Deep Learning Models for the Screening of Cognitive Impairment Using Multimodal Fundus Images.

OBJECTIVE: We aimed to develop a deep learning system capable of identifying subjects with cognitive impairment quickly and easily based on multimodal ocular images. DESIGN: Cross sectional study. SUBJECTS: Participants of Beijing Eye Study 2011 and patients attending Beijing Tongren Eye Center and Beijing Tongren Hospital Physical Examination Center. METHODS: We trained and validated a deep learning algorithm to assess cognitive impairment using retrospectively collected data from the Beijing Eye Study 2011. Cognitive impairment was defined as a Mini-Mental State Examination score < 24. Based on fundus photographs and OCT images, we developed 5 models based on the following sets of images: macula-centered fundus photographs, optic disc-centered fundus photographs, fundus photographs of both fields, OCT images, and fundus photographs of both fields with OCT (multimodal). The performance of the models was evaluated and compared in an external validation data set, which was collected from patients attending Beijing Tongren Eye Center and Beijing Tongren Hospital Physical Examination Center. MAIN OUTCOME MEASURES: Area under the curve (AUC). RESULTS: A total of 9424 retinal photographs and 4712 OCT images were used to develop the model. The external validation sets from each center included 1180 fundus photographs and 590 OCT images. Model comparison revealed that the multimodal performed best, achieving an AUC of 0.820 in the internal validation set, 0.786 in external validation set 1, and 0.784 in external validation set 2. We evaluated the performance of the multi-model in different sexes and different age groups; there were no significant differences. The heatmap analysis showed that signals around the optic disc in fundus photographs and the retina and choroid around the macular and optic disc regions in OCT images were used by the multimodal to identify participants with cognitive impairment. CONCLUSIONS: Fundus photographs and OCT can provide valuable information on cognitive function. Multimodal models provide richer information compared with single-mode models. Deep learning algorithms based on multimodal retinal images may be capable of screening cognitive impairment. This technique has potential value for broader implementation in community-based screening or clinic settings. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Relationships between quantitative retinal microvascular characteristics and cognitive function based on automated artificial intelligence measurements.

Introduction: The purpose of this study is to assess the relationship between retinal vascular characteristics and cognitive function using artificial intelligence techniques to obtain fully automated quantitative measurements of retinal vascular morphological parameters. Methods: A deep learning-based semantic segmentation network ResNet101-UNet was used to construct a vascular segmentation model for fully automated quantitative measurement of retinal vascular parameters on fundus photographs. Retinal photographs centered on the optic disc of 3107 participants (aged 50-93 years) from the Beijing Eye Study 2011, a population-based cross-sectional study, were analyzed. The main parameters included the retinal vascular branching angle, vascular fractal dimension, vascular diameter, vascular tortuosity, and vascular density. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Results: The results showed that the mean MMSE score was 26.34 ± 3.64 (median: 27; range: 2-30). Among the participants, 414 (13.3%) were classified as having cognitive impairment (MMSE score < 24), 296 (9.5%) were classified as mild cognitive impairment (MMSE: 19-23), 98 (3.2%) were classified as moderate cognitive impairment (MMSE: 10-18), and 20 (0.6%) were classified as severe cognitive impairment (MMSE < 10). Compared with the normal cognitive function group, the retinal venular average diameter was significantly larger (p = 0.013), and the retinal vascular fractal dimension and vascular density were significantly smaller (both p < 0.001) in the mild cognitive impairment group. The retinal arteriole-to-venular ratio (p = 0.003) and vascular fractal dimension (p = 0.033) were significantly decreased in the severe cognitive impairment group compared to the mild cognitive impairment group. In the multivariate analysis, better cognition (i.e., higher MMSE score) was significantly associated with higher retinal vascular fractal dimension (b = 0.134, p = 0.043) and higher retinal vascular density (b = 0.152, p = 0.023) after adjustment for age, best corrected visual acuity (BCVA) (logMAR) and education level. Discussion: In conclusion, our findings derived from an artificial intelligence-based fully automated retinal vascular parameter measurement method showed that several retinal vascular morphological parameters were correlated with cognitive impairment. The decrease in retinal vascular fractal dimension and decreased vascular density may serve as candidate biomarkers for early identification of cognitive impairment. The observed reduction in the retinal arteriole-to-venular ratio occurs in the late stages of cognitive impairment.

Analysis of risk and protective factors associated with retinal nerve fiber layer defect in a Chinese adult population.

AIM: To investigate the risk and protective factors associated with the retinal nerve fiber layer defect (RNFLD) in a Chinese adult population. METHODS: This study was a cross-sectional population-based investigation including employees and retirees of a coal mining company in Kailuan City, Hebei Province. All the study participants underwent a comprehensive systemic and ophthalmic examination. RNFLD was diagnosed on fundus photographs. Binary logistic regression was used to investigate the risk and protective factors associated with the RNFLD. RESULTS: The community-based study included 14 440 participants. There were 10 473 participants in our study, including 7120 males (68.0%) and 3353 females (32.0%). The age range was 45-108y, averaging 59.56±8.66y. Totally 568 participants had RNFLD and the prevalence rate was 5.42%. A higher prevalence of RNFLD was associated with older age [P<0.001, odds ratio (OR): 1.032; 95% confidence interval (CI): 1.018-1.046], longer axial length (P=0.010, OR: 1.190; 95%CI: 1.042-1.359), hypertension (P=0.007, OR: 0.639; 95%CI: 0.460-0.887), and diabetes mellitus (P=0.019, OR: 0.684; 95%CI: 0.499-0.939). The protective factors of RNFLD were visual acuity (P=0.038, OR: 0.617; 95%CI: 0.391-0.975), and central anterior chamber depth (P=0.046, OR: 0.595; 95%CI: 0.358-0.990). CONCLUSION: In our cross-sectional community-based study, with an age range of 45-108y, RNFLD is associated with older age, longer axial length, hypertension, and diabetes mellitus. The protective factors of RNFLD are visual acuity and central anterior chamber depth. These can help to predict and evaluate RNFLD related diseases and identify high-risk populations early.

The Influence of Diabetes, Hypertension, and Hyperlipidemia on the Onset of Age-Related Macular Degeneration in North China: The Kailuan Eye Study.

Objective: To analyze the prevalence of dry and wet age-related macular degeneration (AMD) in patients with diabetes, hypertension and hyperlipidemia, and to analyze the risk factors for AMD. Methods: A population-based cross-sectional epidemiologic study was conducted involving 14,440 individuals. We assessed the prevalence of dry and wet AMD in diabetic and non-diabetic subjects and analyzed the risk factors for AMD. Results: The prevalence of wet AMD in diabetic and non-diabetic patients was 0.3% and 0.5%, respectively, and the prevalence of dry AMD was 17% and 16.4%, respectively. The prevalence of wet AMD in healthy, hypertensive, hyperlipidemic, and hypertensive/hyperlipidemic populations was 0.5%, 0.3%, 0.2%, and 0.7%, respectively. The prevalence of dry AMD in healthy, hypertensive, hyperlipidemic, and hypertensive/hyperlipidemic populations was 16.6%, 16.2%, 15.2%, and 17.2%, respectively. Age, sex, body mass index, and use of hypoglycemic drugs or lowering blood pressure drugs were corrected in the risk factor analysis of AMD. Diabetes, diabetes/hypertension, diabetes/hyperlipidemia, and diabetes/hypertension/hyperlipidemia were analyzed. None of the factors analyzed in the current study increased the risk for the onset of AMD. Conclusion: There was no significant difference in the prevalence of wet and dry AMD among diabetic and non-diabetic subjects. Similarly, there was no significant difference in the prevalence of wet and dry AMD among subjects with hypertension and hyperlipidemia. Diabetes co-existing with hypertension and hyperlipidemia were not shown to be risk factors for the onset of dry AMD.

Retinal nerve fiber layer thickness and retinal vascular caliber alterations in coal miners in northern China: a community-based observational study.

AIM: To evaluate retinal nerve fiber layer thickness and retinal vascular caliber alterations in coal mine workers. METHODS: The community-based observational cross-sectional study included 4004 participants of a sub-population of the Kailuan Study. All the study participants underwent structured interviews with a standardized questionnaire, fundus photography and spectral-domain optical coherence tomography (OCT) examinations performed by trained doctors. RESULTS: The retinal nerve fiber layer thickness was significantly higher (P=0.006) and the central macular thickness was lower in coal miners (n=659, 51.0±7.8y) as compared to the control (working above the ground; n=477, 51.8±7.5y; P=0.032). Additionally, the downhole workers showed a significantly thicker retinal artery (P=0.012) and vein diameters (P<0.001). In multivariable regression, a thicker retinal nerve fiber layer was associated with a higher cumulative silica dust exposure (P=0.005) after adjusting for younger age and larger spherical equivalent. In a reverse pattern, a higher cumulative silica dust exposure (P=0.004) was significantly associated with a thicker retinal nerve fiber layer after adjusting for age, high-density lipoproteins and uric acid. Wider retinal vein diameters were associated with higher cumulative silica dust exposure (P=0.036) after adjusting for younger age and larger spherical equivalent. CONCLUSION: The retinal vessels diameters and retinal nerve fiber layer thickness are significantly thicker in long term of coal mining. The results of our study indicate that underground working environment may lead to retinal vessel dilation and inflammation. Thus, ocular examination might be needed within coal miners in order to monitor the occupational eye health as well as the incidence and progression of eye diseases.

Retinal nerve fibre layer thickness in association with gamma zone width and disc-fovea distance.

PURPOSE: Previous studies have shown that the retinal nerve fibre layer (RNFL) thickness as surrogate of the optic nerve decreases with longer axial length. We explored which explanatory parameters might explain that association. METHODS: Participants of the population-based Beijing Eye Study 2011 without any retinal or optic nerve disease were selected based on a refractive error-based stratified randomization. RESULTS: The study included of 632 participants (age: 59.1 ± 7.3 years; axial length: 23.5 ± 1.2 mm; range: 20.88-28.68 mm). Thicker RNFL (mean: 101.0 ± 10.0 µm) was associated (multivariable analysis) with smaller parapapillary gamma zone (defined as Bruch's membrane-free parapapillary region) (standardized regression coefficient beta: -0.13; non-stadardized regression coefficient B: -0.008; 95% confidence interval (CI): -0.014, -0.003; p = 0.005) and shorter disc-fovea distance (beta: -0.15; B: -3.91; 95% CI: -6.60; -1.22; p = 0.004), after adjusting for age (beta: -0.22; B: -030; 95% CI: -0.41, -0.19; p < 0.001), gender (beta: 0.12; B: 2.37; 95% CI 0.77, 3.97; p = 0.004) and larger optic disc area (beta: 0.12; B: 0.12; 95% CI: 2.14; 95% CI: 0.54, 3.73; p = 0.009). RNFL thickness decreased by 8 µm (95% CI: 3, 14) for each mm increase in gamma zone width, and by 3.91 µm (95% CI: 1.22, 6.60) for each mm elongation of the disc-fovea distance. If disc-fovea distance and gamma zone width were replaced by axial length, the latter was correlated with RNFL thickness (beta: -0.37; B: -3.12; 95% CI: -3.88, -2.35; p < 0.001). Longer disc-fovea distance was directly associated with larger gamma zone (beta: 0.50; B: p < 0.001). CONCLUSIONS: The RNFL thickness decrease with longer axial length is associated with a longer optic disc-fovea distance and larger parapapillary gamma zone. Longer disc-fovea distance and larger gamma zone lead to an elongation and stretching of the retinal nerve fibres, potentially causing a thinning or loss of the nerve fibres. It may explain the occurrence of visual field defects in some non-glaucomatous highly myopic eyes without macular correlates of the perimetric defects.

Choroidal shift in myopic eyes in the 10-year follow-up Beijing eye study.

The aim of the study was to assess longitudinal changes in the spatial relationship of the choroidal vasculature to retinal vasculature in myopic eyes. In the population-based longitudinal Beijing Eye Study in 2001/2011, we examined all highly myopic eyes with assessable fundus photographs and a randomized group of non-highly myopic. Using fundus photographs, we qualitatively assessed changes in the location of major choroidal vessels in relationship to retinal vessels. The study consisted of 85 highly myopic eyes (58 participants;age:64.8 ± 9.4 years) and 85 randomly selected non-highly myopic eyes. A choroidal shift in relationship to the retinal vessels was detected more often in the highly myopic group than the non-highly myopic group (47/85 (55%) vs 6/85 (7%); P < 0.001). In the highly myopic group, the choroidal vessel shift occurring on the disc-fovea line in 39 (44%) eyes, was similar to, or smaller than, the enlargement in gamma zone width in 26 (67%) eyes and in 11 (28%) eyes respectively. The choroidal vessel shift was larger (P = 0.002) in eyes without choroidal vessels in gamma zone than in eyes with large choroidal vessels in gamma zone. In 14 (17%) eyes, a localized centrifugal choroidal shift was observed in association with an increase in the stage of myopic maculopathy. The results suggest that highly myopic eyes show a change in the position of large choroidal vessels in relationship to retinal vessels, in association with development or enlargement of gamma zone and an increase in the stage of myopic maculopathy.

RETINAL MICROVASCULAR CHANGES IN UVEAL MELANOMA FOLLOWING CONBERCEPT INJECTION AFTER PLAQUE RADIOTHERAPY AS DETECTED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To investigate macular microvascular characteristics imaged by optical coherence tomography angiography in patients with uveal melanoma following conbercept injections after plaque radiotherapy. METHODS: Prospective comparative analysis comprising 15 patients with uveal melanoma with conbercept injections and 30 patients without conbercept injections after plaque radiotherapy by optical coherence tomography angiography. The conbercept group received intravitreal conbercept injections at the time of plaque removal, 1 month, 3 months, 6 months , 9 months and 12 months after plaque removal (total, 6 injections). The control group had no intravitreal conbercept injection. RESULTS: After initiation of conbercept injections, superficial retinal vascular density in the whole image and parafoveal region were significantly higher at 6 months, whereas there was no significant difference at 9 months and 12 months. In analysis of variance analysis, superficial retinal vascular density in the whole image remained stable after conbercept injections (P = 0.069), whereas the superficial retinal vascular density decreased significantly after plaque radiotherapy in the control group (P = 0.011). In multivariable linear regression, a higher superficial retinal vascular density in the whole image region at 6 months was significantly associated with intravitreal conbercept injection (P = 0.018), wider tumor base (P = 0.026), and thinner tumor thickness (P = 0.04). CONCLUSION: Optical coherence tomography angiography can provide a quantitative evaluation of early retinal microvascular changes after radiotherapy. Intravitreal conbercept treatment could partly relieve the retinal vascular damage in response to radiation therapy at early stage in patients with uveal melanoma; however, it may not be able to provide long-term positive functional outcomes.

Deep Learning-Based Estimation of Axial Length and Subfoveal Choroidal Thickness From Color Fundus Photographs.

This study aimed to develop an automated computer-based algorithm to estimate axial length and subfoveal choroidal thickness (SFCT) based on color fundus photographs. In the population-based Beijing Eye Study 2011, we took fundus photographs and measured SFCT by optical coherence tomography (OCT) and axial length by optical low-coherence reflectometry. Using 6394 color fundus images taken from 3468 participants, we trained and evaluated a deep-learning-based algorithm for estimation of axial length and SFCT. The algorithm had a mean absolute error (MAE) for estimating axial length and SFCT of 0.56 mm [95% confidence interval (CI): 0.53,0.61] and 49.20 µm (95% CI: 45.83,52.54), respectively. Estimated values and measured data showed coefficients of determination of r 2 = 0.59 (95% CI: 0.50,0.65) for axial length and r 2 = 0.62 (95% CI: 0.57,0.67) for SFCT. Bland-Altman plots revealed a mean difference in axial length and SFCT of -0.16 mm (95% CI: -1.60,1.27 mm) and of -4.40 µm (95% CI, -131.8,122.9 µm), respectively. For the estimation of axial length, heat map analysis showed that signals predominantly from overall of the macular region, the foveal region, and the extrafoveal region were used in the eyes with an axial length of < 22 mm, 22-26 mm, and > 26 mm, respectively. For the estimation of SFCT, the convolutional neural network (CNN) used mostly the central part of the macular region, the fovea or perifovea, independently of the SFCT. Our study shows that deep-learning-based algorithms may be helpful in estimating axial length and SFCT based on conventional color fundus images. They may be a further step in the semiautomatic assessment of the eye.

Elongation of the disc-fovea distance and retinal vessel straightening in high myopia in a 10-year follow-up of the Beijing eye study.

To assess changes in the disc-fovea distance (DFD) in highly myopic eyes in a 10-year population-based follow-up study. The case control study included all highly myopic eyes (myopic refractive error ≥ - 6.0 diopters or axial length ≥ 26.0 mm) and a randomized group of non-highly myopic eyes examined in the population-based Beijing Eye Study 2001 and 2011. Using fundus photographs and optical coherence tomographic images, we assessed changes in DFD, parapapillary gamma zone, angle kappa (angle between the temporal arterial arcades), and course of papillo-macular retinal vessels. The study included 89 highly myopic eyes and 86 non-highly myopic eyes. DFD elongation, gamma zone widening, angle kappa decrease and straightening of papillo-macular retinal vessels were detected more often (all P < 0.001) in the highly myopic group than in the non-highly myopic group (63/89 versus 9/86;75/89 versus 18/86;61/89 versus 9/86; and 58/89 versus 7/86,respectively). Gamma zone enlargement, angle kappa reduction and papillo-macular retinal vessel straightening were significantly (all P < 0.001) associated with DFD elongation. The length of macular Bruch's membrane on the disc-fovea line and the vertical distance between the temporal arterial arcade did not change during follow-up. DFD elongation (10-year incidence 70.8% in highly myopic eyes) was associated with gamma zone enlargement, while macular Bruch's membrane length remained unchanged. It supports the notion of a temporal shift of an otherwise stable posterior Bruch's membrane in axially elongated eyes. Straightening of the papillo-macular vessels with increasing gamma zone width suggests a coincident stretching of the papillo-macular retinal nerve fibers and inner limiting membrane.

Albuminuria and retinal vessel density in diabetes without diabetic retinopathy: the Kailuan Eye Study.

BACKGROUND: Diabetic retinopathy and chronic kidney disease are both major complications of diabetes mellitus. We explored the relationship between retinal vessel density (VD) and albuminuria in diabetic patients without conventionally defined diabetic retinopathy. METHODS: The cross-sectional community-based Kailuan Diabetic Retinopathy Study included patients with type 2 diabetes without diabetic retinopathy who participated in the community-based longitudinal Kailuan study and who had undergone ocular fundus photography, kidney function assessment, and optical coherence tomographic angiography (OCT-angiography) for the assessment the retinal perfusion density (PD) and retinal VD. RESULTS: The study included 447 patients (mean age: 60.9 ± 9.7 years). Higher PD and VD were associated with a lower urinary albumin-creatinine ratio (uACR) (macular region: p = 0.007: standardized regression coefficient beta: -0.14; and p = 0.008, beta: -0.13, respectively; parafoveal region: p = 0.006, beta: -0.14; and p = 0.007, beta: -0.14, respectively) after adjusting for age and ocular axial length. In a reverse manner, higher uACR was associated with lower PD and VD (macular region: p = 0.009, beta: -0.14; and p = 0.01, beta: -0.14, respectively; parafoveal region: p = 0.008, beta: -0.14; and p = 0.01, beta: -0.14, respectively), after adjusting for diabetes duration, blood pressure, serum concentration of C-reactive protein and high-density lipoprotein cholesterol and ocular axial length. In a multivariable model, the prevalence of macroalbuminuria increased by 11% (95% CI: 2%, 18%) and 17% (95% CI: 3%, 30%), respectively, for each mm-1 decrease in VD and each unit decrease in PD. CONCLUSIONS AND RELEVANCE: After adjusting for systemic and ocular parameters, diabetic patients without diabetic retinopathy showed a reduction in OCT-angiographic retinal vascular measurements in association with systemic parameters indicating chronic kidney disease. Optical coherence tomographic (OCT)-angiographic retinal microvascular parameters may serve as markers for chronic kidney disease.

Prevalence and Risk Factors of Epiretinal Membranes in a Chinese Population: The Kailuan Eye Study.

Purpose: To investigate the prevalence of epiretinal membranes (ERMs) and their risk factors in a Chinese population. Methods: The community-based Kailuan Eye Study included 14,440 participants (9835 male, 4605 female) with a mean age of 54.0 ± 13.3 years (range, 20-110 years). They underwent a systemic and ophthalmologic examination. ERMs were diagnosed on fundus photographs. Results: Retinal photographs assessable for the presence of ERMs were available for 13,295 (92.0%) individuals (9094 male) with a mean age of 53.6 ± 13.3 years (range, 20-110 years). ERMs were found in 1013 participants (1489 eyes) with a prevalence of 7.6% (95% confidence interval [CI], 7.1%-8.1%). Secondary ERMs caused by intraocular reasons were found 46 (4.5%) individuals (69 [4.6%] eyes). A higher prevalence of any ERMs (and of primary ERMs) was associated with older age (odds ratio [OR]: 1.08; 95% CI:1.07-1.10), higher body mass index (OR: 1.05; 95% CI: 1.00-1.11), higher prevalence of smoking (OR:1.43; 95% CI: 1.01-2.03), higher serum concentration of glucose (OR: 1.08; 95% CI: 1.04-1.13), and lower serum concentration of uric acid (OR: 0.99; 95% CI: 0.99-1.00). Visual acuity was significantly (P = 0.002) lower in eyes with premacular fibroses than in eyes with cellophane macular reflexes. Conclusions: In our cross-sectional community-based study, the prevalence of all ERMs was 7.6%. Among the group of participants with ERMs, secondary ERMs caused by intraocular reasons were detected in 46 (4.5%) individuals (69 [4.6%] eyes). A higher prevalence of any ERM and of primary ERMs was associated with older age, higher body mass index, higher prevalence of smoking, a higher serum concentration of glucose, and a lower serum concentration of uric acid.

Influencing factors for peripheral and posterior lesions in mild non-proliferative diabetic retinopathy-the Kailuan Eye Study.

AIM: To explore the influencing factors of diabetes type 2 patients with mild non-proliferative diabetic retinopathy (NPDR) in the Kailuan area of Tangshan, Hebei Province, China. METHODS: In this non-interventional, retrospective study, 683 patients with type 2 diabetes were included in the Kailuan Diabetic Retinopathy Study involving participants with diabetes in the community-based longitudinal Kailuan Study. Based on the undilated ultra-wide field (200°; UWF) images and partial dilated digital fundus images, the diabetic retinopathy (DR) of the surveyed population was graded. Interobserver agreement was estimated by using Cohen's Kappa statistics. The main outcome indicators included gender, age, weight, height, body mass index, blood pressure, circumferences of neck, waist and hip, current smoking, levels of fasting plasma glucose (FPG), hypersensitive C-reactive protein, creatinine, and cholesterol, etc. According to different lesions' locations of patients with mild NPDR, logistic regression models were used to estimate the odds ratios (ORs) and their 95%CIs of each risk factor. RESULTS: The study group of 683 patients included 570 males and 113 females. The mean age of the patients was 62.18±9.41y. Compared with dilated fundus examinations, there was fair agreement with the level of DR identified on UWF images in 63.91% of eyes (k=0.369, 95%CI, 0.00-0.00). Detected by UWF images, there were 98 patients with mild NPDR having peripheral retinal lesions, 35 patients with mild NPDR having posterior lesions, 44 patients with mild NPDR whose lesions were detected both in and out the standard two fields area, and 336 patients with non obvious DR. Parameters that conferred a statistically significant increased risks for mild NPDR with having peripheral retinal lesions were neck circumstance (OR, 1.124; 95%CI, 1.044-1.211), and with posterior lesions were FPG (OR, 1.052; 95%CI, 1.007-1.099). CONCLUSION: UWF is an effectiveness means of DR screening. Moreover, it is necessary to evaluate peripheral diabetic retinal lesions which can help to estimate the severity of DR. The phenomenon that nonuniform and inhomogeneous distribution of DR lesions has been found. And the influencing factors in mild NPDR are differing by different lesions' locations.

MicroRNA-145 suppresses uveal melanoma angiogenesis and growth by targeting neuroblastoma RAS viral oncogene homolog and vascular endothelial growth factor.

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. It has been demonstrated that microRNA-145 (miR-145) is correlated with the progression of various cancers by regulating the expression of multiple target genes, especially a number of genes that regulate angiogenesis and proliferation. However, the underlying mechanisms of miR-145 in tumor angiogenesis of UM are still not well illustrated. Thus, we aimed to explore the potential target genes or pathways regulated by miR-145 in UM and the effect of miR-145 on invasion and angiogenesis. METHODS: Totally, 24 choroid samples were collected in our study, including 12 UM samples and 12 normal uveal tissues. The expression of neuroblastoma RAS viral oncogene homolog (N-RAS), phosphorylated protein kinase B (p-AKT), and vascular endothelial growth factor (VEGF) in UM tissues and normal uveal tissues was analyzed using Western blotting analysis. Lentivirus expression system was used to construct MUM-2B and OCM-1 cell lines with stable overexpression of miR-145. Transwell and endothelial cell tube formation assay were used to measure the effects of miR-145 on the invasion and angiogenesis of UM in vitro. The downstream target genes of miR-145 were predicted by bioinformatics and confirmed using a luciferase assay. BALB/c nude mice models were established to investigate the mechanisms of miR-145 on tumor growth and angiogenesis in vivo. Group data comparisons were performed using analysis of Student's t test. A two-tailed P < 0.05 was considered as statistically significant. RESULTS: The results of Western blotting analysis indicated that the expressions of N-RAS (1.10 ±â€Š0.35 vs. 0.41 ±â€Š0.36, t = 3.997, P = 0.012), p-AKT (1.16 ±â€Š0.22 vs. 0.57 ±â€Š0.03, t = 7.05, P = 0.001), and VEGF (0.97 ±â€Š0.32 vs. 0.45 ±â€Š0.21, t = 3.314, P = 0.008) in UM tumor tissues were significantly higher than those in normal uveal tissue. Luciferase assay demonstrated N-RAS and VEGF as downstream targets of miR-145. Moreover, tube formation assay revealed that miR-145-transfected human microvascular endothelial cell line formed shorter tube length (36.10 ±â€Š1.51 mm vs. 42.91 ±â€Š0.94 mm, t = 6.603, P = 0.003) and less branch points (350.00 ±â€Š19.97 vs. 406.67 ±â€Š17.62, t = 3.685, P = 0.021) as compared with controls. In addition, the numbers of invaded MUM-2B and OCM-1 cells with miR-145 overexpression were significantly lower than the controls (35.7 ±â€Š3.3 vs. 279.1 ±â€Š4.9, t = 273.75, P < 0.001 and 69.5 ±â€Š4.4 vs. 95.6 ±â€Š4.7, t = 21.27, P < 0.001, respectively). In vivo, xenografts expressing miR-145 had smaller sizes (miR-145 vs. miR-scr, 717.41 ±â€Š502.62 mmvs. 1694.80 ±â€Š904.33 mm, t = 2.314, P = 0.045) and lower weights (miR-145 vs. miR-scr, 0.74 ±â€Š0.46 g vs. 1.65 ±â€Š0.85 g, t = 2.295, P = 0.045). CONCLUSION: Our results indicated that miR-145 is an important tumor suppressor and the inhibitory strategies against N-RAS/VEGF signaling pathway might be potential therapeutic applications for UM in the future.

Thickness of individual layers at the macula and associated factors: the Beijing Eye Study 2011.

BACKGROUND: Diagnosis and follow-up of retinal diseases may be improved if the thickness of the various retinal layers, in addition to the total retinal thickness, is taken into account. Here we measured the thickness of the macular retinal layers in a population-based study group to assess the normative values and their associations. METHODS: Using spectral-domain optical coherence tomographic images (Spectralis®, wavelength: 870 nm; Heidelberg Engineering Co, Heidelberg, Germany), we measured the thickness of the macular retinal layers in participants of the population-based Beijing Eye Study without ocular diseases and without systematic diseases, such as arterial hypertension, hyperlipidemia, diabetes mellitus, cardiovascular diseases, previous myocardial infarction, cerebral trauma and stroke. Segmentation and measurement of the retinal layers was performed automatically in each of the horizontal scans. RESULTS: The study included 384 subjects (mean age:60.0 ± 8.0 years). The mean thickness of the whole retina, outer plexiform layer, outer nuclear layer,retinal pigment epithelium, inner retinal layer and photoreceptor layer was 259.8 ± 18.9 µm, 19.4 ± 3.9 µm, 93.4 ± 9.6 µm, 17.6 ± 1.9 µm, 169.8 ± 18.6 µm, and 90.0 ± 4.2 µm, respectively. In multivariable analysis, the thickness of the foveola and of all retinal layers in the foveal, parafoveal and perifoveal region decreased with older age (all P < 0.05), except for the thickness of the parafoveal outer plexiform layer which increased with age. Men as compared to women had higher thickness measurements of the photoreceptor layer and outer nuclear layer in all areas, and of all layers between the retinal nerve fiber layer and inner nuclear layer in the parafoveal area (all P < 0.05). The associations between the macular retinal layers thickness and axial length were not consistent. The inner plexiform layer was thicker, and the ganglion cell layer and inner nuclear layer were thinner, in the temporal areas than in the nasal areas, CONCLUSIONS: The associations between decreasing thickness of most retinal layers with older age and the correlation of a higher thickness of some retinal layers with male gender may clinically be taken into account.

Microvascular retinal changes in pre-clinical diabetic retinopathy as detected by optical coherence tomographic angiography.

PURPOSE: To investigate microvascular abnormalities in diabetic patients without conventional clinical signs of diabetic retinopathy (DR). METHODS: In this cross-sectional observational cohort study, the study group included randomly chosen participants of a community-based cohort with diabetes type 2 without DR, and the control group consisted of non-diabetic individuals from a population-based study. All participants underwent optical coherence tomographic angiography (OCTA). RESULTS: Upon OCTA, 118 (40.4%) eyes of the study group (n = 292 eyes) showed microvascular abnormalities including foveal avascular zone erosion (95 (32.5%) eyes), non-perfusion areas in the superficial and deep retinal layers (39 (13.4%) eyes and 19 (6.5%) eyes, respectively), and microaneurysms in the superficial and deep retinal layers (22 (7.5%) eyes and 31 (10.6%) eyes, resp.). None of these abnormalities was detected in the control group (n = 80). The study group showed a lower vessel density in the superficial retinal vascular layer in all regions except for the foveal region (P < 0.001), and higher vessel density in the parafoveal region in the deep retinal vascular layer (P = 0.01). Higher diabetes prevalence was associated with lower superficial retinal vascular density (P = 0.005) in multivariable analysis. A lower radial peripapillary capillary flow density was correlated (regression coefficient r, 0.62) with higher fasting blood concentration of glucose (P < 0.001) in multivariable analysis. CONCLUSIONS: OCTA revealed microvascular abnormalities in 40% of eyes of diabetic patients without ophthalmoscopically detectable diabetic fundus changes in a community-based population. The early stage of DR may be re-defined upon OCTA.

Ocular Axial Length and Diabetic Retinopathy: The Kailuan Eye Study.

Purpose: To examine the role of ocular axial length as an ocular parameter for the prevalence and severity of diabetic retinopathy (DR). Methods: The cross-sectional Kailuan Diabetic Retinopathy Study included patients with diabetes who participated in the community-based longitudinal Kailuan Study and who had undergone ocular fundus photography. The fundus photographs were graded using the Early Treatment of Diabetic Retinopathy Study criteria. Results: The study included 1096 patients with diabetes (mean age: 60.8 ± 9.4 years; axial length: 23.37 ± 0.92 mm). In binary regression analysis, a higher DR prevalence was associated with shorter axial length (P = 0.007; odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.70, 0.95) after adjusting for longer known duration of diabetes (P = 0.02; OR: 1.13; 95%CI: 1.02, 1.24) and higher fasting blood glucose concentration (P < 0.001; OR: 1.38; 95%CI: 1.26, 1.52). A more severe DR stage was associated (regression coefficient r: 0.46) with shorter ocular axial length (P = 0.047; standardized regression coefficient ß: -0.06) after adjusting for higher fasting blood glucose (P < 0.001; ß: 0.41) and longer known duration of diabetes (P = 0.045; ß: 0.07). Longer axial length was associated with a lower DR prevalence (P = 0.003; ß: -0.10) after adjusting for younger age (P < 0.001), male sex (P < 0.001), higher body mass index (P = 0.016), and lower fasting blood glucose concentration (P = 0.036). Conclusions: After adjusting for systemic risk factors, DR prevalence decreased by 19% (95%CI: 5, 30) for each millimeter increase in axial length. With longer axial length being a surrogate for axial myopia, the marked increase in myopia prevalence worldwide may lead to a relative decrease in the prevalence and incidence of DR in future.

10-year fundus tessellation progression and retinal vein occlusion.

AIM: To access the 10-year fundus tessellation progression in patients with retinal vein occlusion. METHODS: The Beijing Eye Study 2001/2011 is a population-based longitudinal study. The study participants underwent a detailed physical and ophthalmic examination. Degree of fundus tessellation was graded by using fundus photographs of the macula and optic disc. Progression of fundus tessellation was calculated by fundus tessellation degree of 2011 minus degree of 2001. Fundus photographs were used for assessment of retinal vein occlusion. RESULTS: The Beijing Eye Study included 4403 subjects in 2001, 3468 subjects was repeated in 2011. Assessment of retinal vein obstruction and fundus tessellation progression were available for 2462 subjects (71.0%), with 66 subjects fulfilled the diagnosis of retinal vein occlusion. Of the 66 participants, 59 participants with unilateral branch retinal vein occlusion, 5 participants with unilateral central retinal vein occlusion, 1 participant with bilateral branch retinal vein occlusion, and 1 participant with branch retinal vein occlusion in one eye and central retinal vein occlusion in the other eye. Mean degree of peripapillary fundus tessellation progression were significantly higher in the whole retinal vein occlusion group (0.33±0.39, P<0.001), central retinal vein occlusion group (0.71±0.8, P=0.025) and branch retinal vein occlusion group (0.29±0.34, P=0.006) than the control group (0.20±0.26). After adjustment for age, prevalence of tilted disc, change of best corrected visual acuity, axial length, progression of peripapillary fundus tessellation was associated with the presence of retinal vein occlusion (P=0.004; regression coefficient B, 0.094; 95%CI, 0.029, 0.158; standardized coefficient B, 0.056). As a corollary, after adjusting for smoking duration, systolic blood pressure, anterior corneal curvature, prevalence of RVO was associated with more peripapillary fundus tessellation progression (P<0.001; regression coefficient B: 1.257; OR: 3.517; 95%CI: 1.777, 6.958). CONCLUSION: Peripapillary fundus tessellation progresses faster in individuals with retinal vein occlusion. This may reflect the thinning and hypoperfusion of choroid in patients with retinal vein occlusion.

Long-term Progression and Risk Factors of Fundus Tessellation in the Beijing Eye Study.

To assess the progression of fundus tessellation, color fundus photographs of the participants of the longitudinal population-based Beijing Eye Study were examined. The study included 4439 subjects in 2001 and 2695 (66.4% of the surviving) individuals in 2011. Larger progression in macular fundus tessellation (mean: 0.24 ± 0.48 grades) was associated (multivariate analysis; correlation coefficient r: 0.53) with thinner subfoveal choroidal thickness in 2011 (P < 0.001; standardized regression coefficient beta: -0.37), older age (P < 0.001; beta: 0.22), higher level of education (P < 0.001; beta: 0.09), more myopic change in refractive error (P < 0.001; beta: -0.09) and lower cognitive function score (P = 0.02; beta: -0.05). Larger increase in peripapillary fundus tessellation (mean: 0.19 ± 0.26 grades) correlated with thinner peripapillary choroidal thickness in 2011 (P < 0.001; beta: -0.35), older age (P < 0.001; beta: 0.20), worse best corrected visual acuity (P = 0.001; beta: 0.07), more myopic change in refractive error (P < 0.001; beta: -0.07) and higher prevalence of ever smoking (P = 0.004; beta: 0.05). The increase in macular fundus tessellation, as a surrogate for thinning of the posterior choroid, was associated with lower cognitive function, after adjusting for choroidal thickness, age, educational level and change in refractive error. The findings point to the clinical value of the assessment of fundus tessellation and suggest potential associations between cognitive function and fundus tessellation/choroidal thickness.

Ten-year cumulative incidence of epiretinal membranes assessed on fundus photographs. The Beijing Eye Study 2001/2011.

PURPOSE: To assess the 10-year incidence and progression of epiretinal membranes (ERMs). METHODS: The population-based longitudinal Beijing Eye Study, which included 4439 subjects (age:40+years) in 2001, was repeated in 2011 with 2695 subjects participating (66.4% of the survivors). The study participants underwent a detailed ophthalmic examination, including retinal photography. Assessing fundus photograohs, ERMs were classified as cellophane macular reflex (CMR) without retinal folds, or as preretinal macular fibrosis (PMF) without or with retinal folds. RESULTS: Fundus photographs were available for 2476 subjects with a mean age of 69.0±7.8 years (range:51-93 years) and mean axial length of 23.3±0.9 mm (range:19.92-26.33mm). The 10-year incidence of ERMs was 8.4% (208/2476 participants; 95% confidence interval (CI):7.4,9.5). ERMs developed bilaterally in 50 (24%) individuals and unilaterally in 158 (76%) persons. The incidence of PMFs with 2.5% (95% CI: 1.9, 3.1) was lower than the incidence of CMRs with 5.9% (95% CI: 5.0, 6.9). Higher 10-year incidence of ERMs was associated with older age (P<0.001; odds ratio (OR): 1.06; 95%CI:1.04,1.09), previous cataract surgery (P = 0.003;OR:3.32;95%CI:1.51,7.29) and presence of a complete posterior vitreous detachment (P = 0.02;OR:1.84;95%CI:1.12,3.02). In the age groups of <60 years, 60-69 years, 70-79 years and 80+years, incidence of ERMs was 3.1%, 10.0%, 14.4% and 10.9%, respectively, with no significant gender difference. CONCLUSIONS: In Chinese aged 40+ years, the 10-year incidence of ERMs (8.4%) increased with older age, previous cataract surgery and complete posterior vitreous detachment. The ten-year incidence was lower for PMFs (2.5%) than for CMRs (5.9%).