Severe Age-related Macular Degeneration Research Articles

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

CLINICAL-OPHTHALMOLOGICAL INDICATORS WHICH DETERMINE THE SEVERITY OF AGE-MACULAR DEGENERATION

Background. The search for biomarkers and simple mathematical systems for predicting the severity of age-related macular degeneration (AMD) is necessary and relevant.
 Aim: to determine prognostic clinical and ophthalmological indicators that determine the severity of AMD.
 Material and methods. The study included observational data of 302 eyes (152 patients), in which the stage of AMD was determined according to the recommendations of the AREDS study. The age of the patients was 71.18 years, 59.9% were women, 40.1% were men. Visual acuity, maximum corrected visual acuity (MCVA), the number of drusen of various calibers, the presence of changes in the retinal pigment epithelium, subretinal neovascular membrane (SNM) and geographic atrophy were determined.
 Results. By age, patients with a mild course of AMD were younger than those with a severe course by 6.9 years (p<0.001). Smokers accounted for 31.5% of patients, the course of AMD in such patients was more often severe – 37.2% versus 21.9% in non-smokers (p=0.006). Visual acuity and MCVA were significantly worse in patients with severe AMD (p<0.001). There was no significant difference in the number of small and medium-sized drusen (p>0.5). Large drusen, pigmentary changes and SNM were found almost only in patients with severe AMD. Moreover, pigmentary changes were present in almost all patients with severe AMD (92.6%), and SNM and geographic atrophy – in 23.9% and 21.8%, respectively. According to the data of the discriminant analysis, almost all indicators had a clear relationship with the course of AMD, but the F coefficient was the largest for pigmentary changes, MCVA, the number of large drusen and age. These indicators were included in the system of discriminant equations for determining the AMD severity.
 Conclusion. With the help of discriminant analysis, the indicators determining the severity of the course of AMD were found.

Short term effects of extremely low irradiance photobiomodulation on retinal function, in age related macular degeneration.

recently much studies evidenced the potential role of photo-biomodulation (PBM) in patients affected by Age-related Macular Degeneration (AMD). We designed a new wearable device for self-medication that employs the same broadband red light described in literature, but with extremely low irradiance. to demonstrate the safety and effectiveness of low-fluence light stimulations emitted by a LED source with appropriate wavelengths through our new device in improving short-term visual function in patients affected by severe non neovascular AMD. we prospectively enrolled patients affected by severe non-neovascular AMD with a relative sparing of the foveal region. All the patients were randomly assigned in placebo or in treatment group. The treatment consisted of 10 sessions of 10-min each, using the new device comprised of micro-LEDs that emitted light onto an amorphous support assembled within Metallic eyeglasses. The placebo group blindly underwent the same number of PBM sessions with the micro-LED turned off. Before and after each placebo/treatment sessions all the patients received: optical coherence tomography (OCT), Best-Corrected Visual Acuity (BCVA) and Microperimetry (MP). no significant differences in the anatomical parameters were observed in the two groups. The MP mean sensitivity and the central visual function both far and near significantly improved in the treated group (respectively p < 0.001, p < 0.001). our pivotal demonstrated that the LED PBM delivered through our new device is a safe and effective tool for improving short-term visual function in patients affected by severe non-neovascular AMD.

Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration

ObjectiveA recent genome-wide association study of age-related macular degeneration (AMD) has identified new AMD-associated risk variants. These variants can now be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated polygenic risk score (PRS2023) in an independent cohort of older individuals with retinal imaging data, and compare performance with an older PRS (PRS2016). DesignCross-sectional study. ParticipantsA total of 4,175 participants of European ancestry aged ≥70 years with genotype and retinal imaging data from the ASPirin in Reducing Events in the Elderly trial. MethodsWe used logistic regression models and area under the curve (AUC) to assess the performance of the PRS2023 compared with PRS2016. AMD status and severity were graded using colour fundus photography. Main Outcome MeasuresAssociation of PRS2023 and PRS2016 with AMD risk at baseline. ResultsAt enrolment among 4,175 participants, 2,605 (62.4%) had no AMD, 853 (20.4%), 671 (16.1%) and 46 (1.1%) had early, intermediate and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with <15% for those in the middle two quartiles and <13% for those in the lowest quartile. Both PRS2023 and PRS2016 were significantly associated with AMD after adjustment for age, sex, smoking status and lipid levels, with increasing odds ratios (OR) for worsening AMD grades. The PRS2023 outperformed PRS2016 (DeLong test comparing AUC, P=0.03 for all AMD, P=0.03 for late AMD). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 [3.41-7.47] per standard deviation. Assuming a population prevalence of 10% for late-stage AMD, the PRS2023 explained 42.2% of disease liability. The AUC of a model containing conventional/non-genetic risk factors and the PRS2023 was 91% [87%-95%] for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC=79%, P<0.001 for difference). ConclusionsA new PRS (PRS2023) for AMD outperforms a previous PRS, and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD.

Adverse COVID-19 outcomes in American Veterans with age-related macular degeneration: a case–control study

ObjectivesPrior studies suggest that patients with age-related macular degeneration (AMD) have poorer COVID-19 outcomes. This study aims to evaluate whether AMD is associated with adverse COVID-19 outcomes in a large...

Genetic Risk Score Analysis Supports a Joint View of TwoClassification Systems for Age-Related Macular Degeneration.

The purpose of this study was to evaluate the utility of combining the Clinical Classification (CC) and the Three Continent age-related macular degeneration (AMD) Consortium Severity Scale (3CACSS) for classification of AMD. In two independent cross-sectional datasets of our population-based AugUR study (Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg), we graded AMD via color fundus images applying two established classification systems (CC and 3CACSS). We calculated the genetic risk score (GRS) across 50 previously identified variants for late AMD, its association via logistic regression, and area under the curve (AUC) for each AMD stage. We analyzed 2188 persons aged 70 to 95 years. When comparing the two classification systems, we found a distinct pattern: CC "age-related changes" and CC "early AMD" distinguished individuals with 3CACSS "no AMD"; 3CACSS "mild/moderate/severe early AMD" stages, and distinguished CC "intermediate AMD". This suggested a 7-step scale combining the 2 systems: (i) "no AMD", (ii) "age-related changes", (iii) "very early AMD", (i.e. CC "early"), (iv) "mild early AMD", (v) "moderate early AMD", (vi) "severe early AMD", and (vii) "late AMD". GRS association and diagnostic accuracy increased stepwise by increased AMD severity in the 7-step scale and by increased restriction of controls (e.g. for CC "no AMD without age-related changes": AUC = 55.1%, 95% confidence interval [CI] = 51.6, 58.6, AUC = 62.3%, 95% CI=59.1, 65.6, AUC = 63.8%, 95% CI=59.3, 68.3, AUC=78.1%, 95% CI=73.6, 82.5, AUC = 82.2%, 95% CI = 78.4, 86.0, and AUC = 79.2%, 95% CI = 75.4, 83.0). A stepwise increase was also observed by increased drusen size and area. The utility of a 7-step scale is supported by our clinical and GRS data. This harmonization and full data integration provides an immediate simplification over using either CC or 3CACSS and helps to sharpen the control group.

Analysis of Retinol Binding Protein 4 and ABCA4 Gene Variation in Non-Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) may be associated with ABCA4 variants and is characterized by the accumulation of visual cycle-byproduct lipofuscin. Reducing retinol-binding protein 4 (RBP4), a retinol transporter protein, may reduce lipofuscin production. This study aims to assess the associations between plasma RBP4, the ABCA4 variation, and AMD severity. Sixty-seven participants were grouped into healthy/mild AMD (n = 32) and severe AMD (n = 35) groups. The latter group was older than the former group and had higher levels of RBP4 (36.8 ± 8.3 vs. 30.4 ± 7.0 μg/mL, p = 0.0012). The ten participants with six ABCA4 linked-variants had higher RBP4 than those without (37.8 ± 7.7 vs. 32.4 ± 7.9 μg/mL; p = 0.026), and eight of them had severe AMD. Univariate analyses showed that severe AMD was related to older age (OR, 1.26; 95% CI, 1.13-1.40; p < 0.0001) and to higher RBP4 levels (OR, 1.12; 95% CI, 1.04-1.20; p = 0.003), whereas the linked ABCA4 variants had no associations. After adjustment, however, only age remained significantly associated with severe AMD. This pilot study shows a trend of higher plasma RBP4 levels in severe AMD or the ABCA4-linked variants, and further age-matched studies are warranted.

108-OR: Clinical and Biochemical Factors Are Inversely Correlated in Diabetic Retinopathy and Age-Related Macular Degeneration

Although diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the two most common sight-threatening conditions in the elderly population, our understanding of the associated risks for these diseases have not been studied. Thus, we examined the association between AMD and DR in people with type 1 and type 2 diabetes from the Joslin 50-Year Medalist Study, composed of individuals who have had insulin-dependent diabetes for 50 years or longer and Beetham Eye Institute. In Medalists, there was an inverse association between DR severity and the presence of AMD (N=1163, P=&amp;lt;0.0001, AMD: 23.4%, 18.6, 7.9% for no-mild, moderate-severe, and proliferative DR, respectively). Similarly, the presence of AMD was associated with milder DR in the BEI cohort (N=58, P=0.004). There were no eyes with neovascular (severe AMD). The presence of AMD was associated with older age (P=0.03), increased diabetes duration (P&amp;lt;0.0001), less severe DR (P&amp;lt;0.0001), and the absence of neuropathy (P=0.003). In contrast, younger age (P=0.02) and the presence of neuropathy (P&amp;lt;0.0001) were associated with the presence of proliferative DR. Higher vitreous retinol-binding protein 3 (RBP3) to vascular endothelial growth factor (VEGF) ratios were associated with AMD and less severe DR in both postmortem Medalist and surgical BEI samples (N=187, P&amp;lt;0.05, all). The presence of milder DR was associated with increased risk of AMD development (24.8%, 10.0%, 5.0% for no-mild, moderate-severe, and proliferative DR, respectively, P=0.047), and risk of DR progression was decreased in eyes with versus without AMD (P=0.04) in a subset of Medalists with longitudinal follow up (22.9%). These novel findings that the inverse risk of DR and AMD is not likely due to similar pathogenic mechanisms and ageing factors. Further studies are needed to clarify the interactions between AMD and DR, that may provide new pathways to target against their development. Disclosure W.Fickweiler: None. G.L.King: Research Support; Janssen Research &amp; Development, LLC. C.Jacoba: None. S.Jangolla: None. J.Gauthier: None. N.A.Ziemniak: None. I.Wu: None. J.D.Cavallerano: None. L.P.Aiello: Consultant; KalVista Pharmaceuticals, Inc., Novo Nordisk, MantraBio, Ceramedix, Research Support; Optos plc., Stock/Shareholder; KalVista Pharmaceuticals, Inc. J.Sun: Research Support; Adaptive Sensory Technology, Boehringer Ingelheim Inc., Roche Pharmaceuticals, Janssen Pharmaceuticals, Inc., Physical Sciences, Inc, Novo Nordisk, Optovue, Incorporated. Funding American Diabetes Association (7-21-PDF-022 to W.F.); National Eye Institute (R01EYE26080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK09433301); JDRF (17-2013-310); Dianne Nunnally Hoppes Fund; Beatson Pledge Fund

Severity of age-related macular degeneration at first presentation in Bhutan: a 3-year national study

BackgroundMedical services are still developing in Bhutan. There is no published national report on age-related macular degeneration (AMD). We therefore aim to determine the demographic characteristics and severity of AMD at first presentation among Bhutanese patients attending their recently inaugurated vitreoretinal (VR) clinics over a 3-year national survey, and to inform national health policy to develop suitable health program to prevent AMD-related blindness and visual impairment.MethodsA retrospective cross-sectional consecutive case series study was conducted on all new AMD cases in Bhutan. If a patient presented with asymmetrical AMD, the eye with more severe AMD was considered. If both the eyes had the same severity one eye was chosen randomly. Collection of demographic data and clinical details including diagnostic testing (fundus photography, OCT and fluorescent angiography) and clinical staging were performed.ResultsOf 521 new AMD patients aged 71.9 ± 11.3 years, 306/521 (58.7%) were males (p = 0.005). At their first presentation, 234/521 patients (44.9%) already had late-stage AMD. Importantly, 69/234 patients (29.5%), that is half of total neovascular AMD (nAMD) patients, had disciform scars (DS) which were beyond treatment, and 7/234 patients (3.0%) had geographic atrophy (GA). Seven patients had retinal pigment epithelium tear at presentation. Fourteen of nineteen polypoidal choroidal vasculopathy (PCV) patients were younger than 50 years.ConclusionsHalf of nAMD cases presented as DS not amenable to the treatment. Many potentially treatable nAMD patients had already lost central vision and were legally blind. Young people with PCV losing vision early in life with longer morbidity-affected life and socio-economic burden was concerning. GA and DS cases need visual rehabilitation to improve their QoL. Incorporating a screening program for AMD with effective health education, and maintaining a national AMD Registry, would potentially lower AMD-related blindness and visual impairment.

Dust Storms Increase the Risk of Age-Related Macular Degeneration.

The main purpose of this study was to examine the association between dust storms (DSs) and age-related macular degeneration (AMD) using a 5 year representative national dataset with one million participants, according to information on DS, meteorology, and air pollution in Taiwan. There were 18,855 AMD outpatient cases and 1080 AMD inpatient cases during 2008–2012. A Poisson time-series model was used for the analysis. The results show that AMD cases are significantly associated with exposure to dust storm events. Average daily numbers of wet and dry AMD outpatient cases increased from 6.03 and 4.26 on no-event days to 8.25 and 6.67, 2 days after DSs. Average daily numbers of wet and dry AMD inpatient cases increased from 0.26 and 0.33 on no-event days to 0.58 and 0.75, 1 day after DSs. Both genders and different age groups are all affected by the occurrence of DSs, especially 1 and 2 days after DS events. Women are at a higher risk of outpatient visits and hospitalizations for relatively severe wet AMD. Although AMD highly correlated with age, this study also found that dry AMD outpatient visits in people under the age of 50 were also found to be significantly associated with DS events. In order to protect the health of eyes and avoid AMD, one should reduce or avoid outdoor activities when DS events occur.

MicroRNA-184 attenuates hypoxia and oxidative stress-related injury via suppressing apoptosis, DNA damage and angiogenesis in an in vitro age-related macular degeneration model

Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide, particularly in developed countries. Recently, microRNAs (miRs) have become popular research area to develop new treatment options of AMD. However, interaction between hsa-miR-184 and AMD remain largely unexplored. In this study, sub-lethal levels of Deforoxamine Mesylate salt (DFX) and H2O2 were applied to ARPE-19 cells to establish a severe in vitro AMD model, via durable hypoxia and oxidative stress. We found that up-regulation of miR-184 level in AMD can suppress hypoxia-related angiogenic signals through HIF-1α/VEGF/MMPs axis. Also, miR-184 suppressed the hypoxia sensor miR-155 and genes in the EGFR/PI3K/AKT pathway, which is an alternative pathway in angiogenesis. To investigate the mechanism behind this protective effect, we evaluated the impact of miR-184 on retinal apoptosis in a model of AMD. miR-184 inhibited retinal apoptosis by upregulating BCL-2 and downregulating pro-apoptototic BAX, TRAIL, Caspase 3 and 8 signals as well as p53. Taken together, miR-184 attenuates retinal cell damage induced by severe AMD pathologies through suppressing hypoxia, angiogenesis and apoptosis. The safety profile of miR-184 was observed to be similar to Bevacizumab, which is in wide use clinically, but miR-184 was found to provide a more effective therapeutic potential by regulating simultaneously multiple pathologies.

LXA4 protects against blue-light induced retinal degeneration in human A2E-laden RPE cells and Balb-c mice.

BackgroundAge-related macular degeneration (AMD) is one of the leading causes of permanent visual impairment in the elderly. Blue light (BL) has been reported to cause retinal damage and contribute to the onset and development of severe AMD. N-retinylidene-N-retinylethanolamine (A2E), a lipofuscin fluorophore, accumulates with ageing in the retinal pigment epithelium (RPE) cells. Once exposed to BL, A2E easily oxidizes to A2E-epoxides, causing oxidative-stress injury to the retina. Lipoxin A4 (LXA4), an endogenous anti-antioxidant lipid, plays a key role in multiple organs by binding to the formyl-peptide receptor-like 1 (FPRL1). This study examined the protective effects of LXA4 on oxidative–stress injury induced by BL exposure, and clarified the underlying mechanisms in cultured RPE cells and Balb-c mice.MethodsLXA4 diluent was orally administered to mice before retinal degeneration was established. Optical coherence tomography, retinal histology, and RPE cell injury were assessed.ResultsLXA4 administration significantly ameliorated retinal damage as evidenced by the thicknesses of the retinal layers and the tight junctions of RPE cells in vivo. LXA4 inhibited BL-induced reactive oxygen species (ROS) production, reduced tight junctions, and the death of A2E-laden RPE cells. LXA4 also potently increased the expression of haem oxygenase-1 (HO1) and NAD(P)H quinone oxidoreductase 1 (NQO1), probably by decreasing the association between nuclear factor erythroid 2-related factor 2 (NRF2) and Kelch-like ECH (Epichlorohydrin) -associated protein 1 (Keap1), and ameliorating NRF2 nuclear translocation and the antioxidant response element (ARE) deoxyribonucleic acid (DNA) binding activity.ConclusionsOur results showed that LXA4 ameliorated retinal degeneration, and should be considered in the prevention and treatment of AMD.

Association of Systemic Inflammatory Factors with Progression to Advanced Age-related Macular Degeneration

ABSTRACT Purpose Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. The role of systemic inflammation in AMD remains unclear specifically in patients with intermediate AMD (iAMD). We sought to determine whether systemic inflammation was associated with future iAMD progression. Methods Combinations of 27 circulating inflammatory markers including complement factors, cytokines, chemokines, and high-sensitivity C-reactive protein (hsCRP) were evaluated in iAMD patients recruited into a Colorado AMD registry. Systemic inflammatory markers were combined using principal component analysis. Risk factors for AMD progression were evaluated using Cox regression models. Results This study included 99 subjects with iAMD, 21 of which progressed to advanced AMD. Two principal components (PCs) were identified that contributed to the risk of progression to advanced AMD, after adjusting for age and bilateral reticular pseudodrusen. The strongest associated PC was explained largely by the pro-inflammatory cytokine TNFα and the anti-inflammatory IL1ra antagonist of IL1. The additional PC was largely explained by IL6, IL8, C3 and factor D in the positive direction and CRP, MCP1, factor B and factor I in the negative direction. Conclusion When evaluated through multivariate analyses, combinations of biomarkers distinguished patients who did and did not progress to future advanced AMD. Increased risk could result from different combinations of analyte levels indicating a complex relationship rather than a simple increase in a few markers. This suggests that studying systemic inflammation in iAMD can provide insights into early pathologic events and potentially identify patients at highest risk for the development of severe AMD.

Measurement of drusen and their correlation with visual symptoms in patients affected by age-related macular degeneration.

Age-related macular degeneration (AMD) is a common retinal disorder, which became more and more prevalent in the last decades. AMD is now the most prevalent cause of blindness in the western world. The disorder is classified into two phenotypes named dry and wet AMD. This is based on the recruitment of novel blood vessels and inflammatory exudates in wet AMD. In both phenotypes, the pathological hallmark is the presence of proteinaceous aggregates called drusen, which mostly accumulate between the choroid and the retinal pigment. Drusen in dry AMD represent the evident pathological finding although they are present, though less defined, in wet AMD. In AMD drusen are supposed to be a pathogenic trigger of the disorder. In fact, drusen may mechanically alter retinal function. A novel hypothesis exists, suggesting that a metabolic defect (systemic or focal within the retinal pigment epithelium) may be the real determinant of visual impairment, while causing the concomitant accumulation of proteinaceous debris and lipids forming the drusen. Here we face such an issue by analyzing the retinal anatomy to correlate visual impairment with the occurrence of drusen number, size and the extent of a drusenoid area in the foveal region. A comparison is made with wet AMD where new vessels and retinal exudates prevail. The study is carried out in 120 patients affected by dry or wet AMD and 21 patients where paradoxical findings are described. The main question consists in inferring whether the occurrence of visual impairment is due, in fact, to a drusen-dependent mechanical damage or drusen just occurs as an independent consequence of an upstream metabolic alteration, which concomitantly impairs the visual process. The present data indicate that, despite a significant difference in visual function between mild and severe AMD patients in the amount of drusen exists, a strong correlation between drusen and visual impairment does not occur. This suggests that drusen and visual deterioration develop as a consequence of similar upstream biochemical alterations but it is likely that drusen do not produce visual deterioration. This is strengthened here by extreme clinical conditions, where visual impairment is severe with a slight alteration in the planar pattern of the retina or, vice versa an extended drusenoid area occurs concomitantly with fair visual acuity, contrast sensitivity and lack of metamorphopsia. A biochemical analysis of key areas in the function of specific domains in the pigment epithelium as described in the accompanying manuscript should help to better disclose the real morpho-functional deficit, which takes place in AMD.

The Positive Legacy of Vision Loss: Pathways to Posttraumatic Growth

This mixed method study describes posttraumatic growth (PTG) accruing form experience with vision loss caused by severe age related macular degeneration (AMD) and explores relationships between depression, social support, and cognitive processing, on the path to PTG. Research describing the psychological and social issues surrounding AMD has focused on negative outcomes. However, learning from highly challenging experiences, such as vision loss, can offer benefits. In this study, these included an increased sense of personal strength, increased spirituality, and empathy for others (all domains of PTG). 89 participants with severe vision loss (mean age = 85.3 years, age range = 74–98 years) completed the interviewer-administered composite questionnaire, which identified elements of Tedeschi and Calhoun’s model of PTG. Relationships between variables were examined using path analysis. Findings were contextualized with data from 15 qualitative interviews. Findings underscored the importance of supportive others and deliberate cognitive processing in the path to PTG.

Protective effect of Prunella vulgaris var. L extract against blue light induced damages in ARPE-19 cells and mouse retina

Age-related macular degeneration (AMD) is one of leading causes that induce severe visual impairment and loss in the elderly. Previous studies have suggested that blue light (BL) could induce retinal degeneration, which is a major cause of the onset and development of severe AMD. In the retinal pigment epithelium (RPE) cells, A2E, a lipofuscin fluorophore, is accumulated with aging. When A2E is exposed to BL, it is easily oxidized to A2E-epoxides, leading to oxidative stress and inflammatory response in retina. The aim of this study was to investigate protective effect of Prunella vulagris (P.V) extract against oxidative stress and inflammation caused by BL, and to elucidate the underlying mechanisms in the cultured RPE cells and balb-c mice. In both model studies, P.V extract activated NF-E2 related factor 2 (Nrf-2)/hemeoxygenase-1 (HO-1) signaling pathway, followed by inhibition of ROS/MDA production, GSH depletion and reduction in SOD activity. Furthermore, P.V extract inhibited upregulation of inflammatory related genes (interlukin (IL)-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor A (VEGF A)) and BL induced RPE cell death, determined by cell viability and histological analyses. The mechanism of protection against inflammation by P.V extract involves inhibition of nuclear translocation of nuclear factor kappa beta (NF-kB) along with degradation of NF-kB inhibitor alpha (IkB alpha). The results suggest that P.V extract could be a potential intervention to prevent the onset and development of severe AMD.

Late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration

To report the clinical and genetic characteristics of 6 cases with late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration. Clinical and genetic data were collected from 6 independent patients who complained of night blindness in their fifth to eighth decade of life. The ophthalmological examinations included ophthalmoscopy, fundus autofluorescence (FAF), and full-field electroretinography (ERG). Whole exome sequencing with target gene analysis was performed to determine the causative genes and variants. All of the patients first complained of night blindness at the ages of 40-71years. Funduscopic examinations demonstrated white or atrophic flecks scattered in the posterior pole and peripheral retina bilaterally. FAF showed patchy hypo-autofluorescence spots in the posterior pole similar to that of the trickling type of age-related macular degeneration (AMD). The region of abnormal FAF rapidly expanded with age, and one eye developed a choroidal neovascularization. The full-field scotopic ERGs with 20min of dark adaptation were severely reduced or extinguished in all cases. There was partial recovery of the ERGs after 180min of dark adaptation. The cone ERGs were reduced in all cases. Whole exome sequencing revealed no pathogenic variants of 301 retinal disease-associated genes. The six cases had some common features with the flecked retina syndrome, familial drusen, and late-onset retinal degeneration although none had pathogenic variants causative for these disorders. These cases may represent a subset of severe trickling AMD or a new clinical entity of acquired pan-retinal visual cycle deficiency of unknown etiology.

First Results of a New Hyperaspheric Add-on Intraocular Lens Approach Implanted in Pseudophakic Patients with Age-Related Macular Degeneration

To determine the visual outcomes of the EyeMax Mono intraocular lens (IOL) technology (London Eye Hospital Pharma, London, UK), which is a foldable and injectable hydrophobic acrylic IOL implanted as an add-on solution in pseudophakic eyes with age-related macular degeneration, in a pilot study. A prospective, interventional case series. A total of 22 pseudophakic eyes (11 patients) with bilateral severe or intermediate dry age-related macular degeneration (AMD) (13 eyes) or stable wet AMD or disciform scarring (9 eyes) meeting the criteria for sulcal IOL implantation. Both eyes of participating subjects underwent small-incision ciliary sulcal implantation of a hyperaspheric, soft hydrophobic acrylic intraocular lens designed to improve the quality of the retinal image in all areas of the macula ≤10° from fixation and to generate a moderate hypermetropic correction for magnification. The primary outcome was safety as determined by intra- and postoperative complications, raised intraocular pressure requiring medical or surgical intervention, postoperative diplopia, reduction in visual field, and loss of ≥2 lines of visual acuity. Secondary outcomes were improvements in subjective and objective visual acuity (logarithm of the minimum angle of resolution). No intraoperative complication occurred. Elevated intraocular pressure values were measured directly after the operative procedure in 2 eyes (25 mmHg and 27 mmHg) and at the 1-week postoperative visit in 1 eye (22 mmHg) but not later. The mean postoperative spherical equivalent of refraction changed to+2.5 diopters, and all eyes had gained ≥2 lines of visual improvement (corrected distance visual acuity) by 6 months after surgery. Corrected near visual acuity as well as corrected distance visual acuity improved over time, suggesting a neuroadaptive component to improved visual function with the device. Devices were implanted bilaterally in all patients, and there were no reported symptoms of dysphotopsia or diplopia. Safety concerns were not identified in the short-term or medium term. These results indicate the potential of the EyeMax Mono IOL to improve near and distance visual acuity in pseudophakic eyes with intermediate to severe AMD.

Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration

Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.

Hypersensitivity toward bacterial stimuli in patients with age-related macular degeneration.

Although the pathogenesis of age-related macular degeneration (AMD) is unclear, genetic screening has revealed that polymorphisms in the complement system may be associated with AMD development. Production of autoantibodies was also found in AMD patients. In this study, we analyzed the antibody response in AMD patients. We found that purified B cells from AMD patients tended to respond to lower concentrations of bacterial antigen stimulation, and produced higher amounts of antibodies, especially in IgM and IgA secretions. When examining clinical symptoms, patients with more severe wet-form AMD tended to exhibit higher sensitivity to bacterial antigens and secreted more IgM and IgA antibodies than those with less severe dry-form cases. In conclusion, our study discovered an altered B-cell antibody production in response to bacterial antigens in AMD patients, which potentially contributes to AMD pathogenesis.