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Age-related macular degeneration (AMD) is the most common cause of vision loss in America for people over the age of 60. Due to damage to the retina, symptoms normally include blurred central vision, difficulty reading, and seeing shadows. While there is no cure for the disease, there are treatments that slow its progression and can restore vision. The treatments explored in this paper are: anti-vascular endothelial growth factor (VEGF) drugs, photodynamic therapy (PDT) and steroids. All three require invasive eye procedures that carry their own risks. The possibility of more effective treatments by combining these therapies is being tested through clinical trials. Studies of combined PDT and anti-VEGF, combined PDT and steroids, and anti-VEGF monotherapy were reviewed, comparing changes in average visual acuity, foveal thickness, and number of injections administered. PDT and anti-VEGF was concluded to be the most efficient of the three, requiring fewer injections while showing an increase in visual acuity similar to anti-VEGF monotherapy.

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Age-related Macular Degeneration (AMD) is the leading cause of irreversible vision loss among elderly people in developed countries. The non-neovascular or “dry” form of AMD accounts for 85%, whereas the neovascular or “wet” accounts for 15%, of all cases. There are no effective treatments for dry AMD mainly because the molecular mechanisms that lead to the development and progression of AMD are not fully understood. Similarly, while wet AMD is being treated with antibodies against vascular endothelial growth factor (VEGF), the underlying cause that results in the development of wet AMD remains elusive. Cytosolic accumulation of nuclear-DNA (nDNA) fragments has been found to trigger inflammation and mediate the development of multiple diseases. Because inflammation plays a pivotal role in AMD pathogenesis, we thus investigated if accumulation of cytosolic nDNA also contributes to AMD. Our data show that cytosolic nDNA is enriched in macular retinal pigment epithelium (RPE) cells of AMD patients. To study the effect of cytosolic nDNA on RPE cells, we mimicked this pathology by deleting the lysosomal endonuclease Dnase2a, which is responsible for degrading DNA fragments, using CRISPR/Cas9. This resulted in cytosolic accumulation of nDNA in cultured primary human RPE cells as well as in the RPE cell line ARPE-19. Importantly, both RPE cell types with Dnase2a loss became senescent and secreted higher levels of VGEF and pro-inflammatory cytokines compared to control. These effects were mediated by the DNA sensor STING and mTOR pathway. Additionally, similar to other senescent cells, these senescent RPE cells secreted factors that acted in a paracrine manner turning otherwise healthy RPE cells into senescent cells that start secreting VEGF as well as pro-inflammatory cytokines. Finally, we found that mice with Dnase2a deletion develop features of AMD-like retinopathy, including drusen- like deposits, thickened Bruch’s membrane, RPE damage, photoreceptor atrophy, and reduced electroretinogram. The pleiotropic downstream effects of cytosolic accumulation of nDNA in RPE cells, which are consistent with the complex AMD pathology, suggest that this phenomenon contributes to the pathogenesis of AMD and thereby opens new opportunities for therapeutic interventions. / 2020-10-24T00:00:00Z

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No description available.

The purpose of this study is to examine the association between serum bilirubin and the development of age-related macular degeneration (AMD). The study design includes the utilization of a USA-nationally representative population based cross-sectional study in the National Health and Nutrition Examination Survey: specifically, the NHANES III and continuous NHANES from years 2005-2008. 15,501 survey participants from the NHANES studies chosen for this analysis were interviewed for demographic, behavioral, and medical information, put through a comprehensive medical examination segment, and a laboratory analysis portion. The 15,501 participants were chosen based on their age (40 and above) and the presence of fundus photographs. Fundus photographs were graded using standardized protocol to diagnose early and later AMD, which were combined to form the outcome "AMD" in a binary variable. Serum bilirubin levels were measured using spectrophotometry. Of the 15,501 participants in the study, 1305 (8.9%) were diagnosed with AMD. In a multivariate logistic regression adjusted for age, sex, smoking status, race, and serum C-reactive protein (CRP) levels, bilirubin was significantly associated with AMD (odds ratio, 0.728; confidence interval, 0.547-0.969; P value, 0.0296). The findings of this study indicate that the antioxidative effects of bilirubin may play protective role in the pathology of AMD.

Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years. Environmental and genetic risk-factors contribute to the development of AMD. An AMD-risk locus on chromosome 10q26 spans two genes, ARMS2 and HTRA1, and controversy exists as to which variants are responsible for increased risk of disease. Recent work suggests that HTRA1 expression levels are significantly increased in carriers of the risk haplotype associated with AMD. However, relatively little is known about the interactions, substrate specificity and roles in disease played by this secreted serine protease. This thesis aims to elucidate the potential role played by HTRA1 in AMD pathogenesis. A combination of tandem affinity purification (TAP) and yeast two-hybrid techniques was used to identify interacting partners of HTRA1. A number of proteins, with diverse roles in the alternative complement pathway, cell signaling, cell-matrix interactions, inflammation, angiogenesis and fibrosis, were identified. These are attractive candidates for further study as such processes are disturbed in AMD, implicating HTRA1 and its binding partners in disease development. One interacting partner, Complement Factor D (CFD), is a key activator in the alternative complement pathway. CFD, a 24 kDa serine protease, is expressed as an inactive zymogen, from which a signal peptide and activation peptide are cleaved before release of the mature, active protein into the circulation. In vitro studies show that CFD interacts with, and can be a substrate for, HTRA1. The interacting domain between the two proteins is localised to a region of 30 amino acids at the N-terminal end of proCFD. The 5 amino acid pro-peptide of CFD appears to be both necessary and sufficient for proteolysis of CFD by HTRA1. Investigation of the functional relevance of the interaction between HTRA1 and CFD shows that proCFD is cleaved by HTRA1, whilst mature CFD is not subjected to proteolysis. HTRA1-mediated cleavage of CFD forms an active protease, leading to activation of factor B in the alternative complement pathway in in vitro assays. Furthermore, a normal complement response is restored to CFD-depleted serum by addition of proCFD activated by HTRA1. Thus, an HTRA1- mediated increase in alternative complement pathway activity may explain a proportion of the AMD-risk attributed to the chr10q26 locus. Genetic and protein-based approaches were used to study the potential role of CFD in AMD pathogenesis, independent of an interaction with HTRA1. An intronic SNP, rs3826945, was significantly associated with increased risk of AMD in two British case-control cohorts, and in a combined meta-analysis with 4 additional cohorts from North America and Europe (p-value = 0.032, Odds Ratio = 1.112 in 4765 cases and 2693 controls). Assessment of copy number variation and sequencing of CFD did not identify any functional variants which may explain the association with disease. However, plasma levels of CFD were measured by ELISA in 751 AMD cases and 474 controls, and were found to be significantly elevated in AMD cases compared to controls (p-value = 0.00025). This further implicates complement activation in AMD pathogenesis, and makes CFD an attractive candidate for therapeutic intervention. An alteration in the level of activated CFD, possibly mediated via an interaction with HTRA1, either at the systemic or local tissue level, may play a role in disease development and progression.

Age-related macular degeneration (AMD) is the leading cause of vision loss in individuals aged 50 years and older and is estimated to affect as many as 11 million individuals in the United States. The purpose of this study was to examine the association between vitamin D and AMD disease progression. The life course epidemiology framework model was used to explore how vitamin D level as a risk factor may have an association to AMD disease through time. Data in the 2005-2008 National Health and Nutrition Examination Survey (NHANES) database were collected on vitamin D levels and identified stages of AMD level based on graded fundus eye exams from an available sample size of 5,604 participants. A quantitative cross-sectional study approach was used to address this gap in knowledge. A bivariate analysis was used to examine each independent variable (age, race/ethnicity, smoking status, and diabetes) to the dependent variable AMD from the 2005-2008 NHANES dataset. A multivariate logistic regression analysis was performed with AMD including each independent variable found to be significant. The findings from this study failed to suggest an association between vitamin D levels to AMD, with or without the covariates included in the model. There was not an association found between vitamin D level and presence of AMD. An association was found between age, smoking, and race to presence of AMD in each of the bivariate models. The findings from this study could be used for positive social change by encouraging medical and public health agencies to target screening programs at high-risk age, smoking, and race groups. There remains to be conflicting data in the literature. This study adds to the body of literature suggesting that higher levels of vitamin D are not necessarily beneficial as they pertains to AMD.

Ongoing efforts to quantify changes in quality of life attributable to low vision rehabilitation have focused on the utility of a single test instrument to measure this multidimensional concept. It is hypothesized that quality of life is best assessed using multiple instruments to capture some of its component facets, including functional status and psychosocial impact. Low vision devices have a predictably spontaneous impact on functional vision status, but associated psychosocial impact occurs with different magnitudes and over more protracted time intervals. The National Eye Institute Visual Function Questionnaire (NEI VFQ-25) measures the functional status of individuals in key vision areas that are associated with quality of life. The Psychosocial Impact of Assistive Devices Scale (PIADS) is an instrument that measures the psychosocial impact of assistive device intervention in three quality of life domains: competence, adaptability, and self-esteem. 68 participants were obtained from an ongoing parent study. These participants were recruited through the Low Vision Clinic at the University of Waterloo. They had a primary diagnosis of age-related macular degeneration (ARMD) and were obtaining a CCTV system for the first time. Assessments from the parent study used in this thesis included follow-up from 2 weeks, 1 month, 3 months, and 6 months post-adoption of the CCTV. The two tests administered were to measure functional vision status (NEI VFQ-25) and perceived psychosocial impact (PIADS), according the framework outlined by the Consortium for Assistive Technology Outcomes Research (CATOR). Multivariate repeated-measures ANVOA results confirmed that CCTV systems have an immediate and robust effect on the daily visual functioning of their users, and that this effect is stable over long periods of device use. The psychosocial impact of CCTV device use peaks in the shorter term and then seems to wane in the longer term for reasons that are not yet understood. The NEI VFQ-25 and the PIADS appear to have differential sensitivity to important influences on low vision rehabilitation outcomes. This project has demonstrated the value of longitudinal outcomes research in low vision rehabilitation. After obtaining a CCTV, visual function status remains static while psychosocial impact is dynamic during 6-months of follow-up.