{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T02:14:42Z","timestamp":1776392082528,"version":"3.51.2"},"reference-count":14,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2019,2,20]],"date-time":"2019-02-20T00:00:00Z","timestamp":1550620800000},"content-version":"vor","delay-in-days":76,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:p>The objective of this study was to evaluate the prevalence of different disease pathways (ischemia, neurodegeneration, and edema) in the initial stages of diabetic retinopathy. In this retrospective cross-sectional study, eyes were grouped by diabetic retinopathy severity using the 7-field Early Treatment Diabetic Retinopathy Study (ETDRS) protocol (levels 10\u201320, 35, and 43\u201347). Neurodegeneration was identified by thinning of the retinal nerve fiber layer and\/or ganglion cell layer. Edema was identified by thickening of the inner nuclear layer, outer plexiform layer, or full retina. Ischemia was identified by metrics of retinal vessel density. Imaging was performed in 142 eyes from 142 patients (28% women) aged 52\u201388 years. Vessel density (ischemia) was significantly different between the ETDRS groups (P &amp;lt; 0.020). On multivariate regression analysis, it remained significantly different between stages of the disease and showed associations with age (P &amp;lt; 0.001), sex (P = 0.028), and metabolic control (P = 0.034). No significant differences between ETDRS groups were found in retinal thinning (neurodegeneration) or retinal thickness (edema). Eyes with the same ETDRS retinopathy grading from different patients with diabetes showed that the prevalence of different disease pathways varies between patients, even within the same severity group. Ischemia (capillary dropout) is the only disease pathway that shows correlation with retinopathy severity and metabolic control.<\/jats:p>","DOI":"10.2337\/db18-1077","type":"journal-article","created":{"date-parts":[[2018,12,6]],"date-time":"2018-12-06T22:56:16Z","timestamp":1544136976000},"page":"648-653","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":38,"title":["Multimodal Imaging of the Initial Stages of Diabetic Retinopathy: Different Disease Pathways in Different Patients"],"prefix":"10.2337","volume":"68","clinical-trial-number":[{"clinical-trial-number":"nct03010397","registry":"10.18810\/clinical-trials-gov","type":"results"},{"clinical-trial-number":"nct03010397","registry":"10.18810\/clinical-trials-gov","type":"results"}],"author":[{"given":"In\u00eas P.","family":"Marques","sequence":"first","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"}]},{"given":"Dalila","family":"Alves","sequence":"additional","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"}]},{"given":"Torcato","family":"Santos","sequence":"additional","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"}]},{"given":"Lu\u00eds","family":"Mendes","sequence":"additional","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"}]},{"given":"Ana Rita","family":"Santos","sequence":"additional","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"}]},{"given":"Concei\u00e7\u00e3o","family":"Lobo","sequence":"additional","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"},{"name":"University of Coimbra, Coimbra, Portugal"}]},{"given":"Mary","family":"Durbin","sequence":"additional","affiliation":[{"name":"Advanced Development, Carl Zeiss Meditec, Inc., Dublin, CA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0947-9850","authenticated-orcid":false,"given":"Jos\u00e9","family":"Cunha-Vaz","sequence":"additional","affiliation":[{"name":"Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal"},{"name":"University of Coimbra, Coimbra, Portugal"}]}],"member":"1167","published-online":{"date-parts":[[2018,12,6]]},"reference":[{"key":"2022031303404423200_B1","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.2337\/diacare.27.10.2540","article-title":"Diabetic retinopathy","volume":"27","author":"Fong","year":"2004","journal-title":"Diabetes Care"},{"key":"2022031303404423200_B2","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.2337\/dc06-1136","article-title":"Impact of recent increase in incidence on future diabetes burden: U.S., 2005-2050","volume":"29","author":"Narayan","year":"2006","journal-title":"Diabetes Care"},{"key":"2022031303404423200_B3","doi-asserted-by":"crossref","first-page":"4595","DOI":"10.1167\/iovs.13-11895","article-title":"Three different phenotypes of mild nonproliferative diabetic retinopathy with different risks for development of clinically significant macular edema","volume":"54","author":"Nunes","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022031303404423200_B4","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":"Cunha-Vaz","year":"2014","journal-title":"Prog Retin Eye Res"},{"key":"2022031303404423200_B5","doi-asserted-by":"crossref","unstructured":"Gardner\u2008TW, Sundstrom\u2008JM. A proposal for early and personalized treatment of diabetic retinopathy based on clinical pathophysiology and molecular phenotyping. Vision Res\u20082017;139:153\u2013160.","DOI":"10.1016\/j.visres.2017.03.006"},{"key":"2022031303404423200_B6","unstructured":"Santos T, Correia A, Neves CA, et al. Feasibility of automated interface segmentation of Cirrus HD-OCT data in normal and mild non proliferative diabetic retinopathy eyes [Internet]. Invest Ophthalmol Vis Sci 2015;56:5953. Available from http:\/\/iovs.arvojournals.org\/article.aspx?articleid=2336041&resultClick=1. Accessed 17 October 2017"},{"key":"2022031303404423200_B7","doi-asserted-by":"crossref","unstructured":"Diabetic Retinopathy Clinical Research Network; Bressler NM, Miller KM, Beck RW, et al. Observational study of subclinical diabetic macular edema. Eye 2012;26:833\u2013840.","DOI":"10.1038\/eye.2012.53"},{"key":"2022031303404423200_B8","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1097\/IAE.0000000000000403","article-title":"Topical nepafenec in eyes with noncentral diabetic macular edema","volume":"35","author":"Friedman","year":"2015","journal-title":"Retina"},{"key":"2022031303404423200_B9","doi-asserted-by":"crossref","unstructured":"Sohn\u2008EH, van Dijk\u2008HW, Jiao\u2008C, et al. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proc Natl Acad Sci U S A\u20082016;113:E2655\u2013E2664.","DOI":"10.1073\/pnas.1522014113"},{"key":"2022031303404423200_B10","doi-asserted-by":"crossref","unstructured":"Vujosevic\u2008S, Midena\u2008E. Retinal layers changes in human preclinical and early clinical diabetic retinopathy support early retinal neuronal and M\u00fcller cells alterations. J Diabetes Res\u20082013;2013:905058.","DOI":"10.1155\/2013\/905058"},{"key":"2022031303404423200_B11","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":"2022031303404423200_B12","doi-asserted-by":"crossref","unstructured":"Durbin\u2008MK, An\u2008L, Shemonski\u2008ND, et al. Quantification of retinal microvascular density in optical coherence tomographic angiography images in diabetic retinopathy. JAMA Ophthalmol\u20082017;135:370.","DOI":"10.1001\/jamaophthalmol.2017.0080"},{"key":"2022031303404423200_B13","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.2337\/dc12-1491","article-title":"Microaneurysm turnover at the macula predicts risk of development of clinically significant macular edema in persons with mild nonproliferative diabetic retinopathy","volume":"36","author":"Ribeiro","year":"2013","journal-title":"Diabetes Care"},{"key":"2022031303404423200_B14","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/978-1-59745-563-3_11","article-title":"Capillary dropout in diabetic retinopathy","volume-title":"Diabetic Retinopathy","author":"Kowluru","year":"2008"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/68\/3\/648\/431363\/db181077.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/68\/3\/648\/431363\/db181077.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:37:05Z","timestamp":1667407025000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/68\/3\/648\/39821\/Multimodal-Imaging-of-the-Initial-Stages-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,6]]},"references-count":14,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,12,6]]},"published-print":{"date-parts":[[2019,3,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db18-1077","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,6]]}}}