Onset Of Age-related Macular Degeneration Research Articles

Statins for age-related macular degeneration.

Age-related macular degeneration (AMD) is a progressive late onset disorder of the macula affecting central vision. Age-related macular degeneration is the leading cause of blindness in people over 65 years in industrialized countries. Recent epidemiologic, genetic, and pathological evidence has shown AMD shares a number of risk factors with atherosclerosis, leading to the hypothesis that statins may exert protective effects in AMD. The objective of this review was to examine the effectiveness of statins compared with other treatments, no treatment, or placebo in delaying the onset and progression of AMD. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to June 2014), PubMed (January 1946 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 5 June 2014. We included randomized controlled trials (RCTs) that compared statins with other treatments, no treatment, or placebo in participants who were either susceptible to or diagnosed as having early stages of AMD. We used standard methodological procedures expected by The Cochrane Collaboration. Two authors independently evaluated the search results against the selection criteria, abstracted data, and assessed risk of bias. We did not perform meta-analysis due to heterogeneity in the interventions and outcomes among the included studies. Two RCTs with 144 total participants met the selection criteria. Both trials compared simvastatin versus placebo in older people (> 50 or 60 years) with high risk of developing AMD (drusen present on examination). The larger trial with 114 participants was conducted in Australia and used a higher dose (40 mg daily) of simvastatin for three years. Participants and study personnel in this trial were adequately masked; however, data were missing for 30% of participants at three years follow-up. The smaller trial of 30 participants was conducted in Italy and used a lower dose (20 mg) of simvastatin for three months. This trial reported insufficient details to assess the risk of bias.Neither trial reported data for change in visual acuity. Analysis of 30 participants in the smaller trial did not show a statistically significant difference between the simvastatin and placebo groups in visual acuity values at three months of treatment (decimal visual acuity 0.21 ± 0.56 in simvastatin group and 0.19 ± 0.40 in placebo group) or 45 days after the completion of treatment (decimal visual acuity 0.20 ± 0.50 in simvastatin group and 0.19 ± 0.48 in placebo group). The lack of a difference in visual acuity was not explained by lens or retina status, which remained unchanged during and after the treatment period for both groups.Preliminary analyses of 42 participants who had completed 12 months follow-up in the larger trial did not show a statistically significant difference between simvastatin and the placebo groups for visual acuity, drusen score, or visual function (effect estimates and confidence intervals were not available). Complete data for these outcomes at three years follow-up were not reported. At three years, the effect of simvastatin in slowing progression of AMD compared with placebo was uncertain (odds ratio 0.51, 95% confidence interval 0.23 to 1.09).One trial did not report adverse outcomes. The second trial reported no difference between groups in terms of adverse events such as death, muscle aches, and acute hepatitis. Evidence from currently available RCTs is insufficient to conclude that statins have a role in preventing or delaying the onset or progression of AMD.

Long-lasting effects of anti-VEGF/photodynamic combination therapy in the treatment of exudative age-related macular degeneration: a retrospective chart review.

PurposeTo examine the potential long-term benefit of an anti-VEGF/photodynamic therapy (PDT) combination on patients treated for wet age-related macular degeneration (AMD).MethodsA retrospective chart review was conducted on 29 eyes (subjects) from 26 patients (eight male and 18 female) that showed sustained, positive response to combination therapy for exudative AMD for a minimum of 1 year. Collected data included: visual acuity, central retinal thickness, intraocular pressure and history of glaucoma, wet AMD onset and treatment history, concomitant use of anticoagulants and past history or development of cerebrovascular or cardiovascular disease while receiving combination therapy.ResultsSubjects underwent an average of five injections and two PDT treatments in total over 16 months before the choroidal neovascular membrane (CNVM) stabilized and became inactive for at least 1 year. Prior to the effective anti-VEGF/PDT combination therapy the median Snellen visual acuity ranged from 20/200 to 20/250 and presented at no worse than 20/200 at 1 year after treatment. Some subjects were followed for up to 5 years and remained inactive.ConclusionCombination therapy can cause long-lasting closure of the CNVM, even with advanced disease resistant to anti-VEGF monotherapy.

Risk Factors Associated With Reticular Pseudodrusen Versus Large Soft Drusen

To investigate genetic, environmental, and systemic risk factors in prospectively identified subjects with the age-related macular degeneration (AMD) phenotypes of (1) reticular pseudodrusen without large soft drusen and (2) large soft drusen without reticular pseudodrusen. Prospective case-case comparison. In a clinical practice setting, patients with AMD were sequentially screened using clinical examination and scanning laser ophthalmoscopy imaging to prospectively identify subjects (n= 73) with the phenotypes of (1) reticular pseudodrusen without large soft drusen (n= 30) or (2) large soft drusen without reticular pseudodrusen (n= 43). Subjects were genotyped for 2 alleles associated with AMD, age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH). A questionnaire was administered to collect history of smoking, hypertension, diabetes, and hyperlipidemia, as well as personal and family history of AMD. The reticular pseudodrusen group was older (median age 87 vs 81 years, P= .04) and had more female subjects (83.3% vs 48.8%, P= .003), later ages of AMD onset (83 vs 70 years, P= .0005), and a greater frequency of hypertension (76.7% vs 55.8%, P= .08). No significant differences were found in the distribution of the ARMS2 risk allele (P= .4) between the reticular pseudodrusen (homozygous= 20.0%; heterozygous= 56.7%) and large soft drusen (homozygous= 19.0%; heterozygous= 42.9%) phenotypes, or in the distribution of the CHF risk allele (P= .7) between the reticular pseudodrusen (homozygous= 26.7%; heterozygous= 56.7%) and large soft drusen (homozygous= 21.4%; heterozygous= 66.7%) phenotypes. The reticular pseudodrusen phenotype was associated with increased age, later age of AMD onset, and female sex.

Nature and nurture- genes and environment- predict onset and progression of macular degeneration

Age-related macular degeneration (AMD) is a common cause of irreversible visual loss and the disease burden is rising world-wide as the population ages. Both environmental and genetic factors contribute to the development of this disease. Among environmental factors, smoking, obesity and dietary factors including antioxidants and dietary fat intake influence onset and progression of AMD. There are also several lines of evidence that link cardiovascular, immune and inflammatory biomarkers to AMD. The genetic etiology of AMD has been and continues to be an intense and fruitful area of investigation. Genome-wide association studies have revealed numerous common variants associated with AMD and sequencing is increasing our knowledge of how rare genetic variants strongly impact disease. Evidence for interactions between environmental, therapeutic and genetic factors is emerging and elucidating the mechanisms of this interplay remains a major challenge in the field. Genotype-phenotype associations are evolving. The knowledge of non-genetic, modifiable risk factors along with information about heritability and genetic risk variants for this disease acquired over the past 25 years have greatly improved patient management and our ability to predict which patients will develop or progress to advanced forms of AMD. Personalized medicine and individualized prevention and treatment strategies may become a reality in the near future.

Diminishing Risk for Age-Related Macular Degeneration with Nutrition: A Current View

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Clinical hallmarks of AMD are observed in one third of the elderly in industrialized countries. Preventative interventions through dietary modification are attractive strategies, because they are more affordable than clinical therapies, do not require specialists for administration and many studies suggest a benefit of micro- and macro-nutrients with respect to AMD with few, if any, adverse effects. The goal of this review is to provide information from recent literature on the value of various nutrients, particularly omega-3 fatty acids, lower glycemic index diets and, perhaps, some carotenoids, with regard to diminishing risk for onset or progression of AMD. Results from the upcoming Age-Related Eye Disease Study (AREDS) II intervention trial should be particularly informative.

Innate and adaptive immunity against oxidative damage cooperate in the pathogenesis of age-related macular degeneration (P3367)

Abstract While our knowledge of acute immune responses is extensive, the cooperation of innate and adaptive immunity in chronic inflammatory diseases remains poorly defined. Age-related macular degeneration (AMD) is the leading cause of legal blindness in the developed world. Recently, the immune system has been shown to play a role in AMD. However, the specific roles of the adaptive immune system and different types of macrophages have not been studied in detail. Oxidative stress is a major contributing factor in the development of pathological inflammatory conditions, including atherosclerosis and AMD. Carboxyethylpyrrole (CEP) is a lipid peroxidation product associated with AMD and mice immunized with CEP-adducted self proteins develop AMD-like pathology. Here, we show CEP-specific T cell activation, pro-inflammatory cytokine production (IFN- γ, IL-17) and infiltration of M1 macrophages in the subretinal space, linking both the adaptive and innate immune systems in the onset of AMD. In vitro, CEP-specific T cells specifically promote M1 macrophage differentiation, while CEP directly induces TLR-2-independent M1 polarization. Moreover, CEP-immunized Ccr2-deficient mice lack macrophage infiltration and retinal lesions, suggesting a deleterious role for macrophages in this model. Our data provide new insights into the pathogenesis and possible treatment of AMD, while providing a more general view of chronic inflammation applicable to other settings.

HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway

Genetic predisposition and senescence of retinal pigment epithelium induced by oxidative stress are major contributors to age-related macular degeneration (AMD). Single-nucleotide polymorphisms in HTRA1 are strongly linked to the onset of AMD. In this study, we examine the role of HtrA1 in premature senescence and cell death induced by oxidative stress. HtrA1 mRNA and protein were up-regulated during premature senescence induced by H2O2 in both mouse embryonic fibroblasts (MEFs) and ARPE-19 cells. Expression of the senescence markers p21CIP1/WAF1 and p16INK4a, and SA-β-galactosidase activity, were higher in HtrA1+/− MEFs than in HtrA1−/− MEFs. HtrA1+/+ and HtrA1+/− MEFs were more resistant than HtrA1−/− MEFs to H2O2-induced cell death. Activation of p38 MAPK by oxidative stress was quicker in HtrA1+/− MEFs than in HtrA1−/− MEFs. The effects of excess HtrA1 were examined by transient transfection of cells with HtrA1 expression vectors or by addition of recombinant proteins. Excess wild type HtrA1 accelerated premature senescence of MEFs and ARPE-19 cells, while the protease-inactive HtrA1 S328A did not. HtrA1-induced senescence was abrogated by inhibition of p38 MAPK. We conclude that HtrA1 is induced by oxidative stress and promotes premature cell senescence through p38 MAPK in a protease activity-dependent manner.

Improving patient outcomes: role of the primary care optometrist in the early diagnosis and management of age-related macular degeneration

Not long ago, the management of age-related macular degeneration (AMD) was confined to rehabilitating whatever vision had not been damaged by the disease. The recent suc - cesses of the anti-vascular endothelial growth factor agents and the antioxidant clinical trials have revolutionized AMD treatment. For the first time, there is realistic hope that the progression of AMD can be slowed down or stopped and near normal vision can be preserved. Developments in new vision tests, imaging modalities, and genetic testing have greatly improved the chance of detecting the onset of AMD and choroidal neovascularization. However, because the current treatments still cannot revive degenerated retinal cells, the best patient outcome that can be achieved is early detection of the disease and application of the appropriate treatment before too much retinal damage has occurred. The opportunities and challenges offered by the new treat- ment options and disease detection methods have redefined the role of primary care optometrists in AMD management. This review of literature and practice guidelines demonstrates that, in addition to the traditional roles of refraction and visual rehabilitation, the unique position of optometrists as the first-line eye-care providers has allowed them to play an important role in the early detection of AMD, patient education, lifestyle-change counseling, disease monitor- ing and referral, and nutrition supplement counseling. The active participation of primary care optometrists in the shared care of AMD management is likely to result in great improvement in patient outcomes. Optometrists also need to improve their competence in these areas to meet the new challenges. Although primary care optometrists have always managed patients with AMD, their role in managing this sight-threatening disease has not been adequately documented. In light of the recent game-changing developments in AMD treatment, it is important to review what primary care optometrists are doing, what they can do, and what they should do to improve patient outcomes in the new era of AMD management.

Autophagy Regulating Kinases As Potential Therapeutic Targets For Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly in the developed countries. The number of AMD patients will double during the next decades due to increasing number of aged people. Chronic oxidative stress, inflammation and accumulation of protein-rich deposits both in the retinal pigment epithelium lysosomes and under the retinal pigment epithelium herald the onset of AMD. The disease can be divided into dry and wet AMD forms. The dry form of the disease is more prevalent accounting for up to 90% of all cases. Continued intraocular injections are the current treatment strategy to prevent progression of wet AMD. It is a major challenge to develop new drugs that could prevent or at least ease the symptoms of the increasing population of AMD patients. Since AMD pathology is clearly associated with accumulated protein deposits, the autophagy clearance system might represent a potential future therapeutic target for AMD as is thoroughly discussed here.

Age-related macular degeneration and coronary heart disease: Evaluation of genetic and environmental associations

An association between coronary heart disease (CHD) and age-related macular degeneration (AMD) has long been postulated but results from epidemiological case-control studies, and genetic analyses have been ambiguous. In this study we illuminate the association between AMD and CHD with respect to genetic and environmental risk factors, age of disease onset and AMD subgroups. AMD patients (n = 1036) and age-matched control subjects (n = 412) between 68 and 95 years of age were included in the case-control study. A medical history of CHD, cerebral stroke and arterial hypertension was determined for each individual. The assessment of interacting factors included the current use of systemic medications and smoking habits. Analysis of AMD associated genetic variants included frequent polymorphisms at the complement factor H (CFH, MIM 134370) gene (rs1061170 [p.Y402H], rs800292 [p.I62V]), the complement factor H-related 3 (CFHR3, MIM 605336)/complement factor H-related 1 (CFHR1, MIM 134371) locus (rs6677604; proxy for ΔCFHR3/CFHR1; r2 = 0.97) as well as the age-related maculopathy susceptibility 2 (ARMS2, MIM 611313) gene (rs10490924 [p.A69S]).Logistic regression identified a significant positive association of AMD with AMD-risk variants in CFH, ARMS2, and smoking ≥20 packs/year. A history of CHD and the current use of antihyperuricemic agents were inversely associated with the disease. Significantly fewer patients with rs6677604 nonrisk genotype A/A regularly used statins. ARMS2:p.A69S risk variant was significantly associated with exsudative AMD. AMD patients with risk variants at rs1061170 (CFH:p.Y402H) and ARMS2 and smokers (≥20 packs/year) were significantly earlier affected by AMD than those carrying the non-risk variants at each locus.Our data support three major conclusions. First, the age of AMD onset is significantly influenced by genetic and environmental risk factors. Second, in support of previous reports we also show that the ARMS2 rs10490924:T allele is significantly linked to exsudative AMD. And finally, a self-reported history of CHD was inversely associated with AMD in this study. Novel therapeutic strategies aiming at preventing the development of AMD may considerably differ from those that have been developed to treat cardiovascular disorders as both common disorders likely underlie different pathomechanisms.

A Novel Source of Methylglyoxal and Glyoxal in Retina: Implications for Age-Related Macular Degeneration

Aging of retinal pigment epithelial (RPE) cells of the eye is marked by accumulations of bisretinoid fluorophores; two of the compounds within this lipofuscin mixture are A2E and all-trans-retinal dimer. These pigments are implicated in pathological mechanisms involved in some vision-threatening disorders including age-related macular degeneration (AMD). Studies have shown that bisretinoids are photosensitive compounds that undergo photooxidation and photodegradation when irradiated with short wavelength visible light. Utilizing ultra performance liquid chromatography (UPLC) with electrospray ionization mass spectrometry (ESI-MS) we demonstrate that photodegradation of A2E and all-trans-retinal dimer generates the dicarbonyls glyoxal (GO) and methylglyoxal (MG), that are known to modify proteins by advanced glycation endproduct (AGE) formation. By extracellular trapping with aminoguanidine, we established that these oxo-aldehydes are released from irradiated A2E-containing RPE cells. Enzyme-linked immunosorbant assays (ELISA) revealed that the substrate underlying A2E-containing RPE was AGE-modified after irradiation. This AGE deposition was suppressed by prior treatment of the cells with aminoguanidine. AGE-modification causes structural and functional impairment of proteins. In chronic diseases such as diabetes and atherosclerosis, MG and GO modify proteins by non-enzymatic glycation and oxidation reactions. AGE-modified proteins are also components of drusen, the sub-RPE deposits that confer increased risk of AMD onset. These results indicate that photodegraded RPE bisretinoid is likely to be a previously unknown source of MG and GO in the eye.

Choroidal Neovascular Membrane in Age-Related Macular Degeneration is Associated with Increased Interleukin-6

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness among persons aged 60 years and older. Although inflammation has been postulated to have a role in the pathogenesis of AMD, epidemiologic studies have not shown a relationship between systemic inflammation or presence of inflammatory markers at AMD. The aim of our study was to evaluate the differences in various types of cytokines and intracelluler signaling molecules for the onset and progression of AMD. There were two groups in our study; Group 1, which acted as the control group ( n = 30, mean age 67.60 ± 8.32 years), and Group 2, consisting of AMD patients ( n = 22, mean age 70.10 ± 10.33 years). From serum samples, vascular endothelial growth factor (VEGF) (pg/mL), interleukin-6 (IL-6) and interleukin-1β (IL-1β) (pg/mL), nitrotyrosine (nmol/L) levels were determined by enzyme linked-immuno-sorbent assay method. Nitrite/Nitrate levels were measured by photometric method (μmol/L). There were no significant differences between the groups with regard to age, VEGF, IL-1β, nitrite/nitrate, and nitrotyrosine. The significant result was the mean IL-6 levels that were higher in the AMD group (55.03 ± 60.03 pg/mL) than in the control group (16.08 ± 8.24 pg/mL, p < 0.001). IL-6 induces an ocular inflammatory response often accompanied by the breakdown of the blood–ocular barrier. The increased levels of IL-6 can support the hypothesis that AMD may be partially mediated through inflammatory mechanisms.

Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks

Age-related macular degeneration (AMD) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (RPE), choroid, and neural retina. Initially characterized by an accumulation of sub-RPE deposits, AMD leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. Although genetic analysis, animal models, and cell culture systems have yielded important insights into AMD, the molecular pathways underlying AMD's onset and progression remain poorly delineated. We sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of AMD and normal human donor eyes. RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD, and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort. We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of AMD clinical diagnosis. We also discovered functionally enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in AMD pathogenesis. We discovered new global biomarkers and gene expression signatures of AMD. These results are consistent with a model whereby cell-based inflammatory responses represent a central feature of AMD etiology, and depending on genetics, environment, or stochastic factors, may give rise to the advanced AMD phenotypes characterized by angiogenesis and/or cell death. Genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for AMD-directed therapeutics and diagnostics. Please see related commentary: http://www.biomedcentral.com/1741-7015/10/21/abstract

Age-Related Macular Degeneration-Susceptibility Single Nucleotide Polymorphisms in a Han Chinese Control Population

Purpose: Our study aimed to detect the frequency of age-related macular degeneration (AMD)-susceptibility single nucleotide polymorphisms (SNPs) in control subjects of Han Chinese in a population-based study.Methods: A total of 419 subjects of Han Chinese without AMD were recruited from our population-based Nantong Eye Study. Nine AMD-susceptibility SNPs were genotyped. The allele/genotype frequencies were compared with the data from the literature and NCBI Reference Assembly.Results: The call rates of genotyping were > 98%. All tested SNPs except for HTRA1 rs11200638 were in Hardy-Weinberg Equilibrium (HWE). The allele distributions of some AMD-susceptibility SNPs were different from the records for the Chinese population in the National Center for Biotechnology Information (NCBI) Reference Assembly. Compared to those in a Caucasian population, the frequency of minor alleles of CFH rs800292 (48% vs. 19.2%) and HTRA1 rs11200638 were much higher (47% vs. 25%), while the frequency of minor alleles of CFH rs1061170 (9% vs. 35%), CX3CR1 rs3732379 (3% vs. 21%), CX3CR1 rs3732378 (3% vs. 11%) and SERPING1 rs2511989 (11% vs. 48%) were much lower in the Han Chinese population. Minor differences were observed in the frequency of minor alleles of CFB rs4151667, C2 rs547154 and TLR3 rs3775291. The allele/genotype frequencies of CFH rs1061170 and HTRA1 rs11200638, two well-confirmed AMD-susceptible SNPs, were close to each other in the Han Chinese and Japanese population.Conclusion: The distribution of AMD-susceptibility SNPs shows ethnicity specificity. Substantial differences of the SNPs’ distribution were noted from study to study, even within the same ethnic group. The genotype data will be used for longitudinal observation of AMD onset in the follow-up of the cohort.

Dietary Glycemic Index as a Modulator of Age‐Related Macular Degeneration

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the US. Efficacious treatments are limited, prompting the need for preventative therapies. Epidemiological evidence indicates that consumption of a low glycemic index diet reduces the risk for onset and progression of AMD, but the biological mechanism underlying this association is not known. We utilized hydroquinone to simulate early AMD in mice, and fed them either a high or low glycemic index (GI) diet to study the effect of carbohydrate quality on disease progression. Retinas were examined by transmission electron microscopy for the development of indicators of early AMD, and by immunohistochemistry for deposition of advanced glycation end products (AGE) and inflammatory markers. Compared to low GI-fed mice, high GI-fed mice exhibited greater stress to retinal pigment epithelial (RPE) cells, as indicated by basal RPE structural damage and deposition of MG-H1, a type of AGE. We have discovered a new mouse model for early AMD and have shown that a high GI diet accelerates retinal damage that is comparable to damage seen in human cases of early AMD. It is likely that the adverse effects on the RPE are due a wide array of inflammatory and oxidative stresses. This research was funded by USDA 1950-510000-060-01A, Johnson and Johnson Focused Giving, and the American Health Assistance Foundation.

Update on the role of genetics in the onset of age-related macular degeneration

Age-related macular degeneration (AMD), akin to other common age-related diseases, has a complex pathogenesis and arises from the interplay of genes, environmental factors, and personal characteristics. The past decade has seen very significant strides towards identification of those precise genetic variants associated with disease. That genes encoding proteins of the (alternative) complement pathway (CFH, C2, CFB, C3, CFI) are major players in etiology came as a surprise to many but has already lead to the development of therapies entering human clinical trials. Other genes replicated in many populations ARMS2, APOE, variants near TIMP3, and genes involved in lipid metabolism have also been implicated in disease pathogenesis. The genes discovered to date can be estimated to account for approximately 50% of the genetic variance of AMD and have been discovered by candidate gene approaches, pathway analysis, and latterly genome-wide association studies. Next generation sequencing modalities and meta-analysis techniques are being employed with the aim of identifying the remaining rarer but, perhaps, individually more significant sequence variations, linked to disease status. Complementary studies have also begun to utilize this genetic information to develop clinically useful algorithms to predict AMD risk and evaluate pharmacogenetics. In this article, contemporary commentary is provided on rapidly progressing efforts to elucidate the genetic pathogenesis of AMD as the field stands at the end of the first decade of the 21st century.

Reading speed in the peripheral visual field of older adults: Does it benefit from perceptual learning?

Enhancing reading ability in peripheral vision is important for the rehabilitation of people with central-visual-field loss from age-related macular degeneration (AMD). Previous research has shown that perceptual learning, based on a trigram letter-recognition task, improved peripheral reading speed among normally-sighted young adults ( Chung, Legge, & Cheung, 2004). Here we ask whether the same happens in older adults in an age range more typical of the onset of AMD. Eighteen normally-sighted subjects, aged 55–76 years, were randomly assigned to training or control groups. Visual-span profiles (plots of letter-recognition accuracy as a function of horizontal letter position) and RSVP reading speeds were measured at 10° above and below fixation during pre- and post-tests for all subjects. Training consisted of repeated measurements of visual-span profiles at 10° below fixation, in four daily sessions. The control subjects did not receive any training. Perceptual learning enlarged the visual spans in both trained (lower) and untrained (upper) visual fields. Reading speed improved in the trained field by 60% when the trained print size was used. The training benefits for these older subjects were weaker than the training benefits for young adults found by Chung et al. Despite the weaker training benefits, perceptual learning remains a potential option for low-vision reading rehabilitation among older adults.

Inflammation and the pathogenesis of age-related macular degeneration

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. Many changes occur in various areas of the eye as it ages. These include choroidal thinning, thickening of Bruch's membrane and drusen formation. Each of these is associated with the onset of AMD. Methods: Recent findings on how those changes contribute to the pathogenesis of AMD with a focus on inflammation are examined. Results: There is evidence suggesting that all changes identified so far as being involved in the pathogenesis of AMD are not able to cause AMD alone. Instead, susceptibility genes, and in particular a coding variant of a gene on chromosome 1 result in dysfunction of the immune system. This leads to an inappropriate inflammatory response, which then sets the stage for AMD onset. Conclusions: It is now well-known that AMD is a multi-factorial disease, with environmental causes and genetics all playing a role.

A human apoB100 transgenic mouse expresses human apoB100 in the RPE and develops features of early AMD

apoB100 lipoprotein particles have been found to accumulate in Bruch membrane prior to the development of age-related macular degeneration (AMD). This work was performed to determine whether mice that overexpress apoB100 in the RPE/choroid and liver develop landmarks of early AMD over time. Mice transgenic for a human genomic fragment encoding the full length human apoB (“apoB100” mice) and litter-mate control mice were given a normal chow or high-fat diet for 12 months. Mice were evaluated for human apoB mRNA expression in the RPE/choroid and liver by RT-qPCR. Phenotypic changes associated with early AMD were evaluated by ultrastructural analysis using transmission electron microscopy. Changes were semi-quantified using linear regression analysis. Both the RPE/choroid and liver of apoB100 mice expressed both human and mouse apoB mRNA. Transmission electron microscopy showed ultrastructural changes consistent with early human AMD including loss of basal infoldings and accumulation of cytoplasmic vacuoles in the RPE, and basal laminar deposits containing long-spacing collagen and heterogeneous debris in Bruch membrane of apoB100 mice. In apoB100 mice given a high-fat diet, basal linear-like deposits were identified in 12-month-old mice. Linear regression analysis showed that the genotype (human apoB transgene) was a stronger influencing factor than high-fat diet in producing AMD-like lesions used in this study. Human apoB100 transgenic mice overexpress apoB in RPE and, with time, develop validated phenotypic changes that are seen in early human AMD. The phenotypic changes were aggravated by feeding a high-fat diet. The apoB100 mouse model could be valuable in determining the role of apoB-containing lipoproteins in triggering the onset of early AMD.

Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study

Little is known about the role of genetic variants in the early stages of age-related macular degeneration (AMD). We aimed to investigate how genetic variations within five well-defined genes relate to AMD severity. We analysed SNPs in the genes for complement factor H (CFH), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HtrA1), complement factor B (CFB), and complement component 2 (C2)in 183 controls and 730 patients with increasing severity of AMD from the Muenster aging and retina study (MARS). Severity scoring was based on the Rotterdam classification of fundus photographs. Compared with controls, patients with very early AMD showed a significantly increased minor allele frequency (MAF) only for CFH-rs1061170. With increasing severity of AMD, SNPs in CFH-rs1061170,as well as ARMS2-rs10490924, became consistently more common (P<0.001). Likewise, HtrA1-rs11200638 was less clearly associated with AMD severity, whereas C2-rs9332739 and CFB-rs641153 showed no relation. Multifactorial models confirmed CFH and ARMS2 as major determinants of AMD severity, whereas addition of HtrA1, C2 and CFB did not improve model prediction. In the models, age did not contribute to very early but to all more severe AMD stages, whereas smoking history had a significant impact only for late AMD. Our findings indicate that the CFH gene is involved in the onset of AMD, whereas both, the CFH and ARMS2 genes, and more weakly, the HtrA1 gene, appear to account for the advancement of AMD. The results for SNPs in the C2 and CFB genes were inconclusive. Genetic factors dominated in their impact over age and smoking history.