Quantitative retinal capillary measures using optical coherence tomography angiography (OCT-A) in diabetic eyes

Ph.D.Diabetes mellitus (DM), one of the world's most common chronic diseases, is a central healthcare and social problem across the globe. Diabetic retinopathy (DR) is its most common specific microvascular complication, afflicting a third of patients with DM. DR is characterized by the presence of typical microvascular changes at the posterior pole of the retina, such as microaneurysm, exudate, and growth of new blood vessels. Advanced DR severely impaired patient's visual function, and consume large amount of social health-care resource. Thus, an early identification of DR, particular before vision-threatening stage, is a key starting point for patients as regards receiving surveillance and preventative treatment.Optical coherence tomography-angiography (OCT-A), has been developed to provide depth-resolved visualization of the retinal microvasculature without intravenous dye injection. Studies have quantitatively measured the size of foveal vascular zone (FAZ) and vessel density (VD) and correlated with severity of DR, indicating quantitative OCT-A metrics have great potential serve as biomarkers of DR. However, there is a paucity of clinical data examining if OCT-A metrics are affected by ocular, systemic, DM-associated and demographic factors. Furthermore, there is lack of data to correlate with OCT-A metrics and visual function in diabetic eyes. Finally, the characteristics of progressive changes of microvasculature are unclear.This thesis aimed to 1) quantify the retinal microvasculature from OCT-A images using a customized automated image analysis program; 2) examine the influence of a wide range of ocular, systemic, DM-associated and demographic factors on different OCT-A metrics; and finally 3) characterize the rate of microvascular changes in diabetic eyes with different DR severity levels over time.In the first study, we developed a customized automated image analysis program for quantifying OCT-A images for superficial capillary plexus (SCP) and deep capillary plexus (DCP), obtained with a commercial swept-source OCT (Triton DRI-OCT, Topcon, Inc, Tokyo, Japan). A spectrum of quantitative OCT-A metrics were measured on SCP image (foveal avascular zone, [FAZ] area, FAZ circularity, vessel density [VD], fractal dimension [FD], and intercapillary area [ICA]) and DCP image (FAZ area, VD and FD). Good agreement between FA and OCT-A, and good reliability of OCT-A measurements were found.In the second study, we investigated the influence of systemic and DM-associated (e.g. HbA1c, fasting glucose, blood pressure, body mass index [BMI], history of stroke), demographic factors (e.g. age), and ocular factors (e.g. DR severity, axial length [AL], visual acuity [VA], macular thickness, subfoveal choroidal thickness) on quantitative OCT-A metrics in both SCP and DCP in a cohort of patients with DM. We found that DR severity was associated with increased FAZ area, decreased FAZ circularity, and lower FD both in SCP and DCP. VA was found to be associated with ICA and FAZ circularity in SCP.In the final study, we characterize the rate of microvascular changes measured from OCT-A in different DR severity over time. We included eyes without progression of DR with at least three follow-up visits over two years from the cohort. FAZ area, FAZ circularity, VD and FD from SCP image were measured using our customized analysis program. We found FD in eyes among those eyes without DR progression was decreased over time after adjusting for duration of DM, HbA1c level and LogMAR visual acuity.In summary, multiple ocular (e.g. DR severity, axial length and thinner central subfield macular thickness, and macular ganglion-cell inner plexiform layer) and DM-associated (e.g. fasting glucose) factors affect microvasculature in diabetic eyes, suggesting that these factors should be considered for meaningful interpretations of changes in the retinal microvasculature identified in OCT-A. In regard to visual function, decreased FAZ circularity and increased ICA were found to be associated with VA, indicating that are potential marker to quantify retinal microvascular abnormalities relating to vision among individuals with DM. Furthermore, significant decreases of FD in eyes with all levels of severity were found, indicating that progressive changes of retinal microvascular disorganization in all states of DR may prior than clinical defined progression, progressive changes of microvasculature measured by OCT-A may provide a new way to stage DR objectively and quantitatively.糖尿病是最常見的慢性疾病之一，是世界范围内醫療保健和社會問題的重要源头。糖尿病視網膜病變（糖網）是糖尿病最常見的特異性微血管並發症，見於三分之一的糖尿病患者。其特徵為出现于視網膜後部的微血管病變，例如微血管瘤、滲出物和新生血管。晚期的糖網嚴重損害患者的視覺功能，損耗大量的社會保健資源。因此，糖網的早期預測、檢測和治療對於預防視力喪失至關重要。研究顯示，眼部糖尿病微血管變化，可以在顯著的視力喪失之前通過各種影像技術檢測出來。因此，研究糖尿病眼中的微血管變化對於本病的治療至關重要，即使是那些尚未出現視網膜病的糖尿病眼也是如此。光學相干斷層掃描血管造影（OCT-A），已被開發用於提供深層視網膜微血管的成像，而無需靜脈注射熒光染料。其原理基於給定橫截面上的連續掃描，描繪紅細胞隨時間的運動（運動對比度）。一些研究測量了中央凹無血管區和血管密度的大小，並發現與糖網的嚴重程度相關，表明定量OCT-A指標具有很大的潛力作為糖網發生發展的觀測標指標。然而，對於OCT-A指標是否受眼、全身性和人口統計學因素的影響，目前仍缺乏臨床數據。此外，OCT-A指標和視覺功能的相關性也缺乏臨床研究證明。最後，糖尿病眼微血管的進行性變化的特徵尚不清楚。本論文旨在：1）用定制的软件，量化測量OCT血管造影中視網膜微血管的形態。2）研究各種眼、全身和人口因素對不同OCT-A指標的影響，並研究OCT-A指標與視覺功能之間的相關性。3）最後，研究不同嚴重程度的糖尿病眼的微血管的進行性變化特征。在第一項研究中，我們基於Matlab開發了一個自動圖像分析程序，用於量化表層和深層的毛細血管叢的影像。此影像使用拓普康扫频OCT采集。我們測量了表層血管叢的中央無血管區（FAZ）面積、FAZ圓形度、血管密度、血管間面積以及分形維數，深層血管叢的FAZ面積，血管密度及分形維數。FA 和OCT-A之間的一致性，OCT-A的可重複性和可靠性均佳。在第二項研究中，我們調查了全身（例如糖化血紅蛋白、空腹血糖、血壓、體重指數、卒中史）、人口統計學因素（如年齡、糖尿病病程）和眼部因素（如糖網嚴重程度、軸長、視力、黃斑厚度、中心凹下脈絡膜厚度）對OCT-A 測量的影響。我們在千層及深層毛細血管叢均發現，糖網嚴重程度與FAZ面積增加，FAZ圓形度降低和FD降低有關。我們進一步發現視力與毛細血管內區域和FAZ圓形度相關。在最後一項研究中，我們使用OCT-A來測量不同嚴重程度的糖尿病眼中，微血管形態的進行性變化。而在統計分析中納入了沒有疾病進展的眼睛。我們使用前述分析程序測量OCT-A圖像的FAZ面積，FAZ圓度，血管密度和分形維數。我們在所有嚴重程度分組的眼睛中均發現，分形維數會顯著地隨時間變化。本論文所述研究發現，多種眼、全身以及人口因素對糖尿病眼中的微血管系統有顯著影響，提示在未來的分析中這些因素應該被充分考慮。另外，FAZ圓形度性和血管間面積與視覺功能相關。此外，所有嚴重程度的患眼中的分型維數均顯著地進行性降低，提示微血管改變的發生可能早於臨床定義的疾病進展，表明OCT-A可能在糖網的監測和治療觀察中發揮重要的作用。 Tang, Fangyao.Thesis Ph.D. Chinese University of Hong Kong 2019.Includes bibliographical references (leaves 102-167).Abstracts also in Chinese.Title from PDF title page (viewed on 29, December, 2020)