Biomarkers of diabetic retinopathy on optical coherence tomography angiography

Petrachkov D.V.; Budzinskaya M.V.

doi:https://doi.org/10.17116/oftalma2020136042344

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Abstract:

Pathogenesis of diabetic retinopathy (DR) is complex and multifactorial, giving rise to a wide range of potential biomarkers — quantitatively and objectively measurable indicators of the biological, pathological processes or pharmacological response to therapy. This non-systemic review is devoted to a vital problem — possibility of using biomarkers acquired with optical coherence tomography angiography (OCTA-biomarkers) in DR. The review examines the qualitative and quantitative indicators obtained using OCTA as potential biomarkers of DR. Of greatest interest is the assessment of diabetic microvascular abnormalities such as microaneurysms, intraretinal microvascular abnormalities, neovascularization and non-perfusion (ischemia) zones. A separate section is devoted to currently well-studied indices reflecting the area and regularity of the foveolar avascular zone, and microcirculation indices such as capillary perfusion density, blood flow indices, fractal dimension of retinal microcirculation vessels, etc. The relationship of OCTA-biomarkers and diabetic macular edema is also discussed. Biomarkers obtained with wide-field OCTA, such as indices quantitatively reflecting ischemia and neovascularization are paid special attention in the review. The problems and solutions associated with the use of OCTA-biomarkers in DR are also considered. In general OCTA-biomarkers in DR are becoming an important tool for screening, diagnosis, monitoring of DR, and for predicting and preventing patients’ clinical response to treatment.

Keywords:

diabetic retinopathy

OCTA derived biomarker

biomarker

diabetic macular edema

DME

optical coherence tomography angiography

OCTA

VEGF

wide-field OCTA

Authors:

Petrachkov D.V.

Research Institute of Eye Diseases

Budzinskaya M.V.

Krasnov Research Institute of Eye Diseases

SPIN RSCI: 3552-7061
Scopus AuthorID: 6508005851
ResearcherID: C-3026-2014
ORCID: 0000-0002-5507-8775

Received:

12.05.2020

Accepted:

17.06.2020

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References:

Standards of specialized diabetes care. Edited by Dedov I.I., Shestakova M.V., Mayorov A.Yu. 9th edition. Saharnyj diabet. 2019;22(1-1):1-121. (In Russ.). https://doi.org/10.14341/DM221S1
Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabeticmacular edema and related vision loss. Eye and Vision (London, England). 2015;2:17. https://doi.org/10.1186/s40662-015-0026-2
Pusparajah P, Lee LH, Abdul Kadir K. Molecular Markers of Diabetic Retinopathy: Potential Screening Tool of the Future? Frontiers in Physiology. 2016;7:200. https://doi.org/10.3389/fphys.2016.00200
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics. 2001;69(3):89-95. https://doi.org/10.1067/mcp.2001.113989
Don ES, Tarasov AV, Epshtein OI, Tarasov SA. The biomarkers in medicine: search, choice, study and validation. Klinicheskaya laboratornaya diagnostika. 2017;62(1):52-59. (In Russ.). https://doi.org/10.18821/0869-2084-2017-62-1-52-59
Budzinskaya MV, Lipatov DV, Pavlov VG, Petrachkov DV. Biomarkers for diabetic retinopathy. Saharnyj diabet. 2020;23(1):88-94. (In Russ.). https://doi.org/10.14341/DM10045
Jenkins AJ, Joglekar MV, Hardikar AA, Keech AC, O’Neal DN, Januszewski AS. Biomarkers in Diabetic Retinopathy. Review of Diabetic Studies. 2015;12(1-2):159-195. https://doi.org/10.1900/RDS.2015.12.159
Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged byfluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmoogy. 2015;133(1):45-50. https://doi.org/10.1001/jamaophthalmol.2014.3616
Choi W, Waheed NK, Moult EM, Adhi M, Lee B, De Carlo T, Jayaraman V, Baumal CR, Duker JS, Fujimoto JG. Ultrahigh speed swept source optical coherence tomography angiography of retinal and choriocapillaris alterations in diabetic patients with and without retinopathy. Retina. 2017;37(1):11-21. https://doi.org/10.1097/IAE.0000000000001250
Chan G, Balaratnasingam C, Yu PK, Morgan WH, McAllister IL, Cringle SJ, Yu DY. Quantitative morphometry of perifoveal capillary networks in the human retina. Investigative Ophthalmology and Visual Science. 2012;53(9): 5502-5514. https://doi.org/10.1167/iovs.12-10265
Hirano T, Hoshiyama K, Hirabayashi K, Wakabayashi M, Toriyama Y, Tokimitsu M,Murata T. Vitreoretinal Interface Slab in OCT Angiography for Detecting Diabetic Retinal Neovascularization. Ophthalmology Retina. 2020: 2468-6530(20)30017-8. https://doi.org/10.1016/j.oret.2020.01.004
Gildea D. The diagnostic value of optical coherence tomography angiography indiabetic retinopathy: a systematic review. International Ophthalmology. 2019;39(10):2413-2433. https://doi.org/10.1007/s10792-018-1034-8
Park JJ, Soetikno BT, Fawzi AA. Characterization of the middle capillary plexus using optical coherence tomography angiography in healthy and diabetic eyes. Retina. 2016;36(11):2039-2050. https://doi.org/10.1097/IAE.0000000000001077
Al-Sheikh M, Akil H, Pfau M, Sadda SR. Swept-Source OCT Angiography Imaging of the Foveal Avascular Zone and Macular Capillary Network Density in Diabetic Retinopathy. Investigative Ophthalmology and Visual Science. 2016;57(8):3907-3913. https://doi.org/10.1167/iovs.16-19570
Hirano T, Kitahara J, Toriyama Y, Kasamatsu H, Murata T, Sadda S. Quantifying vascular density and morphology using different swept-source optical coherence tomography angiographic scan patterns in diabetic retinopathy. British Journal of Ophthalmology. 2019;103(2):216-221. https://doi.org/10.1136/bjophthalmol-2018-311942
Gass JD. A fluorescein angiographic study of macular dysfunction secondary to retinal vascular disease. IV. Diabetic retinal angiopathy. Archives of Ophthalmology. 1968;80(5):583-591. https://doi.org/10.1001/archopht.1968.00980050585004
Alibhai AY, De Pretto LR, Moult EM, Or C, Arya M, McGowan M, Carrasco-Zevallos O, Lee B, Chen S, Baumal CR, Witkin AJ, Reichel E, de Freitas AZ, Duker JS, Fujimoto JG, Waheed NK. Quantification of retinal capillary nonperfusion in diabetics using wide-field optical coherence tomography angiography. Retina. 2020;40(3):412-420. https://doi.org/10.1097/IAE.0000000000002403
Kwiterovich KA, Maguire MG, Murphy RP, Schachat AP, Bressler NM, Bressler SB, Fine SL. Frequency of adverse systemic reactions after fluorescein angiography. Results of a prospective study. Ophthalmology. 1991;98(7): 1139-1142. https://doi.org/10.1016/s0161-6420(91)32165-1
Russell JF, Shi Y, Hinkle JW, Scott NL, Fan KC, Lyu C, Gregori G, Rosenfeld PJ. Longitudinal Wide-Field Swept-Source OCT Angiography of Neovascularization in Proliferative Diabetic Retinopathy after Panretinal Photocoagulation. Ophthalmoogy Retina. 2019;3(4):350-361. https://doi.org/10.1016/j.oret.2018.11.008
Schwartz R, Khalid H, Sivaprasad S, Nicholson L, Anikina E, Sullivan P, PatelPJ, Balaskas K, Keane PA. Objective Evaluation of Proliferative Diabetic Retinopathy Using OCT. Ophthalmology Retina. 2020;4(2):164-174. https://doi.org/10.1016/j.oret.2019.09.004
Freiberg FJ, Pfau M, Wons J, Wirth MA, Becker MD, Michels S. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2016;254(6):1051-1058. https://doi.org/10.1007/s00417-015-3148-2
Couturier A, Mané V, Bonnin S, Erginay A, Massin P, Gaudric A, Tadayoni R. Capillary plexus anomalies in diabetic retinopathy on optical coherence tomography angiography. Retina. 2015;35(11):2384-2391. https://doi.org/10.1097/IAE.0000000000000859
Ishibazawa A, Nagaoka T, Takahashi A, Omae T, Tani T, Sogawa K, Yokota H, Yoshida A. Optical Coherence Tomography Angiography in Diabetic Retinopathy: A Prospective Pilot Study. American Journal of Ophthalmology. 2015;160(1):35-44. https://doi.org/10.1016/j.ajo.2015.04.021
Grading diabetic retinopathy from stereoscopic color fundus photographs — an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 suppl):786-806. https://doi.org/10.1016/S0161-6420(13)38012-9
Khalid H, Schwartz R, Nicholson L, Huemer J, El-Bradey MH, Sim DA, Patel PJ, Balaskas K, Hamilton RD, Keane PA, Rajendram R. Widefield optical coherence tomography angiography for early detection and objective evaluation of proliferative diabetic retinopathy. British Journal of Ophthalmology. 2020:bjophthalmol-2019-315365. https://doi.org/10.1136/bjophthalmol-2019-315365
Ostri C, Lund-Andersen H, Sander B, Hvidt-Nielsen D, Larsen M. Bilateraldiabetic papillopathy and metabolic control. Ophthalmology. 2010;117(11): 2214-2217. https://doi.org/10.1016/j.ophtha.2010.03.006
Chu Z, Lin J, Gao C, Xin C, Zhang Q, Chen CL, Roisman L, Gregori G, Rosenfeld PJ, Wang RK. Quantitative assessment of the retinal microvasculature using optical coherence tomography angiography. Journal of Biomedical Optics. 2016;21(6):66008. https://doi.org/10.1117/1.JBO.21.6.066008
Conti FF, Qin VL, Rodrigues EB, Sharma S, Rachitskaya AV, Ehlers JP, Singh RP. Choriocapillaris and retinal vascular plexus density of diabetic eyes using split-spectrum amplitude decorrelation spectral-domain optical coherence tomography angiography. British Journal of Ophthalmology. 2019; 103(4):452-456. https://doi.org/10.1136/bjophthalmol-2018-311903
Hwang TS, Gao SS, Liu L, Lauer AK, Bailey ST, Flaxel CJ, Wilson DJ, Huang D, Jia Y. Automated Quantification of Capillary Nonperfusion Using Optical Coherence Tomography Angiography in Diabetic Retinopathy. JAMA Ophthalmology. 2016;134(4):367-373. https://doi.org/10.1001/jamaophthalmol.2015.5658
Neroev VV, Okhotsimskaya TD, Fadeeva VA. An account of retinal microvascular changes in diabetes acquired by OCT-angiography. Rossijskij oftal’mologicheskij zhurnal. 2017;10(2):40-45. (In Russ.). https://doi.org/10.21516/2072-0076-2017-10-2-40-45
Agemy SA, Scripsema NK, Shah CM, Chui T, Garcia PM, Lee JG, Gentile RC, HsiaoYS, Zhou Q, Ko T, Rosen RB. Retinal vascular perfusion density mapping using optical coherence tomography angiography in normals and diabetic retinopathypatients. Retina. 2015;35(11):2353-2363. https://doi.org/10.1097/IAE.0000000000000862
Ting DSW, Tan GSW, Agrawal R, Yanagi Y, Sie NM, Wong CW, San Yeo IY, Lee SY, Cheung CMG, Wong TY. Optical Coherence Tomographic Angiography in Type 2 Diabetes and Diabetic Retinopathy. JAMA Ophthalmoogy. 2017;135(4):306-312. https://doi.org/10.1001/jamaophthalmol.2016.5877
Sambhav K, Abu-Amero KK, Chalam KV. Deep Capillary Macular Perfusion Indices Obtained with OCT Angiography Correlate with Degree of Nonproliferative Diabetic Retinopathy. European Journal of Ophthalmology. 2017; 27(6):716-729. https://doi.org/10.5301/ejo.5000948
Alam M, Zhang Y, Lim JI, Chan RVP, Yang M, Yao X. Quantitative optical coherence tomography angiography features for objective classification and staging of diabetic retinopathy. Retina. 2020;40(2):322-332. https://doi.org/10.1097/IAE.0000000000002373
Gendelman I, Alibhai AY, Moult EM, Levine ES, Braun PX, Mehta N, Zhao Y, Ishibazawa A, Sorour OA, Baumal CR, Witkin AJ, Reichel E, Fujimoto JG, Duker JS, Waheed NK. Topographic analysis of macular choriocapillaris flow deficits in diabetic retinopathy using swept — source optical coherence tomography angiography. International Journal of Retina and Vitreous. 2020;6:6. https://doi.org/10.1186/s40942-020-00209-0
Zueva MV. Nonlinear fractals: applications in physiology and ophthalmology. Oftal’mologiya. 2014;11(1):4-11. (In Russ.). https://doi.org/10.18008/1816-5095-2014-1-4-11
Zahid S, Dolz-Marco R, Freund KB, Balaratnasingam C, Dansingani K, Gilani F,Mehta N, Young E, Klifto MR, Chae B, Yannuzzi LA, Young JA. Fractal Dimensional Analysis of Optical Coherence Tomography Angiography in Eyes with Diabetic Retinopathy. Investigative Ophthalmology and Visual Science. 2016;57(11):4940-4947. https://doi.org/10.1167/iovs.16-19656
Ashraf M, Nesper PL, Jampol LM, Yu F, Fawzi AA. Statistical Model of Optical Coherence Tomography Angiography Parameters That Correlate With Severity of Diabetic Retinopathy. Investigative Ophthalmology and Visual Science. 2018;59(10):4292-4298. https://doi.org/10.1167/iovs.18-24142
Tsai ASH, Gan ATL, Ting DSW, Wong CW, Teo KYC, Tan ACS, Lee SY, Wong TY, Tan GSW, Gemmy Cheung CM. Diabetic macular ischemia: Correlation of Retinal Vasculature Changes by Optical Coherence Tomography Angiography and Functional Deficit. Retina. 2019. Online ahead of print. https://doi.org/10.1097/IAE.0000000000002721
Takase N, Nozaki M, Kato A, Ozeki H, Yoshida M, Ogura Y. Enlargement of foveal avascular zone in diabetic eyes evaluated by en face optical coherence tomography angiography. Retina. 2015;35(11):2377-2383. https://doi.org/10.1097/IAE.0000000000000849
Krawitz BD, Mo S, Geyman LS, Agemy SA, Scripsema NK, Garcia PM, Chui TYP, Rosen RB. Acircularity index and axis ratio of the foveal avascular zone in diabetic eyes and healthy controls measured by optical coherence tomography angiography. Vision Research. 2017;139:177-186. https://doi.org/10.1016/j.visres.2016.09.019
Johannesen SK, Viken JN, Vergmann AS, Grauslund J. Optical coherence tomography angiography and microvascular changes in diabetic retinopathy: asystematic review. Acta Ophthalmologica. 2019;97(1):7-14. https://doi.org/10.1111/aos.13859
Kim AY, Chu Z, Shahidzadeh A, Wang RK, Puliafito CA, Kashani AH. Quantifying Microvascular Density and Morphology in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography Angiography. Investigative Ophthalmology and Visual Science. 2016;57(9):362-370. https://doi.org/10.1167/iovs.15-18904
de Carlo TE, Chin AT, Joseph T, Baumal CR, Witkin AJ, Duker JS, Waheed NK. Distinguishing Diabetic Macular Edema From Capillary Nonperfusion Using Optical Coherence Tomography Angiography. Ophthalmic Surgery, Lasers and Imaging Retina. 2016;47(2):108-114. https://doi.org/10.3928/23258160-20160126-02
Sun Z, Tang F, Wong R, Lok J, Szeto SKH, Chan JCK, Chan CKM, Tham CC, Ng DS, Cheung CY. OCT Angiography Metrics Predict Progression of Diabetic Retinopathy and Development of Diabetic Macular Edema: A Prospective Study. Ophthalmology. 2019;126(12):1675-1684. https://doi.org/10.1016/j.ophtha.2019.06.016
Hirano T, Kakihara S, Toriyama Y, Nittala MG, Murata T, Sadda S. Wide-field enface swept-source optical coherence tomography angiography using extended fieldimaging in diabetic retinopathy. British Journal of Ophthalmology. 2018;102(9):1199-1203. https://doi.org/10.1136/bjophthalmol-2017-311358
Uji A, Yoshimura N. Application of extended field imaging to optical coherencetomography. Ophthalmology. 2015;122(6):1272-1274. https://doi.org/10.1016/j.ophtha.2014.12.035
Schaal KB, Munk MR, Wyssmueller I, Berger LE, Zinkernagel MS, Wolf S. Vascular abnormalities in diabetic retinopathy assessed with swept-source optical coherence tomography angiography widefield imaging. Retina. 2019; 39(1):79-87. https://doi.org/10.1097/IAE.0000000000001938
Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, Aiello LM, Sun JK, Aiello LP. Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography. Ophthalmology. 2015;122(12):2465-2472. https://doi.org/10.1016/j.ophtha.2015.07.034
Ishibazawa A, Nagaoka T, Yokota H, Takahashi A, Omae T, Song YS, Takahashi T, Yoshida A. Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography. Investigative Ophthalmology and Visual Science. 2016;57(14): 6247-6255. https://doi.org/10.1167/iovs.16-20210
You QS, Guo Y, Wang J, Wei X, Camino A, Zang P, Flaxel CJ, Bailey ST, Huang D, Jia Y, Hwang TS. Detection of clinically unsuspected retinal neovascularizationwith wide-field optical coherence tomography angiography. Retina. 2020;40(5):891-897. https://doi.org/10.1097/IAE.0000000000002487
Couturier A, Rey PA, Erginay A, Lavia C, Bonnin S, Dupas B, Gaudric A, Tadayoni R. Widefield OCT-Angiography and Fluorescein Angiography Assessments of Nonperfusion in Diabetic Retinopathy and Edema Treated with Anti-Vascular Endothelial Growth Factor. Ophthalmology. 2019;126(12): 1685-1694. https://doi.org/10.1016/j.ophtha.2019.06.022