Age related macular degeneration (AMD) is the most common cause of irreversible vision loss in the elderly. At present, there are an estimated one million people in Canada with some form of AMD and this number is expected to double to two million by 2031. These estimates are sobering, and it is predicted that costs for treatment and care of individuals who suffer vision loss from AMD will have significant impact on the social and public health systems in Canada in the next two decades. There are treatments to slow the progression of vision loss, but unfortunately, there are currently no cures available for AMD. In order to develop effective second generation therapies and cures, further insights into how and why AMD develops are greatly needed. Recent studies have provided novel insights into the role of inflammation in the pathogenesis of AMD. Inflammation, or swelling of the retinal tissues, causes harmful processes that promote macular degeneration. The proposed studies will focus on the triggers of inflammation in the retina. It is hypothesized that macular degeneration may be slowed or stopped by eliminating the molecules that cause inflammation in the retina. This study will focus on amyloid beta (Aβ), a toxic molecule that has been implicated in retinal inflammation, and the role that it may play in gene expression of the retinal pigment epithelial cell. Amyloid beta is a well studied peptide in another age related disorder, Alzheimer’s disease. It is the major extracellular deposit in Alzheimer’s disease plaques, and has recently been discovered as a component of drusen, the hallmark extracellular deposits in the retina of patients with the ‘dry’ form of AMD. These studies will allow the development of new treatment regimens that target retinal inflammation and thus minimize the processes that ‘trigger’ the onset of macular degeneration.

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.

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.

This study evaluated whether cortical reorganization occurs in response to macular degeneration (MD), a progressive disorder of the retina that results in central vision loss. Past research has observed the ability of V1 to adapt to retinal damage, demonstrating that deafferented cortex is activated by the stimulation of intact retinal areas. It is still unclear, however, if and to what degree cortical reorganization is associated with specific forms of macular degeneration. This study evaluated the retinal health of MD participants (both age-related and juvenile) as well age-matched controls with computerized microperimetry. Contrast-reversing stimuli were then presented to different parts of the visual field while participants were scanned with functional magnetic resonance imaging (fMRI). For MD participants, stimulation of peripheral retinal areas elicited activation in deafferented cortex. This activation occurred for retinal areas adapted for eccentric viewing (preferred retinal locations), but not in preserved retina at the same eccentricity. These findings add to the scientific knowledge of plasticity in sensory systems by supporting an experience driven understanding of cortical reorganization. They could also have a meaningful impact on how macular degeneration is treated by informing the design of therapeutic training regimes.

In recent years there have been two cycloterpenals, molecules consisting of a cyclohexadienal core, isolated from nature. Cyclocitral, the condensation product of citral, has been isolated from the North Sea bryozoans Flustra foliacea. In the human eyes, cycloretinal has been isolated and is a toxic by product of the vision cycle. This retinal dimer is believed to contribute to age related macular degeneration, the leading cause of blindness in the elderly. In 1992, it was discovered that if [beta]-ionylideneacetaldehyde was incubated with beta-lactoglobulin ([beta]-LG), the principal whey protein in dairy milk, that it would mediate the formation of cyclo-[beta]-ional. No follow up studies were performed on this protein mediated reaction or what biological activities these cycloterpenals may possess. This dissertation investigates the biological roles of substituted cyclohexadienes including cycloterpenals and cyclohexadiene enaminonitriles. To mimic the protein mediated reaction, we developed a synthetic procedure to produce a wide array of cycloterpenal by utilizing L-proline. Over 100 cycloterpenals were synthesized and screened for their biological activities against an array of cell based screens. The phenotypic effects of these cycloterpenals were screened against a PC12 assay where dramatic effects were observed on neurite outgrowth. During the synthesis of starting materials for the production of our cycloterpenal library, it was discovered that if excess base was added to the Horner-Wadsworth-Emmons reaction between a methyl-ketone and diethyl-(cyanomethyl)-phosphonate, conversion of the [alpha]-[beta]-unsaturated nitrile into an enaminonitrile was observed. This new synthetic procedure was optimized to generate a library of enaminonitriles as well as their quinazoline derivatives. The work within also includes the investigation of the [beta]-LG mediated reaction formation of cycloterpenals with natural and unnatural [beta]-methyl aldehydes. We were able to demonstrate that [beta]-LG could mediate the conversion of [alpha],[beta]-unsaturated aldehydes into their corresponding cycloterpenal. In vitro analysis was also performed with store bought milks and the [beta]-LG present was able to mediate the formation of cyclocitral. An in vivo experiment was also performed by utilizing New Zealand White rabbits to demonstrate the formation of cycloretinal within the blood stream by feeding a source of [beta]-LG with retinal. Interestingly, in human blood, [beta]-LG is present at concentrations of 0.7-1.2 g/dL. The protein has been identified within drusen pigments and lipofuscin granules that accumulate in the retina of macular degeneration patients. As humans do not produce beta-lactoglobulin, the source of this protein is from milk and milk products. With these experiments, we clearly demonstrate that under the appropriate conditions, cycloretinal can be produced with [beta]-LG. We have clearly established a direct link between [beta]-LG chemistry and age-related macular degeneration.

Although bevacizumab is one of the most commonly used treatments for DME and AMD, there are concerns regarding safety and effectiveness due to its off-label use. The study objectives were to determine if: 1) the risk of cardiovascular/ hemorrhagic events (safety) and visual impairment (effectiveness) differed by bevacizumab use (i.e., use vs. non-use and number of treatments) among DME and AMD patients; and 2) direct medical costs differed between DME and DME control patients. A retrospective cohort analysis was conducted with Texas Medicaid medical and prescription data (9/1/07-12/31/12) for patients: 18- 63 years, continuously enrolled 1-year pre- and post-index, and diagnosed with DME or AMD. The index date was the first date of diagnosis. The dependent variables were: 1) cardiovascular/hemorrhagic risk; 2) visual impairment; 3) direct medical costs. The independent variables were bevacizumab use and number of bevacizumab treatments. Covariates were disease state, Charlson Comorbidity Index (CCI) score, total medication use, number of laser treatments, and demographics. Propensity scoring technique was used to match: 1) bevacizumab users and non-users; and 2) DME and DME control cohorts. Descriptive analyses, logistic regression, Cox-regression, and generalized linear models were employed. A final cohort of 3,647 DME, 297 AMD, and 57,897 DME control patients were included. The majority (DME and AMD) was between 45-63 years of age (86.6%), Hispanic (54.0%), and female (65.1%). The mean total number of unique medications and mean CCI were 2.7 ± 3.4 and 6.0 ± 3.3, respectively. Total direct medical costs/person (Mean (±SD)) incurred by DME, DME control, and AMD subjects in the post-index period were $6,704(±9,338), $5,495(±10,153), and $4,935(±12,702), respectively. No differences in cardiovascular/ hemorrhagic risk were found between bevacizumab users and non-users. The claims data lacks the detail to determine the effectiveness of bevacizumab. DME control patients had lower overall direct medical costs than DME patients (p<0.0001). In conclusion, although bevacizumab is a less expensive off-label alternative of ranibizumab, the choice between bevacizumab and ranibizumab should be made through careful consideration. However, as the use of anti-VEGF agent increases, further research should be conducted to determine if any changes in cardiovascular adverse events occur. / text

Age related macular degeneration (AMD) is the most common cause of irreversible vision loss in the elderly. At present, there are an estimated one million people in Canada with some form of AMD and this number is expected to double to two million by 2031. These estimates are sobering, and it is predicted that costs for treatment and care of individuals who suffer vision loss from AMD will have significant impact on the social and public health systems in Canada in the next two decades. There are treatments to slow the progression of vision loss, but unfortunately, there are currently no cures available for AMD. In order to develop effective second generation therapies and cures, further insights into how and why AMD develops are greatly needed. Recent studies have provided novel insights into the role of inflammation in the pathogenesis of AMD. Inflammation, or swelling of the retinal tissues, causes harmful processes that promote macular degeneration. The proposed studies will focus on the triggers of inflammation in the retina. It is hypothesized that macular degeneration may be slowed or stopped by eliminating the molecules that cause inflammation in the retina. This study will focus on amyloid beta (Aβ), a toxic molecule that has been implicated in retinal inflammation, and the role that it may play in gene expression of the retinal pigment epithelial cell. Amyloid beta is a well studied peptide in another age related disorder, Alzheimer’s disease. It is the major extracellular deposit in Alzheimer’s disease plaques, and has recently been discovered as a component of drusen, the hallmark extracellular deposits in the retina of patients with the ‘dry’ form of AMD. These studies will allow the development of new treatment regimens that target retinal inflammation and thus minimize the processes that ‘trigger’ the onset of macular degeneration.

No description available.

Eine retrospektive Studie über das Progressionsrisiko asymptomatischer früher Altersabhängiger Makuladegeneration in die symptomatische Spätphase überzugehen. Anhand von Lipofuszin-Mustern, die per Fundusautofluoreszenzmessung erkannt werden können, lassen sich Risikopatienten identifizieren. Diese Methode könnte zukünftig im klinischen Alltag als nicht-invasive, kostengünstige Screening-Methode zur Anwendung kommen, um Risikopatienten einer intensivierten Therapie unterziehen zu können, bevor sie eine Beeinträchtigung ihrer Sehkraft erfahren.

Age-related macular degeneration (AMD) is the leading cause of Government-registered blindness in the elderly of the Western world and has two forms: wet and dry. No current AMD therapies are curative, and most are provided after retinal damage from the disease has already occurred (to preserve what is left of the retina). We have constructed a multi-factorial Phase II randomized, controlled clinical trial, titled: “Omega-3 docosahexaenoic acid(DHA) and eicosapentaenoic acid (EPA) nutritional supplementation to delay the progression of age-related macular degeneration (AMD): The OMEGAlberta Study”. Each day, participants in the experimental arm of this study will receive 600mg DHA and 1200mg EPA, plus Vitalux AREDS antioxidant formula. Based on the physicochemical properties of DHA, EPA, and Vitalux, our aim is to delay the 5-year incident rate of progression of intermediate dry AMD to wet AMD. Several tests will be performed, not only to quantify the incident rate of progression of AMD, but also to gain insight of the physiological mechanisms behind the supplements being provided. If the supplements are proven to delay AMD progression, this knowledge should be implemented by changes in health services and policy relating to public education and the treatment of AMD.