet al\u003c/em\u003e using OCTA with ED technology (CIRRUS HD-OCT model 5000, Carl Zeiss Meditec, Dublin, CA) compared 25 patients diagnosed with type 1 DM with more than five years of disease and no DR findings on fundus examination with 25 patients in the control group without DM. It showed that there was no increase in the FAZ in the superficial and deep plexuses in the different groups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], contrary to the findings of the present study, which showed an increase in the FAZ area in patients in the case group (type 2 DM\u0026thinsp;\u0026gt;\u0026thinsp;5 years of diagnosis without signs of DR) compared to the control group. A likely explanation is that this study evaluated patients withtype 2 DM, which is known to be a silent disease in its early stages, and therefore it is difficult to determine the time of exposure to the disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Another factor that may have contributed to these findings is the lower sensitivity of the spectrum domain technology compared to the scanning source used in this study [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother point to emphasize when interpreting the results is the fact that not finding an increase in FAZ area does not mean a complete absence of changes. For example, the study by Inanc \u003cem\u003eet al\u003c/em\u003e. showed that the irregularity of the FAZ is part of the pathophysiological mechanism of the disease and that it occurs before the increase in its \u0026aacute;rea [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], unlike the present study, which used a cross-sectional approach and evaluated only the area of the FAZ. Cao \u003cem\u003eet al\u003c/em\u003e. used a methodology similar to the present study, but with limitations that should be considered. Although they also evaluated patients with type 2 DM and no signs of DR on fundus examination, they found no difference in SCP FAZ area between the groups analyzed (type 2 DM vs. control without DM) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, the study was not randomized by disease duration and the section size used was 6 x 6 mm. In the present study, the section used was 3 x 3 mm, which has important limitations that may directly affect the outcome. For example, Ho \u003cem\u003eet al\u003c/em\u003e. showed that the 3 x 3 mm slice was superior to the 6 x 6 mm OCTA scan, justifying a higher diagnostic accuracy due to the better image quality of the foveal area, which optimizes the ability to assess retinal vessels [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOther studies have shown increased FAZ in people with DM without signs of DR [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In a study of 55 DM2 patients without signs of DR and 48 non-diabetics with an average disease duration of 17.9 years, significant differences in FAZ area of the SCP were found. The FAZ area of the DCP in the DM2 group was (0.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 mm2) compared to the control group (0.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 mm2; P\u0026thinsp;=\u0026thinsp;0.012) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Another study showed that in DM patients without evidence of DR, DV decreased in the superficial and deep vascular plexus, while ZAF increased in the superficial vascular plexus, suggesting that retinal vascular changes precede retinal structural changes [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], which is consistent with the hypothesis of the present study, although the patients were not followed longitudinally.\u003c/p\u003e \u003cp\u003eEven in the present study, although the aim was not to follow patients longitudinally, when comparing groups with different exposure times (type 2 DM 5\u0026ndash;10 years vs. type 2 DM\u0026thinsp;\u0026gt;\u0026thinsp;10 years), an increase in FAZ was seen only in the deep plexus (p\u0026thinsp;=\u0026thinsp;0.04), highlighting the importance of exposure time to the disease and that the involvement really begins in the deep layers. Therefore, longitudinal studies with longer exposure to type 2 DM are needed to better understand the progression of changes to the more superficial layers. However, it seems clear from this study that patients with longer duration of disease (type 2 DM\u0026thinsp;\u0026gt;\u0026thinsp;10 years) tend to have a smaller VD and a larger FAZ than patients with type 2 DM 5\u0026ndash;10 years, and these in turn have a larger FAZ and a smaller VD than patients without diagnosed DM and without retinal disease.\u003c/p\u003e \u003cp\u003eIn the present study, type 2 DM patients without signs of DR showed an increase in the area of the FAZ in the superficial and deep plexus. In addition, other studies have shown an increased FAZ in individuals without signs of DR (preclinical changes), demonstrating that there may be changes in type 2 DM [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These studies support the findings of the present study, which showed an increase in FAZ in diabetic patients without evidence of DR. In this context, we can conclude the importance of OCTA in the evaluation of diabetic patients, as it is a non-invasive test and can show changes that cannot be detected by clinical examination.\u003c/p\u003e \u003cp\u003eHowever, this study has several limitations. First, fluorescein angiography (FA) was not performed on the eyes with preclinical DR and the control group. Patient evaluation and screening for inclusion were determined by clinical examination by two unmasked examiners, which may have introduced some error and bias. Another factor that may have affected the results was the size of the sample analyzed: 52 eyes in the case group and 34 eyes in the control group. In addition, OCTA scans performed with a 3 x 3 mm slice may include a small area of analysis in the posterior pole, which may limit the understanding of microvascular changes in the peripheral retina in eyes without evidence of DR on fundoscopic examination.\u003c/p\u003e \u003cp\u003eStill from the same perspective of limitation, this is a cross-sectional study with images taken at a single point in time, making it clear that a follow-up with longitudinal data from patients with DR could be even more useful to determine the role of OCTA in the assessment of VD and FAZ in patients with DM. Another source of bias was the assessment of the case and control groups using only the questionnaire to obtain information on disease duration and exclusion of DM diagnosis. Many patients did not have glycated hemoglobin or fasting glucose tests at the time of assessment. In addition, time since diagnosis of type 2 DM is a difficult factor to assess, as patients may have had type 2 DM for longer than reported. Finally, artifacts may affect the assessment of VD and FAZ, especially with DCP.\u003c/p\u003e \u003cp\u003eIn the present study, we emphasized the presence of preclinical changes detected by OCTA in relation to FAZ area and VD in SCP and DCP, which precede any apparent abnormalities on clinical examination of the retina. These findings are relevant because they identify retinal microvascular changes in diabetic eyes before fundoscopic signs, using a non-invasive and rapid test. Therefore, OCTA may become an important tool not only in ophthalmology, allowing the observation of preclinical lesions of diabetic retinopathy, but also in internal medicine, allowing the early detection of target organ damage and the possibility of clinical-medical adjustments of glycemic control to prevent further damage. In the future, as the cost of the technology decreases and access to the population increases, OCTA may become a more widely used method for risk stratification of patients with DM.\u003c/p\u003e \u003cp\u003eThe relevance of these findings is that OCTA can detect early changes in the retinal vasculature of diabetic eyes before they are visible on fundoscopy. Screening of DM patients by dilated pupil fundoscopy is important and will not replace this assessment. In fact, by using OCTA, one could better assess VD and FAZ and detect the onset of DR even if the patient has normal visual acuity and no symptoms. Individuals with DM with \"preclinical\" changes may be more likely to develop retinopathy and therefore could be examined more frequently than those without changes.\u003c/p\u003e \u003cp\u003eIn conclusion, OCTA may in the near future become a screening test in the ophthalmologic routine of patients with DM, thus contributing to the early diagnosis of DR and consequently reducing late diagnosis and major complications such as blindness. However, longitudinal studies are needed to determine the real value of using this type of technology to establish the relationship between foveal microvascular findings of VD and FAZ area and the onset of clinically detectableDR.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn patients with DM for more than 5 years without signs of DR on fundoscopy, we observed a decrease in the vascular density of the superficial and deep plexuses and an increase in the foveal avascular zone of the superficial and deep plexuses compared to the group of healthy patients.\u003c/p\u003e \u003cp\u003eConsidering patients with DM between 5 and 10 years of disease without signs of DR, we observed a decrease in vascular density in the superficial and deep plexuses and an increase in the foveal avascular zone in the superficial and deep plexuses compared to the group of healthy patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eANOVA Analysis of Variance\u003c/p\u003e\n\u003cp\u003eCBO Brazilian Council of Ophthalmology\u003c/p\u003e\n\u003cp\u003eCEROF-UFG Ophthalmology Reference Center\u003c/p\u003e\n\u003cp\u003eDCP Deep Capillary Plexus\u003c/p\u003e\n\u003cp\u003eDM Diabetes mellitus\u003c/p\u003e\n\u003cp\u003eDM Diabetes mellitus \u003c/p\u003e\n\u003cp\u003eDME Diabetic Macular Edema \u003c/p\u003e\n\u003cp\u003eDR Diabetic retinopathy\u003c/p\u003e\n\u003cp\u003eFA Fluorescein angiography \u003c/p\u003e\n\u003cp\u003eFAZ Foveal Avascular Zone\u003c/p\u003e\n\u003cp\u003eHOA Eye Hospital of Aparecida \u003c/p\u003e\n\u003cp\u003eIPL Inner Plexiform Layer \u003c/p\u003e\n\u003cp\u003eIRMAs Intraretinal Microvascular Abnormalities \u003c/p\u003e\n\u003cp\u003emm Millimeters \u003c/p\u003e\n\u003cp\u003eNPDR Non Proliferative Diabetic Retinopathy (voc\u0026ecirc; n\u0026atilde;o utilizou eu acho)\u003c/p\u003e\n\u003cp\u003eNV Neovascularization (voc\u0026ecirc; n\u0026atilde;o utilizou eu acho)\u003c/p\u003e\n\u003cp\u003eOCT Optical Coherence Tomography\u003c/p\u003e\n\u003cp\u003eOCTA Optical Coherence Tomography Angiography\u003c/p\u003e\n\u003cp\u003ePDR Proliferative Diabetic Retinopathy (voc\u0026ecirc; n\u0026atilde;o utilizou eu acho)\u003c/p\u003e\n\u003cp\u003ePFC Panphotocoagulation (voc\u0026ecirc; n\u0026atilde;o utilizou eu acho)\u003c/p\u003e\n\u003cp\u003eSBD Brazilian Diabetes Society (voc\u0026ecirc; n\u0026atilde;o utilizou eu acho)\u003c/p\u003e\n\u003cp\u003eSCP Superficial Capillary Plexus\u003c/p\u003e\n\u003cp\u003eSS Swept Source\u003c/p\u003e\n\u003cp\u003eTD Temporal Domain (voc\u0026ecirc; n\u0026atilde;o utilizou eu acho)\u003c/p\u003e\n\u003cp\u003eUFG Federal University of Goi\u0026aacute;s\u003c/p\u003e\n\u003cp\u003eVD Vascular Density\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was approved by the Ethics Research Committee of the Federal University of Goi\u0026aacute;s (number 51283221.2.0000.5078). Informed consent was obtained from all participants included. The procedures used were in accordance with the tenets of the Declaration of Helsinki for research involving human beings.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMA is a reviewer in this journal. The authors declare no other potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the author himself.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eACFP, JMN, HSA, KFI, LLN, RTR, LPF,ACT, DLCI and MPA participated in the design, interpretation of the studies and analysis of the data; ACFP, LLN JMN and DLCI reviewed the manuscript; ACFP and HSA performed ophthalmological examination in the patients included in the study; ACFP, JMN and DLCI Isaac wrote the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTao Z, Shi A, Zhao J. Epidemiological Perspectives of Diabetes. Cell Biochem Biophys. 2015;73(1):181-5. doi: 10.1007/s12013-015-0598-4. \u003c/li\u003e\n\u003cli\u003eSabanayagam C, Banu R, Chee ML, Lee R, Wang YX, Tan G, Jonas JB, Lamoureux EL, Cheng CY, Klein BEK, Mitchell P, Klein R, Cheung CMG, Wong TY. Incidence and progression of diabetic retinopathy: a systematic review. Lancet Diabetes Endocrinol. 2019;7(2):140-149. doi: 10.1016/S2213-8587(18)30128-1. \u003c/li\u003e\n\u003cli\u003eAntcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. 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Acta Diabetol. 2017;54(7):695-702. doi: 10.1007/s00592-017-0996-8. \u003c/li\u003e\n\u003cli\u003eKitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-43. doi: 10.2337/dc09-9032. \u003c/li\u003e\n\u003cli\u003eWaldstein SM, Faatz H, Szimacsek M, Glodan AM, Podkowinski D, Montuoro A, Simader C, Gerendas BS, Schmidt-Erfurth U. Comparison of penetration depth in choroidal imaging using swept source vs spectral domain optical coherence tomography. Eye (Lond). 2015;29(3):409-15. doi: 10.1038/eye.2014.319\u003c/li\u003e\n\u003cli\u003eInanc M, Tekin K, Kiziltoprak H, Ozalkak S, Doguizi S, Aycan Z. Changes in Retinal Microcirculation Precede the Clinical Onset of Diabetic Retinopathy in Children With Type 1 Diabetes Mellitus. Am J Ophthalmol. 2019;207:37-44. doi: 10.1016/j.ajo.2019.04.011. \u003c/li\u003e\n\u003cli\u003eCao D, Yang D, Huang Z, Zeng Y, Wang J, Hu Y, Zhang L. 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Early Detection of Microvascular Impairments with Optical Coherence Tomography Angiography in Diabetic Patients Without Clinical Retinopathy: A Meta-analysis. Am J Ophthalmol. 2021;222:226-237. \u003c/li\u003e\n\u003cli\u003eDimitrova G, Chihara E, Takahashi H, Amano H, Okazaki K. Quantitative Retinal Optical Coherence Tomography Angiography in Patients With Diabetes Without Diabetic Retinopathy. Invest Ophthalmol Vis Sci. 2017;58(1):190-196. doi: 10.1167/iovs.16-20531. PMID: 28114579.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Profile characterization of patients in control and diabetes Groups \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"101%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 44px;\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 15px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eDM 5 to 10 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eDM \u0026gt; 10 years\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eAge (years) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eMean value \u0026nbsp;\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e65.7 \u0026plusmn; 10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e62.5 \u0026plusmn; 10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e65.4 \u0026plusmn; 10.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e64.5 \u0026plusmn; 10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.43**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eAge group n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e43 to 59 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e10 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e10 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e28 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.85*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e60 to 83 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e24 (70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e20 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e58 (67.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eEye n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e17 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e15 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e11 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e43 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1.00*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e17 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e15 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e11 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e43 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e*Chi-square; **ANOVA; n, absolute frequency; %, relative frequency; SD, standard deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. Results of comparison of FAZ and VD in the control and DM groups without DR.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eDM \u0026gt; 5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eFAZ \u003cem\u003e\u003cstrong\u003eSCP\u003c/strong\u003e\u003c/em\u003e (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e0.24 \u0026plusmn; 0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e0.37 \u0026plusmn; 0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eVD \u003cem\u003e\u003cstrong\u003eSCP\u003c/strong\u003e\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e62.38 \u0026plusmn; 0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e56.52 \u0026plusmn; 3.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eFAZ \u003cem\u003e\u003cstrong\u003eDCP\u003c/strong\u003e\u003c/em\u003e (mm\u003csup\u003e2\u003c/sup\u003e)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e0.36 \u0026plusmn; 0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e0.47 \u0026plusmn; 0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eVD \u003cem\u003e\u003cstrong\u003eDCP\u003c/strong\u003e\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e73.67 \u0026plusmn; 1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e65.32 \u0026plusmn; 5.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eANOVA*\u003c/p\u003e\n\u003cp\u003eFAZ: foveal avascular zone; SCP: superficial capillary plexus; DCP: deep capillary plexus\u003c/p\u003e\n\u003cp\u003eVD: vascular density \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. Results of FAZ and VD comparisons all groups.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 54px;\"\u003e\n \u003cp\u003eGroups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003csup\u003ea\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003csup\u003eb\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003csup\u003ec\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eDM 5 to 10 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eDM \u0026gt; 10 years\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eFAZ/\u003cem\u003e\u003cstrong\u003e\u0026nbsp;SCP\u003c/strong\u003e\u003c/em\u003e (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0.24 \u0026plusmn; 0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0.36 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.38 \u0026plusmn; 0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eVD/\u003cem\u003e\u003cstrong\u003e\u0026nbsp;SCP\u003c/strong\u003e\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e62.38 \u0026plusmn; 0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e59.03 \u0026plusmn; 1.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e53.73 \u0026plusmn; 1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eFAZ/ \u003cem\u003e\u003cstrong\u003eDCP\u003c/strong\u003e\u003c/em\u003e (mm\u003csup\u003e2\u003c/sup\u003e)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0.36 \u0026plusmn; 0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0.45 \u0026plusmn; 0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.49 \u0026plusmn; 0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eVD/\u003cem\u003e\u003cstrong\u003e\u0026nbsp;DCP\u003c/strong\u003e\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e73.67 \u0026plusmn; 1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e68.98 \u0026plusmn; 1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e61.67 \u0026plusmn; 1.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eControl vs DM 5 to 10 years; \u003csup\u003eb\u003c/sup\u003eControl vs DM \u0026gt; 10 years; \u003csup\u003ec\u003c/sup\u003eDM 5 to 10 years vs DM \u0026gt; 10 years\u003c/p\u003e\n\u003cp\u003eFAZ: foveal avascular zone; SCP: superficial capillary plexus; DCP: deep capillary plexus\u003c/p\u003e\n\u003cp\u003eVD: vascular density; DM: diabetes mellitus\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"optical coherence tomography angiography, foveal avascular zone, vascular density, diabetic retinopathy, type 2 diabetes","lastPublishedDoi":"10.21203/rs.3.rs-6256471/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6256471/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe aim of this study was to compare vascular density (VD) and foveal avascular zone (FAZ) using optical coherence tomography angiography (OCTA) in patients with type 2 diabetes mellitus (DM) without signs of diabetic retinopathy (DR) with non-diabetic patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA total of 26 type 2 DM and 17 non-diabetic subjects were included in a case-control study. All subjects underwent OCTA (DRI OCT-1 SS TRITON PLUS; Topcon, Tokyo, Japan). Average vessel density (VD) in superficial capillary plexus (SCP), deep capillary plexus (DCP), FAZ area (mm2) in SCP, and FAZ area (mm2) in DCP were included in the analysis. The comparisons were evaluated using the analysis of variance (ANOVA) and Tukey’s post hoc test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eParafoveal vessel density in both SCP and DCP decreased in eyes without clinical DR compared to non-diabetic controls (p \u0026lt; 0.001). Statistical significance was also observed when comparing controls with patients diagnosed with type 2 DM 5-10 years ago (p \u0026lt; 0.001), controls with patients diagnosed with type 2 DM more than 10 years ago (p \u0026lt; 0.001), and patients diagnosed with type 2 DM 5-10 years ago with those diagnosed more than 10 years ago (p \u0026lt; 0.001). In addition, the FAZ area in both plexuses increased in case eyes compared to controls (p \u0026lt; 0.001). However, there was no significance of FAZ area in SCP when comparing cases diagnosed between 5-10 years ago to those diagnosed more than 10 years ago (p = 0.06).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: It was demonstrated that OCTA can detect preclinical DR before the manifestation of clinically apparent retinopathy in diabetic eyes, especially in long-term diagnosed disease. In type 2 DM patients without DR, SCP and DCP were affected, and the changes were progressive and significant with increasing time to diagnosis. Our results suggest that OCTA may be a promising tool for regular screening of diabetic eyes for DR.\u003c/p\u003e","manuscriptTitle":"Evaluation of foveal microvasculature changes by optical coherence tomography angiography in eyes of pacientes with type 2 diabetes diagnosed more than 5 years ago without clinical signs of diabetic retinopathy versus patients without diabetes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-31 08:59:54","doi":"10.21203/rs.3.rs-6256471/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d88c0676-9f6e-494b-abad-4858b70d3966","owner":[],"postedDate":"March 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-06T09:38:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-31 08:59:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6256471","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6256471","identity":"rs-6256471","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}