Peripapillary vessel density and retinal nerve fiber layer thickness changes in early diabetes retinopathy

INTRODUCTION

Diabetic retinopathy (DR) is a potentially fatal complication with diabetes mellitus (DM) and the primary cause of blindness worldwide

. Previous studies have shown that early diagnosis of type 2 diabetes mellitus (T2DM) and screening for retinopathy is associated with a lower incidence and severity of retinopathy

. However, when retinal lesions become clinically evident, it is impossible to reverse the injury, and the likelihood of DR progression increases

. The present DR management is focused on the late stages, where retinal systems and vision acuity have also been compromised

. Thus, understanding the pathogenesis of neurovascular impairments could lead to novel and efficient preventive strategies. As a result, diagnosis and tracking slight neurovascular changes that are in the early stages of DR are essential.

The tomography/OCTA volumes of optical coherence were obtained covering a 6×6 mm

retinal region and were based on the optic disk. Every volume of 6×6 mm

consisted of 512A scans for the B-scan (24 mm space between adjacent A-shapes) and 512B-scan spaces for scanning by voltage(24 mm spaces between adjacent B-shapes). To detect the motion contrast for OCTA, the optical microangiography(OMAGC) algorithm was used. Both OCTA photography was carried out by professional ophthalmic photographers, who, if possible, repeated the image acquisition to ensure photographs with intense OCT signal penetration and minimal motion artifacts. Scans with an signal-to-noise ratio (SNR) ＞8 decibels(dB) were considered good quality. The quality ratings for the scans were expressed as SNR in dB over a spectrum of 1 (poor quality) to 10 (excellent quality). Only photographs with a score of ≥8 were considered.

Of these neuronal modifications, the thinning of the retinal nerve fiber layer (RNFL) is an essential feature of the inner retinal layers and is speculated as to the earliest improvement in DR neurodegenerative lesions. RNFL loss leads to defects in various ophthalmological tests, including electroretinograms,contrast sensitivity, dark adaptation, and microperimetry.Optical coherence tomography angiography (OCT-A) is a noninvasive and reproducible imaging procedure that was recently used to study macular and peripapillary vascular structures with unlikely details and clarification

. Early variations in the peripapillary vessel anatomy and vessel density (VD)of the radial peripapillary plexus have been linked to RNFL thinning in patients with DM but without DR

.

The new technique, swept-source OCT (SS-OCT), improves the imaging depth and scanning speed that facilitates anterior segment assessment with corneal graft inspection,

, it allows a precise qualitative and quantitative assessment of vascular improvements in the fundus and presents various application prospects. Additionally, Garway-Heath

constructed a clinical map that relates visual field test points to the regions of the optic nerve head (ONH). The map is valuable in the clinical diagnosis of glaucoma patients and suspects and the research of the connection between retinal light sensitivity and ONH structure. Therefore, we used swept-source optical coherence tomography angiography (SS-OCTA) technology and Garway-Heath map-based ONH measurement software to explore the peripapillary VD, capillary vessel density (CVD), and RNFL thickness changes in early DR.

SUBJECTS AND METHODS

The study was approved by the Shanghai Sixth People’s Hospital Institutional Review Board. All the protocols followed the principles of Helsinki Declaration,and informed consent was obtained prior to participation in the study. The study was registered in the Chinese clinical trial registry (http://www.chictr.org.cn/, Registration number:ChiCTR1900028607). Between October 2020 and March 2021, diabetic patients were recruited from the Shanghai Diabetes Center at the Shanghai Sixth People’s Hospital Affiliated University. Healthy adults were recruited from the same hospital at the same time.

Pearson’s correlation analysis was used to calculate the correlation between RNFL thickness and peripapillary VD and CVD (Table 3 and Figure 5). Furthermore, in diabetic patients,the average RNFL thickness and the mean peripapillary VD and CVD were positively correlated but not significantly(

=0.141,

=0.240;

=0.175,

=0.145). In the correlation analysis of each region, the RNFL thickness in the NS region was positively correlated with peripapillary VD and CVD(

=0.233,

=0.05;

=0.288,

=0.015; Table 3), while in the TI region, the RNFL thickness was positively correlated with peripapillary CVD (

=0.237,

=0.047; Table 3).

All participants underwent ophthalmological analysis, including health history, visual acuity evaluation, biomicroscopy of the anterior segment using a slit lamp, ophthalmoscopy of the posterior segment, wide-field color fundus photography using Optos California (Optos plc, Dunfermline, UK), and Spectralis SD-OCT scans (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). Based on the widefield color fundus photography and the International Clinical Diabetic Retinopathy Disease Severity Scale

, two senior graders (Long D and Cai X) graded each subject’s DR as no DR, mild to moderate, or severe non-proliferative diabetic retinopathy (NPDR), or proliferative diabetic retinopathy(PDR). Each subject had one eye chosen as the research object,and if both eyes matched the eligibility criteria, the eye with higher visual acuity or a lower refractive error was chosen. All the participants were at least 18-year-old, had a logMAR visual acuity of at least 0.5 log units, and a refractive error of no more than -3.00 diopters (D) or +3 D-equivalent spheres. The exclusion criteria were as follows: 1) unable to give informed consent or consent to a full examination; 2) glaucoma, cup/disc(C/D)＞0.4, or intraocular pressure ＞21 mm Hg; 3) pregnant or nursing; 4) active eye infections (such as blepharitis, keratitis,scleritis, conjunctivitis,

); 5) history of ocular disorders that affecting the neural and vascular structures of the eye (ocular trauma, amblyopia, retinal vein occlusion, retinal detachment,macular disease, multiple sclerosis, Alzheimer disease,hypertensive retinopathy,

), and history of ocular procedures other than cataract surgery (laser, intravitreal injections, and vitreoretinal surgery); 6) degree of DR classification greater than moderate NPDR; 7) presence of diabetic macular edema(DME).

為保障淄博市森林防火指揮系統正常運轉，確保全市森林防火指揮系統暢通、高效，市森林防火指揮部辦公室于11月1日對森林防火通訊指揮系統進行調試，與各區縣及市直林場逐一進行信號測試，反復查測通信盲區，重點調試了火情監測、無線通訊等項目，強化各單位之間的連通共享，為實現“縱向貫通、橫向互連、實時感知、精確指揮”的一體化指揮體系夯實基礎。調試結束后，市森林公安局局長王尊慶對調試情況進行了講評，對做好下一步防火值班、督導檢查、宣傳教育、培訓演練等工作進行安排部署，并提出了具體要求。

The SSOCT/OCTA device was designed for the central wavelength laser (VG200S; SVision Imager, Henan, China) of 1050 nm with a scan rate of 200 000 A-scans/s. The device was equipped with an eye monitoring tool based on an integrated confocal laser ophthalmoscope for the removal of objects of eye movement. The axial and lateral resolutions were 5 and 13 μm,respectively. The depth of the scan was 3 mm.

Recent studies on DR pathogenesis found that neuronal dysfunction and neurodegeneration are closely associated with microvascular dysfunction and that neurovascular unit degeneration could be regarded as an essential component of DR pathology

. In addition, evidence from diabetic donors’and diabetic animal models’ retinas demonstrated that retinal neuronal cell degeneration or apoptosis develops early in diabetes

.

In order to analyze the VD quantitatively in different regions, non-parametric Kruskal-Wallis with Bonferroni’s post hoc test was applied. The statistical results are displayed in Table 2 and Figure 2. In the central ring, the mean VD of the control, no-DR, and mild-moderate NPDR groups was 47.54±8.23, 46.01±9.17, 48.93±9.84, with no significant differences between the groups (

=0.466). In the 2-4 mm circle, significant differences were detected among the three groups (

=0.006). VD in the no-DR and mild-moderate NPDR groups was significantly lower than that in the normal group, but no significant difference was observed between the no-DR and mild-moderate NPDR groups. In the eight regions of 2-4-mm circle, differences were observed in the superior,inferior, NS, and IN quadrants (

=0.007, 0.026, 0.007, and 0.039). Among these, the VD of the mild-moderate NPDR group was lower than that of the control group (

＜0.05);however, the difference between the mild-moderate NPDR

no-DR and no-DR

control groups were not significant(

＞0.05).

The ONH program installed in the machine assessed the data automatically. The ONH was a 4 mm diameter ring. The middle was a 2 mm circle, and the 2-4 mm circle was separated using nerve fiber flux (NFF) cartographies in eight areas (Garway-Heath

scheme). The eight regions include nasal superior (NS), nasal inferior (NI), inferior nasal (IN), inferior temporal (IT), temporal inferior (TI),temporal superior (TS), superior temporal (ST), and superior nasal (SN). The built-in program was utilized to assess each pattern of the average retinal VD of the inner retina (from ILM-5 mm to IPL/INL+(INL/OPL-IPL/INL)/2) was measured(version1.31.6; VG200D, SVision Imaging Ltd, Henan Province, China). The density of peripapillary CVD was then calculated using the procedure of removing massive blood vessels. Simultaneously, the corresponding RNFL thickness was also calculated (Figure 1).

All data analyses were carried out using the SPSS version 19.0 program (IBM Co., Chicago, IL, USA).The data are presented as the mean±standard deviation (SD)for continuous and categorical variables. One-way variation analysis (ANOVA) was conducted to compare the continuous variables with Bonferroni post hoc tests, independent

-test or Mann-Whitney

test.

test was used to compare the proportions between groups. Pearson’s correlation and multivariable linear regression analysis investigated the correlation between retinal neurodegeneration and intrinsic risk factors. The two-tailed

-values were recorded. To evaluate statistical significance, a 0.05-type I error level was used.

Diabetic microangiopathy is also known as retinal ischemia.One of the lesions in early DR, retinal capillary damage, is not fully formed into a local, visible non-perfusion region but manifests as decreased retinal blood flow density (RVD). It also found that the RVD of eyes with severe NPDR and PDR were significantly lower than those with mild NPDR and the normal control group, and the RVD of the eyes with DME was more significantly reduced

. In the eyes of NPDR without DME, the RVD decreased significantly with the severity of the disease

. Decreased VD in patients with non-DR and mild DR indicated a loss of papillary or lack of perfusion in the early stages of the disease

. In diabetic patients without DR, the superficial and deep decreased compared to healthy participants

. Li

analyzed the VD of 97 DM patients and 48 controls and found that VD was decreased in the diabetic patient group. According to the anatomy, the capillaries in the inner layer of the retina are continuously branched from the central retinal artery that runs from the center of the optic disc. The retinal capillaries are distributed in layers, with the thickest next to the optic disc. Thus, it is speculated that when the retinal ischemic disease shows decreased RVD in the macular area at the end of the blood supply, the peripapillary blood supply should also decrease.The present study demonstrated that the peripapillary VD in diabetic patients decreased, and after removing the influencing factors of large blood vessels, CVD was also decreased.

RESULTS

Based on the inclusion/exclusion criteria, the study included 104 participants (32 controls on health and 72 diabetes patients; 45 males and 59 females),of which 32 comprised the control group, 34 were T2DM without DR (no-DR group), and 38 were mild-moderate DR.The sample participants’ demographic characteristics are summarized in Table 1.

The mean age of the subjects in the three groups was 57.46±9.39y, 63.59±9.69y, and 58.15±10.38y, respectively;the difference was significant among the groups (

=0.112;Table 1). No statistically significant differences were identified in patients’ sex (

=0.953), laterality (

=0.734), visual acuity(

=0.421), and mean spherical equivalent (

=0.685) among three groups. Among the diabetic patients, the comparison[duration of diabetes, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and glycated albumin] showed that only FBG was significantly different between the mild-moderate NPDR and no-DR groups (

=-2.004,

=0.049).

The repeatability test was carried out for 12 patients with a mean (SD) age of 59.46±6.24 (range: 50-74)y.Among these participants, six had diabetes. The intraclass correlation coefficient (ICC) scores were 0.89 for VD, 0.91 for CVD, and 0.92 for RNFL.

湖南省制圖數據的制作很長一段時間都采用先通過GIS軟件制作地形數據，再通過制圖軟件導入地形數據用以制作制圖數據這一模式。這種模式減少了格式轉換次數，制圖數據修改時庫體數據不需要返回到原始庫體修改。由于制圖軟件可根據制圖規則模板快速生產制圖數據，因此制圖數據也隨著建庫數據而自動更新，但建庫與出圖仍分開進行，這種模式也稱為半一體化模式。

F2=3.90×105+3.91×105+1.95×105+1.95×105+2.58×105+2.58×105=16.87×105N

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