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(tǒng)正常運(yùn)轉(zhuǎn)，確保全市森林防火指揮系統(tǒng)暢通、高效，市森林防火指揮部辦公室于11月1日對(duì)森林防火通訊指揮系統(tǒng)進(jìn)行調(diào)試，與各區(qū)縣及市直林場(chǎng)逐一進(jìn)行信號(hào)測(cè)試，反復(fù)查測(cè)通信盲區(qū)，重點(diǎn)調(diào)試了火情監(jiān)測(cè)、無線通訊等項(xiàng)目，強(qiáng)化各單位之間的連通共享，為實(shí)現(xiàn)“縱向貫通、橫向互連、實(shí)時(shí)感知、精確指揮”的一體化指揮體系夯實(shí)基礎(chǔ)。調(diào)試結(jié)束后，市森林公安局局長(zhǎng)王尊慶對(duì)調(diào)試情況進(jìn)行了講評(píng)，對(duì)做好下一步防火值班、督導(dǎo)檢查、宣傳教育、培訓(xùn)演練等工作進(jìn)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(shù)據(jù)的制作很長(zhǎng)一段時(shí)間都采用先通過GIS軟件制作地形數(shù)據(jù)，再通過制圖軟件導(dǎo)入地形數(shù)據(jù)用以制作制圖數(shù)據(jù)這一模式。這種模式減少了格式轉(zhuǎn)換次數(shù)，制圖數(shù)據(jù)修改時(shí)庫(kù)體數(shù)據(jù)不需要返回到原始庫(kù)體修改。由于制圖軟件可根據(jù)制圖規(guī)則模板快速生產(chǎn)制圖數(shù)據(jù)，因此制圖數(shù)據(jù)也隨著建庫(kù)數(shù)據(jù)而自動(dòng)更新，但建庫(kù)與出圖仍分開進(jìn)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

“云南少數(shù)民族傳統(tǒng)體育發(fā)展成就展”將在臨滄開展 云南省第十一屆少數(shù)民族傳統(tǒng)體育運(yùn)動(dòng)會(huì)將于12月4日至13日在臨滄舉行，期間，云南民族博物館將推出特展——“云南少數(shù)民族傳統(tǒng)體育發(fā)展成就展”，該展覽主要展示云南少數(shù)民族傳統(tǒng)體育的發(fā)展脈絡(luò)和云南在少數(shù)民族傳統(tǒng)體育事業(yè)方面的工作成就，使觀眾深切感受到少數(shù)民族傳統(tǒng)體育項(xiàng)目的魅力。

表2數(shù)據(jù)顯示,國(guó)內(nèi)女性主義翻譯研究的主要被引文獻(xiàn)多集中于該理論的引介與闡發(fā)初期,此間發(fā)刊的論文篇數(shù)不多,但被引率極高,影響極大。在被引前十的文獻(xiàn)中,有9篇屬于理論分析文章,被引合計(jì)2 077頻次,篇均被引230.78次,幾乎構(gòu)成了國(guó)內(nèi)女性主義翻譯研究的理論基石,奠定了作者自身在該研究領(lǐng)域的理論話語(yǔ)地位。比如,被引頻次最多的一篇是蔣驍華的《女性主義對(duì)翻譯理論的影響》[3],364次被引中有158條期刊論文引證,說明該文獻(xiàn)在同類研究中具有重要的理論基礎(chǔ)性、影響力和導(dǎo)向性。

A similar finding was observed in RNFL. The RNFL thickness did not differ significantly in mild-moderate NPDR

no-DR and no-DR

control groups (

＞0.05). However, the RNFL thickness in the mild-moderate NPDR group was significantly lower than that in the control group in the ST quadrants(

=0.030; Table 2 and Figure 4).

首先將本文方法所需數(shù)據(jù)量與文獻(xiàn)[5]中基于矩陣分析的方法、文獻(xiàn)[10]中基于GFFT的方法和文獻(xiàn)[11]中基于Gr?bner基改進(jìn)的GFFT方法進(jìn)行對(duì)比，m取值為3～8，仍然選取與圖4中相同的6種RS碼進(jìn)行研究，且每種RS碼對(duì)應(yīng)誤比特率分別為0.02、0.01、0.005、0.002、0.001和0.0004.本文方法在各種條件下所需數(shù)據(jù)量可由式(32)獲得；對(duì)于文獻(xiàn)[5]中方法，其分析矩陣必須滿足行數(shù)大于列數(shù)，因此所需數(shù)據(jù)量至少為m2n2；基于GFFT的方法至少需要50組完整碼字，相應(yīng)的數(shù)據(jù)量為50mn.最終，得到對(duì)比結(jié)果如表4所示.可以看出，相同條件下本文方法所需數(shù)據(jù)量更小.

Furthermore, we estimated the changes in peripapillary CVD after removing large blood vessels. The sectored analyses of each CVD in the ONH grid are shown in Table 2 and Figure 3.In the 2-4 mm circle, the mean CVD did not differ significantly among the control, no-DR, and mild-moderate NPDR groups(

=0.117). In the eight regions of the 2-4 mm circle, no significant differences were detected in the ST quadrants(

=0.018). In addition, the CVD of the mild-moderate NPDR group decreased significantly compared to the control group(

＜0.05).

著名哲學(xué)家黃克劍先生提出教育的終極目標(biāo)——生命化教育：人的道德的自我完善，心靈的自我督責(zé)，人格的自我提升，境界的自我超越。大家知道，孩子的認(rèn)識(shí)是立體的、全面的，但是在傳統(tǒng)課堂中，學(xué)科是孤立、自成體系的?；诖耍谥袑W(xué)語(yǔ)文教學(xué)中，抓住課堂主陣地，利用網(wǎng)絡(luò)信息技術(shù)，充分利用校內(nèi)外資源，探索與實(shí)踐“一課雙師”語(yǔ)文教學(xué)模式，開闊學(xué)生視野、擴(kuò)散學(xué)生思維、發(fā)展學(xué)生能力，促進(jìn)教育資源的均衡發(fā)展，提高中學(xué)語(yǔ)文教學(xué)質(zhì)量，實(shí)現(xiàn)生命化教育。

DISCUSSION

This study was based on the Garway-Heath map to explore the changes in peripapillary VD, CVD, and RNFL thickness in the early stage of DR. Consequently, we found that functional and structural impairments had already begun in the early stages of DR. Correlation research analysis demonstrated a correlation between neural and vascular structures.

Garway-Heath

produced a clinically useful map that related the visual field test points to ONH regions. The map in this analysis was asymmetric, representing the location of the ONH above the horizontal meridian. Paracentral and arcuate regions of the visual field are defined by sectors in proximity to the poles of the ONH in the map. Subsequently, a peripapillary RNFL thickness map was used in the study by Tan

.to derive nerve fiber trajectories in the peripapillary region,and an over nerve fiber tracking algorithm was presented. The study devised a system to construct the NFF map and quantify it by track and sector in any test subject. On peripapillary OCT scans, the NFF tracks and sectors matched the typical nerve fiber trajectory over a wide area, potentially allowing efficient detection of focal damage and precise quantification of regional loss

. Therefore, in the current study, the measurement based on the ONH topographic map accurately detected the neural and vascular structural changes in early DR.

4)采用云計(jì)算方式進(jìn)行數(shù)據(jù)處理。隨著導(dǎo)航應(yīng)用的進(jìn)一步深入，數(shù)據(jù)量越來越龐大，數(shù)據(jù)關(guān)系更加復(fù)雜，應(yīng)采用云計(jì)算的方式快速處理和提供信息。

These results were in line with the above theoretical speculation,

, the VD in the mild-moderate DR was significantly lower than in the normal control group, thereby suggesting that clinical examination should focus on whether the VD of DM patients can detect meaningful ischemic manifestations at the early stage.

When the large retinal vessels around the disc were removed,we found that in the ST area, the peripapillary CVD and RNFL thickness in the mild-moderate NPDR group was lower than that in the normal group, indicating a positive correlation.From an anatomical point of view, the macular area and the surrounding retina converge toward the optic disc in arcs on the upper and lower sides of the macular optic disc axis, and hence, the optic nerve and blood vessels in the supratemporal and infratemporal positions of the optic disc are denser than those in other parts

. After removing the large blood vessels, the changes in blood flow around the supply disc were observed accurately, and significant changes were detected in the blood vessels and nerves around the optic disc of DR,which were investigated further.

The superficial capillary layer at the optic disc, especially the radial peripapillary capillaries (RPC) blood vessels, run parallel to the direction of the nerve axons. The blood vessels are straight and lacking a large amount of intervascular anastomosis; also, the tolerance to hypoxia and injury was poor. However, the dense nerves in the superior and IT quadrants lead to high oxygen demand, thereby effectuating the cause of structural changes in the optic nerve that is susceptible to hyperglycemia

.

The current results do not show how the progression of DR(DME and PDR) affects the peripapillary VD. Since macular edema distorts OCTA segmentation (which is critical for accurate measurements) and falsely increases peripapillary RNFL thickness, these factors are pre-specified as exclusion criteria

. In addition, panretinal photocoagulation and focal laser therapy are linked to declining RNFL thickness independently

. Therefore, if we recruited such patients, we would introduce uncontrollable confusion.

Nevertheless, the present study has a few limitations. First, this was a cross-sectional observational study. Thus, the association between improvements in peripapillary VD and development in the early-stage DR could be explained by longitudinal analysis. Second, the sample size was limited and insignificant to draw reasonable conclusions. Third, with the built-in program of the computer, we analyzed the microvasculature using a 4×4 mm

scan pattern. The RPC that supplies an RNFL blood flow extends to 8 mm from the optical disk temporal tip.Thus, a wide area for scanning the modifications of the VD could be useful

.

In conclusion,

the measurement based on the ONH topographic map may be more accurate than the traditional four-classification method. The peripapillary VD, CVD, and RNFL decreased in early DR, the changes in RNFL thickness were correlated with the CVD and/or VD in some regions. The current study provides mechanistic insight into DR, demonstrating functional and structural impairments around the optic disc in early DR and a correlation between these conditions. Furthermore, to validate the usefulness of peripapillary outcomes as biomarkers of early DR, longitudinal studies are warranted.

Supported by College-level Project Fund of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (No.ynlc201909).

None;

None;

None;

None;

None.

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