The Alzheimer's-related amyloid beta peptide is internalised by R28 neuroretinal cells and disrupts the microtubule associated protein 2 (MAP-2).

Age-related Macular Degeneration (AMD) is a common, irreversible blinding condition that leads to the loss of central vision. AMD has a complex aetiology with both genetic as well as environmental risks factors, and share many similarities with Alzheimer's disease. Recent findings have contributed significantly to unravelling its genetic architecture that is yet to be matched by molecular insights. Studies are made more challenging by observations that aged and AMD retinas accumulate the highly pathogenic Alzheimer's-related Amyloid beta (Aß) group of peptides, for which there appears to be no clear genetic basis. Analyses of human donor and animal eyes have identified retinal Aß aggregates in retinal ganglion cells (RGC), the inner nuclear layer, photoreceptors as well as the retinal pigment epithelium. Aß is also a major drusen constituent; found correlated with elevated drusen-load and age, with a propensity to aggregate in retinas of advanced AMD. Despite this evidence, how such a potent driver of neurodegeneration might impair the neuroretina remains incompletely understood, and studies into this important aspect of retinopathy remains limited. In order to address this we exploited R28 rat retinal cells which due to its heterogeneous nature, offers diverse neuroretinal cell-types in which to study the molecular pathology of Aß. R28 cells are also unaffected by problems associated with the commonly used RGC-5 immortalised cell-line, thus providing a well-established model in which to study dynamic Aß effects at single-cell resolution. Our findings show that R28 cells express key neuronal markers calbindin, protein kinase C and the microtubule associated protein-2 (MAP-2) by confocal immunofluorescence which has not been shown before, but also calretinin which has not been reported previously. For the first time, we reveal that retinal neurons rapidly internalised Aß1-42, the most cytotoxic and aggregate-prone amongst the Aß family. Furthermore, exposure to physiological amounts of Aß1-42 for 24 h correlated with impairment to neuronal MAP-2, a cytoskeletal protein which regulates microtubule dynamics in axons and dendrites. Disruption to MAP-2 was transient, and had recovered by 48 h, although internalised Aß persisted as discrete puncta for as long as 72 h. To assess whether Aß could realistically localise to living retinas to mediate such effects, we subretinally injected nanomolar levels of oligomeric Aß1-42 into wildtype mice. Confocal microscopy revealed the presence of focal Aß deposits in RGC, the inner nuclear and the outer plexiform layers 8 days later, recapitulating naturally-occurring patterns of Aß aggregation in aged retinas. Our novel findings describe how retinal neurons internalise Aß to transiently impair MAP-2 in a hitherto unreported manner. MAP-2 dysfunction is reported in AMD retinas, and is thought to be involved in remodelling and plasticity of post-mitotic neurons. Our insights suggest a molecular pathway by which this could occur in the senescent eye leading to complex diseases such as AMD.

An evaluation of intracameral mydriasis for routine cataract surgery.

BACKGROUND: Intracameral Mydrane might facilitate a more streamlined cataract service and improve the patient experience. There is limited 'real-world' evidence of its use in a UK setting. METHODS: As part of a local evaluation of cataract surgery using intracameral Mydrane (group 2; n=60), data were collected on intraoperative pupil size and postoperative visual acuity (VA), as well as the rate of mechanical pupil dilation, intraoperative floppy iris syndrome (IFIS) and complications. Preoperative and theatre turnaround time was recorded and patients completed a validated measure of satisfaction postoperatively. Data were compared with a previous cohort subjected to the existing standard regime of preoperative topical mydriatics (group 1; n=60). RESULTS: Postoperative VA was comparable between groups (0.09±0.16 vs 0.08±0.15; p=0.59). Pupil size in group 2 was 7.0±1.0 mm prior to capsulorhexis and 6.5±0.29 mm after cortical aspiration, with a smaller pupil in patients on alpha-antagonists (4.7±1.1 mm; p=0.004) at this later time point. Comparing group 2 with group 1, preoperative waiting was less (87 vs 146 min; p<0.0001) and satisfaction was higher (76.0±11.2 vs 66.3±8.6; p<0.0001), although theatre turnaround time was longer (25 min vs 22 min). CONCLUSION: Intracameral mydriasis was clinically effective in most patients undergoing cataract surgery and might be associated with an improved patient experience and a more streamlined preoperative flow. Mydrane represents a licensed alternative to the off-label use of other intracameral mydriatic agents, but was not judged to be a cost-effective intervention for routine use in this particular setting.

Fine-scale linkage disequilibrium mapping of age-related macular degeneration in the complement factor H gene region.

AIM: To present results from a nested association study of the complement factor H (CFH) gene region using a novel methodology that uses a high-resolution genetic linkage disequilibrium map to estimate a point location for a causal mutation. METHOD: Age-related macular degeneration (AMD) case-control data from a genomewide single-nucleotide polymorphism (SNP) panel were used to identify the target interval to be genotyped at higher density in a second independent panel. The pattern of linkage disequilibrium (LD) and segmental duplications across this region are described in detail. RESULT: Data were consistent with other studies in that strong association between the Y402H variant and AMD is observed. However, composite likelihood analysis, which combines association data from all SNPs in the region, and uses genetic locations on a high-resolution LD map, gave a point location for a causal variant between exons 1 and 2 of the CFH gene. CONCLUSION: The findings are consistent with evidence that, in addition to the widely described Y402H variant, there is at least one and, most probably, several other mutations in the CFH gene which determine disease manifestation in AMD. A genetic model in which multiple mutations contribute to a varying degree to disease aetiology has been previously well described in ophthalmic genetics, and is typified by the COL2A1 and ABCA4 genes.

Fixed bimonthly aflibercept in naïve and switched neovascular age-related macular degeneration patients: one year outcomes.

AIM: To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen. METHODS: This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated. RESULTS: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year. CONCLUSION: Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.

The Evolution of Teleophthalmology Programs in the United Kingdom: Beyond Diabetic Retinopathy Screening.

Modern ophthalmic practice in the United Kingdom is faced by the challenges of an aging population, increasing prevalence of systemic pathologies with ophthalmic manifestations, and emergent treatments that are revolutionary but dependent on timely monitoring and diagnosis. This represents a huge strain not only on diagnostic services but also outpatient management and surveillance capacity. There is an urgent need for newer means of managing this surge in demand and the socioeconomic burden it places on the health care system. Concurrently, there have been exponential increases in computing power, expansions in the strength and ubiquity of communications technologies, and developments in imaging capabilities. Advances in imaging have been not only in terms of resolution, but also in terms of anatomical coverage, allowing new inferences to be made. In spite of this, image analysis techniques are still currently superseded by expert ophthalmologist interpretation. Teleophthalmology is therefore currently perfectly placed to face this urgent and immediate challenge of provision of optimal and expert care to remote and multiple patients over widespread geographical areas. This article reviews teleophthalmology programs currently deployed in the United Kingdom, focusing on diabetic eye care but also discussing glaucoma, emergency eye care, and other retinal diseases. We examined current programs and levels of evidence for their utility, and explored the relationships between screening, teleophthalmology, disease detection, and monitoring before discussing aspects of health economics pertinent to diabetic eye care. The use of teleophthalmology presents an immense opportunity to manage the steadily increasing demand for eye care, but challenges remain in the delivery of practical, viable, and clinically proven solutions.

Association of HLA class I and class II polymorphisms with age-related macular degeneration.

PURPOSE: To evaluate whether HLA genotypes are associated with age-related macular degeneration (AMD). METHODS: HLA class I-A, -B, and -Cw and class II DRB1 and DQB1 principal allele groups were genotyped in two stages: initially for principal allele groups in a cohort of 100 AMD cases and 92 control subjects, and then, in the next 100 cases and controls from the same cohort, for alleles or allele groups with P < 0.1 on initial typing. Genotype frequencies were compared by 2 x 2 contingency tables. The strongest associations for individual HLA alleles were calculated with two-locus stratification analysis and logistic regression for all possible pair-wise HLA combinations. Bonferroni corrections were applied for multiple measurements (P(c)). Each HLA allele was subjected to logistic regression for known AMD covariates. HLA immunohistochemistry for class I antigens was performed on elderly donor eyes. RESULTS: Allele Cw*0701 (P = 0.004, P(c) = 0.036) correlated positively with AMD, whereas alleles B*4001 (P = 0.003, P(c) = 0.027) and DRB1*1301(P = 0.001, P(c) = 0.009) were negatively associated. These HLA associations were independent of any linkage disequilibrium. Immunohistochemistry demonstrated differential HLA class I expression in choriocapillary endothelial cells. CONCLUSIONS: Significant positive and negative associations exist between HLA alleles and AMD. HLA polymorphisms influence the development of AMD, possibly via modulating choroidal immune function.

Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration.

Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and "real-world" outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography.

Impact of graft thickness on visual acuity after Descemet's stripping endothelial keratoplasty.

Objective To evaluate the relationship, over time, between central graft thickness and visual acuity following Descemet's stripping endothelial keratoplasty (DSEK). Methods A retrospective analysis of 70 consecutive cases of DSEK. All donor lenticules were dissected manually. Serial postoperative measurements of central graft and total corneal thicknesses were made using anterior segment optical coherence tomography. Visual acuity, refraction and patient demographics were collected from case notes. The correlation between central graft thickness and visual acuity at serial time points was calculated. Results The median age at surgery was 75 years (lower quartile (LQ) 66, upper quartile (UQ) 83, range 36-90 years). Nineteen eyes were excluded from statistical analysis, leaving 51 eyes of 46 patients remaining. Last follow-up occurred a median of 12 months postoperatively (LQ 6, UQ 23, range 4-38 months). The median preoperative visual acuity was 0.71 logarithm of the minimum angle of resolution (logMAR), improving to 0.34 logMAR postoperatively (p<0.001, n=43). Median graft thickness decreased from 209 µm at day 1 to 142 µm at last follow-up (p<0.001). No statistically significant correlation was found between central total corneal thickness and visual acuity at any time point. Except for a single time point, no statistically significant correlation was found between central graft thickness and visual acuity. Conclusion There is no clear association between central graft, or total corneal, thickness and visual acuity following DSEK.

Shorter axial length and increased astigmatic refractive error are associated With socio-economic deprivation in an adult UK cohort.

PURPOSE: To evaluate whether socio-economic deprivation is associated with ocular axial length and refractive error in a British cohort. METHODS: The study population consisted of 7,652 individuals who provided data to the prospective cataract database at Portsmouth Eye unit, UK over a 4 year period (January 2004 to June 2008). Indices of multiple deprivation (IMD) scores measuring both social and economic domains for each patient's locality were calculated. The association of these measures of deprivation with axial length and refractive error (astigmatic and spherical) were evaluated using regression analyses after adjusting for age and sex. RESULTS: Socio-economically deprived areas (higher IMD scores) were inversely associated with axial lengths and astigmatic refraction. After controlling for age and sex, an inverse linear association was observed between axial length and IMD scores (-0.24 mm in highest quintile compared to lowest; 95% confidence intervals: -0.33 to -0.15) and between astigmatic refraction and IMD scores (-0.12 dioptres in highest quintile compared to lowest; 95% confidence intervals: -0.21 to -0.03). There was no association between spherical refraction and IMD scores. CONCLUSIONS: Axial length and astigmatic refraction were inversely associated with socio-economic deprivation in this population. Identification of the environmental exposures involved may identify reversible risk factors for impaired vision.