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.