{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:05:29Z","timestamp":1790899529293,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T00:00:00Z","timestamp":1604016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: To evaluate the earliest retinal morphological and functional changes in diabetic eyes without or with early signs of diabetic retinopathy (DR). Methods: Twenty-two eyes with no DR (noDR group), 22 eyes with mild DR (DR group), and 18 healthy nondiabetic eyes (controls) were enrolled. All eyes were studied by means of spectral domain optical coherence tomography (OCT), OCT angiography (OCTA), and multifocal electroretinogram (mfERG). Results: A significantly higher number of OCT hyperreflective intraretinal foci (HRF) was found in both noDR and DR groups versus controls, but not between DR groups. The OCTA parameters of the superficial vascular plexus (SVP) were significantly reduced in the noDR group both versus controls and DR group (p &lt; 0.05). The OCTA parameters of the intermediate capillary plexus (ICP) were significantly reduced in the DR group versus controls. An increased number of altered hexagons on mfERG was found in the noDR versus the DR group (p = 0.0192). Conclusions: Retinal vascular and functional parameters are differently involved in diabetic eyes; major vascular changes in the SVP and functional alterations of the mfERG are present in diabetic eyes with no clinical microvascular signs of DR, while ICP is mainly involved when early ophthalmoscopic signs of DR are present. The integrated use of mfERG and OCTA provides new significant insights into the pathogenesis of diabetic related retinal disease.<\/jats:p>","DOI":"10.3390\/jcm9113514","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T09:29:32Z","timestamp":1604050172000},"page":"3514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Early Retinal Changes by OCT Angiography and Multifocal Electroretinography in Diabetes"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1749-2737","authenticated-orcid":false,"given":"Luisa","family":"Frizziero","sequence":"first","affiliation":[{"name":"IRCCS\u2014Fondazione Bietti, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4712-6631","authenticated-orcid":false,"given":"Giulia","family":"Midena","sequence":"additional","affiliation":[{"name":"Institute of Ophthalmology, Policlinico Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Longhin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Berton","sequence":"additional","affiliation":[{"name":"ASST Rhodense, Garbagnate Milanese, 20024 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5535-9350","authenticated-orcid":false,"given":"Tommaso","family":"Torresin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0216-727X","authenticated-orcid":false,"given":"Raffaele","family":"Parrozzani","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Pilotto","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.2337\/diabetes.47.12.1953","article-title":"Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: Vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group","volume":"47","author":"Antonetti","year":"1998","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"42201","DOI":"10.1038\/srep42201","article-title":"Detailed Vascular Anatomy of the Human Retina by Projection-Resolved Optical Coherence Tomography Angiography","volume":"7","author":"Campbell","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.mvr.2015.04.006","article-title":"In vivo optical imaging of human retinal capillary networks using speckle variance optical coherence tomography with quantitative clinico-histological correlation","volume":"100","author":"Chan","year":"2015","journal-title":"Microvasc. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1097\/IAE.0000000000000882","article-title":"Detection of microvascular changes in eyes of patients with diabetes but not clinical diabetic retinopathy using optical coherence tomography angiography","volume":"35","author":"Chin","year":"2015","journal-title":"Retina"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1097\/IAE.0000000000000716","article-title":"Optical coherence tomography angiography features of diabetic retinopathy","volume":"35","author":"Hwang","year":"2015","journal-title":"Retina"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ajo.2015.04.021","article-title":"Optical Coherence Tomography Angiography in Diabetic Retinopathy: A Prospective Pilot Study","volume":"160","author":"Ishibazawa","year":"2015","journal-title":"Am. J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4239\/wjd.v1.i2.57","article-title":"Neurodegeneration: An early event of diabetic retinopathy","volume":"1","author":"Villarroel","year":"2010","journal-title":"World J. Diabetes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1096\/fj.03-1476fje","article-title":"A central role for inflammation in the pathogenesis of diabetic retinopathy","volume":"18","author":"Joussen","year":"2004","journal-title":"FASEB J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.ajo.2019.04.035","article-title":"Measurable Aspects of the Retinal Neurovascular Unit in Diabetes, Glaucoma, and Controls","volume":"207","author":"Spaide","year":"2019","journal-title":"Am. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Altmann, C., and Schmidt, M.H.H. (2018). The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010110"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/491835","article-title":"Hyperreflective Intraretinal Spots in Diabetics without and with Nonproliferative Diabetic Retinopathy: AnIn VivoStudy Using Spectral Domain OCT","volume":"2013","author":"Vujosevic","year":"2013","journal-title":"J. Diabetes Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1159\/000342159","article-title":"Hyperreflective Dots: A New Spectral-Domain Optical Coherence Tomography Entity for Follow-Up and Prognosis in Exudative Age-Related Macular Degeneration","volume":"229","author":"Coscas","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1001\/archophthalmol.2007.65","article-title":"Microglial Activation in Human Diabetic Retinopathy","volume":"126","author":"Zeng","year":"2008","journal-title":"Arch. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40942-015-0001-z","article-title":"Diabetes induces changes in neuroretina before retinal vessels: A spectral-domain optical coherence tomography study","volume":"1","author":"Rodrigues","year":"2015","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1159\/000459687","article-title":"Emerging Insights into Pathogenesis","volume":"60","author":"Midena","year":"2017","journal-title":"Dev. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.visres.2017.05.006","article-title":"OCT angiography and visible-light OCT in diabetic retinopathy","volume":"139","author":"Nesper","year":"2017","journal-title":"Vis. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Schmetterer, L., Sim, R., Tan, B., Wong, D., Yao, X., Liu, X., Ting, D.S.W., Schmidl, D., Ang, M., and Garh\u00f6fer, G. (2020). Optical Coherence Tomography Angiography in Diabetes and Diabetic Retinopathy. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061723"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.1167\/iovs.05-1141","article-title":"Diabetic Macular Edema: Correlation between Microperimetry and Optical Coherence Tomography Findings","volume":"47","author":"Vujosevic","year":"2006","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1001\/archopht.122.12.1809","article-title":"Multifocal Electroretinogram and Short-Wavelength Automated PerimetryMeasures in Diabetic Eyes with Little or No Retinopathy","volume":"122","author":"Han","year":"2004","journal-title":"Arch. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF00155037","article-title":"Steady-state pattern electroretinogram in insulin-dependent diabetics with no or minimal retinopathy","volume":"73","author":"Falsini","year":"1989","journal-title":"Doc. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1001\/archopht.1985.01050010055018","article-title":"Contrast Sensitivity in Diabetics With and Without Background Retinopathy","volume":"103","author":"Sokol","year":"1985","journal-title":"Arch. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/eye.2017.27","article-title":"Structure\u2013function relationship in early diabetic retinopathy: A spatial correlation analysis with OCT and microperimetry","volume":"31","author":"Montesano","year":"2017","journal-title":"Eye"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ratra, D., Nagarajan, R., Dalan, D., Prakash, N., Kuppan, K., Thanikachalam, S., Das, U., and Narayansamy, A. (2020). Early structural and functional neurovascular changes in the retina in the prediabetic stage. Eye, 1\u201310.","DOI":"10.1038\/s41433-020-0984-z"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Early Treatment Diabetic Retinopathy Study Research Group (1991). Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs\u2014An Extension of the Modified Airlie House Classification: ETDRS report number 10. Ophthalmology, 98, 786\u2013806.","DOI":"10.1016\/S0161-6420(13)38012-9"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1136\/bjophthalmol-2018-312461","article-title":"Early retinal and choroidal OCT and OCT angiography signs of inflammation after uncomplicated cataract surgery","volume":"103","author":"Pilotto","year":"2018","journal-title":"Br. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10633-011-9296-8","article-title":"ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition)","volume":"124","author":"Hood","year":"2012","journal-title":"Doc. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1159\/000444396","article-title":"Correlation between Retinal Vessel Calibre and Neurodegeneration in Patients with Type 2 Diabetes Mellitus in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR)","volume":"56","author":"Hansen","year":"2016","journal-title":"Ophthalmic Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1097\/IAE.0000000000000986","article-title":"Hyperreflective intraretinal spots in radiation macular edema on spectral domain optical coherence tomography","volume":"36","author":"Frizziero","year":"2016","journal-title":"Retina"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/491835","article-title":"Retinal Layers Changes in Human Preclinical and Early Clinical Diabetic Retinopathy Support Early Retinal Neuronal and M\u00fcller Cells Alterations","volume":"2013","author":"Vujosevic","year":"2013","journal-title":"J. Diabetes Res."},{"key":"ref_30","first-page":"e292","article-title":"Ganglion cell layer thickening in well-controlled patients with type 1 diabetes: An early sign for diabetic retinopathy?","volume":"98","author":"Gerendas","year":"2019","journal-title":"Acta Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1167\/iovs.10-6012","article-title":"Long-Term In Vivo Imaging and Measurement of Dendritic Shrinkage of Retinal Ganglion Cells","volume":"52","author":"Leung","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1167\/iovs.11-8997","article-title":"Early Neurodegeneration in the Retina of Type 2 Diabetic Patients","volume":"53","author":"Verbraak","year":"2012","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1159\/000438792","article-title":"Retinal Layer Location of Increased Retinal Thickness in Eyes with Subclinical and Clinical Macular Edema in Diabetes Type 2","volume":"54","author":"Bandello","year":"2015","journal-title":"Ophthalmic Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3686","DOI":"10.1167\/iovs.13-13562","article-title":"Pathologic Alterations of the Outer Retina in Streptozotocin-Induced Diabetes","volume":"55","author":"Szalay","year":"2014","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/jdi.12312","article-title":"Photoreceptors in diabetic retinopathy","volume":"6","author":"Kern","year":"2015","journal-title":"J. Diabetes Investig."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Frizziero, L., Parrozzani, R., Londei, D., Pilotto, E., and Midena, E. (2020). Quantification of vascular and neuronal changes in the peripapillary retinal area secondary to diabetic retinopathy. Br. J. Ophthalmol.","DOI":"10.1136\/bjophthalmol-2020-316468"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11504","DOI":"10.1523\/JNEUROSCI.1971-14.2014","article-title":"Regulation of Blood Flow in the Retinal Trilaminar Vascular Network","volume":"34","author":"Kornfield","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1167\/iovs.17-23304","article-title":"Importance of Considering the Middle Capillary Plexus on OCT Angiography in Diabetic Retinopathy","volume":"59","author":"Onishi","year":"2018","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kim, M., Kim, R.-Y., Park, W., Park, Y.-G., Kim, I.-B., and Park, Y.-H. (2020). Electroretinography and retinal microvascular changes in type 2 diabetes. Acta Ophthalmol.","DOI":"10.1111\/aos.14421"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"OCT348","DOI":"10.1167\/iovs.15-18782","article-title":"New Insights into Microaneurysms in the Deep Capillary Plexus Detected by Optical Coherence Tomography Angiography in Diabetic Macular Edema","volume":"57","author":"Hasegawa","year":"2016","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1097\/IAE.0000000000001077","article-title":"Characterization of the middle capillary plexus using optical coherence tomography angiography in healthy and diabetic eyes","volume":"36","author":"Park","year":"2016","journal-title":"Retina"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.preteyeres.2014.03.003","article-title":"Phenotypes and biomarkers of diabetic retinopathy","volume":"41","author":"Ribeiro","year":"2014","journal-title":"Prog. Retina Eye Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1167\/iovs.17-21873","article-title":"Approach for a Clinically Useful Comprehensive Classification of Vascular and Neural Aspects of Diabetic Retinal Disease","volume":"59","author":"Abramoff","year":"2018","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e811","DOI":"10.1111\/aos.14041","article-title":"Capillary dropout is dominant in deep capillary plexus in early diabetic retinopathy in optical coherence tomography angiography","volume":"97","author":"Kaizu","year":"2019","journal-title":"Acta Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1136\/bjophthalmol-2017-311240","article-title":"Optical coherence tomography angiography in pseudophakic cystoid macular oedema compared to diabetic macular oedema: Qualitative and quantitative evaluation of retinal vasculature","volume":"102","author":"Sacconi","year":"2018","journal-title":"Br. J. Ophthalmol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/11\/3514\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:26:49Z","timestamp":1760178409000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/11\/3514"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,30]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["jcm9113514"],"URL":"https:\/\/doi.org\/10.3390\/jcm9113514","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,30]]}}}