Early Stages Of Age-related Macular Degeneration Research Articles

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy: Longitudinal Evaluation in Age-Related Macular Degeneration

To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). Retrospective analysis of data from a longitudinal study. A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. Association with and variance explained in time to GA development. A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent orincident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P= 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P= 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R2= 43%) was significantly lower than explained by nGA alone (R2= 91%; P= 0.010). In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD.

P2X7-mediated alteration of membrane fluidity is associated with the late stages of age-related macular degeneration.

We have shown deficits in monocyte phagocytosis from patients with age-related macular degeneration (AMD). Cell membrane fluidity is known to affect phagocytic capacity and leucocyte functionality more generally. Therefore, we examined membrane fluidity of peripheral blood leucocytes in human patients with AMD and in the P2X7 null mouse model of AMD using flow cytometry with a fluorescent probe for fluidity, TMA-DPH. The results showed that membrane fluidity was decreased in all leucocyte types of late AMD relative to healthy controls (HC) including monocytes, neutrophils and lymphocytes but this was not apparent in earlier stages of AMD. Further analysis of factors contributing to membrane fluidity indicated that pre-treatment of monocytes and lymphocytes with ATP greatly increased membrane fluidity in humans and mice. Evidence from P2X7 null mice and P2X7 antagonists confirmed that these ATP-driven increases in membrane fluidity were mediated by P2X7 but were not associated with the classic P2X7 functions of pore formation or phagocytosis. Analysis of P2X7 expression indicated that receptor levels were elevated in classic monocytes of late AMD patients, further suggesting the P2X7 may contribute to altered plasma membrane properties. Our findings identified a novel biological function of P2X7 in modulating membrane fluidity of leucocytes and demonstrated reduced membrane fluidity in cellular changes associated with the late stage of AMD.

Potential Mechanisms of NUR77‐Mediated Signaling in the Aging Retinal Pigment Epithelium: Implications for Age‐Related Macular Degeneration

PurposeRetinal pigmented epithelium (RPE) dysfunction is associated with age‐related macular degeneration (AMD), the leading cause of vision loss in the elderly in the western world. A better understanding of RPE‐related signaling pathways is the key to developing therapies and potential drug treatments for the early stages of AMD. Nuclear receptors are master regulators of cellular processes including lipid metabolic dysregulation, apoptosis, and inflammation, pathogenic pathways associated with AMD development and progression. Previously we found that orphan nuclear receptor member 1(NR4A1) or NUR77 is expressed by human RPE. The role of NUR77 in the eye or RPE‐mediated signaling pathways, however is not known. Given NUR77’s purported role in regulating inflammation, angiogenesis, and apoptosis in a number of body tissues, herein we investigated the role of NUR77 in RPE as a function of age.MethodsTotal RNA was extracted from RPE/choroid fractions of young and old mouse eyes, RPE/choroid from human donors, and human primary RPE cultures harvested from young and old eye tissue (ages 18‐93). Expression of NUR77/Nurr77 and its target genes were measured by qRT‐PCR. Cellular bioenergetics of young versus old RPE and NUR77 overexpressing RPE were measured using the Seahorse XF Real‐Time ATP Rate Assay. RPE cells overexpressing NUR77 were analyzed for expression of senescence‐related and epithelial‐mesenchymal transition (EMT) markers. To investigate the function of Nur77, in vivo, ocular imaging and retinal function assessments of 4‐8 month old Nur77‐null mice was done. Ex vivo, ocular morphology was examined. Statistical methods for data analysis included two‐tailed Student’s t‐test and two‐way ANOVA. Values were considered statistically significant at p &lt; 0.05.ResultsNur77/NUR77 expression in mouse and human RPE decreases with age. Overexpression of NUR77 (induction of the ‘young phenotype’) in RPE cells isolated from old donors results in a decrease in expression of the senescence associated genes p21 and p16, while low levels of NUR77 were associated with elevated senescence. Expression of the metabolic markers COX III, pyruvate kinase M1 and 2were differentially regulated in the RPE/choroid fractions from old versus young mice. Seahorse assays revealed that overexpression of NUR77 in RPE cells from young but not old donors resulted in a metabolic shift from glycolysis towards mitochondrial respiration. In the absence of Nur77, enhanced expression of markers of inflammation (CCL2, TNFa), oxidative stress (HMOX1, SOD1), metabolism (COXIII, PKM2) and EMT (N‐cadherin, Snail 2, ZEB1, FN1, Vimentin) was observed in the mouse RPE/choroid. Initial assessments of ocular imaging revealed the presence of hypopigmented regions within the posterior pole of Nur77‐null mice at 4 months of age.ConclusionsOur preliminary results indicate an age‐dependent role of NUR77 in balancing a metabolic switch towards mitochondrial respiration in the RPE. Studies are ongoing to further dissect the NUR77‐mediated signaling pathways in aging and ocular disease, and in determining if NUR77 overexpression may serve as potential therapy in diseases wherein RPE is compromised.

Rapid Objective Testing of Visual FunctionMatched to the ETDRS Grid and ItsDiagnostic Power in Age-Related MacularDegeneration.

PurposeTo study the power of an 80-second multifocal pupillographic objective perimetry (mfPOP) test tailored to the ETDRS grid to diagnose age-related macular degeneration (AMD) by Age-Related Eye Disease Study (AREDS) severity grade.DesignEvaluation of a diagnostic technology.MethodsWe compared diagnostic power of acuity, ETDRS grid retinal thickness data, new 80-second M18 mfPOP test, and two wider-field 6-minute mfPOP tests (Macular-P131, Widefield-P129). The M18 stimuli match the size and shape of bifurcated ETDRS grid regions, allowing easy structure–function comparisons. M18, P129, and P131 stimuli test both eyes concurrently. We recruited 34 patients with early-stage AMD with a mean ± standard deviation (SD) age of 72.6 ± 7.06 years. The M18 and P129 plus P131 stimuli had 26 and 51 control participants, respectively with mean ± SD ages of 73.1 ± 8.17 years and 72.1 ± 5.83 years, respectively. Multifocal pupillographic objective perimetry testing used the Food and Drug Administration-cleared Objective FIELD Analyzer (OFA; Konan Medical USA).Main Outcome MeasuresPercentage area under the receiver operator characteristic curve (AUC) and Hedge’s g effect size.ResultsAcuity and OCT ETDRS grid thickness and volume produced reasonable diagnostic power (percentage AUC) for AREDS grade 4 eyes at 83.9 ± 9.98% and 90.2 ± 6.32% (mean ± standard error), respectively, but not for eyes with less severe disease. By contrast, M18 stimuli produced percentage AUCs from 72.8 ± 6.65% (AREDS grade 2) to 92.9 ± 3.93% (AREDS grade 4), and 82.9 ± 3.71% for all eyes. Hedge’s g effect sizes ranged from 0.84 to 2.32 (large to huge). Percentage AUC for P131 stimuli performed similarly and for P129 performed somewhat less well.ConclusionsThe rapid and objective M18 test provided diagnostic power comparable with that of wider-field 6-minute mfPOP tests. Unlike acuity or OCT ETDRS grid data, OFA tests produced reasonable diagnostic power in AREDS grade 1 to 3 eyes.

THE PLACE OF PROGRESSIVE SPECTACLES CORRECTION IN AN INTEGRATED APPROACH TO THE THERAPY OF THE EARLY STAGES OF AGE-RELATED MACULAR DEGENERATION

The purpose: to determine the place of progressive spectacles correction in an integrated approach for the treatment of early stages of age-related macular degeneration (AMD) in hyperopic patients. Material and methods: 30 patients (60 eyes) aged 42-75 y.o., average age (58,8 ± 6,5) years, with early stages of AMD and hyperopia were under observation. The observation group was represented by 20 patients (40 eyes). After AMD revealing they applied progressive spectacles correction of «universal» type and received orally dietary supplement Retinorm® 3 capsules one time per day. The comparison group consisted of 10 patients (20 eyes). They received the same oral dietary supplement and used the previous monofocal correction. Methods of examination of patients included: checking of visual acuity with correction, refractometry, tonometry, computer static perimetry, ophthalmobiomicroscopy with Goldmann lens, optical coherence tomography of the central fundus area with measurement of retinal thickness in the fovea zone and choroid in manual mode. The duration of observation in both groups was 4 months. Results. The thickness of the retina in the fovea zone after the use of correction and prescribed treatment did not change either in the observation group (p &gt; 0,1) or in the comparison group (p &gt; 0,1). The thickness of the choroid after the prescribed therapeutic measures significantly increased in the observation group (p &lt; 0,05) and remained without changes in the comparison group (p &gt; 0,1). An increase of visual acuity was established, as well as a decrease in the number of relative scotomas in the central part of the visual field both in the observation group (p &lt; 0,02) and in the comparison group (p &lt; 0,05). Conclusion. The use of «universal» type of progressive spectacles correction in combination with taking dietary supplement Retinorm® increases the effectiveness of treatment of early stages of AMD in hyperopic patients due to both the activation of choroidal blood circulation, and the improvement of metabolic processes in the choroid and retina.

Dose Response in the Subthreshold Nanosecond Laser Trial in Early Stages of AMD: A LEAD Study Report.

To examine the association between treatment parameters and the progression to late age-related macular degeneration (AMD) in the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a randomized, controlled trial of a subthreshold nanosecond laser (SNL) for slowing disease progression in the early stages of AMD. The association between treatment parameters early in the trial period for participants in the SNL arm of the LEAD study and time to develop late AMD during the 3-year trial duration was examined. Parameters included treatment energy at the baseline and 6-month visits and the number of laser spots visible on fundus autofluorescence (FAF) imaging taken at 6 and 12 months (taken as a proxy measure of early, adequate delivery of the laser treatment at the baseline and 6-month visits, respectively). A multivariable analysis revealed there were no significant associations between time to develop late AMD and number of FAF-visible laser spots at 6-months (adjusted P = .537) nor laser energy used at baseline (adjusted P = .910). No significant associations were also observed when evaluating FAF-visible spots at 12-months (adjusted P = .107) and the average laser energy used at baseline and 6 months (adjusted P = .558). This study did not find any evidence to suggest that there was a dose response for the effect of laser treatment using these treatment parameters on the progression of AMD. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:380-386.].

AN AUTOMATED METHOD TO DETECT AGE-RELATED MACULAR DEGENERATION FROM OPTICAL COHERENCE TOMOGRAPHIC IMAGES

Age-related macular degeneration (AMD) is an eye disease that affects the elderly. AMD’s prevalence is increasing as society’s population ages; thus, early detection is critical to prevent vision loss in the elderly. Arrangement of a comprehensive examination of the eye for AMD detection is a challenging task. This paper suggests a new poly scale and dual path (PSDP) convolutional neural network (CNN) architecture for early-stage AMD diagnosis automatically. The proposed PSDP architecture has nine convolutional layers to classify the input image as AMD or normal. A PSDP architecture is used to enhance classification efficiency due to the high variation in size and shape of perforation present in OCT images. The poly scale approach employs filters of various sizes to extract features from local regions more effectively. Simultaneously, the dual path architecture incorporates features extracted from different CNN layers to boost features in the global regions. The sigmoid function is used to classify images into binary categories. The Mendeley data set is used to train the proposed network and tested on Mendeley, Duke, SD-OCT Noor, and OCTID data sets. The testing accuracy of the network in Mendeley, Duke, SD-OCT Noor, and OCT-ID is 99.73%,96.66%,94.89%,99.61%, respectively. The comparison with alternative approaches showed that the proposed algorithm is efficient in detecting AMD. Despite having been trained on the Mendeley data set, the proposed model exhibited good detection accuracy when tested on other data sets. This shows that the suggested model can distinguish AMD/Normal images from various data sets. As compared to other methods, the findings show that the proposed algorithm is efficient at detecting AMD. Rapid eye scanning for early detection of AMD could be possible with the proposed architecture. The proposed CNN can be applied in real-time due to its lower complexity and less learnable parameters.

Subthreshold Nanosecond Laser in Age-Related Macular Degeneration: Observational Extension Study of the LEAD Clinical Trial

To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD). Observational extension study of a randomized, sham-controlled trial. Two hundred twelve participants with bilateral large drusen. The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data. Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment. Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36-1.09; P= 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P= 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16-0.71; P= 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67-4.88; P= 0.239). A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.

Automatic Drusen Segmentation for Age-Related Macular Degeneration in Fundus Images Using Deep Learning

Drusen are the main aspect of detecting age-related macular degeneration (AMD). Ophthalmologists can evaluate the condition of AMD based on drusen in fundus images. However, in the early stage of AMD, the drusen areas are usually small and vague. This leads to challenges in the drusen segmentation task. Moreover, due to the high-resolution fundus images, it is hard to accurately predict the drusen areas with deep learning models. In this paper, we propose a multi-scale deep learning model for drusen segmentation. By exploiting both local and global information, we can improve the performance, especially in the early stages of AMD cases.

Association of Choroidal Thickness with Intermediate Age-Related Macular Degeneration in a Japanese Population

To determine the relationship of choroidal thickness with the early stages of age-related macular degeneration (AMD) and their disease features in a Japanese population. Cross-sectional survey. A total of 1293 Japanese persons 65 to 86 years of age residing in the Saku area who underwent eye screening as part of the Japan Public Health Center-based Prospective Study. Comprehensive ophthalmic assessment included fundus photography, measurement of intraocular pressure, and determination of refractive status. OCT with enhanced depth imaging mode was performed and subfoveal choroidal thickness was assessed. Multinomial logistic regression models were used to assess the relationships of choroidal thickness with the early stages of AMD, namely early AMD and intermediate AMD, and their disease features, after adjustment for potential confounders. Relationship of choroidal thickness with early AMD, intermediate AMD, and their disease features. Of 1293 potential participants, 901 (mean age, 73.2 years) had choroidal thickness data, fundus photographs of sufficient quality, and no concomitant retinal disease (including 5 with late AMD). Mean choroidal thickness was 246.1 μm, 15.1% had early AMD, and 9.0% had intermediate AMD. After adjustment for age, gender, and refractive status, choroidal thickness was associated positively with presence of intermediate AMD (for each 1- standard deviation [SD] μm increase: odds ratio [OR], 1.43; 95% confidence interval [CI], 1.13-1.81), whereas no significant association was found with presence of early AMD. Among intermediate AMD features, choroidal thickness was associated positively with presence of AMD pigmentary abnormalities (associated with at least medium drusen; for each 1-SD μm increase: OR, 2.21; 95% CI, 1.42-3.42), whereas no significant association was found with presence of large drusen alone. In addition, among large drusen subtypes, choroidal thickness was associated positively with presence of pachydrusen (for each 1-SD μm increase: OR, 1.53; 95% CI, 1.10-2.13). Furthermore, exploratory analysis revealed that choroidal thickness was associated positively with presence of non-AMD pigmentary abnormalities (for each 1-SD μm increase: OR, 1.92; 95% CI, 1.31-2.18). Choroidal thickness seems to be associated with the pathology of intermediate AMD and its features in Asians.

In Vitro Maturation of Retinal Pigment Epithelium Is Essential for Maintaining High Expression of Key Functional Genes.

Age-related macular degeneration (AMD) is the leading cause of blindness in the industrialized world. AMD is associated with dysfunction and atrophy of the retinal pigment epithelium (RPE), which provides critical support for photoreceptor survival and function. RPE transplantation is a promising avenue towards a potentially curative treatment for early stage AMD patients, with encouraging reports from animal trials supporting recent progression toward clinical treatments. Mature RPE cells have been reported to be superior, but a detailed investigation of the specific changes in the expression pattern of key RPE genes during maturation is lacking. To understand the effect of maturity on RPE, we investigated transcript levels of 19 key RPE genes using ARPE-19 cell line and human embryonic stem cell-derived RPE cultures. Mature RPE cultures upregulated PEDF, IGF-1, CNTF and BDNF—genes that code for trophic factors known to enhance the survival and function of photoreceptors. Moreover, the mRNA levels of these genes are maximized after 42 days of maturation in culture and lost upon dissociation to single cells. Our findings will help to inform future animal and human RPE transplantation efforts.

Role of the Choroid in Automated Age-related Macular Degeneration Detection from Optical Coherence Tomography Images.

Automatic detection of age-related macular degeneration (AMD) from optical coherence tomography (OCT) images is often performed using the retinal layers only and choroid is excluded from the analysis. This is because symptoms of AMD manifest in the choroid only in the later stages and clinical literature is divided over the role of the choroid in detecting earlier stages of AMD. However, more recent clinical research suggests that choroid is affected at a much earlier stage. In the proposed work, we experimentally verify the effect of including the choroid in detecting AMD from OCT images at an intermediate stage. We propose a deep learning framework for AMD detection and compare its accuracies with and without including the choroid. Results suggest that including the choroid improves the AMD detection accuracy. In addition, the proposed method achieves an accuracy of 96.78% which is comparable to the state-of-the-art works.

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration.

Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.

Association of Visual Function Measures with Drusen Volume in Early Stages of Age-Related Macular Degeneration.

PurposeTo assess which visual function measures are most strongly associated with overall retinal drusen volume in age-related macular degeneration (AMD).MethodsA total of 100 eyes (16 eyes with early AMD, 62 eyes with intermediate AMD, and 22 eyes from healthy controls) were recruited in this cross-sectional study. All subjects underwent several functional assessments: best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), visual acuity (VA) measured with the Moorfields Acuity Chart (MAC-VA), contrast sensitivity with the Pelli–Robson test, reading speed using the International Reading Speed texts, and mesopic and dark-adapted microperimetry. Drusen volume was automatically determined based on optical coherence tomography using an approach based on convolutional neural networks. The relationship between drusen volume and visual function was assessed with linear regressions controlling for confounders.ResultsMean drusen volume and MAC-VA differed significantly among all AMD stages and controls (P < 0.001). In univariate linear regression, LLVA, MAC-VA, contrast sensitivity, and mesopic and dark-adapted microperimetry were significantly negatively associated with the overall drusen volume (all P < 0.006). After controlling for AMD stage, age, and the presence of subretinal drusenoid deposits, MAC-VA and mesopic and dark-adapted microperimetry were still significantly associated with drusen volume (P = 0.008, P = 0.023, and P = 0.022, respectively).ConclusionsOur results suggest that MAC-VA, as well as mesopic and dark-adapted microperimetry, might indicate structural changes related to drusen volume in early stages of AMD.

Alzheimer's Disease and Retinal Degeneration: A Glimpse at Essential Trace Metals in Ocular Fluids and Tissues.

Life expectancy is increasing all over the world, although neurodegenerative disorders might drastically affect the individual activity of aged people. Of those, Alzheimer's Disease (AD) is one of the most social-cost age-linked diseases of industrialized countries. To date, retinal diseases seem to be more common in the developing world and characterize principally aged people. Agerelated Macular Degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with AD, including stress stimuli such as oxidative stress, inflammation and amyloid formations. In both diseases, the detrimental intra/extra-cellular deposits have many similarities. Aging, hypercholesterolemia, hypertension, obesity, arteriosclerosis and smoking are risk factors to develop both diseases. Cellular aging routes have similar organelle and signaling patterns in retina and brain. The possibility to find out new research strategies represent a step forward to disclose potential treatment for both of them. Essential trace metals play critical roles in both physiological and pathological condition of retina, optic nerve and brain, by influencing metabolic processes chiefly upon complex multifactorial pathogenesis. Hence, this review addresses current knowledge about some up-to-date investigated essential trace metals associated with AD and AMD. Changes in the levels of systemic and ocular fluid essential metals might reflect the early stages of AMD, possibly disclosing neurodegeneration pathways shared with AD, which might open to potential early detection.

Age-related Macular Degeneration (AMD): A Review on its Epidemiology and Risk Factors

Age-related Macular Degeneration (AMD) is a type of maculopathy that results in irreversible visual impairment among the aged population in developed countries. The early stages of AMD can be diagnosed by the presence of drusen beneath the retinal pigment epithelial (RPE) cells. The advanced stages of AMD are geographical atrophy (dry type) and neovascular AMD (wet type), which lead to progressive and severe vision loss. The advanced stage of dry AMD can be identified by extensive large drusen, detachment of the RPE layer and finally degeneration of photoreceptors leading to central vision loss. The late stage of wet AMD is diagnosed by the presence of Choroidal Neovascularization (CNV) identified by Optical Coherence Tomography (OCT) or retinal angiography. The principal of AMD management is to impede the progression of early AMD to advanced levels. Patients with CNV are treated with anti-VEGF (Vascular Endothelial Growth Factor) compounds to inhibit blood vessel growth and thereby reducing vision loss. Although preventive methods for dry AMD are under investigation, there are no proven effective treatments.A variety of environmental and genetic related risk factors are associated with increased incidence and progression of AMD. The genetic factors are found in the complement, angiogenic and lipid pathways. However, environmental factors, such as smoking and nutrition, are also major risk factors. Smoking is a modifiable environmental risk factor, which greatly increases the incidence and progress of AMD compared to non-smokers. There is growing evidence for the positive influence of a healthy diet containing high levels of anti-oxidant supplements. The reduction of serum lipids is another effective strategy for prevention AMD. Although no single preventive approach has been identified, knowing the high risk factors of AMD, along with modification of lifestyle is important for this multifactorial disease, especially in populations with higher genetic susceptibility. Though recent progress in early diagnosis of the disease has facilitated early and efficient intervention, further studies are required to gain more clarification of specific pathophysiology.In spite of decades of focused research on AMD, the pathogenesis of AMD is still not completely understood. Recently, numerous novel methods, including imaging techniques, new drug delivery routes, and therapeutic strategies, are improving the management of AMD. In this review, we discuss the current knowledge related to epidemiology and classifications of AMD.

Prospective Longitudinal Evaluation of Nascent Geographic Atrophy in Age-Related Macular Degeneration

Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP). Prospective, longitudinal, observational study. A total of 284 eyes from 142 participants with bilateral large drusen and without nGA nor late age-related macular degeneration (AMD) at baseline were included. OCT volume scans and CFP images were obtained from all participants at baseline and then at 6-month intervals for up to 36 months. OCT and CFP images were graded independently for the presence of nGA and GA, respectively. Eyes that developed neovascular AMD were censored at the day of its detection. Time to development of GA. A total 12 eyes from 10 participants progressed to GA over 36 months of follow-up, and nGA was detected in 10 of these eyes (83%) at a preceding visit (median, 13 months prior; interquartile range, 6-25 months). A total of 40 eyes from 28 participants developed nGA or GA over 36 months of follow-up, and the probability of progression to nGA and GA after 36 months was 20% (95% confidence interval [CI], 14%-28%) and 9% (95% CI, 6%-13%), respectively. After the detection of nGA, the probability of progression to GA was 38% (95% CI, 15%-55%) after 24 months. The development of nGA was associated with a markedly increased risk of progression to GA compared with when it did not develop (adjusted hazard ratio, 78.1; 95% CI, 13.6-448.0; P < 0.001), and the development of nGA explained 91% of the variance in the time to GA development. This study prospectively demonstrated that nGA was a strong predictor for the development of GA, providing supportive evidence of the potential value of nGA as a surrogate endpoint in future intervention trials for the early stages of AMD to improve their feasibility substantially.

AB019. A proposed test of stereovision to identify local retinal abnormalities

Background: The human visual system extracts depth information from disparity in the images seen by the two eyes. The ability to calculate depth from disparity will be disrupted if local retinal abnormalities distort parts of those images, especially if these distortions are different in the two eyes. In its early stages, age-related macular degeneration (AMD) causes slight distortions in the central vision field which differ in the two eyes. AMD is the most common form of irreversible blindness in people over the age of 50. The goal of this project is to develop a stereoscopic perception test which leverages the sensitivity of binocular depth perception to detect the interocular differences symptomatic of either early-stage AMD or other diseases affecting the retina.

Prognostic Value of Retinal Layers in Comparison with Other Risk Factors for Conversion of Intermediate Age-related Macular Degeneration

To analyze longitudinal thickness changes of retinal layers in comparison with established risk factors in eyes with age-related macular degeneration (AMD) with regard to their prognostic value for conversion into advanced AMD stages. Prospective, longitudinal natural history study. Ninety-one eyes of 91 patients with AMD (73.3±7.3 years; 62 female patients [50.4%]) of the Molecular Diagnostic of Age-related Macular Degeneration (MODIAMD) study without exudative or nonexudative late-stage AMD in the study eye at baseline. At each annual follow-up visit, all subjects underwent ophthalmic examination with assessment of best-corrected visual acuity (BCVA) and retinal imaging, including spectral-domain OCT (SD-OCT), over a study period of 6 years. To analyze longitudinal thickness changes of retinal layers in comparison with established risk factors in eyes with age-related macular degeneration (AMD) with regard to their prognostic value for conversion into advanced AMD stages. Qualitative structural AMD features and SD-OCT-based quantitative thickness changes of different retinal layers, such as the retinal pigment epithelium-drusen complex (RPEDC), were assessed by multimodal imaging. Their prognostic relevance regarding disease conversion was determined using Cox regression (cloglog link function). In the multivariable analysis, the presence of focal hyperpigmentation, almost reaching statistical significance, showed the strongest effect regarding the development of nonexudative late-stage AMD (hazard ratio [HR], 5.88; 95% confidence interval [CI], 0.69-50.2; P= 0.052) followed by the presence of refractile drusen (HR, 4.82; 95% CI, 1.33-17.44; P= 0.0164). A thickening of the RPEDC was the only assessed retinal layer that exhibited a significant effect on the development of nonexudative advanced AMD (HR, 1.03; 95% CI, 1.0-1.07; P= 0.0393), whereas no association was observable for the other retinal layers. Neither qualitative nor quantitative markers were significant predictors for the development of exudative late-stage AMD (P > 0.05). The results indicate that the development of both exudative and nonexudative AMD is associated with distinct prognostic features. However, compared with the assessment of qualitative AMD features, the quantification of retinal layers on average across the central retina had less prognostic impact. Further studies are needed to identify and validate robust biomarkers in early AMD stages.

Early local activation of complement in aqueous humour of patients with age-related macular degeneration.

To investigate complement activation in aqueous humour of patients with early, intermediate and neovascular age-related macular degeneration (AMD). Aqueous humour of 79 AMD patients (early, intermediate and neovascular) and 77 age-matched controls was prospectively collected. The levels of the complement protein 3 (C3), activation products complement factor 3a (C3a) and Ba, C3b/iC3b, complement factors B, H and I (CFB, CFH and CFI), and total protein concentration were measured. Data were modelled using covariate analysis to assess the impact of age and glaucoma status of patients and total protein concentration of samples on complement protein concentration across groups. C3a concentration was significantly increased in the aqueous humour of early (p = 0.016), intermediate (p = 0.003) and neovascular (p = 0.018) AMD patients, whilst C3 concentration was significantly increased in early AMD patients only (p = 0.019). Levels of CFB and CFH were significantly increased in the aqueous humour of neovascular AMD patients (p = 0.023 and p = 0.018, respectively). Our findings provide evidence for early local complement dysregulation in AMD patients, suggesting that complement pathway inhibition may be a clinically relevant intervention for early stages of AMD.