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We used the chemical mutagen, N-ethyl-N-nitrosourea, to induce random point mutations in the germline of the mouse strain C57BL/6 in order to generate models of retinal diseases. 1163 mutagenised first generation mice produced using this approach were examined for eye abnormalities. Approximately one-third (412) presented with some form of ocular abnormality. Most changes were unilateral and confined to the anterior segment of the eye. Less than 10% (44) of identified changes affected the posterior segment of the eye. 21 mice with varying ocular abnormalities, including 17 with retinal changes, were bred to produce second generation mice to confirm genetic inheritance. Genetic inheritance was confirmed in several of these lines including three with retinal changes.

PURPOSE: To design and evaluate an instrument appropriate for assessing vision-related quality of life (VRQoL) in persons with severe vision loss. METHODS: A total of 603 legally blind persons (better eye visual acuity of

Objective To evaluate the association between dietary patterns and age-related macular degeneration (AMD). Design Food frequency data were collected from Melbourne Collaborative Cohort Study (MCCS) participants at the baseline study in 1990–1994. During follow-up in 2003–2007, retinal photographs were taken and evaluated for AMD. Participants At baseline, 41 514 participants aged 40 to 70 years and born in Australia or New Zealand (69%), or who had migrated from the United Kingdom, Italy, Greece, or Malta (31%) were recruited. Of these, 21 132 were assessed for AMD prevalence at follow-up. Methods Principal component analysis was used to identify dietary patterns (Factors F1–6) among the food items. Logistic regression was used to assess associations of dietary patterns with AMD. Main Outcome Measures Odds ratios (ORs) for early stages and advanced AMD in association with dietary patterns. Results A total of 2508 participants (12.8%) had early stages of AMD, and 108 participants (0.6%) had advanced AMD. Six factors characterized by predominant intakes of fruits (F1); vegetables (F2); grains, fish, steamed or boiled chicken, vegetables, and nuts (F3); red meat (F4); processed foods comprising cakes, sweet biscuits, and desserts (F5); and salad (F6) were identified. Higher F3 scores were associated with a lower prevalence of advanced AMD (fourth vs. first quartile) (OR, 0.49; 95% confidence interval [CI], 0.28–0.87), whereas F4 scores greater than the median were associated with a higher prevalence of advanced AMD (OR, 1.46; 95% CI, 1.0–2.17). Conclusions Rather than specific individual food items, these factors represent a broader picture of food consumption. A dietary pattern high in fruits, vegetables, chicken, and nuts and a pattern low in red meat seems to be associated with a lower prevalence of advanced AMD. No particular food pattern seemed to be associated with the prevalence of the earliest stages of AMD.

Purpose To determine the effect of a statin (simvastatin) on the ultrastructure and function of the RPE, Bruch's membrane (BM), and photoreceptor interface in a high-fat atherogenic mouse model of thickened BM. Methods Wild-type C57BL/6 mice (6-weeks old) were divided into three study groups according to their diet and treatment given; Group 1, normal chow diet-fed mice; Group 2, high fat diet (HFD) fed mice; and Group 3, HFD-fed mice treated with simvastatin daily for 30 weeks. All mice were followed-up for 30 weeks. The retinal morphology and function was examined in vivo using fundus imaging and electroretinography at 15- and 30-weeks follow-up. At the end of the study, at 36 weeks of age, eye tissues were collected and retinal sections were examined using light microscopy and transmission electron microscopy. Results Fundus images of the HFD-fed mice showed the presence of discrete, multiple white spots, which was significantly reduced by approximately 73% in the simvastatin-treated animals. In the HFD-fed mice, there was an increase in the empty cytoplasmic vacuoles of the RPE, presence of lipid droplets in the BM, thickening and fragmentation of the elastic lamina of the BM, and a reduction in retinal function; these ultrastructural and functional changes were significantly improved in the simvastatin-treated group. Conclusions Chronic administration of simvastatin significantly improves the ultrastructure and function of the RPE, BM, and photoreceptor in a high-fat atherogenic mouse model of thickened BM.

"McCarty CA et al. Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. MJA 2001; 175: 340-. ©Copyright 2001. The Medical Journal of Australia - reproduced with permission".

Objectives To investigate the role of 2 specific alleles of the Stargardt disease gene ( ABCA4 ) in the pathogenesis of age-related macular degeneration (AMD). Secondary objectives were to investigate differences in frequency of the G1961E allele in selected ethnic groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families with AMD. Methods Five hundred forty-four patients with AMD and 689 controls were ascertained from 3 continents. Blood samples from 62 normal individuals of Somalian ancestry were also obtained. Participants were screened for the presence of these ABCA4 alleles with a combination of restriction digestion and single-strand conformation polymorphism analysis of polymerase chain reaction amplification products. Detected alleles were confirmed by DNA sequencing. The number of subjects exhibiting the G1961E or D2177N variants were compared between AMD and control groups using a 2-tailed Fisher exact test. Results There was no significant difference ( P >.1) in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). In contrast, there was a significant difference ( P G1961E alleles between normal individuals of Somali ancestry (11.3%) and normal individuals from other populations(0.4%). There was no evidence of cosegregation of these alleles and the AMD phenotype in the 5 multiplex families with AMD examined. These two ABCA4 alleles were slightly more frequent in patients with AMD with choroidal neovascularization (2.7%) than those without this complication (2.5%). Conclusions Somali ancestry is more than 100 times more strongly associated with presence of the G1961E allele than the AMD phenotype. This study did not find any statistically significant evidence for involvement of the G1961E or D2177N alleles of the ABCA4 gene in AMD. Clinical Relevance The ABCA4 gene is definitively involved in the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration. However, it does not seem to be involved in a statistically significant fraction of AMD cases.

PurposeTo assess the impact of VA loss on patient reported utilities taking both eyes into account compared to taking only the better or the worse eye into account.MethodsIn this cross-sectional study 1085 patients and 254 controls rated preferences with the generic health-related (EQ-5D; n = 868) and vision-specific (Vision and Quality of Life Index (VisQoL); n = 837) multi-attribute utility instruments (MAUIs). Utilities were calculated for three levels of VA in the better and worse eyes, as well as for 6 different vision states based on combinations of the better and worse eye VA.ResultsUsing the VisQoL, utility scores decreased significantly with deteriorating vision in both the better and worse eyes when analysed separately. When stratified by the 6 vision states, VisQoL utilities decreased as VA declined in the worse eye despite stable VA in the better eye. Differences in VisQoL scores were statistically significant for cases where the better eye had no vision impairment and the worse seeing fellow eye had mild, moderate or severe vision impairment. In contrast, the EQ-5D failed to capture changes in better or worse eye VA, or any of the six vision states.ConclusionsCalculating utilities based only on better eye VA or using a generic MAUI is likely to underestimate the impact of vision impairment, particularly when the better eye has no or little VA loss and the worse eye is moderately to severely visually impaired. These findings have considerable implications for the assessment of overall visual impairment as well as economic evaluations within eye health.

Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE). Both loci were mapped to chromosome 2p16-21 (refs 5,6) and this genetic interval has been subsequently narrowed. The importance of these diseases is due in large part to their close phenotypic similarity to age-related macular degeneration (AMD), a disorder with a strong genetic component that accounts for approximately 50% of registered blindness in the Western world. Just as in ML and DHRD, the early hallmark of AMD is the presence of drusen. Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied. This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration. Identification of this mutation may aid in the development of an animal model for drusen, as well as in the identification of other genes involved in human macular degeneration.

Age-related macular disease is a major and growing public health burden in developed Caucasian societies, accounting for about 50% of blind registration. Evidence exists that this is an emerging problem in Eastern Asia, although the phenotype appears to differ from that seen in Western society. It is likely that several genes are involved, and that the genes or allelic variants conferring are common. Environment plays a major role in its pathogenesis, and it is believed that genetic susceptibility becomes apparent only if there are sufficient environmental pressures. There is no therapy currently available that will have an impact on the prevalence of blindness from age-related macular disease. It has been shown that visual loss occurs as a reaction to ageing changes in Bruch's membrane, which is interposed between the choriocapillaris and the retinal pigment epithelium. The age changes in all three structures have been partly characterised, and as a consequence, multiple putative pathogenic mechanisms have been proposed. Cross-sectional studies of populations with different genetic background and life styles would serve to prove the importance of inheritance and environment. Molecular genetic analysis of blood from affected sibling pairs from these sources may indicate the relevant genes, the prevalence of which may differ in different communities. Enquiries as to life styles may determine important environmental influences. Examination of donor eyes from these communities may reveal distinctive features that may reflect the variation in genetic predisposition and environmental pressures. It is hoped that the findings from such studies will lead to novel and potentially successful management strategies.

PURPOSE: To report an occurrence of wound leak from the injection site after intravitreal injection of bevacizumab. A possible underlying etiology is discussed. METHODS: A single injection of bevacizumab was given for treatment of choroidal neovascularization complicating previous choroidal rupture. RESULTS: A reduction in vision and hypotony were noted 1 day after injection. With conservative management, there was spontaneous resolution of the wound leak. CONCLUSION: The risk of wound leak after intravitreal injection may be higher for younger patients and those who have undergone vitrectomy. All patients and clinicians, however, should be alert to vision decline after injection, and prompt evaluation should be performed to ascertain the cause. For patients with persistent wound leak, surgical intervention may be required.

Purpose: To evaluate prophylactic laser treatment of the macula in reducing the risk of visual loss in the fellow eye of patients with a retinal pigment epithelial tear caused by age-related macular degeneration in the first eye. Methods: In a prospective study, 12 patients with a retinal pigment epithelial tear in one eye caused by age-related macular degeneration and drusen in the fellow eye received prophylactic laser treatment of the retina in their fellow eyes and were followed up for 2 years or more after prophylactic treatment. Results: In 12 fellow eyes that received prophylactic laser treatment, a reduction in best-corrected visual acuity to 20/80 or worse occurred in one (8%) of 12 eyes in the first year and two (18%) of the remaining 11 eyes in the second year after treatment. The cumulative risk of visual loss in the treated fellow eye was 25% in 2 years. Conclusions: In historical control subjects in a natural history study of patients with retinal pigment epithelial tear in one eye, central visual loss occurred in 16 (37%) of 43 eyes in the first year and in seven (30%) of 23 eyes in the second year for a cumulative loss of 59% in the first 2 years. Compared with these historical control subjects, our findings suggest that visual loss in the fellow eyes of patients with a retinal pigment epithelial tear in the first eye is reduced by prophylactic low intensity laser photocoagulation of the macula.

PURPOSE: The second hyper-reflective on spectral domain optical coherence tomography (SD-OCT) has been suggested to correlate with the photoreceptor inner segment ellipsoids (ISe). The purpose of our study was to determine the relationship between the intensity of the ISe band and retinal function measured by multifocal electroretinography (mfERG) in patients with early age-related macular degeneration (AMD). METHODS: A high-resolution horizontal line scan through the fovea on SD-OCT and an mfERG recording were performed in one eye of 29 early AMD and 31 control participants. The relative intensity of the ISe band within 1000 μm of the fovea was quantified using ImageJ. The relationships between the relative intensity of the ISe band and the mfERG response parameters (P1 amplitude and implicit time) within the three central hexagons along the horizontal axis were determined. RESULTS: In normal participants, the relative intensity of the ISe band was significantly correlated with age (r = -0.634, P < 0.001) and also exhibited a topographic variation. On average, the relative intensity of the ISe band was significantly lower in patients with early AMD (1.77 ± 0.26) compared to control subjects (1.95 ± 0.27, P < 0.001) of a similar age range. The relative intensity of the ISe band was correlated significantly with the mfERG P1 implicit time (r = -0.745, P < 0.001), but not P1 amplitude (r = 0.144, P = 0.281). CONCLUSIONS: The relative intensity of the ISe band reduced with age and further in early AMD. The relative intensity was significantly correlated with mfERG P1 implicit time.

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p. Arg1210Cys encoded in the CFH gene (case frequency (f(case)) = 0.51%; control frequency (f(control)) = 0.02%; odds ratio (OR) = 23.11) and newly identified p. Lys155Gln encoded in the C3 gene (f(case) = 1.06%; f(control) = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

PURPOSE To determine the retinal function in early age-related macular degeneration (AMD) assessed by the multifocal electroretinogram (mfERG) and flicker perimetry and to seek a relationship between local objective mfERG parameters and subjective flicker perimetry thresholds. METHODS mfERG and flicker perimetry were performed in 15 patients (15 eyes) with early AMD and 14 controls (14 eyes) of similar age. The mfERG P1 response amplitude density (nV/deg²) and P1 implicit time of the first-order kernel and the flicker thresholds of each concentric ring were analyzed. The relationship between individual mfERG responses and the corresponding individual flicker sensitivity outcomes was determined. RESULTS The mfERG response amplitude of the central ring (ring 1) was significantly reduced in early AMD eyes compared with the controls (P = 0.009). No significant difference in mfERG amplitude between early AMD and control eyes was detected in the other rings. The mfERG implicit time was significantly increased in the early AMD eyes but only within the central four rings of 12°. A significant reduction in flicker sensitivity was also detected in early AMD eyes but only within the central 6°. There was a significant, moderate correlation (r = -0.477; P < 0.001) between local mfERG latency and flicker sensitivity from the same tested locations within the central 6°. There was a weak correlation (r = 0.200; P = 0.014) between mfERG amplitude and flicker sensitivity. CONCLUSIONS Both mfERG and flicker perimetry show abnormal retinal function, but only in the very central macula, in early AMD. A novel relationship between mfERG and flicker sensitivity should enhance the clinical monitoring of disease progression.

Age-related macular degeneration (AMD) is the most common cause of severe, irreversible loss of vision among elderly populations in the developed world.1–4 The neovascular, or exudative, form of the disease destroys central vision rapidly and is responsible for most severe vision loss in AMD. Ranibizumab is a recombinant, humanized, monoclonal antibody that neutralizes all isoforms of vascular endothelial growth factor (VEGF), a key mediator of the neovascular process.5–9 The MARINA10 and ANCHOR11 studies demonstrated that ranibizumab was an effective treatment for neovascular disease. Vision remained stable in approximately 90% and improved in approximately one third of treated patients. Published case series of bevacizumab treatment showed similar outcomes.12,13 Unfortunately, approximately 10% of treated patients10,11 continued to lose vision. Trials assessing the efficacy of variable dosage regimens have generally shown a less favorable vision improvement, compared to a monthly regimen. The PIER trial14 used a quarterly regimen of ranibizumab after three loading-dose injections. Although the treated group had better vision at 12 months, compared with the sham-treated patients, the initial gains in visual acuity observed over the loading-dose period were lost, and the vision at 12 months was similar to baseline. It was noted that not all patients treated with this regimen fared equally/ Some patients maintained vision gains that were achieved during the monthly-dose period and others either did not respond at all or initially responded well and then failed to maintain the initial gains. The SUSTAIN trial (Meyer CH, et al. IOVS 2008;49:ARVO E-Abstract 273) provided further evidence of this differential response to treatment. In this trial, ranibizumab treatment was examined on a pro re nata basis, after administration of three initial loading-dose injections, one in each of three consecutive months. Retreatment was based on specific visual acuity and clinical and optical coherence tomography criteria. Of these patients, approximately 50% maintained their initial sharp gains in visual acuity, the so-called gain-and-maintain group. Another third of patients enjoyed an initial gain in visual acuity, but failed to maintain the gain during follow-up: the gain-and-not-maintained group. Most of the acuity increase, in these two groups, occurred in the first 3 months of treatment. Approximately 25% of patients never experienced any gain in vision: the no-initial-gain group. In these patients, vision failed to improve from the outset, with continued losses being noted during the course of the treatment regimen. Overall, approximately 20% of the patients maintained their visual acuity without any further treatment after the initial loading doses. Currently, we do not fully understand what factors dictate this response. If we did, we might be able to predict patient outcomes after anti-VEGF treatment more accurately. Recent studies, including the MARINA and ANCHOR subgroup analyses, suggest that baseline visual acuity, lesion size, and age influence outcomes of anti-VEGF therapy.15–17 The potential role of genetic variation in determining outcome has also been investigated. Although multiple studies have implicated roles for several genes, including CFH, HTRA1/ARMS2, C3, CFB/C2, and APOE, in the risk of developing AMD, there is no consensus in the literature regarding the influence of these genetic polymorphisms in the response to anti-VEGF treatment.18–23 The CFH gene has been the most widely investigated, with conflicting reports that the CFH at risk allele CC is associated with favorable or adverse treatment responses.18–23 No specific associations with polymorphisms of the C3 or ARMS2/HTRA1 genes in determining treatment outcome have been noted, although it has been suggested that polymorphisms within the C-reactive protein (CRP) gene are associated with worse visual outcome after anti-VEGF treatment.20 However, these studies were limited by small patient samples that left them underpowered, and they did not account for all other potentially confounding factors that can affect visual outcome. Nongenetic variables that have been shown to influence visual outcome and should be included in any attempt to identify genetic influences on outcomes include age, presenting visual acuity, and the size and type of lesion.10,11,24 Traditionally, the time delay between the first symptoms of neovascular AMD and initiation of treatment was an important determinant of outcome, when the treatment was thermal laser photocoagulation, which could be applied successfully only if the choroidal neovascularization (CNV) was treated before it became subfoveal. Given that these new medical treatments are used in subfoveal lesions, it is not necessarily a given that delay to treatment would influence outcomes. It has been reported that this variable remains an important parameter in response to anti-VEGF therapy,25,26 although it is difficult to assess accurately and thus is rarely ascertained. We have found in our present cohort of patients that delay of treatment after the first symptoms suggestive of CNV is a highly significant predictor of outcome (Lim et al., manuscript submitted). Lack of consideration of this variable may well explain the contradictory results of previously published studies in which treatment outcomes with anti-VEGF were investigated. Thus, we sought to address the possible genetic variants and their influence on treatment outcome by conducting a study that took into consideration variables that we found to have a significant effect on outcomes. In this study we chose to look at the potential influence of polymorphisms of the APOE gene in determining outcome. We and others27–31 have demonstrated a higher likelihood of development of AMD in individuals with the APOE e2 polymorphism than with the e3 and e4 variants. As such, we were interested in determining whether there is any genetic influence on treatment outcome, within the variants of the APOE gene. We examined visual acuity outcome at 3, 6, and 12 months after initiation of treatment. Several pivotal RCTs,10,11,14 have clearly demonstrated that in most cases, visual acuity increases occurred in the first 3 months of treatment. Also in those patients who responded poorly, vision failed to improve from the outset, with continued losses noted early during treatment. Investigating VA outcomes at 3 months therefore accounted for a very uniform phase in treatment strategy. At 6 and 12 months, other variables such as injection timing and number as well as missed appointments may play a role. Thus, we felt it useful to investigate an early time point as well as later ones during the course of treatment to see the extent of possible genetic influence on outcome.

PURPOSE To determine the longitudinal impact of idiopathic macular telangiectasia (MacTel) type 2 on vision-specific quality of life (QoL). METHODS Participants with MacTel type 2 and controls with no vision impairment were recruited at baseline. All underwent a full ophthalmic examination and the interview-administered 28-item Impact of Vision Impairment (IVI) questionnaire at baseline, to gather information on sociodemographic factors and vision-specific QoL. The MacTel patients were reassessed at 24 months. RESULTS For the MacTel participants (n = 22), the median (range) age and visual acuity were 64 years (45-87) and 20/32 (20/13-20/63) in the better eye, respectively. The corresponding median values in the control group (n = 38) were 57 years (41-68) and 20/25 or better in both eyes, respectively. Rasch analysis showed that the IVI and its three subscales had sufficient psychometric validity and possessed interval level estimates. The control group had almost twice the level of vision-specific QoL than did the MacTel group at baseline on all IVI scores (P < 0.001 for all). At 24 months, we found no significant change in any of the IVI scores in the MacTel group. Similarly, there was no significant difference in visual acuity in the better or worse eyes in that group after 2 years. CONCLUSIONS Persons with MacTel type 2 had poorer overall vision-related QoL than did healthy controls. Several aspects of vision-related QoL and distance visual acuity did not significantly change after 24 months. Longer follow-up assessment periods are needed to determine the longitudinal impact of this condition on vision-related QoL.

Predictive tests for estimating the risk of developing late-stage neovascular age-related macular degeneration (AMD) are subject to unique challenges. AMD prevalence increases with age, clinical phenotypes are heterogeneous and control collections are prone to high false-negative rates, as many control subjects are likely to develop disease with advancing age. Risk prediction tests have been presented previously, using up to ten genetic markers and a range of self-reported non-genetic variables such as body mass index (BMI) and smoking history. In order to maximise the accuracy of prediction for mainstream genetic testing, we sought to derive a test comparable in performance to earlier testing models but based purely on genetic markers, which are static through life and not subject to misreporting. We report a multicentre assessment of a larger panel of single nucleotide polymorphisms (SNPs) than previously analysed, to improve further the classification performance of a predictive test to estimate the risk of developing choroidal neovascular (CNV) disease. We developed a predictive model based solely on genetic markers and avoided inclusion of self-reported variables (eg smoking history) or non-static factors (BMI, education status) that might otherwise introduce inaccuracies in calculating individual risk estimates. We describe the performance of a test panel comprising 13 SNPs genotyped across a consolidated collection of four patient cohorts obtained from academic centres deemed appropriate for pooling. We report on predictive effect sizes and their classification performance. By incorporating multiple cohorts of homogeneous ethnic origin, we obtained >80 per cent power to detect differences in genetic variants observed between cases and controls. We focused our study on CNV, a subtype of advanced AMD associated with a severe and potentially treatable form of the disease. Lastly, we followed a two-stage strategy involving both test model development and test model validation to present estimates of classification performance anticipated in the larger clinical setting. The model contained nine SNPs tagging variants in the regulators of complement activation (RCA) locus spanning the complement factor H (CFH), complement factor H-related 4 (CFHR4), complement factor H-related 5 (CFHR5) and coagulation factor XIII B subunit (F13B) genes; the four remaining SNPs targeted polymorphisms in the complement component 2 (C2), complement factor B (CFB), complement component 3 (C3) and age-related maculopathy susceptibility protein 2 (ARMS2) genes. The pooled sample size (1,132 CNV cases, 822 controls) allowed for both model development and model validation to confirm the accuracy of risk prediction. At the validation stage, our test model yielded 82 per cent sensitivity and 63 per cent specificity, comparable with metrics reported with earlier testing models that included environmental risk factors. Our test had an area under the curve of 0.80, reflecting a modest improvement compared with tests reported with fewer SNPs.

To evaluate associations between past dietary fat intake and the prevalence of age-related macular degeneration (AMD).Six thousand seven hundred thirty-four participants aged 58 to 69 years in 1990-1994 took part in this cohort study. Participants' nutrient intakes were estimated from a food frequency questionnaire at baseline. At follow-up from 2003 to 2006, digital macula photographs of both eyes were evaluated for early and late AMD signs. Logistic regression was used to estimate odds ratios, with adjustment for age, smoking, and other potential confounders.Higher trans-unsaturated fat intake was associated with an increased prevalence of late AMD; the odds ratio comparing the highest with the lowest quartile of trans fat was 1.76 (95% confidence interval, 0.92-3.37; P = .02). Higher omega-3 fatty acid intake (highest quartile vs lowest quartile) was inversely associated with early AMD (odds ratio, 0.85; 95% confidence interval, 0.71-1.02; P = .03). Olive oil intake (or =100 mL/week vs1 mL/week) was associated with decreased prevalence of late AMD (odds ratio, 0.48; 95% confidence interval, 0.22-1.04; P = .03). No significant associations with AMD were observed for intakes of fish, total fat, butter, or margarine.A diet low in trans-unsaturated fat and rich in omega-3 fatty acids and olive oil may reduce the risk of AMD.

Objective To elucidate the contribution of environmental versus genetic factors to the significant losses in visual function associated with normal aging. Design A classical twin study. Participants Forty-two twin pairs (21 monozygotic and 21 dizygotic; age 57–75 years) with normal visual acuity recruited through the Australian Twin Registry. Methods Cone function was evaluated by establishing absolute cone contrast thresholds to flicker (4 and 14 Hz) and isoluminant red and blue colors under steady state adaptation. Adaptation dynamics were determined for both cones and rods. Bootstrap resampling was used to return robust intrapair correlations for each parameter. Main Outcome Measures Psychophysical thresholds and adaptational time constants. Results The intrapair correlations for all color and flicker thresholds, as well as cone absolute threshold, were significantly higher in monozygotic compared with dizygotic twin pairs ( P P = 0.28) and rod and cone recovery rate ( P = 0.83; P = 0.79, respectively) did not show significant differences between monozygotic and dizygotic twins in their intrapair correlations, indicating that steady-state cone thresholds and flicker thresholds have a marked genetic contribution, in contrast with rod thresholds and adaptive processes, which are influenced more by environmental factors over a lifetime. Conclusions Genes and the environment contribute differently to important neuronal processes in the retina and the role they may play in the decline in visual function as we age. Consequently, retinal structures involved in rod thresholds and adaptive processes may be responsive to appropriate environmental manipulation. Because the functions tested are commonly impaired in the early stages of age-related macular degeneration, which is known to have a multifactorial etiology, this study supports the view that pathogenic pathways early in the disease may be altered by appropriate environmental intervention. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

PURPOSE. Several single-nucleotide polymorphisms (SNPs) in the C2 and BF genes have been associated with age-related macular degeneration (AMD) in Caucasian populations from the United States. The study was conducted to evaluate whether these SNPs are also associated with AMD in persons of Anglo-Celtic ethnicity in an Australian population. METHODS. Included in the study were 565 persons with AMD and 204 ethnically matched control subjects. All participants completed a standard health questionnaire, were given a fundus examination, and provided a blood sample for DNA extraction. Alleles were determined by a matrix-assisted desorption ionization-time of flight (MALDI-TOF)- based approach followed by statistical analysis. RESULTS. The C2 and BF genes indicated significant association with AMD of only two SNPs; rs547154 (IVS10) in the C2 gene (P = 9.1 X 10 -5 ) and rs641153 (R32Q) in the BF gene (P = 7.0 X 10 -5 ). No association with AMD was found for SNP rs9332739 (E318D) in the C2 gene or for rs4151667 (L9H), rsl048709 (R150R), rs4151659 (K565E), or rs2072633 (IVS17) in the BF gene. A protective haplotype of variants IVS10 and R32Q was associated with AMD (OR 0.29, 95% CI 0.20-0.42). CONCLUSIONS. In this study, the association of the IVS10 and R32Q variants in the C2 and BF genes in AMD was replicated. Haplotype analysis indicated association of these variants with AMD in an Australian population. Both IVS10 and R32Q variants were in strong linkage disequilibrium with each other (r2 = 0.96). Although the E318D and L9H variants have shown association with AMD in previous studies, the findings were not in agreement. This demonstrates a refined pattern of association of these rare variants with AMD.

Graft rejection requires an initial interaction between donor antigen presenting cells (APC) and recipient T cells; an interaction known to involve a variety of cell surface molecules. We have been investigating an interaction involving two of these molecules: lymphocyte function associated antigen-1 (LFA-1) on the T cell and its ligand, intercellular adhesion molecule-1 (ICAM-1) on the APC, in an effort to assess the effect its interruption would have on the ability of the recipient to reject an allograft. A monoclonal antibody (MAb) against ICAM-1 was given peritransplant to mice with heterotopically grafted corneas. Mice were killed at various time points and the grafts taken for histological assessment of rejection. Mice treated with Mab have a delayed influx of cells into the graft site and marginally better graft viability to day 50 after transplantation compared to controls. These results suggest that it is possible to decrease rejection even with brief peritransplant treatment. This provides encouragement for further experiments using more extensive therapy.

Background Tobacco smoking is a risk factor for age-related macular degeneration, but studies of ex-smokers suggest quitting can reduce the risk. Methods We fitted a function predicting the decline in risk of macular degeneration after quitting to data from 7 studies involving 1,488 patients. We assessed the cost-effectiveness of smoking cessation in terms of its impact on macular degeneration-related outcomes for 1,000 randomly selected U.S. smokers. We used a computer simulation model to predict the incidence of macular degeneration and blindness, the number of quality-adjusted life-years (QALYs), and direct costs (in 2004 U.S. dollars) until age 85 years. Cost-effectiveness ratios were based on the cost of the Massachusetts Tobacco Control Program. Costs and QALYs were discounted at 3% per year. Results If 1,000 smokers quit, our model predicted 48 fewer cases of macular degeneration, 12 fewer cases of blindness, and a gain of 1,600 QALYs. Macular degeneration-related costs would decrease by $2.5 million if the costs of caregivers for people with vision loss were included, or by $1.1 million if caregiver costs were excluded. At a cost of $1,400 per quitter, smoking cessation was cost-saving when caregiver costs were included, and cost about $200 per QALY gained when caregiver costs were excluded. Sensitivity analyses had a negligible impact. The cost per quitter would have to exceed $77,000 for the cost per QALY for smoking cessation to reach $50,000, a threshold above which interventions are sometimes viewed as not cost-effective. Conclusion Smoking cessation is unequivocally cost-effective in terms of its impact on age-related macular degeneration outcomes alone.

Objective To systematically review the evidence on dietary ω-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration (AMD). Methods Seven databases were systematically searched with no limits on publication year or language using standardized criteria. Randomized controlled trials and prospective cohort, case-control, and cross-sectional studies were included. Of 2754 abstracts identified, 3 prospective cohort, 3 case-control, and 3 cross-sectional studies met the criteria. Measures of associations were pooled quantitatively using meta-analytic methods. Results Nine studies provided data on a total sample of 88 974 people, including 3203 AMD cases. A high dietary intake of ω-3 fatty acids was associated with a 38% reduction in the risk of late AMD (pooled odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48-0.82). Fish intake at least twice a week was associated with a reduced risk of both early AMD (pooled OR, 0.76; 95% CI, 0.64-0.90) and late AMD (pooled OR, 0.67; 95% CI, 0.53-0.85). Conclusions Although this meta-analysis suggests that consumption of fish and foods rich in ω-3 fatty acids may be associated with a lower risk of AMD, there is insufficient evidence from the current literature, with few prospective studies and no randomized clinical trials, to support their routine consumption for AMD prevention.

Background Intravitreal ranibizumab prevents vision loss and improves visual acuity in patients with neovascular age-related macular degeneration, but it is expensive, and efficacy beyond 2 years is uncertain. Methods We assessed the cost-effectiveness of ranibizumab compared with no ranibizumab over 10 years, using randomized trial efficacy data for the first 2 years, post-trial efficacy assumptions, and ranibizumab acquisition costs ranging from the wholesale price ($1,950 per dose) to the price of bevazicumab ($50), a similar molecule which may be equally efficacious. We used a computer simulation model to estimate the probability of blindness, the number of quality-adjusted life-years (QALYs), direct costs (in 2004 U.S. dollars), and cost-effectiveness ratios for a 67-year old woman. Costs and QALYs were discounted at 3% per year. Results The probability of blindness over 10 years was reduced from 56% to 34% if ranibizumab was efficacious for only 2 years, 27% if efficacy was maintained for a further 2 years only (base-case scenario), and 17% if visual acuity at 4 years was then sustained. It was cost-saving under all price assumptions, when caregiver costs were included. When caregiver costs were excluded, the cost per QALY for the base-case ranged from $5,600, assuming the bevazicumab price, to $91,900 assuming the wholesale ranibizumab price. The cost per QALY was < $50,000 when the cost of ranibizumab was less than $1000. Conclusion From a societal perspective, ranibizumab was cost-saving. From a health care funder's perspective, ranibizumab was an efficient treatment when it cost less than $1000 per dose.

PURPOSE. A cathode-ray-tube (CRT) monitor– based technique was used to isolate clinically significant components of dark adaptation. The utility of the technique in identifying adaptation abnormalities in eyes with age-related maculopathy (ARM) is described. METHODS. A CRT dark adaptometer was developed to assess cone and rod recovery after photopigment bleach. The following measures were obtained: cone recovery rate (Rc ;i n decades per minute) and absolute threshold (Tfc; log candelas per square meter), rod recovery rate (Rr; decades per minute), and rod– cone transition (rod– cone break [RCB], in minutes). These components were isolated by appropriately selecting stimulus size, stimulus location, pigment bleach, and test duration and by coupling the CRT with judiciously selected neutral-density (ND) filters. The protocol was developed by using 5 young observers and was tested on 27 subjects with ARM in the study eye and 22 age-matched control subjects. RESULTS. The parameters necessary for effective isolation of cone and early phase rod dark adaptation were a 2.6 ND filter (for a standard CRT monitor, 0.08 – 80 cd m 2 luminance output); a 4° foveated, 200-ms, achromatic spot; 30% pigment bleaching; and a 30-minute test duration. These settings returned obvious rod and cone recovery curves in control and ARM eyes that were compatible with conventional test methods and identified 93% of participants with ARM as having delayed dynamics in at least one of the parameters. Cone recovery dynamics were significantly slower in the ARM group when compared with age-matched control subjects (Rc, 0.99 0.35 vs. 2.63 0.61 decades min 1 , P 0.0001). Three of the 27 eyes with ARM did not achieve RCB during the allowed duration (30 minutes). The remaining eyes with ARM (n 24) exhibited a significant delay in rod recovery (Rr, ARM, 0.16 0.03 vs. controls, 0.22 0.02 decades min 1 , P 0.0001) and the average time to RCB (SD) in the ARM group was significantly longer than in the control subjects (19.12 5.17 minutes vs. 10.40 2.49 minutes, P 0.0001). CONCLUSIONS. The CRT dark-adaptation technique described in this article is an effective test for identifying abnormalities in cone and rod recovery. Slowed cone and rod recovery and a delayed RCB were evident in the eyes with ARM. The test method is potentially useful for clinical intervention trials in which ARM progression is monitored. (Invest Ophthalmol Vis Sci. 2008;49:55– 65) DOI:10.1167/iovs.06-1048

PURPOSE. A classic twin study was undertaken to assess the contribution of genes and environment to the development of refractive errors and ocular biometrics in a twin population. METHODS. A total of 1224 twins (345 monozygotic [MZ] and 267 dizygotic [DZ] twin pairs) aged between 18 and 88 years were examined. All twins completed a questionnaire consisting of a medical history, education, and zygosity. Objective refraction was measured in all twins, and biometric measurements were obtained using partial coherence interferometry. RESULTS. Intrapair correlations for spherical equivalent and ocular biometrics were significantly higher in the MZ than in the DZ twin pairs (P < 0.05), when refraction was considered as a continuous variable. A significant gender difference in the variation of spherical equivalent and ocular biometrics was found (P < 0.05). A genetic model specifying an additive, dominant, and unique environmental factor that was sex limited was the best fit for all measured variables. Heritability of spherical equivalents of 88% and 75% were found in the men and women, respectively, whereas, that of axial length was 94% and 92%, respectively. Additive genetic effects accounted for a greater proportion of the variance in spherical equivalent, whereas the variance in ocular biometrics, particularly axial length was explained mostly by dominant genetic effects. CONCLUSIONS. Genetic factors, both additive and dominant, play a significant role in refractive error (myopia and hypermetropia) as well as in ocular biometrics, particularly axial length. The sex limitation ADE model (additive genetic, non-additive genetic, and environmental components) provided the best-fit genetic model for all parameters.

PURPOSE To describe the cytoarchitecture of the choroidal capillary endothelial cells, especially as it relates to cellular processes that protrude through the basal lamina into Bruch's membrane (BM). METHODS Human donor eyes and monkey and hamster eyes were examined by transmission electron microscopy and freeze-fracture replication. The number of endothelial cell processes and the characteristics of the processes and surrounding structures were determined in the maculae of human eyes and correlated with age-related changes in neighboring structures. RESULTS Endothelial cell processes were observed in eyes of all species examined and at all ages. They typically occurred at sites of focally thickened, nonfenestrated regions of the endothelial cells. The basal lamina adjacent to the processes was often hypertrophic and associated deposits of long-spacing collagen (LSC) were observed frequently. In humans, there was no correlation between the number of processes per 100 micro m of the BM with age, sex, cause of death, postmortem time, RPE autofluorescence, or RPE residual body content. There was a weak linear association with the thickness of the BM. CONCLUSIONS The finding of cellular processes of choroidal capillary endothelial cells penetrating their basal laminae is normal. These processes may serve to stabilize choroidal endothelial cells physically and play an important structural role in the maintenance of patency of the choriocapillaris. It is also possible that they have additional functions, as suggested for similar processes in other tissues. They are not necessarily the harbinger of choroidal neovascularization, although growth of new vessels may result from distortion of this normal attribute.

PURPOSE: To evaluate cone visual function of subjects with age-related maculopathy (ARM). METHODS: Cone thresholds in 16 patients with ARM and 14 age-matched control subjects were compared. All subjects had visual acuity of 6/12 or better in the studied eye. A range of contrast thresholds were measured to evaluate diverse aspects of cone visual function under steady state conditions (spatiotemporal, color and luminance, and photopic sensitivity) or after bleaching (adaptation dynamics). RESULTS: ARM produced a diffuse loss across all cone steady state visual functions in 31% to 44% of subjects. The adaptation time constant of cone recovery was significantly prolonged in most (69%) ARM eyes. A cross-correlational analysis found adaptational kinetics to be independent of other steady state losses, with cone photopigment regeneration being the most affected visual function in ARM (chi(2) = 4.03, P < 0.05). CONCLUSIONS: The results show that cone-adaptational kinetics are affected in ARM more so than are steady state thresholds. Given that cone recovery is easy to examine in a clinical setting, this test may provide a useful index of photopic function in patients with ARM.

Objectives: To verify that a few laser lesions in the posterior pole can cause drusen to resolve in patients with age-related macular degeneration, and to document central retinal sensitivity as drusen resolve. Design: In a pilot study, 12 patients considered to be at high risk for sight-threatening complications from age-related macular degeneration were treated with 12 argon laser lesions in the posterior pole, with review for 12 to 24 months. Results: Choroidal neovascularization developed in 1 patient 8 months after treatment, with consequent loss of central vision. In 9 of the remaining 11 patients, high-risk characteristics of drusen were reduced. Four patients had retinal pigment epithelial depigmentation, and all maintained 20/40 visual acuity at 12 months. One patient lost 3 lines of vision due to geographic atrophy after 12 months. Scotopic retinal threshold was elevated before treatment in 8 patients, compared with an age-matched comparison group. Of these, 4 patients underwent retesting 3 to 6 months after treatment, and all had improved thresholds, but only 1 patient sustained the improvement at 12 months. At 12 months, 3 of the 8 patients showed an improvement in their mean retinal threshold. Of those in whom the mean retinal threshold worsened, the mean elevation in threshold was not more than 0.6 log units. Conclusions: A few laser lesions in the posterior pole leads to resolution of drusen. There does not appear to be an increased risk for choroidal neovascularization. Retinal threshold measurements show no indication of geographic atrophy at 1 year, but cannot be excluded as a late outcome. Laser treatment may reduce the risk for profound sightthreatening lesions in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It has been proposed that the polymorphism encoding Y402H (T1277C) in the complement factor H gene (CFH) is one of the main determinants of disease. We genotyped the polymorphism at a number of loci in the region encompassing the Regulators of Complement Activation (RCA) on chromosome 1, including T1277C SNP, in 187 patients and 146 controls. Haplotypes have been classified as protective (P) or susceptible (S) with respect to AMD. This included the identification of an S haplotype with a T at 1277. The results show that no single locus should be assumed to be directly responsible for AMD, but rather argue for the existence of RCA haplotypes, which can be assigned meaningful predictive values for AMD. We conclude that the critical sequences are within a region 450kb centromeric to 128kb telomeric of CFH.

Age-related macular degeneration (AMD) is responsible for the majority of visual impairment in the Western world. Epidemiological studies examining risk factors for AMD are needed to develop strategies for the prevention of blindness from this condition. A number of potentially modifiable risk factors for AMD have been identified; however, only smoking has been a consistent risk factor across the numerous studies. A growing body of evidence suggests that AMD and cardiovascular disease may have common risk factors. The Cardiovascular Health and Age Related Maculopathy (CHARM) Study was established to examine the risk factors for AMD and its progression, in particular risk factors associated with cardiovascular disease. Examining risk factors for prevalent AMD, cases with AMD were compared with age and gender matched controls with no AMD features. For the assessment of AMD progression, the study examined in 2001 and 2002 those participants with early AMD, or age-related maculopathy (ARM), who had undergone baseline examination between 1992 and 1995 and compared the characteristics of those who had progression of AMD with those who did not. The CHARM study involved both ophthalmic and cardiovascular examinations. Standardised clinical eye examination and grading of the macular stereo photographs were used to determine the AMD status and progression. To examine cardiovascular status, carotid artery ultrasound imaging analysis of systemic arterial compliance, augmentation index and pulse wave velocity were performed. The traditional and novel risk factors for CVD such as levels of glucose, cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, fibrinogen, C-reactive protein, immunoglobulins A and M, homocysteine, oxidized LDL and the exposure to the Chlamydia Pneumonia infection were determined. DNA was collected for apolipoprotein E genotyping. The present paper outlines the primary aims of the CHARM study, the methodology involved and the recruitment results.