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1
Gu, Jiayin. "Biomarkers for Age-Related Macular Degeneration." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1225388164.
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Renganathan, Kutralanathan. "Oxidative stress and age related macular degeneration." online version, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1193002743.
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Binns, Alison Mary. "Electrophysiological investigation of age-related macular degeneration." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55964/.
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Age-related macular degeneration (AMD) affects 12.7 million people in Europe and North America (Klein et al., 1995 Klein et al. 1999). As a combination of decreasing birth rate and increasing longevity alter the demographic of the population, the impact of this disease can only increase. This places an immense burden, not only on the individuals afflicted by the condition, but on the financial resources of society as a whole. Unfortunately, treatment for AMD is still very restricted, and even our understanding of the pathogenesis of the disease is far from complete One concern in tackling the growing problem of AMD is that methods used in the assessment of the condition are limited, usually based on fundus appearance and visual acuity. The aim of this study was to develop a battery of electrophysiological tests which would be sensitive to the most subtle changes in retinal function in AMD. Such tests may aid diagnosis, provide a more sensitive measure of disease progression, and allow an early identification of phenotypic subtypes. Protocols were included for the recording of the focal rod ERG, the focal cone ERG, the S-cone ERG and the dynamic focal cone ERG, along with psychophysical tests of colour vision and dark adaptation. These tests were then applied to 31 subjects with ARM (12 with bilateral ARM, 11 with unilateral wet AMD and 8 with unilateral dry AMD), and 28 controls. In the analysis of ERG amplitudes a ratio of focal to full-field amplitude was introduced as a novel means of reducing intersubject variability in response. This was found to increase the accuracy of all tests in distinguishing between subject groups. The greatest separation between ARM and control groups was provided by the dynamic tests of visual function i.e. rod-cone break time of the dark adaptation function, and time constant of recovery of the dynamic focal cone ERG. The time to rod-cone break also showed potential in identifying subjects at increased risk of exudative retinal changes. Subjects were assigned to groups in this study on the basis of fundus appearance. However, individuals within each subject group showed a range of retinal function which belied the homogeneity of retinal signs. This raises the question of whether 'form' or 'function' should form the basis of classification and assessment of individuals with ARM and AMD.
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Evans, Jennifer Rosemary. "Age-related macular degeneration in the UK." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2003. http://researchonline.lshtm.ac.uk/682315/.
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The aim of this thesis was to investigate the prevalence and impact of age-related macular degeneration (AMD) causing visual impairment in people aged 75 years and above in the UK. A secondary objective was to investigate a small number of potential risk factors for AMD. This was an add-on study to the MRC Trial of the Assessment and Management of Older People in the Community. The prevalence of AMD causing visual impairment was estimated at 3.7% (95% confidence interval 3.2% to 4.2%) in people aged 75 years and above. This prevalence increased sharply with age. There was a higher risk of AMD causing visual impairment in women. There were estimated to be approximately 192,000 people aged 75 years and above in the UK living in the community with visual impairment due to AMD (95% confidence interval 144,000 to 239,000) of whom 60,000 are aged 90 years or above. The prevalence of AMD causing visual impairment did not vary by socio-economic group or region. After controlling for appropriate confounding factors, compared to people not visually impaired, people visually impaired due to AMD were more likely to have functional difficulties, report poor health and be depressed. They were more likely to be in the worst quintile for the home management and mobility dimensions of the Sickness Impact Profile (SIP). After controlling for appropriate confounding factors including binocular acuity score, compared to people visually impaired due to other causes, people visually impaired due to AMD were more likely to have functional difficulties and report poor health and less likely to be in the worst quintile for SIP body care and movement dimension or die. There was an association between smoking status and risk of being visually impaired due to AMD. This effect was particularly strong in people aged 75-79 years of age. In these people there was a dose-response relationship between pack years of smoking and risk of AMD causing visual impairment. There were no statistically significant associations between alcohol consumption, cardiovascular disease and reproductive factors (in women) and AMD causing visual impairment.
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Goverdhan, Srinivas. "Immunogenetic pathways in age related macular degeneration." Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/66006/.
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Renganathan, Kutralanathan. "Oxidative Damage and Age Related Macular Degeneration." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1193002743.
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Wang, Yang. "Gene Discovery for Age-related Macular Degeneration." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228364622.
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NI, JIAQIAN. "Plasma Biomarkers for Age-Related Macular Degeneration." Cleveland State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=csu1236700270.
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Wu, Juan. "Dietary Determinants of Age-Related Macular Degeneration." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27201715.
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Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in older Americans. There has been a long standing interest in the role of diet in the development of AMD. As early as the first National Health and Nutrition Examination Survey in the 1970s, higher intakes of fruits and vegetables were inversely correlated with the prevalence of AMD. Carotenoids and omega3 fatty acids are the most studied dietary factors due to strong biological plausibility. However, evidence from epidemiologic studies and clinical trials on the relations has been inconsistent.
Chapter I prospectively examined the intakes of lutein/zeaxanthin and other common carotenoids in relation to the risk of AMD over more than two decades of follow-up among two large US cohorts, the Nurses’ Health Study and Health Professionals Follow-Up Study. We assessed nutrient intakes by repeated food frequency questionnaires. We also computed bioavailable plasma carotenoid scores directly from food intake using validated regression models. Cox proportional hazards models were used to compute the associations. Higher intakes of bioavailable carotenoids (except lycopene) were inversely associated with advanced AMD but not intermediate AMD. Analyses based on bioavailable intakes resulted in stronger associations than conventional nutrient intakes.
Chapter II prospectively evaluated the marine long-chain omega3 fatty acids. We found that long-chain omega3 fatty acids were inversely associated with visually significant intermediate AMD. There was no association with advanced AMD; however, the totality of current evidence for advanced AMD is also discordant.
Chapter III further investigated the plant-derived omega3 fatty acids, α-linolenic acid (ALA). We found that higher intake of ALA was associated with intermediate AMD before 2002 but not after. This coincides with the same time period when trans ALA was found in our participants’ blood and in mayonnaise, a primary food source of ALA. Whether trans ALA mediates this positive association warrants further studies.
Although randomized trials are usually believed as the “gold standard”, dietary factors are hard to be adequately studied by randomized trials due to the complexities of diet and disease relations. Thus, findings in this thesis from large long-term prospective cohort studies provide the next best form of evidence.
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Wang, Yang. "Gene discovery of age-related macular degeneration." Cleveland, Ohio : Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1228364622.
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Hemphill, Mandy. "Vitamin D and Age-Related Macular Degeneration." ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/3448.
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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.
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Whitmore, Steven Scott. "Molecular investigations of age-related macular degeneration." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1798.
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An estimated 170.38 million elderly adults suffer from some stage of age-related macular degeneration (AMD) worldwide, a vision defect that damages the macula, the central region of the retina required for sharp vision, such as reading, driving, and recognizing faces. Genetic factors strongly modify one's risk for developing AMD, and most of these genetic changes are found in genes of the alternative complement cascade, a component of the immune system. The lack of effective AMD prevention calls for the identification of druggable molecules and pathways.
In my research, I use microarrays and RNA sequencing to investigate the events occurring in early AMD, the reasons for macular susceptibility to AMD, and the events triggering aberrant blood vessel growth in late AMD. First, I found that genes associated with endothelial cells tend to be expressed at lower levels in human donors eyes affected by early AMD than in control eyes, concordant with previous studies indicating loss of choriocapillaris in early AMD. Second, I found that molecular signals across regions of the retina, retinal pigment epithelium, and choroid generally mirror the distribution of cell types in these regions. Third, I found that damage to cultured primate chorioretinal endothelial cells by the end product of complement activation, membrane attack complex, produces an environment conducive to choroidal neovascularization, a symptom of late-stage AMD. I propose a model that bridges genetic variants in the complement cascade genes with blood vessel loss in early AMD and the pathological growth of blood vessels in late AMD.
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E, Caldi. "Age related macular degeneration: a molecular insight." Doctoral thesis, Università di Siena, 2018. http://hdl.handle.net/11365/1060781.
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Age-related macular degeneration (AMD) is a progressive and degenerative disease affecting the macula lutea. Late stages include neovascular AMD (nAMD), which represents the most severe form of the disease and is characterized by the abnormal growth of newly formed blood vessels from the pre-existing choroidal vessels. Neovascularization breaks through Bruchʼs membrane reaching the retina where bleeding, fluids extravasation and a chronic inflammatory reaction eventually cause severe vision loss, up to blindness if left untreated.
With the aim to better elucidate the neoangiogenic process underlining nAMD and to evaluate novel targets to treat it, we collected aqueous humour samples and choroidal neovascular membranes (CNVM) from nAMD patients, before and after antiangiogenic treatment, and analyzed them for the content of proteins known to be involved in angiogenesis.
ELISA of the aqueous humour samples revealed the up-regulation of proteins such as VEGF-A, ATRA1, CD93 and TGF-β1 in naïve nAMD patientsʼ samples. While anti-VEGF treatment could efficiently reduce not only VEGF-A but also HTRA1 levels, it exerted little effect on CD93 aqueous concentration that was further confirmed by immunofluorescence of CNVM that displayed a up- regulation of the protein on the endothelium of proliferating vessels both from treated and untreated patients. Since anti-VEGF injections further increased TGF-β1 aqueous content, thus advocating for a possible targeting to treat nAMD, we investigated the concentrations of the active form of all the three TGF-βs, TGF-β1, TGF-β2 and TGF-β3, actually responsible for signalling activation. Using ELISA we could assess that, in the eye, TGF-β2 represents the main active form followed by TGF-β3. TGF-β1 accounted for only a 1,6% of the total active TGF-β. Interestingly, active TGF-β2 was found to be down regulated in naïve nAMD samples, with concentrations lower than the control group even after the second treatment. Since TGF-β signalling can be activated and modulated by several other molecules, the actual activation state of this pathway could not reflect active TGF-βs concentrations. We, therefore, set up a luciferase-based assay to evaluate the real activation state of the pathway and could demonstrate that a significant reduction of the anti- angiogenic SMAD2/3 signalling was evident in naïve nAMD samples and that the pathway activation was restored after the first anti-VEGF treatment.
Taken together our data propose the possibility to evaluate HTRA1 and CD93 as novel targets to treat nAMD and, at the same time, suggest caution when considering TGF-β activity general inhibition.
! 4!
Given the great impact oxidative stress exerts on AMD development, we also carried out in vitro and in vivo studies to evaluate NACET, a novel n-acetyl cysteine (NAC) derivative, as potential antioxidant molecule to prevent or delay AMD onset and progression.
Our results proved NACET to be a safe and powerful antioxidant, able to counteract oxidative stress even in a preventive way. Thank to its improved bioavailability compared to NAC, NACET oral administration to rats led to a significant increase in the ocular glutathione content thus supporting its potential eligibility for ocular therapy.
Further studies are needed to better evaluate NACET activity and toxicity in vivo but our in vitro and in vivo preliminary results advocate for a possible use of this molecule as prevention for AMD development.
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Gaffney, Allannah J. "Characterising adaptational dysfunction in age-related macular degeneration." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/41072/.
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Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world. The prevalence of this disease will continue to increase over the coming decades as the average age of the global population rises. There is consequently an urgent need to develop tests that are sensitive to early visual dysfunction, in order to identify individuals that have a high risk of developing AMD, to identify patients that would benefit from treatment, to assess the outcomes of that treatment and to evaluate emerging treatment strategies. An emerging body of evidence suggests that dark adaptation is a sensitive biomarker for early AMD. Cone dark adaptation is of particular interest to clinicians, as it can identify patients with early AMD in a relatively short recording period. Consequently, this thesis aimed to optimise psychophysical and electrophysiological techniques for the assessment of cone dark adaptation in early AMD, in order to maximise its diagnostic potential. A range of psychophysical methods were shown to be capable of monitoring the rapid changes in threshold that occur during cone dark adaptation. An optimal psychophysical protocol for the assessment of cone dark adaptation in early AMD was developed based on the results of a systematic evaluation of the effect of stimulus parameters and pre-adapting light intensity on the diagnostic potential of cone dark adaptation in early AMD. When compared to the focal cone ERG photostress test, both techniques were shown to be similarly diagnostic for early AMD. In addition, the time constant of cone recovery was shown to be significantly correlated with age, hence the sensitivity and specificity of cone dark adaptation as a biomarker for early macular disease may be further improved by considering these age-related changes. In conclusion, this thesis has confirmed that cone dark adaptation is a sensitive functional biomarker for early AMD. However, as cross-sectional studies are unable to determine the true diagnostic potential of a biomarker, longitudinal investigations are needed to explore the long-term potential of cone dark adaptation and other visual functions as biomarkers for early AMD.
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Pushpoth, Sreekumari. "Use of metabolomics in age-related macular degeneration." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8371/.
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Age-related macular degeneration (AMD) is a major cause of irreversible central sight loss in the elderly. Many factors affect disease onset and progression, and these include age, environmental stressors such as smoking, diet, inflammation and genetic polymorphisms, all of which are likely to influence metabolism. In some complex diseases, metabolomics, which involves the identification of a metabolic fingerprint in a biofluid or tissue, has been shown to discriminate metabolic changes associated with different disease processes and to identify specific phenotypes. We have applied metabolomics, in the first study of its kind, to analyse, using NMR spectroscopy, both serum and urine metabolic characteristics in patients with dry and wet AMD (n=104). NMR spectral analysis showed good clustering as well as separation among the serum and urine from dry and wet AMD patients. The results show that metabolite profiles can distinguish dry and wet AMD, but that the pathways involved, glycolysis, urea cycle and Kreb’s cycle, are involved in both forms of the disease. It is likely that the pathogenesis of dry and wet AMD is similar and that the severity of ocular damage and systemic inflammation would account for the distinguishing profiles. These data support the use of metabolomics in identifying biological pathways involved in pathogenesis of AMD, but not in the diagnosis or prognosis of disease.
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Dandekar, Samantha Sujata. "Detailed clinical phenotyping in Age-related Macular Degeneration." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444668/.
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Age-related Macular Degeneration (AMD) is a degenerative disorder that accounts for about 50% of blindness in England and Wales. At present there is no effective treatment. It occurs in genetically susceptible individuals exposed to environmental factors such as smoking but so far specific factors remain to be identified. For this descriptive study, 879 patients with Age-Related Maculopathy (ARM) and AMD and 44 spouses with normal maculae, to act as a comparison group, were recruited from a tertiary referral centre. The clinical phenotypes were analysed from fundus photographs, fluorescein angiography and autofluorescence (AF) images. Fundus features were characterised as they are thought to reflect the genes conferring risk in an individual and may allow greater understanding of disease mechanisms. These data demonstrated (1) A revised grading system shown to be reproducible for use with digital images (2) A moderate concordance rate for phenotype between eyes with end- stage AMD (kappa statistic=0.48 95% CI = 0.38-0.57, p0.001). (3) Distinct characteristics, including a larger area and higher counts of soft drusen with focal areas of increased AF, in fellow eyes of those with unilateral visual loss due to geographic atrophy (GA). (4) An increased susceptibility of the inferotemporal macula to GA. (5) Preserved integrity of the retinal pigment epithelium (RPE) in the initial stages of CNV development as identified from AF images. (6) Loss of scotopic rather than photopic function over areas of increased AF, as determined by fine matrix mapping, indicating the preferential vulnerability of rods. (7) No difference in smoking history between those with neovascular compared to non-neovascular AMD. Although AMD has been extensively investigated, this study extends our knowledge of retinal AF, the relative susceptibility of rods compared to cones at the macula and suggests both eyes of an individual are more discordant for late stages of AMD compared to drusen.
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Anderson, O. A. "Age-related macular degeneration : pathogenesis and drug delivery." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1457066/.
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Age related macular degeneration (AMD) is the leading cause of blindness amongst the elderly in the developed world. There is currently no effective treatment for the atrophic (dry) form of the disease. The aims of this thesis are twofold: Firstly to investigate the pathogenesis of atrophic AMD, a chronic inflammatory disease, with a view to identifying new potential treatment targets. Secondly to develop a novel method of sustained drug delivery with a view to using this mode of delivery to deliver immune modulating therapy in the treatment of atrophic AMD. We discovered that A2E, the major fluorophore of lipofuscin, induces the release of multiple chemokines and cytokines by retinal pigment epithelial cells in vitro. We showed that IL-1 1 was produced following activation of the NLRP3 inflammasome. Increased levels of IL-1 1 were also seen in the retinal-choroidal interface of ABCA4 knockout mice, known to contain high levels of A2E. A2E appears to be proinflammatory and therefore may be involved in the pathogenesis of age related macular degeneration. We also assessed the use of hyaluronic acid binding peptides as a mode of sustained intravitreal drug delivery. This was with the intention of linking them to a pharmacological agent, hence prolonging the intravitreal half-life of that agent. With regards to the peptide HABP35, we showed that hyaluronic acid binding translated into prolonged retention in the vitreous, in both an in vitro and in vivo setting. We then proposed a method of demonstrating its efficacy in vivo using IL-1 1 as a potential target. In conclusion our results provide novel data concerning a potential inflammatory role of A2E in the pathogenesis of AMD as well as introducing hyaluronic acid binding peptides into the field of ocular drug delivery.
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Lo, David. "Effects of combination therapies on age-related macular degeneration." Thesis, Boston University, 2013. https://hdl.handle.net/2144/21209.
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Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.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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Cherepanoff, Svetlana. "Age-related macular degeneration histopathological and serum autoantibody studies /." Connect to full text, 2007. http://hdl.handle.net/2123/2464.
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Thesis (Ph. D.)--University of Sydney, 2008.Title from title screen (viewed 18 June 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Clinical Ophthalmology and Eye Health, Faculty of Medicine. Degree awarded 2008; thesis submitted 2007. Includes bibliographical references. Also available in print form.
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Cherepanoff, Svetlana. "Age-related macular degeneration: histopathological and serum autoantibody studies." University of Sydney, 2008. http://hdl.handle.net/2123/2464.
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Doctor of Philosophy (PhD)BACKGROUND: The accumulation of abnormal extracellular deposits beneath the retinal pigment epithelium characterises the pathology of early age-related macular degeneration. However, the histopathological threshold at which age-related changes become early AMD is not defined, and the effect of each of the deposits (basal laminar deposit and membranous debris) on disease progression is poorly understood. Evidence suggests that macrophages play a key role in the development of AMD lesions, but the influence of basal laminar deposit (BLamD) and membranous debris on the recruitment and programming of local macrophages has not been explored. Although evidence also suggests that inflammation and innate immunity are involved in AMD, the significance of anti-retinal autoantibodies to disesase pathogenesis is not known. AIMS: (i) To determine the histopathological threshold that distinguishes normal ageing from early AMD; (ii) to determine the influence of BLamD and membranous debris on disease progression; (iii) to examine whether distinct early AMD phenotypes exist based on clinicopathological evidence; (iv) to determine the histopathological context in which Bruch’s membrane macrophages first found; (v) to examine the relationship between Bruch’s membrane macrophages and subclinical neovascularisation; (vi) to determine if the progressive accumulation of BLamD and membranous debris alters the immunophenotype of Bruch’s membrane macrophages and/or resident choroidal macrophages; (vii) to determine if the anti-retinal autoantibody profile differs significantly between normal individuals and those with early AMD, neovascular AMD or geographic atrophy; (viii) to examine whether baseline anti-retinal autoantibodies can predict progression to advanced AMD in individuals with early AMD; and (ix) to examine whether baseline anti-retinal autoantibodies can predict vision loss in individuals with neovascular AMD. METHODS:Clinicopathological studies were performed to correlate progressive accumulation of BLamD and membranous debris to fundus characteristics and visual acuity, as well as to sub-macular Bruch’s membrane macrophage count. Immunohistochemical studies were perfomed to determine whether the presence of BLamD and membranous debris altered the programming of Bruch’s membrane or resident choroidal macrophages. The presence of serum anti-retinal autoantibodies was determined by western blotting, and the association with disease progression examined in early and neovascular AMD. RESULTS: The presence of both basal linear deposit (BLinD) and a continuous layer of BLamD represents threshold early AMD histopathologically, which was seen clinically as a normal fundus in the majority of cases. Membranous debris accumulation appeared to influence the pathway of progression from early AMD to advanced AMD. Bruch’s membrane macrophages were first noted when a continuous layer of BLamD and clinical evidence of early AMD were present, and increased with the amount of membranous debris in eyes with thin BLamD. Eyes with subclinical CNV had high macrophage counts and there was some evidence of altered resident choroidal macrophage programming in the presence of BLamD and membranous debris. Serum anti-retinal autoantibodies were found in a higher proportion of early AMD participants compared with both controls and participants with neovascular AMD, and in a higher proportion of individuals with atrophic AMD compared to those with neovascular AMD. The presence of baseline anti-retinal autoantibodies in participants with early AMD was not associated with progression to advanced AMD. Participants with neovascular AMD lost more vision over 24 months if they had IgG autoantibodies at baseline compared to autoantibody negative participants. CONCLUSIONS: The finding that eyes with threshold early AMD appear clinically normal underscores the need to utilise more sophisticated tests to enable earlier disease detection. Clinicopathological evidence suggests two distinct early AMD phenotypes, which follow two pathways of AMD progression. Macrophage recruitment and programming may be altered by the presence of BLamD and membranous debris, highlighting the need to further characterise the biology of human resident choroidal macropahges. Anti-retinal autoantibodies can be found in both control and AMD sera, and future approaches that allow the examination of subtle changes in complex repertoires will determine whether they are involved in AMD disease pathogenesis.
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Walsh, Rachel. "Optimising dietary modification for age-related macular degeneration (AMD)." Thesis, Aston University, 2018. http://publications.aston.ac.uk/33417/.
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An ageing population has raised the priority of reducing the risk for age-related eye diseases that impair sight and quality of life. Chief among these diseases is age- related macular degeneration (AMD), the leading cause of visual impairment among older adults in the developed world. The dietary xanthophylls lutein and zeaxanthin may be effective at attenuating the risk and/or progression of AMD due to their antioxidant and photo-protective properties in the macula, where they are known as the macular pigment. The macular pigment is entirely of dietary origin therefore it is important that AMD patients adopt appropriate dietary modification. Currently, there is a lack of information regarding the lutein values of specific xanthophyll containing food sources. A lab based investigation was undertaken to determine the lutein concentrations in kale by high-performance liquid chromatography (HPLC); information was established that may improve knowledge on the climate and post-harvest handling, processing and storage effects. Lutein concentrations in minimally processed kale were significantly lower (p < 0.001) than that of kale freshly harvested. Domestic cooking and storage also had substantial negative effects on kale lutein levels. A dietary analysis study and a qualitative based study were conducted to determine dietary habits in AMD patients. In align with previous work, AMD patients were found to be under consuming nutrients regarded as important for their condition. Subjects consumed an average of 1.7 mg of L and Z per day, and calorie intakes were significantly below government DRVs (p < 0.05). Further investigations suggested that this may be attributed to certain physical and psychosocial barriers. Using the results of the laboratory based study, ready meals were created as a novel intervention to improve diet in this population. This body of research adds insights into dietary interventions within visually impaired groups, studies embedded may enrich dietary advice in the context of AMD.
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Kambanarou, Stamatina. "Binocular versus monocular viewing in age-related macular degeneration." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445617/.
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Purpose: This thesis compares monocular versus binocular viewing in AMD patients during fixation and reading, the potential of binocular function and the impact of symmetry of central scotomas on these results. Methods: Thirty patients with bilateral AMD were recruited. Standard clinical tests (distance and near acuity, contrast sensitivity, stereoacuity) were performed monocularly and binocularly. Fusion at the fixation locus was tested with a computer-driven display using shutter glasses. A scanning laser ophthalmoscope was used to map the preferred retinal locus (PRL) and the retinal scotomas under monocular viewing conditions during a fixation task. An infra-red eyetracker was used to investigate gaze position changes (and indirectly retinal locus changes) during monocular versus binocular fixation of the same target. Data from both devices were combined to predict PRL position under binocular viewing. Reading speed and eye movements during reading were measured monocularly and binocularly using the eyetracker. Results: Only 17.3% of AMD patients used the same PRL to fixate in both eyes under monocular versus binocular conditions, of whom 44.5% had symmetrical scotomas and 22.3% had asymmetrical scotomas. Retinal correspondence of the PRLs was retained in 85.2% of patients. Fusion at the PRL was demonstrated for most patients with symmetrical scotomas but for the minority of patients with asymmetrical scotomas (71.4% versus 33.3%). Reading speed binocularly could be accurately predicted by the reading speed of the better eye. There was no difference in eye movements during reading between the two viewing conditions. Conclusions: Overall, there was little advantage in binocular versus monocular viewing. Patients demonstrated different PRL characteristics under these conditions and the symmetry of the retinal scotomas was the main factor to account for these differences. These results provide an insight into how people with bilateral scotomas operate in the real world. This information is essential for developing effective vision rehabilitation.
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Callaghan, Tamsin. "Functional biomarkers of hypoxia in age-related macular degeneration." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/97168/.
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Age-related macular degeneration (AMD) is predicted to affect 196 million people by 2020 (Wong et al. 2014). To date there is no clear pathogenesis for the condition however, hypoxia has been implicated (Stefánsson et al. 2011). Currently, treatment is only available for neovascular AMD. To develop treatments targeted for early AMD a better understanding of the pathogenesis is required. There is also a need for sensitive functional biomarkers to improve diagnosis and monitoring and to expedite the evaluation of therauptics in clinical trials. The aim of this research was to investigate the hypothesis that hypoxia is involved in the pathogenesis of early AMD. Studies were carried out exploring the effect of transient systemic hypoxia (14% oxygen) and hyperoxia (60% oxygen) on scotopic thresholds and electroretinograms (ERGs) of participants with early AMD. It was hypothesised that the visual function of participants with AMD, but not age-matched controls, would improve during the hyperoxic episode and that hypoxia would have a greater detrimental effect on visual function in people with early AMD. There were no significant differences in scotopic thresholds within each group when breathing 60% or 14% oxygen compared to medical air (21% oxygen). There were also no significant differences in full-field ERG parameters between gas conditions or groups, apart from the amplitude of the b-wave which was significantly reduced under hypoxia in the control group. The amplitude of the focal flicker ERG was significantly higher in the control group than the AMD group when breathing both 14% and 21% oxygen. However, there were no significant differences in the parameters of the focal ERG within each group. These findings suggest that hypoxia is not responsible for the elevation of scotopic thresholds reported in AMD. There is also no evidence that ERG changes are attributable to hypoxia. This thesis provides no evidence to support the role of hypoxia in the pathogenesis of early AMD.
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Cherepanoff, Svetlana. "Age-related macular degeneration: histopathological and serum autoantibody studies." Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/2464.
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BACKGROUND: The accumulation of abnormal extracellular deposits beneath the retinal pigment epithelium characterises the pathology of early age-related macular degeneration. However, the histopathological threshold at which age-related changes become early AMD is not defined, and the effect of each of the deposits (basal laminar deposit and membranous debris) on disease progression is poorly understood. Evidence suggests that macrophages play a key role in the development of AMD lesions, but the influence of basal laminar deposit (BLamD) and membranous debris on the recruitment and programming of local macrophages has not been explored. Although evidence also suggests that inflammation and innate immunity are involved in AMD, the significance of anti-retinal autoantibodies to disesase pathogenesis is not known. AIMS: (i) To determine the histopathological threshold that distinguishes normal ageing from early AMD; (ii) to determine the influence of BLamD and membranous debris on disease progression; (iii) to examine whether distinct early AMD phenotypes exist based on clinicopathological evidence; (iv) to determine the histopathological context in which Bruch’s membrane macrophages first found; (v) to examine the relationship between Bruch’s membrane macrophages and subclinical neovascularisation; (vi) to determine if the progressive accumulation of BLamD and membranous debris alters the immunophenotype of Bruch’s membrane macrophages and/or resident choroidal macrophages; (vii) to determine if the anti-retinal autoantibody profile differs significantly between normal individuals and those with early AMD, neovascular AMD or geographic atrophy; (viii) to examine whether baseline anti-retinal autoantibodies can predict progression to advanced AMD in individuals with early AMD; and (ix) to examine whether baseline anti-retinal autoantibodies can predict vision loss in individuals with neovascular AMD. METHODS:Clinicopathological studies were performed to correlate progressive accumulation of BLamD and membranous debris to fundus characteristics and visual acuity, as well as to sub-macular Bruch’s membrane macrophage count. Immunohistochemical studies were perfomed to determine whether the presence of BLamD and membranous debris altered the programming of Bruch’s membrane or resident choroidal macrophages. The presence of serum anti-retinal autoantibodies was determined by western blotting, and the association with disease progression examined in early and neovascular AMD. RESULTS: The presence of both basal linear deposit (BLinD) and a continuous layer of BLamD represents threshold early AMD histopathologically, which was seen clinically as a normal fundus in the majority of cases. Membranous debris accumulation appeared to influence the pathway of progression from early AMD to advanced AMD. Bruch’s membrane macrophages were first noted when a continuous layer of BLamD and clinical evidence of early AMD were present, and increased with the amount of membranous debris in eyes with thin BLamD. Eyes with subclinical CNV had high macrophage counts and there was some evidence of altered resident choroidal macrophage programming in the presence of BLamD and membranous debris. Serum anti-retinal autoantibodies were found in a higher proportion of early AMD participants compared with both controls and participants with neovascular AMD, and in a higher proportion of individuals with atrophic AMD compared to those with neovascular AMD. The presence of baseline anti-retinal autoantibodies in participants with early AMD was not associated with progression to advanced AMD. Participants with neovascular AMD lost more vision over 24 months if they had IgG autoantibodies at baseline compared to autoantibody negative participants. CONCLUSIONS: The finding that eyes with threshold early AMD appear clinically normal underscores the need to utilise more sophisticated tests to enable earlier disease detection. Clinicopathological evidence suggests two distinct early AMD phenotypes, which follow two pathways of AMD progression. Macrophage recruitment and programming may be altered by the presence of BLamD and membranous debris, highlighting the need to further characterise the biology of human resident choroidal macropahges. Anti-retinal autoantibodies can be found in both control and AMD sera, and future approaches that allow the examination of subtle changes in complex repertoires will determine whether they are involved in AMD disease pathogenesis.
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Skeie, Jessica Marie. "Choroidal endothelial cell activation in age-related macular degeneration." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/602.
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Age-related macular degeneration (AMD) is a devastating ocular disease affecting one third of the elderly population in the western world. Some cases of AMD develop neovascular membranes, which are characterized by the pathologic growth of new blood vessels into the retina. This pathology may be initiated by proteins capable of activating endothelial cells to become angiogenic or inflammatory, later causing them to grow abnormally. This investigation aimed to determine the causes of pathologic blood vessel growth in AMD.
Human eyes with AMD have been shown by us and others to have abnormal activities of angiogenin, complement component C5 anaphylatoxin (C5a), and/or elastin fragments. We therefore employed methods including PCR, immunoblotting, immunohistochemistry, morphometrics, tissue culture, ultrastructural observations, and functional assays to determine the effects angiogenin, C5a, and elastin fragments on the angiogenic and inflammatory changes of choroidal endothelial cells in vitro and in vivo.
It was shown that choroidal endothelial cells express the surface receptor for C5a. Also, these cells increase their expression of ICAM-1, a surface protein that mediates leukocyte trafficking, in response to elevated levels of C5a in organ culture. This indicates that increased levels of C5a associated with AMD increase the inflammatory behavior of choroidal endothelial cells. It was demonstrated that choroidal endothelial cells are able to internalize angiogenin, a potent inducer of angiogenesis. Although cells from the choroid did not increase their angiogenic responses to this protein, their ability to internalize it indicates that they may respond to it by a different mechanism. Elevated levels of elastin fragments, however, did increase the migratory response of choroidal endothelial cells in culture, which is a key event in angiogenesis. Elevated levels of elastin fragents also increased the amount of collagen IV deposition within Bruch's membrane in a mouse model. This is relevant to AMD pathology as deposits within Bruch's membrane are common manifestations associated with AMD.
This body of work has provided new insights into the roles of angiogenin, C5a, and elastin fragments in activating choroidal endothelial cells to becoming inflammatory or angiogenic. These endothelial cell behaviors are common characteristics found in neovascular AMD. These new findings will help aid in the further understanding of the pathobiology of this disease in hopes to provide improved treatments in the future.
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Narvekar, Priya P. "Axitinib Loaded PLGA nanoparticles for Age-Related Macular Degeneration." Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7866.
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Despite of all the research going on for the treatment of ocular diseases, age-related macular degeneration (AMD) remains one of the serious vision threatening disease worldwide. Choroidal neovascularization, a pathophysiological characteristic of wet AMD, is the growth of anomalous blood vessels in the eye choroidal layer. Neovascularization is a key factor in AMD and thus anti-angiogenic therapy is beneficial in reducing the development of new abnormal blood vessels to prevent progression of AMD. Axitinib, multi-receptor tyrosine kinase inhibitor, is a small molecule that works by blocking vascular endothelial growth factor receptors (VEGFR) and platelet derived growth factor receptors (PDGFR) responsible for developing neovascularization. Thus, goal of this study was to develop and characterise a sustained release formulation of Axitinib loaded poly (lactic-co-glycolic) acid (PLGA) nanoparticles. The nanoparticles were characterized for particle size and zeta potential as well as using DSC, TEM and in vitro drug release profile. The cytotoxicity of the formulation was evaluated on human retinal pigmented epithelium ARPE19 cells by MTT assay. The cellular uptake, anti-migration assay, and VEGF expression levels were found out in vitro using cells. The optimized formulation was 131.33 ± 31.20 nm in size with -4.63± 0.76 mV zeta potential. Entrapment efficiency was found to be 87.9 ± 2.7%. The cytotoxicity of ARPE19 cells was less than 12% for nanoparticles suggesting the in vitro compatibility at 10 µM concentration of drug. Cellular uptake, anti-migration assay and VEGF expression levels for the nanoparticles had greater uptake, had significant anti-angiogenic potential and exhibited inhibition of VEGF activity. The results showed successful development of axitinib loaded PLGA nanoparticles as an alternative potential treatment option for AMD.
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Kopplin, Laura J. "The indentification of genetic risk factors for age-related macular degeneration." Cleveland, Ohio : Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1251752708.
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Burton, Amy. "The experience of living with age related macular degeneration : a longitudinal study into the impact of age related macular degeneration on quality of life." Thesis, Aston University, 2013. http://publications.aston.ac.uk/19020/.
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In this thesis I contribute to the understanding of the experience of living with Age-Related Macular Degeneration (AMD) and its impact on quality of life through the use of a pragmatically guided mixed methods approach. AMD is a condition resulting in the loss of central vision in old age which can have a huge impact on the lives of patients. This thesis includes: literature reviewing; qualitative meta-synthesis; surveys and descriptive statistics; observation; and analysis of in-depth interviewing, in order to build a picture of what it is like for older people to live with AMD. I present the findings from six separate studies each designed to answer specific research questions. I begin with a mixed methods study to determine how well the most commonly used measure of quality of life for AMD patients’ represents patient experiences. I then go on to investigate the experiences of patients with AMD through a meta-synthesis of qualitative research and finally present four of my own empirical studies three of which investigate the experiences of patients with different types of AMD: early dry AMD, treatable wet AMD and advanced wet AMD and the final study investigates what it is like for a couple living together with AMD. Throughout the qualitative studies I use Interpretative Phenomenological Analysis (IPA) to develop an understanding of the experiences and life contexts of patients with AMD. Through rigorous analysis, I identify a range of themes which highlight the shared and divergent experiences of individuals with AMD and the need to acknowledge patients’ past, present and potential future life contexts and experiences when providing services to older people with AMD. I relate the findings of the six studies to the wider psychological literature on chronic illness and make recommendations for services for patients with AMD to be provided holistically within a lifeworld-led health care model.
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Cao, Sijia. "The role of complement activation in age-related macular degeneration." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58666.
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Purpose:
Age-related macular degeneration (AMD) is a multifactorial degenerative disease that occurs in the central part of the retina − macula. The disease affects approximately one million Canadians and constitutes the number one cause of vision loss after cataract in the elderly. The Y402H polymorphism in the complement factor H (CFH) gene and drusen load are two salient risk factors for AMD. Little is known of the detailed cellular pathway(s) shared by these two factors. Here we investigate their interactions in in vitro models of AMD and in AMD samples.
Methods:
The biological samples came from 44 dry AMD patients, 23 postmortem eyes and retinal pigment epithelial (RPE) cell models. Drusen load and choroidal thickness in patients were measured using spectral-domain optical coherence tomography. We used analytical techniques including genotyping, Bio-Plex suspension assays, immunohistochemistry, immunofluorescence, reverse transcription PCR, Western blot, flow cytometry and lactate dehydrogenase assay
Results:
In dry AMD patients, higher systemic levels of interleukin (IL)-6, IL-18, and tumor necrosis factor (TNF)-α were associated with the at-risk CC variant of CFH Y402H polymorphism. IL-1β while not significant, demonstrated a similar trend. Drusen load was inversely correlated with choroidal thickness and visual acuity. Postmortem eyes genotyped with the Y402H risk variant showed significantly increased levels of GM-CSF in vitreous and immunoreactivity for CD68, C5a, IL-18 and TNF-α in Bruch’s membrane and/or choroid. Exposure to complement activation product C5a in RPE cells promoted NF-κB activation and upregulated inflammatory cytokines and growth factors. The drusen component, Aβ, induced complement activation and downregulated the membrane bound complement inhibitor, CD55, leading to sublytic MAC formation in RPE cells, which was inhibited by aurin tricarboxylic acid complex.
Conclusion:
Two important risk factors for AMD, CFH Y402H polymorphism and drusen load, both promote complement activation. Complement activation can mediate downstream events associated with sublytic changes in RPE, such as proinflammatory cytokine release. These results suggest that complement activation might be the central response to multiple risk factors and the complement activation products may further inflict injury on RPE cells. Complement activation products could be potential therapeutic targets to stop chronic inflammation in AMD.Medicine, Faculty of
Graduate
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Muldrew, K. A. "The enigma of visual function in age-related macular degeneration." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420929.
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Gilchrist, S. E. C. M. "Nutritional determinants of cardiovascular and age-related macular degeneration risk." Thesis, Queen's University Belfast, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438633.
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Butt, T. J. "Valuation of health states associated with age-related macular degeneration." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1471706/.
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Economic evaluation of health technology using cost-utility analysis (CUA) normally applies an extra-welfarist framework in which health, the unit of effectiveness, is maximised. Typically, health status is measured by health-related quality of life (HRQoL) questionnaires to define health states. Preferences for health states are valued on a utility scale and combined with the time spent in the state to calculate quality-adjusted life years (QALYs). This thesis develops methods for measuring and valuing health using the case of age-related macular degeneration (AMD), where there are limitations with current methods for calculating QALYs.
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Heller, Janosch Peter Dave. "Transplantation of retinal pigment epithelium in age-related macular degeneration." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708198.
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Khandhadia, Samir. "Age-related macular degeneration, complement Factor H and liver transplantation." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/375260/.
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Kar, Taner, Yildiray Yildirim, Aytuğ Altundağ, Murat Sonmez, Abdullah Kaya, Kadir Colakoglu, Hakan Tekeli, Melih Cayonu, and Thomas Hummel. "The Relationship between Age-Related Macular Degeneration and Olfactory Function." Karger, 2015. https://tud.qucosa.de/id/qucosa%3A70587.
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Background: Olfactory dysfunction is a common symptom of many neurodegenerative diseases, and age-related macular degeneration (AMD) is a late-onset neurodegenerative disease. Objective: Thus, the aim of this study was to investigate olfactory functions in patients with AMD. Methods: A total of 69 subjects with AMD and 69 age- and sex-matched healthy controls were enrolled. After a complete ophthalmic evaluation, the AMD patients were subclassified as earlyand late-stage AMD. Psychophysical testing of olfactory function was performed using the validated Sniffin’ Sticks test. Results: This study was carried out in 138 subjects, with a mean age of 74.3 ± 8.9 years (range 51–89). The current investigation showed the following two major findings: (1) patients with AMD had decreased olfactory abilities, especially in odor discrimination and odor identification, even at early stages compared to controls, whereas patients had decreased olfactory abilities in all subtasks of olfactory testings in advanced stages of AMD disease, and (2) as the visual acuity of AMD patients decreased, the olfactory abilities of these patients worsened. Conclusion: This study demonstrated that AMD had significant negative effects on all orthonasal olfactory tasks, particularly in advanced stages. Similar to other neurodegenerative diseases, odor discrimination and identification seemed to be more affected than odor detection threshold tasks.
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Acton, Jennifer H. "Visual field and structural alterations in age-related macular degeneration." Thesis, Aston University, 2010. http://publications.aston.ac.uk/8821/.
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The thesis investigated progression of the central 10° visual field with structural changes at the macula in a cross-section of patients with varying degrees of agerelated macular degeneration (AMD). The relationships between structure and function were investigated for both standard and short-wavelength automated perimetry (SWAP). Factors known to influence the measure of visual field progression were considered, including the accuracy of the refractive correction on SWAP thresholds and the learning effect. Techniques of assessing the structure to function relationships between fundus images and the visual field were developed with computer programming and evaluated for repeatability. Drusen quantification of fundus photographs and retro-mode scanning laser ophthalmoscopic images was performed. Visual field progression was related to structural changes derived from both manual and automated methods. Principal Findings: • Visual field sensitivity declined with advancing stage of AMD. SWAP showed greater sensitivity to progressive changes than standard perimetry. • Defects were confined to the central 5°. SWAP defects occurred at similar locations but were deeper and wider than corresponding standard perimetry defects. • The central field became less uniform as severity of AMD increased. SWAP visual field indices of focal loss were of more importance when detecting early change in AMD, than indices of diffuse loss. • The decline in visual field sensitivity over stage of severity of AMD was not uniform, whereas a linear relationship was found between the automated measure of drusen area and visual field parameters. • Perimetry exhibited a stronger relationship with drusen area than other measures of visual function. • Overcorrection of the refraction for the working distance in SWAP should be avoided in subjects with insufficient accommodative facility. • The perimetric learning effect in the 10° field did not differ significantly between normal subjects and AMD patients. • Subretinal deposits appeared more numerous in retro-mode imaging than in fundus photography.
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Ahmad, Hijazi Mohd Hanafi. "Image classification : a study in age-related macular degeneration screening." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/7093/.
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This thesis presents research work conducted in the field of image mining. More specifically, the work is directed at the employment of image classification techniques to classify images where features of interest are very difficult to distinguish. In this context, three distinct approaches to image classification are proposed. The first is founded on a time series based image representation, whereby each image is defined in terms of histograms that in turn are presented as "time series" curves. A Case Based Reasoning (CBR) mechanism, coupled with a Time Series Analysis (TSA) technique, is then applied to classify new "unseen" images. The second proposed approach uses statistical parameters that are extracted from the images either directly or indirectly. These parameters are then represented in a tabular form from which a classifier can be built on. The third is founded on a tree based representation, whereby a hierarchical decomposition technique is proposed. The images are successively decomposed into smaller segments until each segment describes a uniform set of features. The resulting tree structures allow for the application of weighted frequent sub-graph mining to identify feature vectors representing each image. A standard classifier generator is then applied to this feature vector representation to produce the desired classifier. The presented evaluation, applied to all three approaches, is directed at the classification of retinal colour fundus images; the aim is to screen for an eye condition known as Age-related Macular Degeneration (AMD). Of all the approaches considered in this thesis, the tree based representation coupled with weighted frequent sub-graph mining produced the best performance. The evaluation also indicated that a sound foundation has been established for future potential AMD screening programmes.
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Allen, Cynthia. "Egg consumption and age-related macular degeneration : a pilot study /." Search for this dissertation online, 2004. http://wwwlib.umi.com/cr/ksu/main.
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Constable, Ian Jeffrey. "Development of Gene Therapy for Age-related Exudative Macular Degeneration." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/24032.
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Age-related macular degeneration (AMD) became the commonest cause of legal blindness in developed countries by 1990, compounded by the ageing of the population, the absence of any useful therapy and a dearth of knowledge as to the molecular biological underlying abnormalities. The publications embodied in this thesis extend over the following 28 years and contribute original knowledge by way of laboratory experimentation into the pathogenesis and then novel animal and human clinical trials. The programme lead to international pharmaceutical development of unique viral gene therapy for AMD. Tissue culture models for phagocytosis and lysozymal degradation of retinal receptor outer segments showed that excess receptor load or inhibition of the key degradative enzymes, Cathepsin D and Cathepsin S, each resulted in accumulation of intracellular debris and lipofuscin in retinal pigment epithelial cells. Specific Inhibition of cat D or cat S with targeted novel antisense oligonucleotides also lead to the development in small animals of many of the changes seen in AMD. Neovascular AMD caused most of the blindness at that time. Laser photocoagulation could obliterate subretinal blood vessels, but at the expense of loss of remaining central vision. Early studies in this thesis showed a remarkable panretinal activation of the retinal metabolic marker, glial fibrillary acidic protein. Laser also upregulated fibroblastic growth factor, with a therapeutic benefit in the RCS rat model of retinal degeneration, but no FGF abnormality was found in the AMD animal models. Extensive phenotyping of my clinical AMD population allowed haplotype analysis of newly discovered genetic variations in this disease. No differences were found in wet compared to dry AMD, nor in response to photodynamic therapy. This data was contributed to two large multinational publications which reported rare AMD variants and compared the AMD genomic variations to those found with glaucoma. The effect of focal laser on the upregulation of VEGF was described and this finding lead to the creation of novel animal models of VEGF modulated subretinal and intraretinal neovascularization. These models were made with intense laser applications to the retina or by creation of VEGF transgenic mice. The models proved indispensable in assessing potential therapy for wet AMD, first with RNA inhibition with our own antisense oligonucleotide and later with viral gene therapy. The first successful anti VEGF gene therapy in these publications used Adenovirus to transfer the gene for sFlt-1 in order to block corneal neovascularization in animals. When Adeno-associated viral gene transfer became a possibility, these studies confirmed successful RPE- 65 replacement in rodents and then dogs. Corneal vascularization was again inhibited in animals, this time using AAV-sFLT-1 formulated in our laboratories. The efficacy of upregulating sFlt-1 to block VEGF-induced choroidal neovascularization was confirmed in laser-induced and VEGF transgenic models. The next step was the evaluation of this AAV-sFLT-1 construct in non-human primates for local and systemic safety, toxicity and efficacy in blocking laser-induced CNV. This work proved successful and lead to the first investigator sponsored application (CTX) for ocular gene therapy in adults in Australia and in the world for this disease. Phase 1 and randomized phase 2 trials were undertaken on 40 patients with persisting retinal or subretinal fluid from wet AMD despite extensive prior humanised anti-VEGF antibody therapy. These showed excellent reversal of fluid on OCT scans in 50%, but no better response than controls in the others. It was postulated that selection of advanced non-responsive cases, possible under-transfection of the aged retina and insufficient sFLT-1 production may have explained the outcome. The partial success rate was not yet equivalent to that of the current gold standard treatment with VEGF antibodies, but was sufficient to stimulate other groups to design improved AAV gene therapy constructs and to accelerate further development. This pioneering human and preclinical scientific data formed the basis of a major corporate fund-raising on the NASDAQ exchange in New York, which assets have pushed further clinical trials of gene therapy for neovascular AMD by way of intravitreal injection. My latest publication in this series established in non-human primates the value of prior surgical removal of the internal limiting membrane of the retina. This greatly enhanced reporter gene transfection after intravitreal injection and may be the key to therapeutic success. The studies reported here were the first ocular viral gene therapy trials in adults and they have stimulated a large amount of further research and development to better control this major cause of blindness.
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Augood, Cristina. "Association of polyunsaturated fatty acids with age-related macular degeneration." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536759.
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Nau, Jeffrey A. "Association Between Age-Related Macular Degeneration and Sleep-Disordered Breathing." ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/3463.
Full textAbstract:
Age-related macular degeneration (AMD) is a chronic, irreversible disease that robs individuals of vision, quality of life, and independence. It is the leading cause of blindness in industrialized countries. Sleep-disordered breathing (SDB) is a condition characterized by repeated episodes of apnea and/or hypopnea, insomnia, short sleep duration, and/or sleep disturbances (snoring, gasping, etc.). Because SDB has been shown to cause chronic hypoxia resulting in oxidative stress on the retina, it has been proposed that SDB may be associated with AMD. Based on the life course theory of chronic disease, this quantitative, cross-sectional study used data from the 2005-2008 National Health and Nutrition Examination Survey to study whether there was an association between SDB and AMD, including neovascular AMD and geographic atrophy in adults 40 years and older. Descriptive statistics and logistic regression analyses were used. The results suggest that AMD is associated with diagnosed sleep disorders, including sleep apnea and insomnia, as well as sleep apnea symptoms of gasping snoring, snorting, and stopping breathing. The findings of this study highlight the importance of diagnostic screening and therapeutic intervention to treat SDB. Early diagnosis and therapy for SDB could address not only the comorbidities associated with SDB, but could also prevent or slow the progression of AMD. In turn, this would yield lower rates of vision loss, reduced comorbidities associated with vision loss, and reduced impact of AMD on the health care system and social and financial costs to society.
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White, Ursula. "Concern about falling in people with age-related macular degeneration." Thesis, Queensland University of Technology, 2020. https://eprints.qut.edu.au/201804/1/Ursula_White_Thesis.pdf.
Full textAbstract:
Concern about falling (CF) is a significant health issue among older people, leading to activity restriction, physical decline, and increased falls risk. Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among older people, yet little is known about CF in this population. High levels of CF were demonstrated among those with AMD, predicted by reduced visual function, and other physical and psychological factors. Over a 12-month period, CF increased, more so than in general older populations. These results provide an important basis for developing interventions to manage excessive CF, promote activity participation and reduce falls risk.
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Kopplin, Laura J. "The Identification of Genetic Risk Factors for Age-Related Macular Degeneration." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1251752708.
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Tang, Diana. "Closing the Evidence-Practice Gap: Nutrition and Age-related Macular Degeneration." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/25105.
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Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. Despite evidence supporting dietary modification to reduce the risk of AMD development and progression an evidence-practice gap exists as people with AMD are not adhering to the recommendations reported in research literature. In an attempt to close this gap, this thesis describes three research studies: study one aims to evaluate the use of a novel tool (SDQ-AMD) to screen inadequate food intake in people with AMD; study two aims to evaluate the effectiveness of a telephone-delivered dietary intervention for people with AMD and study three aims to evaluate the effectiveness of educational interventions to increase relevant knowledge about AMD and eye health among healthcare professionals. The first chapter provides an overview about AMD including pathophysiology, disease prevalence, and risk factors, particularly modifiable dietary risk factors. Chapter two details the methodology of the three research studies. The third chapter evaluates the SDQ-AMD against a validated food frequency questionnaire (FFQ) using self-reported baseline dietary intakes from the 155 participants enrolled in the study two (telephone intervention). There was relative agreement between the two survey tools as most mean difference scores were within the 95% CI, and no significant bias was evident between the scores as the scores increased. Chapter four evaluates the effectiveness of a telephone-delivered intervention to improve dietary intakes in 155 people with AMD by comparing responses to the SDQ-AMD at baseline, immediately post-intervention and 3-months post-intervention. The intervention did not lead to significant differences between the intervention and control arm, however there were significant improvements (expressed as serves ± SD) within the intervention arm compared to baseline: i) immediately post-intervention, there were higher intakes of daily water intake (5.36 ± 0.27 vs 4.63 ± 0.26; p = 0.01), and weekly intakes of: fish/seafood (2.36 ± 0.18 vs 1.79 ± 0.17; p = 0.006), dark green leafy vegetables (1.95 ± 0.27 vs 1.01 ± 0.17; p = 0.001), and eggs (3.78 ± 0.29 vs 3.32 ± 0.25; p = 0.049); and 3-months post-intervention, intake of dark green leafy vegetables continued to be significantly higher than baseline (1.71 ± 0.22 vs 0.99 ± 0.17, p = 0.003) and there were significantly increased intakes of legumes (1.12 ± 0.16 vs 0.69 ± 0.10, p = 0.02), and significantly reduced intakes of cakes and biscuits (6.54 ± 0.58 vs 8.31 ± 0.76, p = 0.01). Chapter five demonstrated that within 10 dietitians and 5 student dietitians, a two-hour interactive workshop led to significant overall improvement in knowledge (mean pre-post score: 7.07 ±1.94 vs 10.8 ±1.01; p =0.001) with specific improvement in appropriate dietary advice for patients with AMD, food sources of lutein and zeaxanthin, and awareness of supplements for AMD. This chapter also assesses a four-hour educational module on eye health among 179 pharmacy student participants. This module led to significant improvements in overall AMD knowledge (6.25 ± 1.93 vs 6.64 ± 2.0; p=0.011), including significant improvement in knowledge around evidence-based nutritional supplements for AMD, as well as a significant improvement in students’ overall perceptions towards the role of a pharmacist in counselling visually impaired patients (41.54 ± 5.26 vs 42.45 ± 4.95; p=0.004). The overall findings reported in this thesis encourage wider access to educational interventions/modules for both patients and healthcare professionals.
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Stanton, Chloe May. "Investigating the genetic and molecular basis of age-related macular degeneration." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/9608.
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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.
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Broadhead, Geoffrey Kenneth. "Emerging Therapeutic Options in the Management of Age-Related Macular Degeneration." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14720.
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Purpose: To assess the efficacy of two therapies, intravitreal aflibercept and oral saffron supplementation, for the treatment of different aspects of age-related macular degeneration (AMD). Methods: Two prospective clinical trials were conducted, i) one open label, single arm trial investigating intravitreal aflibercept for the management of treatment-resistant neovascular AMD, and ii) the other a randomised control trial investigating oral saffron supplementation for the treatment of intermediate AMD. Outcomes assessed included: mean change in mfERG response, mean change in individual mfERG ring response, mean change in BCVA and safety of saffron as compared to placebo. Results: i) The mean gain in BCVA was 6.7 and 4.7 letters at 6 and 12 months respectively (p<0.001), and the mean reduction in CMT was 100.0 µm at 6 and 12 months respectively. ii) Saffron supplementation was associated with a 2.1% increase in overall mfERG response (p=0.08) and a 0.69 letter increase in BCVA (p=0.001) compared to placebo. In those patients on AREDS supplements, saffron was associated with an increase of 2.8% in mfERG and an increase in BCVA of 0.73 letters (p<0.05 for both). There was no significant difference in adverse event frequency (overall or by subtype) whilst on saffron as compared to placebo. Conclusions: i) Intravitreal aflibercept was an effective therapy for the management of treatment-resistant neovascular AMD. The efficacy of aflibercept waned slightly over time, and further research is needed on the long-term effects of anti-VEGF agents. ii) Oral saffron was effective in improving visual outcomes in patients with intermediate AMD, including those on current standard of care therapy (AREDS supplement or equivalent), suggesting that oral saffron may offer additional benefit. Given the considerable burden that AMD imposes on sufferers and the health-care system in general, further consideration and research should be conducted into the role of saffron as therapy for AMD.
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Deffler, Rebecca Ann. "Socioeconomic factors related to visual outcomes in patients with age-related macular degeneration." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555523090849182.
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Reeves, John A. F. "Longitudinal regression models for a study of age-related macular degeneration." Thesis, Keele University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267456.
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Cassels, Nicola. "Quality-of-life and clinical outcomes in age-related macular degeneration." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/109189/.
Full textAbstract:
Age-related macular degeneration (AMD) is of increasing concern given the ageing population, and the associated economic and social burdens. Vision-related quality-of-life (QoL) is arguably one of the most important factors in the management of those with AMD. Consequently, there is a clear need for an understanding of the clinical outcomes that influence vision-related QoL in order to inform management strategies. The principle aim of the studies described herein was to determine the factors that predict vision-related QoL in those with AMD, over 1 year. Experimental procedures were undertaken at baseline (n=52 individuals with AMD) and repeated after 1 year (n=32 individuals with AMD). These included: visual acuity, contrast sensitivity, reading speed, microperimetry, optical coherence tomography and fundus photography. A questionnaire interview included assessment of vision-related QoL (Impact of Visual Impairment questionnaire), health status (EQ-5D), level of depressive symptoms (PHQ-9) and well-being (Warwick-Edinburgh Well-Being Scale). At baseline, the optimum multiple regression model accounted for 41% of the variance in vision-related QoL and included Mean Total Deviation or Mean Sensitivity with level of depressive symptoms. After 1 year, the optimum model to predict change in vision-related QoL accounted for 43% of the variance and included baseline contrast sensitivity and change in health status and reading speed. The most clinically useful measures of visual function, in identifying those with a reduced QoL or those at risk of a reduced QoL were contrast sensitivity, microperimetry, and reading speed. These outcomes may allow a better understanding of vision-related QoL if they were adopted in a clinical setting. In conclusion, the studies provide sufficient evidence to encourage a review of the clinical outcome measures most relevant to vision-related QoL.
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Gates, D. P. "An investigation into the inflammatory axis of age-related macular degeneration." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501264.
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