Stages Of AMD Research Articles

Age-Related Macular Degeneration and Its Genetic Risk: A Population-based Study

Purpose Specific genetic factors might serve as markers for risk stratification of AMD progression, but their association with key features of AMD has not been fully elucidated. Thus, we investigated the association between overall and pathway-specific genetic risk scores (GRS) and lead loci (ARMS2, CFH) with AMD stages and features of high-risk nonlate AMD, including reticular pseudodrusen (RPD) and large drusen area (LDA). Methods We performed a cross-sectional analysis of data from the Rhineland Study, a population-based study in Bonn, Germany. We included 4016 individuals aged 50 years and older of European descent. GRS and pathway-specific subscores were constructed based on a large genome-wide association study of AMD. Subscores were generated based on gene-pathways associations (complement, extracellular matrix remodeling (ECM) and lipid metabolism). Associations were assessed using logistic and multinomial regression. Results The mean age of participants was 63.36 years and 1813 (45.1%) were men. The GRS was positive in 48.1% of individuals and increased, but did not fully overlap, across AMD stages. Pathway-specific subscores increased across AMD stages except for the ECM subscore, which only showed a trend for increasing in late AMD. Increasing overall GRS was associated with RPD and LDA (OR [95%CI] for RPD: 1.70 [1.33–2.15], for LDA: 1.64 [1.29–2.07]) among individuals with AMD. Similarly, higher complement and ECM subscores was associated with RPD, while for LDA, only an association with complement subscore was observed. Conclusions In a population-based setting, we confirmed higher genetic risk to be associated with more severe AMD and identified associations with high-risk features of intermediate AMD. Conjoint analyses suggested that high-risk features and late AMD might be differentially associated with genetic architecture in AMD, such as ECM remodeling. Incorporation of genetic information such as GRSs might improve AMD risk prediction strategies.

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

BackgroundAge-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death.MethodsA combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question.ResultsUA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy.ConclusionsCollectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.Graphical

Investigation of regional hemodynamics and structural and functional changes in the macular region in patients with intermediate stage of dry AMD against the background of the use of double filtration plasmapheresis

Investigation of regional hemodynamics and structural and functional changes in the macular region in patients with intermediate stage of dry AMD against the background of the use of double filtration plasmapheresis

Clinical and functional eye condition changes in the dry form of age macular degeneration depending on the AREDS stage

Purpose: to assess the functional state of the eyes in age-related macular degeneration depending on the AREDS classification stage.Material and methods. A clinical study of 60 patients (120 eyes) with the dry AMD form, aged 55.1 ± 4.2 years, involved 30 patients (60 eyes) aged 52.7 ± 3.9 years with AREDS 2 category (initial AMD stage, group1) and 30 patients (60 eyes) aged 57.9 ± 7.8 years with AREDS 3 category (intermediate AMD stage, group 2). The complex research involved visual acuity measurement, including the assessment of near vision in various illumination conditions according to the authors’ methodology, fluorescein angiography, refractometry, tonometry, optical coherence tomography (OCT), ultrasound duplex scanning of the eye; and an immunological study aimed at determining interleukins and interferons in blood serum.Results. Visual acuity was found to depend on test illumination in healthy subjects and to substantially drop at all illumination levels in AMD, especially in the 3rd stage. With the development of AMD, the activity of the immune response was recorded.The patients of groups 1 and 2 showed an increase in the inflammatory response and a depression of the anti-inflammatory response. In group 1, an increase was recorded in IL-I by 23.5% (p < 0.05), in IL5 by 25.4% (p < 0.05), and in IL8 by 19.9% (p < 0.05). In group 2, the value of these parameters exceeded the norm by 32.1, 39.5 and 25.4% (p < 0.05), respectively. The parameters of anti-inflammatory immunity (IL10 and TGF l) were lower than the reference level by 18.3 and 24.6% (p < 0.05) of patients of group 1 and by 24.3 and 30.75 (p < 0.05) of group 2. It was established that the degree of imbalance of the immune system is associated with the stage of AREDS. In group 2 patients with AREDS 3, the content of pro-inflammatory interleukins exceeded those of group 1: IL-I by 12.5% (p < 0.05), IL5 by 11.9% (p < 0.05), IL8 by 11, 2% (p < 0.05). IL10 and TGF l in group 2 were lower than in group 1 by 10.2 and 11.8% (p < 0.05).Conclusion. Near visual acuity measurement depending on test illumination may be used as a sensitive diagnostic test in AMD in patients. At an early stage of AMD development, a disorder in the immune defense is observed, taking the form of activation of the pro-inflammatory spectrum and depression of the anti-inflammatory component, as well as microcirculatory changes Homeostatic changes of the eye appear at an early stage of the disease and are progressing as the clinical picture is deteriorating. The changes are the greatest at patients with stage 3 of AREDS.

Association between Subretinal Drusenoid Deposits and Age-Related Macular Degeneration in Multimodal Retinal Imaging.

Multimodal retinal imaging enables the detection of subretinal drusenoid deposits (SDD) with significantly greater accuracy compared to fundus photography. The study aimed to analyze a relationship between the presence of SDD, the clinical picture of AMD, and disease progression in a 3 year follow-up. A total of 602 eyes of 339 patients with a diagnosis of AMD, of which 121 (55%) had SDD confirmed in multimodal retinal imaging, were enrolled in the study. SDD was related to a more advanced stage of AMD (p = 0.008), especially with the presence of geographic atrophy (OR = 4.11, 95% CI 2.02-8.38, p < 0.001). Eyes with SDD presented significantly lower choroidal and retinal thickness (ATC: 210.5 μm, CRT: 277 μm, respectively) and volume (AVC: 0.17 mm3, CRV: 8.29 mm3, p < 0.001, respectively) compared to SDD-negative eyes (ATC: 203 μm, CRT: 277 μm; AVC: 7.08 mm3, 8.54 mm3, p < 0.001). Accordingly, the prevalence of pachychoroids and pachyvessels was significantly lower in the SDD present group than in eyes without SDD (p = 0.004; p = 0.04, respectively). Neither demographic factors, lipid profile, genetic predisposition, systemic vascular disease comorbidities, nor parameters of retinal vessels were affected by the presence of SDD. We found no effect of SDD presence on AMD progression (p = 0.12). The presence of SDD appeared to be related to local rather than systemic factors.

PATHOGENETICALLY DIRECTED METHOD OF PREVENTION AND TREATMENT OF AGE-MACULAR DEGENERATION

Background. Age-related macular degeneration is one of the most common causes of blindness in developed countries, especially in people over 60 years old. The incidence of AMD is projected to increase to 288 million in 2040 compared to 196 million in 2020. Cardiovascular factors, smoking, alcohol consumption, overweight, genetic factors, and metabolic disorders are risk factors for the development of AMD. There are disorders of lipid metabolism, as well as hyperreactivity of platelet purine receptors may be associated with the progression of AMD. The AREDS2 formula is currently used to treat AMD. New therapeutic strategies aimed to correct metabolic disorders are needed to decrease the development of the late stages of AMD.&#x0D; Aim: to investigate the effectiveness of improving pathogenetically directed method of prevention and treatment of age-related macular degeneration.&#x0D; Materials and methods. We observed 40 patients (80 eyes), aged 50-85 years, with AMD of category 3 (intermediate AMD), who were divided into 2 groups. The main group included 20 patients (40 eyes), 14 women and 6 men, who have prescribed a complex drug according to the standard AREDS2 scheme, as well as fenofibrate (200 mg) and clopidogrel bisulfate (75 mg). The control group included 20 patients (40 eyes), 13 women and 7 men. These patients received AREDS2 standard treatment. Progression was evaluated according to the results of OCT of the macular area according to the AREDS classification and control of corrected visual acuity (CVA). The observation period was 2 years.&#x0D; Results. No signs of progression were noted in patients of both observation groups within 6 months from the start of the prescribed therapy. In the patients of the control group, the progression of the disease was recorded after 1 year of observation according to both defined criteria. Changes in OCT were observed in 7,5% of patients in the control group, and a decrease in CVA- in 5%. In the patients of the main group who used the extended therapeutic regimen, after 1 year of follow-up, progression according to OCT signs was noted in 2,5% of cases, but there was no worsening of CVA. After 2 years of observation, signs of progression according to OST were recorded in the main group by 50% less than in the control group. According to CVA, disease progression was detected in 15% of the main group and 30% of the control group.&#x0D; Conclusions. This study complemented already existing therapeutic strategies for the preventive treatment of AMD.

Vessel density changes in choroid, chorio-capillaries, deep and superficial retinal plexues on OCTA in normal ageing and various stages of age-related macular degeneration.

To study vessel density (VD) on optical coherence tomography angiography at choroid, chorio-capillaries (CC) and various retinal levels in normal population and various stages of dry AMD and how these changes progress with increase in severity of the disease. Prospective, observational, cross-sectional study was done on 252 eyes of 132 patients (males: 61, females: 71) presenting to tertiary-care centre in Central India between February 2021 and January 2022. For study purpose, eyes were divided into five groups according to the size and number of the drusen, viz, Group 1: No AMD (< 50years), Group 2: No AMD (> 50years), Group 3: Early AMD, Group 4: Intermediate AMD and Group 5: Advanced AMD. In all eyes, VD was measured at choroid, CC, deep capillary plexus (DCP) of retina and superficial capillary plexus (SCP) of retina. The mean age in case cohort is 61.90 ± 7.97years. The mean vascular density differed significantly across diagnosis types in all the quadrants (p < 0.05) at choroid, CC and DCP level. At SCP level, the differences were significant across the groups except at the central quadrant. Vessel density was found to be more in early AMD cohort when compared to No AMD (> 50years) cohort at SCP and DCP level, while it showed continuous reduction later in intermediate and advanced AMD cohort. With increase in the severity of disease, significant reduction in VD is also seen in retinal plexuses, along with the changes in choroid and CC. These VD maps may play a role as non-invasive biomarkers for healthy and diseased ageing.

Exposure of the retina to subthreshold micro- and nanosecond laser at early stages of age-related macular degeneration

At the moment, there are no effective methods of treatment for age-related macular degeneration at its early stages. The perspective of treatment for age-related macular degeneration may be a method using subthreshold laser radiation.&#x0D; In the present review of literature, analysis is represented of using both subthreshold micro- and nanosecond laser radiation on the retina in intermediate AMD stage. Subthreshold diode micro-pulse laser exposure of the retina in AMD has proven to be a safe procedure that allows for the regression of macular drusen.&#x0D; While some authors noted an improvement in visual functions and a decrease in the probability of developing choroidal neovascularization with such treatment, multicenter trials have not yet confirmed the effectiveness of micro-pulse therapy as a method to prevent the neovascular AMD development.&#x0D; Subthreshold nanosecond laser impact on the retina is safe for the structures of the eye fundus, theoretically more selective stimulates the natural biological and regenerative potential in the pigment epithelium and neuroepithelium due to remodeling of extracellular matrix, restores the thickness of the Bruchs membrane and metabolism between external retinal layers and choriocapillaris.&#x0D; Encouraging results have been achieved from the use of nanopulse therapy as a method of preventing the development of advanced stage AMD in the absence of reticular pseudodrusen, however, it seems premature to recommend this technology for widespread clinical use - further research is needed.&#x0D; The prospects of invading in wide clinical practice of subthreshold nanosecond laser impact on the intermediate stage of AMD on the basis of the obtained clinical research results are encouraging (regression of drusen, preventing of AMD progression in absence of reticular pseudodrusen), but there is currently no evidence base. It is required to conduct further researches.

Lower CXCR3 expression in both patients with neovascular AMD and advanced stages of chronic myeloproliferative blood cancers.

PurposePeripheral T cell CXCR3 expression has been found uniquely lower in patients having neovascular age-related macular degeneration (nAMD) than in healthy individuals. The CXCR3-axis has been shown to have angiostatic and antifibrotic properties. We have recently investigated systemic markers in patients with myeloproliferative neoplasms (MPNs) because of their higher prevalence of AMD, and we have observed higher systemic chronic low-grade inflammation and immunosenescence signs in MPNs with drusen (MPNd) compared to those with normal retinas (MPNn). The MPNs evolve in a biological continuum from early cancer-stages (essential thrombocytosis, polycythemia vera) to the advanced myelofibrosis stage. Especially myelofibrosis is characterized by bone marrow angiogenesis and fibrosis, similarly to retinal observations in nAMD. We speculate if we can find lower CXCR3 expression in MPNs, particularly myelofibrosis and if differences are seen between MPNd and MPNn. We also wanted to compare expression in nAMD and intermediate (i)AMD.MethodsPatients in this cross-sectional study were 29 nAMD, 28 iAMD, 35 MPNd, and 27 MPNn. We performed flowcytometry on blood to measure CXCR3 expression.ResultsCD8+CXCR3 expression in nAMD was 6,1%, significantly lower than in iAMD 16%, MPNd 11%, MPNn 12% (p-values<0.05). Similar results were seen for CD4+CXCR3 expression. We also found CXCR3 expression decreasing over the MPN-continuum. For instance, in myelofibrosis, intermediate monocytes expression was 6.2%, significantly lower than 18% in ET and 18% in PV (p-values<0.05).ConclusionsWe find CXCR3 downregulation on T-cells and some monocyte subset in nAMD compared to iAMD, MPNd, and MPNn, in line with previous nAMD studies. We also find CXCR3 downregulation in most monocyte subsets over the MPN continuum. Systemic leukocyte CXCR3 expression could both be involved in changes seen in the retina and the bone marrow. Further understanding the CXCR3-axis in AMD and MPNs may elucidate underlying pathogenic mechanisms and reveal new targets for treatment.

A Patient Perspective on Quality of Life with wAMD: A Podcast.

Podcast Video (MP4 420470 KB)Wet age-related macular degeneration (wAMD) is an advanced stage of AMD characterised by the rapid onset of acute vision loss. Vision loss limits daily activities, such as reading and driving, and therefore has a notable impact on quality of life. However, there is insufficient research focusing on the patient perspective on wAMD and its effect on quality of life. In this podcast article, a person with wAMD and an expert physician discuss the patient experience of wAMD diagnosis, disease progression and treatment, and the most important aspects of quality of life that should be preserved or improved. wAMD can progress extremely quickly, but diagnostic guidelines vary by region, so the words ‘macular degeneration’ are not heard by some patients until long after vision has been lost, if at all. The potential impact of wAMD on a person’s life may never be explained, leading some people to rely on their own research. Therefore, patients may be unprepared for the subsequent effect on their lives and careers. The support of family is critical for maintaining quality of life. Working with a physician who understands an individual’s communication preferences is also important for ensuring treatment adherence and maintaining good mental health; treatment for wAMD is typically administered via intravitreal injection, which may be alarming to patients who have not been informed well by healthcare professionals. Adapting to vision loss is key to maintaining quality of life, and magnification is especially useful for patients with wAMD. Furthermore, modern technology, such as smart phones and smart watches, greatly improves the accessibility of daily tasks. However, what is most important to patients is access to information about their disease—whether via an advocate, self-led research or a healthcare professional. Crucially, physicians must ensure that they speak to their patients in an informative but accessible manner.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40123-022-00528-5.

Scotopic microperimetric sensitivity and inner choroid flow deficits as predictors of progression to nascent geographic atrophy

Background/AimsTo assess the role of microperimetric retinal sensitivity (MPRS) and inner choroid flow deficits (IC FD) in predicting the development of incomplete retinal pigment epithelial and outer retinal atrophy (iRORA)...

Comparison of Visual Function Tests in Intermediate Age-Related Macular Degeneration.

PurposeIdentifying the most sensitive functional measure in intermediate age-related macular degeneration (iAMD) could help select an appropriate test for monitoring disease progression and evaluating the efficacy of novel interventions for the early stages of AMD. The purpose of the study was to determine which commonly used visual function test is the most discriminatory when comparing individuals with iAMD to normal participants.MethodsIn this prospective observational study, iAMD cases and healthy controls underwent visual function testing (best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), mesopic microperimetry, dark adaptation, and scotopic perimetry following photobleach), clinical eye examination, and multimodal retinal imaging in a single study visit. The data of each functional parameter were converted into z-score so that all the parameters had a common scale to allow a direct comparison between different functional parameters.ResultsForty-eight subjects (23 normal control, 25 iAMD) participated. Although all five parameters showed a significant reduction in function in iAMD eyes compared to controls (P ≤ 0.003), the rod intercept time (RIT) detected the greatest reduction in function followed by the scotopic sensitivity, mesopic sensitivity, BCVA, and LLVA, with the absolute mean z-score of 4.5, 2.2, 1.0, 1.0, and 1.2, respectively.ConclusionsAmong the five visual function parameters commonly used, RIT is the most discriminatory functional parameter in the early stages of AMD.Translational RelevanceThe RIT could be considered for assessing visual function and evaluating efficacy of novel interventions aimed at improving retinal function in eyes with early stages of AMD.

Quantitative deep vascular complex analysis of different AMD stages on optical coherence tomography angiography.

To investigate alterations in deep retinal vascular complex (DVC) in patients with non-neovascular intermediate AMD (iAMD), treatment-naïve quiescent macular neovascularization (qMNV), exudative AMD (eAMD) by means of OCT angiography (OCTA). Patients with iAMD, qMNV, eAMD and healthy controls presenting in the Department of Ophthalmology of the Centre Hospitalier Intercommunal de Créteil between January 2016 and January 2018, were retrospectively included. 3 × 3-mm OCTA (AngioVue RTVue XR Avanti) perfusion density (PD) of DVC was computed in all groups at baseline and follow up (12.0 ± 1.1 months). A total of 46 eyes of 45 patients were enrolled: 11/46 iAMD, 10/46 qMNV, 13/46 eAMD, 12/46 control eyes. PD showed a significant decrease during follow-up in qMNV (p = 0.0059) and iAMD (p = 0.0076) eyes. PD in eAMD and healthy controls didn't show significant changes. PD decreases at the level of DVC in eyes with qMNV and iAMD, while in eAMD eyes, PD is stable throughout follow up, suggesting that repeated anti-vascular endothelial growth factor (VEGF) injections do not impact on the DVC PD.

Baseline characteristics and age-related macular degeneration in participants of the “ASPirin in Reducing Events in the Elderly” (ASPREE)-AMD trial

PurposeTo describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression. MethodsAustralian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants. ResultsASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p < 0.001), risk variants rs570618 and rs10922109 (CFH) with intermediate and late AMD (p < 0.001), and rare variant rs147859257 (C3) with late AMD (p < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors. ConclusionsObserved associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population. Trial registrationAustralian New Zealand Clinical Trial Registry: ACTRN 12613000755730.

CHORIOCAPILLARIS FLOW DEFICITS AS A RISK FACTOR FOR PROGRESSION OF AGE-RELATED MACULAR DEGENERATION.

To evaluate the association between choriocapillaris (CC) flow deficits and structural optical coherence tomography biomarkers and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy. Retrospective analysis of consecutive patients with iAMD with a minimum follow-up of 12 months. Odds ratios of intraretinal hyperreflective foci, hyporeflective drusen cores, subretinal drusenoid deposits, the presence of drusen volume ≥0.03 mm3 within a central 3-mm circle, fellow eye with late stage of AMD, and CC flow deficits at baseline and months of follow-up were estimated from logistic regression. A total of 112 eyes with iAMD were included. Eyes that progressed were significantly more likely to show intraretinal hyperreflective foci, hyporeflective drusen cores, and drusen volume ≥0.03 mm3. The CC flow deficit was also significantly greater in eyes that developed complete retinal pigment epithelial and outer retinal atrophy. Intraretinal hyperreflective foci, hyporeflective drusen cores, drusen volume ≥0.03 mm3, and higher CC flow deficits were significantly and independently associated with the development of complete retinal pigment epithelial and outer retinal atrophy. The CC flow deficit was significantly greater in iAMD eyes that progressed to complete retinal pigment epithelial and outer retinal atrophy and remained an independent risk factor when structural optical coherence tomography biomarkers were considered. CC flow deficits may be useful for enhancing risk stratification and prognostication of patients with iAMD.

Association between Patient-Reported Outcomes and Time to Late Age-Related Macular Degeneration in the Laser Intervention in Early Stages of Age-Related Macular Degeneration Study

To investigate the relationship between patient-reported outcome (PRO) questionnaire responses and time to late age-related macular degeneration (AMD; neovascular AMD [nAMD] or multimodal imaging [MMI]-defined atrophy) among individuals with bilateral large drusen, and the prognostic value of baseline PROs for 36-month AMD status. Exploratory analyses from a multicenter randomized controlled trial of an AMD intervention (Australian New Zealand Clinical Trials Registry identifier, ACTRN12612000704897). Sham treatment group of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) Study (n= 141; age, 50-88 years; 77% female). The 28-item Impact of Vision Impairment (IVI-28) and 10-item Night Vision Questionnaire (NVQ-10) were administered at the baseline visit. The PRO scores were derived using rating scale models. Multivariate Cox regression adjusting for demographics and clinical measures of vision (low-luminance visual acuity, low-luminance deficit, and microperimetric sensitivity) from the poorer-performing eye was used to investigate the association between PRO scores and time to late AMD in either eye. Multivariate competing-risk regression was used to estimate cause-specific subhazard ratios for nAMD and atrophy in either eye. Cross-validated logistic lasso models were used to estimate the predicted probability of AMD at 36 months. The area under the receiver operating characteristic curve was assessed to compare prognostic accuracy between models with and without PROs. Time until nAMD or atrophy in either eye. The PRO scores were skewed toward higher functional vision. Higher IVI-28 scores were associated with a lower risk of progression to MMI-defined atrophy (20 events: adjusted hazard ratio, 0.65/logit increase; P=0.002) but not nAMD (10 events; P= 0.562). Insufficient evidence was found of an association between NVQ-10 score and rate of progression to late AMD (P ≥0.149). Baseline IVI-28 scores were found to contribute to the prognosis of atrophy at the 36-month visit (P= 0.010). On average, PROs were associated with an increased risk of progression from intermediate AMD to MMI-defined atrophy. Continuing development of instruments to record PROs in the early stages of AMD have the potential to produce inexpensive and efficient tools to assist in the assessment of disease severity and risk of AMD progression.

Complement Activation Levels Are Related to Disease Stage in AMD.

PurposeTo study the levels of complement activation in different disease stages of AMD and the influence of genetic polymorphisms in complement genes.MethodsWe included 797 patients with AMD and 945 controls from the European Genetic Database. Patients were grouped into five AMD stages: early AMD, intermediate AMD, central geographic atrophy, active choroidal neovascularization or inactive choroidal neovascularization. Differences in complement activation, as defined by the systemic C3d/C3 ratio, between AMD stages were evaluated using general linear modeling. In addition, we evaluated the influence of 18 genetic AMD polymorphisms in complement genes and their effect on complement activation. Differences in complement activation between stages were evaluated stratifying by complement associated haplotypes.ResultsComplement activation levels differed significantly between AMD disease stages. As compared with controls, the C3d/C3 ratio was higher in patients with intermediate AMD (P < 0.001) and central geographic atrophy (P = 0.001). Two polymorphisms in CFH (rs10922109 and rs570618) and one in CFB (rs116503776) were significantly associated with complement activation. The association between AMD disease stage and complement activation was more pronounced in patients with haplotypes associated with the highest complement activation.ConclusionsIn general, consecutive AMD disease stages showed increasing levels of complement activation, especially in individuals with a genetic burden in complement genes. These findings contribute to the discussion on the pathogenesis of AMD in relation to complement activation and might suggest refinement in patient selection and the optimum window of treatment with complement inhibitors. Prospective studies are needed to confirm these results.

Do Clinical Trial Publications in AMD Healthcare Provide Sufficient Information on the Underlying Samples' Baseline Characteristics to Enable Generalizability Considerations on the Trial Design?

Results of RCTs must enable readers to assess applicability of the presented information into clinical routine. Therefore, the CONSORT statement's item 15 recommends explicit information on (baseline) characteristics for RCT samples. We sought to quantify the adherence to this CONSORT item by evaluation of RCTs on "age-related macular degeneration" (AMD). A full survey comprised of 132 RCTs (01/2004 - 12/2013). Two parallel independent readers evaluated, and then consented, whether baseline characteristics as recommended were provided in the publication, and whether this information was formally and correctly presented. The evaluation was performed hierarchically in accordance to the sub-criteria of the CONSORT-statement. In the case of formally correct documentation, characteristics for age, gender, the primary clinical endpoint outcome, and the stage of AMD were checked, as well as for systemic or ophthalmological pre-existing conditions. 129 of 132 (98%) publications provided the documentation of baseline data, but only 67 (51%) showed a correct implementation. 77 (58%) RCT reports presented baseline data at study initiation, among which n = 67 (87%) publications presented the data stratified for samples. The implementation rate of the CONSORT criterion "baseline data" in publications appeared high. On closer inspection, publications often provided incomplete or even misleading baseline data. As a consequence, everybody in the publication process should be aware of the conditions for publishing.

Epidemiology of Age-Related Macular Degeneration in the Republic of Bashkortostan (Clinical and Statistical Analisys of the “Ural Eye and Medical Study”)

Purpose. Analysis of the AMD prevalence in the Republic of Bashkortostan, depending on the disease stage, gender and the nature of the respondent settlement. Methods. A population-based study of Republic of Bashkortostan residents “Ural Eye and Medical Study” was conducted on the basis of the State Budget Institution “Ufa Research Institute of Eye Diseases of the Academy of Sciences of the Republic of Bashkortostan”. There were 5899 participants in the study, 2581 (43.7 %) were men, 3318 (52.3 %) were women. There were 2501 urban residents (42.3 %), rural residents — 3398 (59.7 %). Study design: cross-sectional one-stage analytical research. Statistical data analysis was performed using the IBM SPSS statistic application package. Results. AMD was diagnosed in 550 individuals (11.5 %): early stage — in 392 (7.9 %), intermediate — in 119 (2.4 %), later — in 39 individuals (0.8 %). The number of men with AMD was 210 (10.8 %), women — 340 (11.4 %). Among men, an early stage was observed in 144 (7.4 %), intermediate — in 52 (2.7 %), later — in 14 individuals (0.7 %). Among women, early AMD was observed in 248 (8.3 %), intermediate — in 67 (2.2 %), later — in 25 individuals (0.8 %). The number of urban residents with AMD was 194 individuals (9.7 %), rural residents — 356 individuals (12.1 %). At the same time, among urban residents, an early stage was observed in 138 (6.9 %), intermediate — in 43 (2.2 %), and later stage — in 13 individuals (0.6 %). Among rural residents, the early stage of AMD is in 254 (8.6 %), intermediate — in 76 (2.6 %), later — in 26 individuals (0.9 %). Conclusion. The prevalence of AMD in the Republic of Bashkortostan according to the “Ural Eye and Medical Study” is 11.1 %, which exceeds the global figure. The lack of prevalence of the AMD among women (among women — 11.4 %, among men — 10.8 %) is a distinctive feature for this region. The prevalence of this pathology among rural residents (12.1 %), among urban (9.7 %). The influence of population characteristics for the prevalence of AMD in regions with a peculiar ethno-cultural composition, geographical features.

The Border of Macular Atrophy in Age-Related Macular Degeneration: A Clinicopathologic Correlation

To correlate invivo imaging to histology in an eye with macular atrophy owing to age-related macular degeneration (AMD; complete retinal pigment epithelium [RPE] and outer retinal atrophy [cRORA]) to evaluate the utility of new optical coherence tomography (OCT) suggested by previous histology. Case study with clinicopathologic correlation. Invivo eye-tracked cross-sectional OCT scans at 13 and 8months before death were compared to postmortem histopathology. On OCT, the atrophy border was identified as either the descent of the external limiting membrane (ELM) toward the Bruch membrane (BrM) (representing gliosis) or the presence of choroidal hypertransmission (representing lack of shadowing by RPE). Thicknesses of RPE, basal laminar deposit (BLamD), and BrM were measured at 500 and 100μm on the nonatrophic and atrophic sides of these borders, on invivo eye-tracked OCT and histology matched to the same location. In all OCT scans, the ELM descent was visible. The RPE-BLamD band significantly thickened toward it (P < .005), over time (P= .015 and P= .043, at 500 and 100μm, respectively). On OCT, the ELM descent delineated a smaller atrophic area than did hypertransmission. RPE-BLamD thicknesses manually measured on OCT overestimated histologic thicknesses. BrM visibility varied with RPE status. Visible on OCT, the ELM descent is a histopathologic atrophy border supporting new terminology of cRORA, whereas hypertransmission reveals RPE degeneration. RPE-BLamD thickening across the macula, toward the atrophy and over time is confirmed. The presence of gliosis and thick RPE-BLamD suggests that macular atrophy is a late stage in disease progression, encouraging anatomic endpoints at earlier AMD stages than atrophy enlargement.