Optometry and Vision Sciences - Theses
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ItemNo Preview AvailableInvestigating Diagnostic and Drug Efficacy Retinal Biomarkers in Parkinson’s Disease( 2023-08)Given the eye is an embryological outpouching of the brain, there is growing interest in the characterisation of retinal biomarkers in neurodegenerative disease to better facilitate timely diagnosis and treatment. Recent studies report a number of visual symptoms in people living with Parkinson's disease (PD), lending evidence to support the need to prioritise non-motor manifestations of PD, given that some precede the onset of motor decline by years if not decades. The retina offers a unique opportunity to directly visualise structural and functional changes in neurons that occur with PD pathogenesis. The development of non-invasive and relatively inexpensive retinal assessment modalities such as optical coherence tomography (OCT) and electroretinography (ERG) has enabled clinicians and researchers to assess these in vivo changes in people living with PD and in animal models of PD. However, the pathological mechanisms underlying visual and retinal dysfunction in PD remain incompletely understood. The overarching aim of this thesis was to explore and investigate retinal changes in function and structure that occur in people living with PD and a Parkinson’s disease rodent model, and to consider if such in vivo measures are sensitive to acute levodopa (L-DOPA) treatment. Using the A53T transgenic (Tg) mouse model of alpha-synuclein (a-syn) overexpression, we demonstrate that the accumulation of phosphorylated (pSer129) a-syn in outer retinal layers was correlated with cone photoreceptor dysfunction and degeneration. We speculate that this association between pSer129 a-syn and dysfunction may be related to an underlying pathophysiology. Moreover, we show that acute L-DOPA treatment can dynamically ameliorate retinal deficits in function in A53T Tg animals. As a proof of principle in translation, we evaluate changes in retinal function and structure in clinical Parkinson's disease, before and after single doses of L-DOPA following partial washout conditions. While no ameliorative effects were observed post L-DOPA treatment in this pilot study, PD participants had altered cone photoreceptor function and structure compared to age-matched controls, as indicated by poorer colour vision performance, reduced macular visual field sensitivity, and attenuated light-adapted a-wave and b-wave amplitudes. Overall, this body of work deepens our understanding of outer retinal changes in function and structure, driven in part by abnormal a-syn deposition, that occur in Parkinson's disease. Collectively, these findings provide further insight into dopamine and alpha-synuclein interactions in the retina as well as highlighting the utility of outer retinal measures as effective biomarkers for future application to Parkinson’s disease medical research and drug discovery.
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ItemRetinal neurovascular coupling in streptozotocin diabetic rats( 2019)Diabetic retinopathy (DR) is a significant cause of vision impairment worldwide, and it is projected to incur a rising global disease burden. Although the pathophysiology of diabetic retinopathy had been historically characterised as a vascular disease, there is a growing body of evidence to suggest that DR is also a process of retinal neurodegeneration. There is also evidence that functional changes occur to the retinal vasculature’s capacity to respond to physiological stimuli, before anatomical changes manifest. Additionally, there is evidence to suggest that neuronal dysfunction precedes anatomical evidence of neurodegeneration in both clinical and experimental studies of diabetes. These findings were examined in Chapter 2, and collectively suggest that functional deficits of both the vascular and neuronal retinal components may be key components of DR pathogenesis. Several research questions were proposed in this thesis in order to further understand vascular and neuronal interactions in the retina, at the earliest stages of diabetes. In order to model an early stage of diabetic disease, 4 weeks of hyperglycaemia was introduced to a cohort of dark Agouti laboratory rats using streptozotocin (STZ). Flickering light was used to stimulate neuronal driven vasodilation in the retina, and the autoregulatory capacity of retinal vasculature was challenged through inhalation of oxygen and carbon dioxide. Electroretinography was conducted to assess retinal function, and the scotopic threshold response (STR) was recorded during gas inhalation as a measure of inner retinal functional response to an autoregulatory challenge. A series of pilot studies were undertaken to optimise the parameters of flicker stimulation, gas delivery, retinal imaging and electroretinography. These materials and methods were described in Chapter 3. Flicker stimulation reliably produced vasodilation of inner retinal arteries and veins, although this response was not significantly affected by 4 weeks of STZ hyperglycaemia. Oxygen and carbon dioxide breathing introduced vasodilation and vasoconstriction of the inner retinal arteries and veins, respectively. The speed of venous vasoconstriction was reduced in STZ animals during oxygen breathing, and carbon dioxide breathing revealed a reduced arterial vasodilatory capacity in STZ animals. These findings were described and discussed in Chapter 4, and they indicate that, despite normal retinal neurovascular coupling, subtle autoregulatory deficits in the retinal vasculature are present at an early stage of diabetes. The oscillatory potentials and STR were found to be reduced after 4 weeks of hyperglycaemia, suggesting a manifest deficit of inner retinal function. Additionally, carbon dioxide breathing introduced an increase in the peak positive STR (pSTR) amplitude in both normal and STZ animals, whereas oxygen breathing resulted in a decrease of pSTR amplitude that was more significant in the STZ cohort. These findings were described and discussed in Chapter 5, and they seem to suggest that that relative inner retinal ischemia may be present early in the course of diabetes. Furthermore, this effect could be exacerbated by vasoconstrictive stimuli. The overall experimental findings suggest that neurovascular coupling is unaffected at an early stage of diabetes, despite findings of inner retinal dysfunction and subtle deficit of vascular autoregulation in the retina. This suggests, in addition to neuronal and vascular activity, that other physiological processes, likely mediated by glial cells, may be implicated in the modulation neurovascular interactions in the retina. These experimental findings and implications were discussed in Chapter 6, as well as study limitations and future directions of research.
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ItemA structural and functional profile of high myopia as a function of eye size( 2018)The prevalence of myopia and its associated sight threatening pathology is anticipated to increase, making high myopia a global health concern, especially in our ageing population. Although pathological sequelae and visual dysfunction have been attributed to excessive elongation in the highly myopic eye, a link between axial elongation and visual dysfunction in the absence of significant pathology is less well described. Furthermore, emmetropia and high myopia are variably defined, and in most instances, defined according to refractive error and not eye size. This thesis was designed to define and distinguish emmetropic and highly myopic eyes with regard to axial length and vitreous chamber depth and to apply these definitions to studies exploring the impact of ocular expansion on visual function and ocular structure. The first experiment (Chapter 2) used meta-analysis to predict the axial length (23.47 ± 0.07 mm) and vitreous chamber depth (16.12 ± 0.14 mm) of an emmetropic eye. Based on gender matched studies, male eyes not selected for refractive error were found to be larger with respect to both axial length (+0.52 ± 0.04 mm) and vitreous chamber depth (+0.40 ± 0.04 mm) relative to female eyes. Male emmetropic eyes displayed longer vitreous chamber depths (+0.47 ± 0.15 mm) relative to female emmetropic eyes, but axial lengths of emmetropic eyes did not vary with gender. Linear and non-linear meta-regressions predicted minimum dimensions of -5, -6 and -8 Dioptre (D) eyes, with a – 5 D high myope characterised by an axial length and vitreous chamber depth of at least 24.66 and 16.94 mm, respectively. Refractive errors of -5, -6 and -8 D were selected as they have previously been used to define high myopia in other studies, and were the refractive error groupings investigated in Chapters 3 and 4 of this thesis. Systematic review showed that vitreous chamber depth is presented less frequently than axial length in published literature. This may reflect instrumentation used to perform biometry and suggests that vitreous chamber elongation is mostly assumed but not demonstrated by researchers. In such cases, the role of posterior segment elongation in the development of structural and/or functional sequelae is hypothetical. The second experiment (Chapter 3) contrasted luminance and S-cone pathway spatial processing of axial high myopes ( -8 D) and emmetropes using psychophysical tools. Luminance and S-cone pathways were both probed to discriminate between pathway selective and non-selective visual dysfunction, given the known redundancy of neuronal elements comprising the S-cone pathway and reports of altered colour vision in high myopia. High spatial frequency loss and increased critical area indicated increased separation of neural elements. Critical area enlargement was consistent with a non-uniform posterior pole model of ocular expansion. Models previously reported in the literature have included non-uniform, posterior pole and global expansion. However, unlike the wrok presented here, these studies did not assess visual function with regards to vitreous chamber depth. Reduced contrast sensitivity for spatial summation tasks in the presence of retained sensitivity at lower spatial frequencies suggested non-selective post-receptoral dysfunction due to ocular enlargement and either normal or enhanced photoreceptor sensitivity. The third experiment (Chapter 4) utilised readily available clinical tools, customised automated perimetry and optical coherence tomography, to investigate structure-function relationships in enlarged highly myopic eyes ( -5 D). Generalised choroidal thinning for the central 4 mm and localised retinal thinning confined to the central ±1 mm were evident for high myopes. Although overall visual sensitivity decreased with increasing eye size, regional relationships between sensitivity and structural thickness or eye size were not evident. However, the nasal region appeared predominantly thinner with ocular enlargement suggesting that it may be more susceptible to visual dysfunction in longer eyes. The finding of marked nasal thinning of the ocular structural layers has been reported previously and is consistent with choroidal watershed zones predominantly affecting the nasal posterior pole. This reduced blood supply could underpin structural and functional changes in eyes demonstrating posterior pole expansion. The findings support that vitreous chamber elongation causes high myopia, visual dysfunction, and generalised choroidal and localised retinal thinning. Psychophysical and available clinical tools supported non-uniform ocular expansion in high myopia, with the nasal region predominantly thinned and potentially at risk of visual dysfunction. Although meta-analysis is not a novel tool, its application to defining emmetropia and high myopes with regards to axial length and vitreous chamber depth is novel, and has application in subsequent research and clinical settings.
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ItemCharacterising the ocular phenotype in a murine model of Alzheimer’s disease( 2018)This thesis shows that amyloid beta found in the brain is also present in the retina of a murine model of Alzheimer’s disease. By applying non-invasive retinal techniques, we show that neuronal structural and functional changes occur early in this model and that these are associated with vascular dysfunction. Such retinal hallmarks differentiate Alzheimer's changes from healthy ageing mice and provide evidence that the retina is a viable biomarker for dementia.
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ItemAge-related changes in structure, function and response to stress in the rat retina( 2016)Ageing is a key risk factor for ocular diseases, though age-related changes in the eye have not been fully characterised. This study investigated age-related changes in retinal function, structure and their response to acute and chronic stress in Long Evans rats. With age, both retinal structure and function decline and the retina loses its ability to cope with acute stress. When exposed to mild chronic stress, older eyes suffered greater functional damage than younger eyes.
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ItemVascular autoregulation: retina as a non-invasive biomarker for the brain( 2016)The retinal vasculature maybe a useful surrogate for the brain blood vascular network. There has yet to be a direct comparison of the capacity of vessels in the eye and brain to respond to changes in blood pressure or blood gas concentration. We showed that arteries in the rat’s eye and brain demonstrated qualitatively similar vascular autoregulatory capacity in response to a wide range of blood pressure and different blood gas concentrations.
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ItemSubcortical pathways for colour vision( 2006-09)Visual sub-modalities, such as colour, form and motion perception, are analysed in parallel by three visual “pathways” – the parvocellular (PC), magnocellular (MC) and koniocellular (KC) pathways. This thesis aims to further elucidate some properties of the subcortical pathways for colour vision. The experimental animal used throughout is a New World monkey, the common marmoset Callithrix jacchus. (For complete abstract open document)
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ItemAgeing effects on ocular blood flow, oxygen tension and function during IOP elevation( 2012)This is the first study to simultaneously measure electroretinography, ocular blood flow, and oxygen tension during intraocular pressure elevation. By doing so it shows that changes in oxygen tension are more closely related to function than blood flow. Moreover, by comparing these parameters in young and older eyes this study shows that older eyes have less oxygen availability with higher intraocular pressure despite having similar function. This argues that older eyes use more oxygen to sustain normal function.
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ItemFunctional correlates between the rat electroretinogram and visual evoked potential( 2012)The ERG and VEP are sequentially-activated responses, widely used for diagnosis of eye and brain diseases. Measuring both simultaneously provides additional information to help localise where in the visual pathway injury has occurred. This thesis shows how retinal information streams are encoded in the VEP. In addition, it shows that changes to ERG components can predict the amount of loss downstream in the retina. However, retinal loss may not predict VEP changes.
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ItemSusceptibility of the diabetic rat retina to intraocular pressure challenge( 2012)This thesis shows that hyperglycaemia makes retinal function and ocular blood flow more sensitive to acute intraocular pressure (IOP) elevation. Increased functional susceptibility was associated with a reduced capacity to upregulate endothelial nitric oxide synthase. Chronic IOP elevation (4 weeks) produced retinal dysfunction and exacerbated the susceptibility of ocular blood flow to IOP challenge in diabetic but not healthy rats. These data suggest that hyperglycaemia-induced blood flow anomalies may contribute to the functional susceptibility of the diabetic eye to IOP.