Myopia, as a common ocular disorder, is caused by both genetic and environmental factors. Conventional genome-wide association studies (GWAS) in humans have limited power to detect myopia genes partly due to the complex interplay between genes and environment. Here, I performed a GWAS in a sample of chicks with form deprivation (FD) myopia, aiming to reduce environmental complexity and increase the statistical power to detect genetic variants that confer susceptibility to this environmentally-induced myopia phenotype. The degree of FD myopia was quantified by measuring the treatment-induced changes in axial length (∆AXL) and mean spherical equivalent (∆MSE). Body weight, sex, and batch were evaluated as potential confounding factors. To reduce costs, chicks in the phenotype extremes (lowest or highest ∆AXL, within each batch) were selected for genotyping. To identify genetic variants conferring susceptibility to myopia, GWA analyses for ∆AXL and ∆MSE were applied to the genotype data. After adjusting for confounding factors, genetic variant rs317386235, located between the genes PRKAR2B and PIK3CG exceeded the Bonferroni corrected significance threshold for ∆AXL. To complement the GWAS findings, an RNA sequencing transcriptomics analysis was performed, using retinal tissue from the treated and control eyes of chicks with high or low-susceptibility to myopia. This revealed 516 differentially-expressed genes, identified using a combination of three analysis tools. In order to discover more about the biological function underlying the GWAS and transcriptomics analysis results, pathway analyses were conducted. The pathway analysis implicated gene sets relating to circadian rhythms, extracellular matrix (ECM) and structural remodelling, energy generation, oxidative stress, glycometabolism and lipid metabolism.

No description available.

No description available.

Thesis (M.D.)--Yale University, 2007. / Includes bibliographical references.

Dry eye disease (DED), and especially work-related dry eye, has an increasing incidence, and is expected to become a significant public health problem, with the increasing age until retirement, and the effect of the modern, digital, working environment causing higher visual demands. The indoor environment and more demanding, eye-related tasks, are risks factors for the development of dry eye symptoms, leading to DED at these workplaces. The current management for diagnosed DED is strongly pharmaceutical-based, and research looking at solutions towards better functioning and well-being of DED patients is rare. There is also a lack of evidence about the role of healthcare professionals in DED management. A substantial proportion of office workers surveyed experienced mild/moderate dry eye symptoms, and that while these were experienced more at work than at home, they had a negative impact on daily activities at work and after work, interfering with their social life. There is a lack of in-depth knowledge in dry eye diagnosis and management in all primary healthcare professionals surveyed and education is needed in management of work-related dry eye; there is a need for a specialised DED optometrist, with a recognised qualification; inter-professional cooperation should be promoted through better communication pathways; OHPs and optometrists should work together at the association level to develop clinical care guidelines; and a chronic care pathway in DED should be developed as part of the Dutch Government healthcare reforms.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world. Whilst the pathogenesis is complex and not fully understood, changes to the choroidal vasculature in AMD have been demonstrated using histology. Advances in imaging technology, particularly long-wavelength optical coherence tomography (OCT), allow in vivo visualisation and investigation of this structure. The aim of this work is to determine whether changes to the choroidal vasculature are detectable in AMD using in vivo imaging. This was achieved through the evaluation of parameters for quantifying the structure, and the application of a machine learning approach to automated disease severity classification, based on choroidal appearance. Participants with early AMD (n=25), neovascular AMD (nAMD; n=25), and healthy controls (n=25) underwent imaging with a non-commercial long-wavelength (λc=1040 nm) OCT device. Subfoveal choroidal thickness, choroidal area, and luminal area were significantly lower in the nAMD group than the healthy and early AMD groups, whilst vessel ratio was significantly greater (P < 0.05 in all cases). There was no significant difference in visible vessel diameter, choroidal vascularity index, luminal area ratio, or luminal perimeter ratio between the groups. No significant differences were found between the healthy and early AMD groups for any of the eight vascular parameters assessed. Classification of the disease groups based on choroidal OCT images was demonstrated using machine learning techniques. Textural features within the images were extracted using Gabor filters, and K-nearest neighbour, support vector machine, and random forest classifiers were assessed for this classification task. Textural changes were most pronounced in late-stage disease, although attribution to pathology or pharmacological intervention (anti-VEGF treatment) was not possible. Changes were also discernible in the early AMD group, suggesting sensitivity of this approach to detecting vascular involvement in early disease. In conclusion, structural changes to the choroidal vasculature in AMD are detectable in vivo using OCT imaging, demonstrated with both manual and automated analysis techniques. Whilst changes were most prominent in late-stage disease, subtle structural changes in early AMD were identified with texture analysis, warranting further investigation to improve our understanding of choroidal involvement in the pathogenesis of early AMD.

The purpose of this thesis was to develop further the Learning Index in perimetry and examine how it performs in different groups, with different algorithms and investigate different procedures of calculation. The Learning Index calculated using concentric rings of visual field data, following the method of Olsson and colleagues (1997), facilitated in a MatLab environment. The used data included visual field assessment for 29 normal, 25 glaucoma and 25 ocular hypertensive individuals who followed perimetry for both eyes, for different strategies and for five consecutive visits once a week. Alternative methods to evaluate the LI were used like the glaucoma hemifield test pattern. The influence of the different strengths of a variety of filters was also used, filtering the perimeter outcome in order to disassociate learning effect from real defects. Mean and Median filters were also used, and dissimilar Adaptive filters as well, that seemed to be robust filters that could help to establish a more sensitive Learning Index. In automated perimetry the innovation of a Learning Index would consider and examine how individuals learn to perform better visual field tests during recurrent visits under different algorithms. The argument is if that Learning Index could allow clinicians performing visual field tests to administer their patients and control possible detected abnormality, after their first or second visual field test. In this way they will prevent development of the disease, confine patient’s fatigue and provide quality of life and simultaneously financial savings for the state and private health organizations. The carried out learning index calculations results were sufficiently encouraging for a next phase of a future index development and with likelihood in the future to be incorporated in automated perimeters algorithms.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world (Wong et al., 2014). The exact causes of AMD are unclear but hypoxia has been implicated (Stefánsson et al., 2011). If hypoxia has a role in the pathogenesis of AMD treatments that mitigate the effect of retinal hypoxia may slow disease progression. This thesis aimed to establish the impact of light therapy, as delivered using a light emitting mask, on the progression of AMD. A phase I/IIa randomised controlled trial was implemented in which 60 participants with early and intermediate AMD were allocated to the intervention or the untreated control group in a 1:1 ratio and monitored over 12 months. The ability of secondary outcome measures (including: rate of cone dark adaptation, 14Hz flicker threshold and chromatic thresholds) to identify the likely risk of progression from early and intermediate AMD to advanced AMD was also assessed in a cross-sectional study evaluating the relationship between each baseline outcome measure and the severity of fundus changes. Sixty participants were recruited of which 47 (20 intervention, 27 control) completed the 12 month follow-up period. No significant difference was found in the change of any parameter between groups apart from the time constant of cone-photoreceptor recovery (cone τ), which was increased to a greater extent in the treated group. An additional 40 participants were recruited to the cross-sectional study (n=100). Measurement of cone τ was identified as the best independent predictor of increased AMD severity based on the AREDS Simplified Severity Scale (Ferris et al., 2005). Although a greater proportion of controls (48%) than mask wearers (38%) showed disease progression over the duration of the trial this difference did not reach statistical significance.

Although there are several publications on the prevalence of AMD in the UK, there remains a paucity of data from population studies from this country. This study provides the most detailed exploration of the epidemiology of AMD within a UK community based population to date. It provides contemporary prevalence rates for different stages of AMD in a UK population, and indicates the prevalence of advanced AMD is more common than previously thought (4.3%), reaching a maximum of 21.2% for the over 90 year age group. Despite this high prevalence of advanced AMD, approximately 50% of the over 65-year old population have no or minimal signs of ARM. This study confirms that persons with the earlier and intermediate stages of AMD are asymptomatic. The prevalence of GA is more common than that of nAMD, with GA being 1.7 and 1.6 times more prevalent in the right and left eyes respectively. This difference remains when analysed for the worse eye, with GA still being 1.3 times more common than nAMD. For the first time in a large population based study, this thesis reports self- satisfaction with participant’s vision and association with AMD severity/grade. It shows that a large proportion of individuals (61.0%) with GA in their worse eye still remain satisfied with their vision. When AMD grade in the worse eye was the variable, nAMD is the only stage at which the majority of participants are dissatisfied (59.4%) with the level of their vision. When the better eye was evaluated, there was a significant increase in subject dissatisfaction with vision, particularly for individuals with bilateral nAMD, with almost 90% of subjects being dissatisfied with the quality of their vision. We describe in detail the features of GA within this UK population. The information will be useful in the design of future clinical trials that evaluate the development or progression of GA or its treatment, as well as modelling the impact of GA on sight loss in the UK. In summary, GA has a prevalence of 2.5% for the worse eye in the over 65 year Bridlington population, increasing with age to a maximum of 9.84% for those aged 85 to 90 years. Bilateral GA is not an infrequent finding, occurring in 34% of subjects with known GA. In the mainstay it is largely an eccentric condition, with only 31.5% of involved eyes having subfoveal GA. The majority of GA appears to occur in the perifoveal region, particularly GA that is associated with conventional drusen. Only a minority eyes with GA in the community have large areas of atrophy over 17.5mm2; the mean area of GA was 4.51mm2. This thesis, in chapter 4, demonstrates there is a clear association between GA phenotype and the phenotype of drusen identified within the remaining fundus. In chapter 4 it is demonstrated that RPD are, in the mainstay, associated with horseshoe shaped GA, and have a high prevalence of 55.9% within this group. This is a previously unreported finding. The prevalence of RPD in eyes with round GA is considerably less (8.3%). There is a suggestion that GA in eyes with RPD may have larger areas of atrophy and are less likely to have foveal involvement. However, the mean VA remains the same secondary to a diffuse, central retinal pigment epitheliopathy that appears to be associated with RPD horseshoe shaped GA. This again, is a previously unreported finding. Unlike in the previous hospital based literature, we demonstrate most multifocal GA is still associated with conventional drusen. In chapter 5, the prevalence of RPD in the over 65 year Bridlington population is estimated as 5.06% for either eye. This is the highest population based prevalence of RPD reported to date, and represents the only detailed report of the epidemiology of RPD within a UK population. Out of all the population based prevalence studies performed to date, the BEAP Study is the only one to utilise and analyse the red-free channel of the FP, which enhanced RPD detection within the study by 13%. As such, this study possibly represents the most accurate measure of RPD prevalence to date. In the present study, the prevalence of RPD increases significantly with age, reaching a maximum of 27% in the over 90-year age group. The BEAP study confirms that RPD occur most frequently in the upper outer subfield. Unlike previously reported, however, RPD do occur within the central subfield, albeit in a form that differs slightly in its appearance, and significantly reduced size. The BEAP study confirms that RPD have a female preponderance, with a higher gender specific prevalence rate in women. They are commonly found in association with other signs of ARM, including drusen over 125μm (50 % of the time) and pigmentary changes. Isolated RPD, in the absence of conventional drusen, is an uncommon finding but does occur. Approximately 1 in 4 subjects with advanced AMD will have evidence of RPD in either eye. This thesis also reports, for the first time, the prevalence of RPD in eyes with PPCNVs. There is a suggestion that RPD are associated with visual dissatisfaction, and this may be associated with a central pigmentary epitheliopathy that is sometimes seen within RPD eyes. We specifically report the population prevalence of PPCNV, as all previous publications on the subject have arisen from hospital based populations, and therefore included predominantly symptomatic individuals, and therefore carried inherent selection bias. PPCNVs (grade 4c AMD) were an infrequent finding, with a prevalence of 0.29% for individuals over 65-years of age. This is considerable lower than nAMD (grade 4b AMD), which within the same population had a prevalence of 1.8% for the worse eye. There was a female preponderance, with 70% of PPCNVs occurring in females. This difference was maintained in gender specific prevalence rates of 0.36% and 0.19% for females and males respectively. Previous publications have reported that PPCNVs accounted for less than 10% of all CNVM. This figure is confirmed in the BEAP, in which PPCNV accounted for 12 out of a total of 90 cases of CNVMs, representing 13.3% of all prevalent CNVs identified. This study reports that the majority of cases of PPCNV are unilateral. There is a myriad of published associations between PPCNV and other conditions. These are mainly single case reports or small case series. In addition, the larger hospital based studies may also give a poor representation of the true associations between PPCNV and other conditions as small, nasal or age-related membranes may remain asymptomatic. In Chapter 6, 90% of eyes with PPCNV had evidence of drusen ≥63μm within the macula, an association which is far higher than previously published. Furthermore, in the current series, 30% of PPCNV were associated with RPD, a finding which had previously been unreported. Previous studies on PPCNV’s have graded the macula for age-related change, but not reported or graded the peripapillary area for degenerative changes. In this report, these features have been investigated for the first time, and find that all (100%) of our subjects had RPE pigmentary changes within half a disc diameter of the disc margin (in both affected and contralateral eyes). As drusen and pigmentary changes within the macula are the known hallmarks of both GA and CNV, it seems logical to consider these changes in the peripapillary area as potentially pathological for PPCNV and for them not to be overlooked. The association of PPCNV with angioid streaks is well established, but in chapter 6 it is reported that in 10% of subjects with PPCNV, there were identifiable angioid streaks. This is a more frequent association than previously published (although the numbers are small), and highlights an overlap between the aetiologies of PPCNV in patients with angioid streaks within the elderly, and suggests a possible tendency for an association with small membranes that remain asymptomatic. / In the present study of asymptomatic individuals, a large proportion of PPCNVs (42%) were nasal to the disc margin and no individual in this series was thought to have developed direct visual loss from PPCNV. This finding is very distinct from that in some previous hospital studies of symptomatic patients. This study suggests, by inference that up to two thirds of PPCVN may remain asymptomatic.

Mutations in OPA1 are the leading cause of autosomal dominant optic atrophy, a disease in which a progressive loss of retinal ganglion cells (RGCs) leads to blindness. In the B6;C3-Opa1Q285STOP (het) mouse, an Opa1 mutation causes a decrease in ATP production and a progressive loss in visual acuity, which coincides with pruning of the predominantly ON-centre RGC dendrites. As 670 nm light can increase ATP production and provide neuroprotective effects, we hypothesise that protection from dendritic pruning will be observed in the ON-centre RGCs of the het mouse with 670 nm light. By Sholl analysis, and other measures of dendritic complexity, we found that ex vivo delivery of 670 nm light to retinal explants provides partial protection against the ex vivo retinal ganglion cell dendropathy, triggered by axotomy, in young wild-type mice. By the same methods of analyses, in vivo delivery of 670 nm light to aged wild-type and het mice partial provided protection against ex vivo RGC dendropathy in RGCs from wild-type mice and partial protection in RGCs from het mice. By immunohistochemistry, the transcription factor NFκB was found to be activated in RGCs from aged het mice treated with in vivo 670 nm light. The oxidative stress sensor, DJ1, was upregulated in RGCs from aged wild-type and het mice, by in vivo 670 nm light. The activation of the serine/threonine protein kinase, AKT, which plays a pivotal role in controlling cell survival and apoptosis, was decreased following in vivo 670 nm light treatment in aged wild-type RGCs.