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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ItemTowards improving the detection of diabetic retinal disease( 2023-08)Diabetic retinopathy is a visual complication of diabetes clinically diagnosed by the presence of visible microvascular lesions in the retina. Since the hallmarks of diabetic retinopathy are vascular in nature, the assumption is that the retinal microvasculature is the main disease casualty. However, the impact of diabetes on the retina is widespread, affecting multiple components within the retinal neurovascular unit. More recent evidence reveals that retinal neuron damage, which can be manifested as visual function deficits and degeneration of the retinal layers, occurs prior to classical diabetic microvascular features. The American Diabetes Association has acknowledged diabetic retinopathy as a neurovascular complication of diabetes (Solomon et al., 2017). Additionally, some groups have also proposed the term “diabetic retinal disease” instead of diabetic retinopathy, as the terminology of the former more comprehensively characterises any retinal change owing to diabetes (Abramoff et al., 2018; Sun et al., 2021). Although new research reinforces vascular retinopathy as a late consequence of diabetic retinal disease, visual acuity (which remains preserved until the end stage of the disease) continues to serve as the main functional outcome for diabetic retinopathy in clinical research. Clinical detection of diabetic vascular lesions associated with an increased risk for visual impairment is also the only management strategy available for individuals at the early stages of the disease. Screening for diabetic retinopathy via ophthalmoscopic inspection remains the mainstay of clinical optometric practice and is still recommended by authoritative guidelines. The cost for diabetic retinopathy screening programmes is significant as persons with diabetes are (1) often working age, (2) will have to undergo several screening eye examinations in their lifetime, and (3) left without any therapeutic options until their vision is close to being compromised. New clinical markers, especially those that are likely to herald vascular damage, have the potential to improve detection of diabetic retinal disease. Numerous studies across the years have revealed a range of visual functional deficits in individuals with diabetes. Advances in retinal imaging technology, notably optical coherence tomography (OCT), have revolutionised clinical diagnosis of several retinal diseases. In the context of diabetic retinal disease, progressive thinning of the retinal neural layer can be measured by OCT in some individuals without diabetic retinopathy, supporting the notion of retinal neurodegeneration. OCT-angiography (OCTA), an update of OCT, can also detect microvasculature changes prior to overt vascular retinopathy. The focus of this thesis will be on clinical assessments of diabetic retinal disease. This thesis explored functional and structural outcomes measures from novel psychophysical techniques as well as structural OCT and OCT-A that could predict future diabetic retinopathy. Altogether, this thesis highlights the need for comprehensive assessment of diabetic retinal disease, which has future implications for improving how clinicians screen for and manage those with diabetic retinopathy.
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ItemThe role of home monitoring in chronic eye disease using smart devices.( 2023-03)Chronic eye disease affects millions of people worldwide and requires ongoing specialist care. Ever-increasing patient numbers has created pressure on the healthcare system, an issue that has been intensified by the COVID-19 pandemic. There is a pressing need to develop new models of eyecare to prevent vision loss. Home monitoring (HM) of vision in-between scheduled clinical visits could help prioritise valuable hospital chair time to those with the highest risk. Smart devices, such as desktops, laptops, tablets, and smartphones are ubiquitous in the community making them an ideal platform for HM due to familiarity of use. Most older individuals use smart devices to access the internet and it is this age group that is at a higher risk for developing chronic eye disease. This thesis considers the role of HM with the Melbourne Rapid Fields (MRF) vision testing application (for the Apple iPad) in the context of two common chronic eye diseases; glaucoma and age-related macular degeneration (AMD). MRF is new technology without a proven clinical record. Chapter 2 reports the clinical application of MRF as a routine and regular test of visual field (VF) by comparing 2-monthly VF testing to that found using the Humphrey Field Analyzer (HFA) for glaucoma patients in-clinic. We find the MRF has a strong correlation to the HFA with excellent medium-term repeatability (6-month period). This means that MRF can produce the same outcomes as the HFA when performed under supervision in the clinic. Chapters 3 and 4 apply the MRF to a weekly HM regime where participants tested themselves at home under application generated audio instructions and in the absence of clinical supervision. HM was undertaken for 12-months, and all participants had access to a clinical assistant who could be contacted to resolve technical difficulties. Chapter 3 finds that glaucoma participants had an uptake of 88% to HM and a weekly compliance of 72% with same-day reminders. A strong correlation was observed between the MRF at-home and the HFA in-clinic, and progression was detected in two participants using MRF home monitoring. Chapter 5 reports the HM uptake to be 85% in patients with intermediate AMD (iAMD) with a weekly compliance of 61% in the absence of reminders. Here, the HM included visual acuity as well as macula visual field sensitivity. Good correlation was observed between MRF and clinical measures with the Early Treatment Diabetic Research Study (ETDRS) letter chart and the Macular Integrity Assessment (MAIA) microperimeter. The overall findings of this thesis are that patients with chronic eye disease are receptive to the concept of HM with smart devices due to promising uptake. The finding of moderate compliance to weekly testing can be considered as a reduced number of tests received from home but, can still provide valuable information for clinical decision making. A survey of participant perceptions reveals that the MRF is easy to use and more comfortable than clinical perimeters. Larger, randomised, clinical trials are required to expose the true ability of MRF to detecting progression before it can be implemented as a new model of patient eye care.
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ItemNeuroregenerative and anti-inflammatory effects of decorin on the injured cornea( 2022)The cornea is densely innervated by sensory nerves that responds to noxious stimuli and produces neurotrophic factors to maintain ocular surface homeostasis. However, corneal sensory nerves are susceptible to damage from a range of ocular and systemic conditions, including dry eye disease, corneal infection, trauma, surgical procedures and diabetes mellitus. Despite corneal nerve impairment being a key pathophysiologic factor in many ocular surface diseases, there are few effective therapeutic approaches to promote corneal nerve regeneration. Decorin is an extracellular matrix protein that belongs to a family of small leucine-rich proteoglycans. Decorin interacts with different signaling molecules to regulate various cellular processes including collagen fibrillogenesis, fibrosis, inflammation and axon growth. There is evidence that decorin is of great potential as a therapeutic for treating spinal cord injury to suppress the formation of a glial scar and promote axon growth. Here, it is hypothesized that exogenous decorin may provide therapeutic benefits in peripheral nerve damage in corneal neuropathy. This thesis aims to explore the neuroregenerative and anti-inflammatory effects of decorin on the injured cornea and to verify its therapeutic potential to restore corneal homeostasis after corneal nerve injury. To assess this, corneal nerve damage was modelled in mice by direct abrasion of the central epithelium. Decorin or vehicle was applied topically after the injury and wholemount immunofluorescence staining was used to assess corneal sensory nerves and immune cell densities. Topical decorin treatment was associated with a higher density of corneal sensory nerves, relative to topical vehicle (control) treatment. This neuroregenerative effect of decorin was not observed in Cx3cr1gfp/gfp mice that spontaneously lack corneal epithelial dendritic cells (DCs), indicating that decorin-induced corneal nerve regeneration depends on the presence of DCs. In addition, topical decorin induced a higher density of DCs after six hours, and a lower density of macrophages at one week post-injury, supporting a role for decorin in modulating corneal immune responses. To further investigate the immunomodulatory effect of decorin during corneal wound healing, the same model was used to evaluate the temporal changes to corneal immune cells at multiple timepoints, including 12 hours, 24 hours, 3 days and 5 days post-injury. After topical decorin application, a higher density of corneal epithelial DCs and a lower density of infiltrating neutrophils were observed at 24 hours after injury. The decorin-induced lower neutrophil density was also DC-dependent. Consistent with the previous study, corneal stromal macrophage density was lower and corneal nerve density was higher in decorin-treated eyes compared to saline-treated controls. Interestingly, a higher percentage of the injured corneal area was re-epithelialized in decorin-treated eyes at 12 hours post-injury. These findings confirmed the neuroregenerative effect of decorin and demonstrated a distinctive pattern of temporal dynamics of corneal immune cells that were modulated by topical decorin. These effects of topical decorin on the injured cornea were associated with altered expression of transforming growth factor beta and chondroitin sulfate proteoglycan 4 signaling mRNA. In addition to evaluating an acute epithelial injury, repeated exposure to a corneal neuro-toxic stimulus was also considered, as this is not uncommon in clinical settings (e.g., in patients with long-term use of preservative-containing eye drops). Therefore, the therapeutic effects of decorin were also investigated in an animal model of chemical-induced corneal neuropathy, with repeated topical exposure to a common preservative benzalkonium chloride (BAK). Topical decorin treatment was also applied during a one-week period of daily BAK exposure. This study showed that decorin-treated eyes had less corneal neutrophil infiltration and a lower density of macrophages, accompanied by a higher density of corneal sensory nerves. In addition, corneal nerve density was negatively correlated with macrophage and neutrophil density, indicating that alterations to corneal immune cells induced by decorin may contribute to a higher density of sensory nerves. Together, these findings advance understanding of the relationship between corneal sensory nerves and immune cells, and more importantly, provide evidence for the therapeutic potential of topical decorin in conditions characterized by corneal nerve damage with local inflammation.
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ItemIncreased spatial sampling in automated static visual field testing( 2022)The overarching aim of this thesis was to explore various approaches to increase spatial sampling in clinical static automated perimetry (SAP) testing. The motivation for this aim arose from observations that clinically implemented SAP methods use a “one-test-fits-all” fixed test pattern, despite the fact that patterns of visual field loss vary markedly between individuals. This thesis explored whether it is possible to increase spatial sampling without increasing test duration, and the pros and cons of such as approach. To approach this problem, this thesis engaged a range of methods, including direct experimental work with patients, survey research with healthcare consumers, and explored the opinions of expert clinicians. The Australian Reduced Range Extended Spatial Test (ARREST) is a new perimetric approach that has been shown to increase spatial sampling individually without increasing the test time. ARREST has previously been developed and evaluated using computer simulations. The first experiment in this thesis (Chapter 3) evaluated the feasibility and performance of the ARREST approach in testing people with established visual field loss. Chapter 4 in this thesis investigated patients’ subjective experience with current SAP testing using a mixed-method survey and asked their preferences and priorities for future perimetric developments. The final experiment in this thesis (Chapter 5) explored potential alternative methods for a glaucoma-specific ARREST approach by utilising clinically available information such as clinicians’ views and data from OCT imaging. Taken together, the results of these experiments demonstrate that increasing spatial sampling without increasing test duration is feasible with the ARREST approach. Furthermore, patients report that they would prefer tests that produce more information about their vision. In order to gain more information about their vision, patients also report being willing to perform more visual field tests and increase the frequency of visits for testing. The ARREST approach is currently agnostic to disease-specific needs hence this thesis also explored other clinically available information that might potentially be useful for stimulus placement for a glaucoma-specific ARREST approach. The results from the final experiment demonstrate that clinical experts vary significantly in their choice of stimulus locations to prioritise for further testing, but tend to favour placement in areas important for quality of life. Overall, this thesis provides possible methods for increasing spatial sampling without increasing test duration and demonstrates the importance of considering user and consumer input in the design of perimetric procedures.
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ItemMapping the Parafoveal Capillary Network and Its Flow Characteristics in Healthy Eyes( 2022)Capillary blood flow plays an essential role in the nourishment and maintenance of healthy neural tissue while, in disease, altered capillary flow patterns form the earliest signs of diabetic vasculopathy and are implicated in other major conditions including stroke and dementia. Despite its obvious importance, the difficult-to-meet demands of high spatial and temporal imaging resolution have hitherto limited detailed characterisation of how blood flows through normal capillary networks to maintain healthy retinal structure and function. In this thesis, capillary flow characteristics were studied in the central retina of three healthy young individuals using an adaptive optics ophthalmoscope to provide the required cellular-level spatial resolution, combined with fast frame rates (200-300 frames/second) adequate to capture the single-file flow of red blood cells in capillaries over the course of about 3 seconds. In the first part of the thesis, an automated kymograph method was validated against manual tracking of single red blood cells over successive movie frames for the measurement of instantaneous flow velocities. The automated method proved much faster, and arguments are presented to demonstrate its superior accuracy and robustness, particularly for vessels in which manual tracking is challenging due to high flow speeds. In the second part of the thesis, using the validated kymography approach, velocities were estimated contemporaneously from many neighbouring vessels of the parafoveal capillary network for each subject. Our findings show that capillaries universally exhibit a pulsatile flow pattern with alternating peaks and troughs in velocity with every heartbeat. A high degree of inter-vessel variability over a range of flow parameters (such as the peak, trough velocities, pulsatility, abruptness and peaktime), within a single subject and even within each retinal field, was `noted. This variability could not be explained by “local” vessel factors such as the vessel diameter, tortuosity, vessel length, linear cell density and hematocrit of the vessel. However, within a vessel, a moderate relation between velocities and hematocrit was noted, suggesting a redistribution of plasma between cells with changes in flow. Given the failure of local vessel factors to explain flow variability, the final part of the thesis explored associations between flow and capillary network variables including vessel depth, branch order, and distance from the feeding arteriole of a network. A detailed network analysis to establish the vessel connections and classifications are also presented. Most of the vessels studied were of terminal capillary type with collecting and supplying junctions on either side. Nearly 47 % of the upstream and downstream vessel junctions were amenable to fitting with a model of relative branch diameters based on Murray’s Law, with only a few adhering to modelled expectations. However, a key parameter of the model (the junction exponent) was found to be inversely related to the average velocity and trough velocity in downstream vessels. Cellular flow velocities were also moderately correlated with the length of vessel segments, and with distance to the upstream “feeding” arteriole. In summary, this thesis presents a validated method for studying retinal capillary flow characteristics in normal subjects and provides insights on flow variability within individual vascular networks.