{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:02:27Z","timestamp":1760144547235,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural program of the National Eye Institute","award":["232300421279"],"award-info":[{"award-number":["232300421279"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Optical coherence tomography (OCT) is widely used to probe retinal structure and function. This study investigated the outer retina band (ORB) pattern and reflective intensity for the region between bands 2 and 3 (Dip) in three mouse models of inherited retinal degeneration (Rs1KO, TTLL5KO, RPE65KO) and in human AMD patients from the A2A database. OCT images were manually graded, and reflectivity signals were used to calculate the Dip ratio. Qualitative analyses demonstrated the progressive merging band 2 and band 3 in all three mouse models, leading to a reduction in the Dip ratio compared to wildtype (WT) controls. Gene replacement therapy in Rs1KO mice reverted the ORB pattern to one resembling WT and increased the Dip ratio. The degree of anatomical rescue in these mice was highly correlated with level of transgenic RS1 expression and with the restoration of ERG b-wave amplitudes. While the inner retinal cavity was significantly enlarged in dark-adapted Rs1KO mice, the Dip ratio was not altered. A reduction of the Dip ratio was also detected in AMD patients compared with healthy controls and was also positively correlated with AMD severity on the AMD score. We propose that the ORB and Dip ratio can be used as non-invasive early biomarkers for retina health, which can be used to probe therapeutic gene expression and to evaluate the effectiveness of therapy.<\/jats:p>","DOI":"10.3390\/bioengineering11050449","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T08:59:39Z","timestamp":1714553979000},"page":"449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["OCT Intensity of the Region between Outer Retina Band 2 and Band 3 as a Biomarker for Retinal Degeneration and Therapy"],"prefix":"10.3390","volume":"11","author":[{"given":"Yong","family":"Zeng","sequence":"first","affiliation":[{"name":"Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shasha","family":"Gao","sequence":"additional","affiliation":[{"name":"Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichao","family":"Li","sequence":"additional","affiliation":[{"name":"Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario","family":"Marangoni","sequence":"additional","affiliation":[{"name":"Section for Translational Research in Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tharindu","family":"De Silva","sequence":"additional","affiliation":[{"name":"Unit on Clinical Investigation of Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wai T.","family":"Wong","sequence":"additional","affiliation":[{"name":"Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-9802","authenticated-orcid":false,"given":"Emily Y.","family":"Chew","sequence":"additional","affiliation":[{"name":"Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Sun","sequence":"additional","affiliation":[{"name":"Neurobiology Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiansen","family":"Li","sequence":"additional","affiliation":[{"name":"Neurobiology Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2918-577X","authenticated-orcid":false,"given":"Paul A.","family":"Sieving","sequence":"additional","affiliation":[{"name":"National Eye Institute\/NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1114-4697","authenticated-orcid":false,"given":"Haohua","family":"Qian","sequence":"additional","affiliation":[{"name":"Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1097\/IAE.0b013e3182247535","article-title":"Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: Literature review and model","volume":"31","author":"Spaide","year":"2011","journal-title":"Retina"},{"key":"ref_2","first-page":"603","article-title":"State-of-the-art in retinal optical coherence tomography image analysis","volume":"5","author":"Baghaie","year":"2015","journal-title":"Quant. Imaging Med. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/ncpneuro0950","article-title":"Optical coherence tomography: A window into the mechanisms of multiple sclerosis","volume":"4","author":"Frohman","year":"2008","journal-title":"Nat. Clin. Prac. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/APO.0000000000000179","article-title":"Optical Coherence Tomography Imaging for Glaucoma\u2014Today and Tomorrow","volume":"5","author":"Leung","year":"2016","journal-title":"Asia-Pacific J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-3-319-95046-4_3","article-title":"Optical Coherence Tomography","volume":"1085","author":"Tsang","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1055\/s-0035-1549098","article-title":"Applications of optical coherence tomography in pediatric clinical neuroscience","volume":"46","author":"Rajjoub","year":"2015","journal-title":"Neuropediatrics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1097\/IAE.0000000000002688","article-title":"Handheld Spectral Domain Optical Coherence Tomography Findings of X-Linked Retinoschisis in Early Childhood","volume":"40","author":"Ling","year":"2020","journal-title":"Retina"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fischer, M.D., Huber, G., Beck, S.C., Tanimoto, N., Muehlfriedel, R., Fahl, E., Grimm, C., Wenzel, A., Rem\u00e9, C.E., and van de Pavert, S.A. (2009). Noninvasive, In Vivo assessment of mouse retinal structure using optical coherence tomography. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007507"},{"key":"ref_9","first-page":"OCT277-87","article-title":"Retinal Structure and Gene Therapy Outcome in Retinoschisin-Deficient Mice Assessed by Spectral-Domain Optical Coherence Tomography","volume":"57","author":"Zeng","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1136\/bjo.2010.189720","article-title":"Spectral-domain OCT peripapillary retinal nerve fibre layer thickness measurements in patients with Stargardt disease","volume":"95","author":"Genead","year":"2011","journal-title":"Br. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.1016\/j.ophtha.2017.07.015","article-title":"Detecting Structural Progression in Glaucoma with Optical Coherence Tomography","volume":"124","author":"Tatham","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hu, Q.R., Huang, L.Z., Chen, X.L., Xia, H.K., Li, T.Q., and Li, X.X. (2017). X-Linked Retinoschisis in Juveniles: Follow-Up by Optical Coherence Tomography. BioMed Res. Int., 2017.","DOI":"10.1155\/2017\/1704623"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11892-019-1226-2","article-title":"Imaging and Biomarkers in Diabetic Macular Edema and Diabetic Retinopathy","volume":"19","author":"Kwan","year":"2019","journal-title":"Curr. Diabetes Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9703","DOI":"10.1167\/iovs.11-8650","article-title":"The inner segment\/outer segment border seen on optical coherence tomography is less intense in patients with diminished cone function","volume":"52","author":"Hood","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4662","DOI":"10.1167\/iovs.15-16955","article-title":"Objective Analysis of Hyperreflective Outer Retinal Bands Imaged by Optical Coherence Tomography in Patients with Stargardt Disease","volume":"56","author":"Park","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1097\/IAE.0b013e31829c3765","article-title":"Outer retinal atrophy after regression of subretinal drusenoid deposits as a newly recognized form of late age-related macular degeneration","volume":"33","author":"Spaide","year":"2013","journal-title":"Retina"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1167\/iovs.14-15256","article-title":"RefMoB, a Reflectivity Feature Model-Based Automated Method for Measuring Four Outer Retinal Hyperreflective Bands in Optical Coherence Tomography","volume":"56","author":"Ross","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"srep42545","DOI":"10.1038\/srep42545","article-title":"GARP2 accelerates retinal degeneration in rod cGMP-gated cation channel beta-subunit knockout mice","volume":"7","author":"DeRamus","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tanabu, R., Sato, K., Monai, N., Yamauchi, K., Gonome, T., Xie, Y., Takahashi, S., Ishiguro, S.-I., and Nakazawa, M. (2019). The findings of optical coherence tomography of retinal degeneration in relation to the morphological and electroretinographic features in RPE65\u2212\/\u2212 mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210439"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7904","DOI":"10.1167\/iovs.14-14907","article-title":"The cellular origins of the outer retinal bands in optical coherence tomography images","volume":"55","author":"Jonnal","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1177\/15353702211022674","article-title":"Interpretation of anatomic correlates of outer retinal bands in optical coherence tomography","volume":"246","author":"Yao","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10260","DOI":"10.1038\/s41598-021-89599-1","article-title":"Functional regulation of an outer retina hyporeflective band on optical coherence tomography images","volume":"11","author":"Gao","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_23","first-page":"2405","article-title":"Relation of optical coherence tomography to microanatomy in normal and rd chickens","volume":"39","author":"Huang","year":"1998","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.exer.2013.05.003","article-title":"Evaluation of multimodal imaging in carriers of X-linked retinitis pigmentosa","volume":"113","author":"Acton","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1097\/IAE.0b013e31829234e6","article-title":"Outer retina analysis by optical coherence tomography in cone-rod dystrophy patients","volume":"33","author":"Lima","year":"2013","journal-title":"Retina"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1167\/iovs.14-13955","article-title":"Correlation between spectral-domain oct findings and visual acuity in X-linked retinoschisis","volume":"55","author":"Yang","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_27","first-page":"78","article-title":"Outer Retinal Layers as Predictors of Vision Loss","volume":"15","author":"Marco","year":"2015","journal-title":"Rev. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1167\/iovs.15-18354","article-title":"Structure\/Psychophysical Relationships in X-Linked Retinoschisis","volume":"57","author":"Bennett","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1089\/hum.2019.162","article-title":"A Common Outer Retinal Change in Retinal Degeneration by Optical Coherence Tomography Can Be Used to Assess Outcomes of Gene Therapy","volume":"30","author":"Joe","year":"2019","journal-title":"Hum. Gene Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E2925-34","DOI":"10.1073\/pnas.1523201113","article-title":"Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations","volume":"113","author":"Sun","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/3813","article-title":"Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle","volume":"20","author":"Redmond","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1001\/archopht.123.11.1570","article-title":"a simplified severity scale for age-related macular degeneration: AREDS Report No. 18","volume":"123","author":"Ferris","year":"2005","journal-title":"Arch. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ophtha.2012.07.004","article-title":"Spectral-Domain optical coherence tomography characteristics of intermediate age-related macular degeneration","volume":"120","author":"Leuschen","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1167\/iovs.04-0576","article-title":"RS-1 Gene Delivery to an Adult Rs1h Knockout Mouse Model Restores ERG b-Wave with Reversal of the Electronegative Waveform of X-Linked Retinoschisis","volume":"45","author":"Zeng","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15167","DOI":"10.1074\/jbc.M113.453936","article-title":"Disruption of Ttll5\/stamp gene (tubulin tyrosine ligase-like protein 5\/src-1 and tif2-associated modulatory protein gene) in male mice causes sperm malformation and infertility","volume":"288","author":"Lee","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_36","unstructured":"(2022). American National Standard for Safe Use of Lasers (Standard No. ANSI Z136.1-2022)."},{"key":"ref_37","first-page":"OCT105-11","article-title":"Light-induced thickening of photoreceptor outer segment layer detected by ultra-high resolution oct imaging","volume":"57","author":"Li","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1089\/hum.2015.142","article-title":"Preclinical Dose-Escalation Study of Intravitreal AAV-RS1 Gene Therapy in a Mouse Model of X-linked Retinoschisis: Dose-Dependent Expression and Improved Retinal Structure and Function","volume":"27","author":"Bush","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.1167\/iovs.07-0203","article-title":"Retinoschisin gene therapy and natural history in The rs1h-KO mouse: Long-term rescue from retinal degeneration","volume":"48","author":"Kjellstrom","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1172\/JCI81380","article-title":"Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer","volume":"125","author":"Ou","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"453","DOI":"10.3389\/fnmol.2017.00453","article-title":"Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation","volume":"10","author":"Chen","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41434-021-00290-6","article-title":"Rs1h(\u2212\/y) exon 3-del rat model of X-linked retinoschisis with early onset and rapid phenotype is rescued by RS1 supplementation","volume":"29","author":"Zeng","year":"2022","journal-title":"Gene Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6222","DOI":"10.1073\/pnas.092528599","article-title":"Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure","volume":"99","author":"Weber","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eabn2070","DOI":"10.1126\/sciadv.abn2070","article-title":"Mitochondria in cone photoreceptors act as microlenses to enhance photon delivery and confer directional sensitivity to light","volume":"8","author":"Ball","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1167\/tvst.10.12.27","article-title":"Challenges Associated with Ellipsoid Zone Intensity Measurements Using Optical Coherence Tomography","volume":"10","author":"Lee","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7417","DOI":"10.1167\/iovs.14-15013","article-title":"A comparison of progressive loss of the ellipsoid zone (EZ) band in autosomal dominant and X-linked retinitis pigmentosa","volume":"55","author":"Cai","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1016\/j.ophtha.2014.02.023","article-title":"Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: The IN*OCT consensus","volume":"121","author":"Staurenghi","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1001\/archopht.1996.01100130270007","article-title":"Clinical features in affected males with X-linked retinoschisis","volume":"114","author":"George","year":"1996","journal-title":"Arch. Ophthalmol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e1221","DOI":"10.1016\/S2214-109X(17)30393-5","article-title":"Global causes of blindness and distance vision impairment 1990\u20132020: A systematic review and meta-analysis","volume":"5","author":"Flaxman","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cmpb.2018.05.033","article-title":"Automatic macular edema identification and characterization using OCT images","volume":"163","author":"Samagaio","year":"2018","journal-title":"Comput. Methods Programs Biomed"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Rajagopalan, N., Venkateswaran, N., Josephraj, A.N., and Srithaladevi, E. (2021). Diagnosis of retinal disorders from Optical Coherence Tomography images using CNN. 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