Ophthalmology (Eye & Ear Hospital) - Research Publications

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    Characterising the diagnosis of genetic maculopathies in a real-world private tertiary retinal practice in Australia: protocol for a retrospective clinical audit
    Britten-Jones, AC ; Markakis, D ; Guymer, RH ; Lin, M-L ; Skalicky, S ; Ayton, LN ; Mack, HG (TAYLOR & FRANCIS LTD, 2023-12-12)
    PURPOSE: Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients. METHODS: Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing. DISCUSSION: Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available.
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    A semi-automated pipeline for quantifying drusen-like deposits in human induced pluripotent stem cell-derived retinal pigment epithelium cells.
    Hall, J ; Daniszewski, M ; Cheung, S ; Shobhana, K ; Kumar, H ; Liang, HH ; Beetham, H ; Cho, E ; Abbott, C ; Hewitt, AW ; Simpson, KJ ; Guymer, RH ; Paull, D ; Pébay, A ; Lidgerwood, GE (Elsevier BV, 2023-08-30)
    Age-Related Macular Degeneration (AMD) is a highly prevalent form of retinal disease amongst Western communities over 50 years of age. A hallmark of AMD pathogenesis is the accumulation of drusen underneath the retinal pigment epithelium (RPE), a biological process also observable in vitro. The accumulation of drusen has been shown to predict the progression to advanced AMD, making accurate characterisation of drusen in vitro models valuable in disease modelling and drug development. More recently, deposits above the RPE in the subretinal space, called reticular pseudodrusen (RPD) have been recognized as a sub-phenotype of AMD. While in vitro imaging techniques allow for the immunostaining of drusen-like deposits, quantification of these deposits often requires slow, low throughput manual counting of images. This further lends itself to issues including sampling biases, while ignoring critical data parameters including volume and precise localization. To overcome these issues, we developed a semi-automated pipeline for quantifying the presence of drusen-like deposits in vitro, using RPE cultures derived from patient-specific induced pluripotent stem cells (iPSCs). Using high-throughput confocal microscopy, together with three-dimensional reconstruction, we developed an imaging and analysis pipeline that quantifies the number of drusen-like deposits, and accurately and reproducibly provides the location and composition of these deposits. Extending its utility, this pipeline can determine whether the drusen-like deposits locate to the apical or basal surface of RPE cells. Here, we validate the utility of this pipeline in the quantification of drusen-like deposits in six iPSCs lines derived from patients with AMD, following their differentiation into RPE cells. This pipeline provides a valuable tool for the in vitro modelling of AMD and other retinal disease, and is amenable to mid and high throughput screenings.
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    An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access.
    Jones, AV ; Curtiss, D ; Harris, C ; Southerington, T ; Hautalahti, M ; Wihuri, P ; Mäkelä, J ; Kallionpää, RE ; Makkonen, E ; Knopp, T ; Mannermaa, A ; Mäkinen, E ; Moilanen, A-M ; Tezel, TH ; SCOPE Study group, ; Waheed, NK ; Swaroop, A (Public Library of Science (PLoS), 2022)
    PURPOSE: Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities. METHODS: Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls. RESULTS: Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities. CONCLUSIONS: The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.
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    Impact of Reticular Pseudodrusen on Choriocapillaris Flow Deficits and Choroidal Structure on Optical Coherence Tomography Angiography
    Wu, Z ; Zhou, X ; Chu, Z ; Gregori, G ; Wang, RK ; Rosenfeld, PJ ; Guymer, RH (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-11)
    PURPOSE: To examine the impact of reticular pseudodrusen (RPD) on choriocapillaris blood flow and choroidal structure in individuals with intermediate age-related macular degeneration (AMD). METHODS: Individuals with bilateral large drusen underwent optical coherence tomography (OCT), color fundus photography, near-infrared reflectance, and fundus autofluorescence imaging to determine the presence of RPD. These participants also underwent swept-source OCT angiography (SS-OCTA) imaging to determine (1) choriocapillaris flow deficit (FD) parameters, including the percentage, mean size, and number of FDs present; and (2) choroidal structural parameters, including mean choroidal thickness and choroidal vascularity index. Differences in these parameters between eyes with and without coexistent RPD were examined with and without adjustment for potential key confounders such as drusen volume from the SS-OCTA scans and age. RESULTS: This study included 102 eyes from 51 individuals with bilateral large drusen, and the analyses showed that there were no significant differences in the choriocapillaris FD parameters (P ≥ 0.062 for all) and choroidal structural parameters (P ≥ 0.059 for all), with or without adjustment for potential confounders in this cohort. However, the percentage of FDs and the mean FD size were both significantly greater with increasing drusen volume (P ≤ 0.038 for both). CONCLUSIONS: The coexistence of RPD in eyes of individuals with intermediate AMD was not associated with significant impairments in choriocapillaris blood flow and choroidal vascular structural changes, with or without adjustment for key confounders. These findings suggest that macular changes in these vascular parameters may not be associated with the presence of RPD.
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    A Deep Learning Framework for the Detection and Quantification of Reticular Pseudodrusen and Drusen on Optical Coherence Tomography
    Schwartz, R ; Khalid, H ; Liakopoulos, S ; Ouyang, Y ; de Vente, C ; Gonzalez-Gonzalo, C ; Lee, AY ; Guymer, R ; Chew, EY ; Egan, C ; Wu, Z ; Kumar, H ; Farrington, J ; Mueller, PL ; Sanchez, CI ; Tufail, A (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-12)
    PURPOSE: The purpose of this study was to develop and validate a deep learning (DL) framework for the detection and quantification of reticular pseudodrusen (RPD) and drusen on optical coherence tomography (OCT) scans. METHODS: A DL framework was developed consisting of a classification model and an out-of-distribution (OOD) detection model for the identification of ungradable scans; a classification model to identify scans with drusen or RPD; and an image segmentation model to independently segment lesions as RPD or drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with a self-reported diagnosis of age-related macular degeneration (AMD) and 250 UKBB controls. Drusen and RPD were manually delineated by five retina specialists. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), kappa, accuracy, intraclass correlation coefficient (ICC), and free-response receiver operating characteristic (FROC) curves. RESULTS: The classification models performed strongly at their respective tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans classifier, the OOD model, and the drusen and RPD classification models). The mean ICC for the drusen and RPD area versus graders was 0.74 and 0.61, respectively, compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that the model's sensitivity was close to human performance. CONCLUSIONS: The models achieved high classification and segmentation performance, similar to human performance. TRANSLATIONAL RELEVANCE: Application of this robust framework will further our understanding of RPD as a separate entity from drusen in both research and clinical settings.
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    Genetics of reticular pseudodrusen in age-related macular degeneration
    Farashi, S ; Ansell, BRE ; Wu, Z ; Abbott, CJ ; Pebay, A ; Fletcher, EL ; Guymer, RH ; Bahlo, M (CELL PRESS, 2022-04)
    Reticular pseudodrusen (RPD) are subretinal deposits and when observed with age-related macular degeneration (AMD) form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk-associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by utilising adequate imaging methods should improve our understanding of the pathophysiology of RPD.
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    Reticular pseudodrusen: A critical phenotype in age-related macular degeneration
    Wu, Z ; Fletcher, EL ; Kumar, H ; Greferath, U ; Guymer, RH (PERGAMON-ELSEVIER SCIENCE LTD, 2022-05)
    Reticular pseudodrusen (RPD), or subretinal drusenoid deposits (SDD), refer to distinct lesions that occur in the subretinal space. Over the past three decades, their presence in association with age-related macular degeneration (AMD) has become increasingly recognized, especially as RPD have become more easily distinguished with newer clinical imaging modalities. There is also an increasing appreciation that RPD appear to be a critical AMD phenotype, where understanding their pathogenesis will provide further insights into the processes driving vision loss in AMD. However, key barriers to understanding the current evidence related to the independent impact of RPD include the heterogeneity in defining their presence, and failure to account for the confounding impact of the concurrent presence and severity of AMD pathology. This review thus critically discusses the current evidence on the prevalence and clinical significance of RPD and proposes a clinical imaging definition of RPD that will help move the field forward in gathering further key knowledge about this critical phenotype. It also proposes a putative mechanism for RPD formation and how they may drive progression to vision loss in AMD, through examining current evidence and presenting novel findings from preclinical and clinical studies.
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    Exploring the contribution of ARMS2 and HTRA1 genetic risk factors in age-related macular degeneration
    Pan, Y ; Fu, Y ; Baird, PN ; Guymer, RH ; Das, T ; Iwata, T (PERGAMON-ELSEVIER SCIENCE LTD, 2023-11)
    Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the region at chromosome 10q26, where the age-related maculopathy susceptibility (ARMS2/LOC387715) and HtrA serine peptidase 1 (HTRA1) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the ARMS2/HTRA1 risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed Bruch's membrane (BM) damage, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the ARMS2 and HTRA1 susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.
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    Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration
    Wu, Z ; Kumar, H ; Hodgson, LAB ; Guymer, RH (ELSEVIER SCIENCE INC, 2022-07)
    PURPOSE: To examine the association between reticular pseudodrusen (RPD) and progression to late age-related macular degeneration (AMD) in individuals with intermediate AMD. DESIGN: Prospective cohort study. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent multimodal imaging (MMI), including optical coherence tomography (OCT), near-infrared reflectance (NIR), fundus autofluorescence, and color fundus photography (CFP), at 6-monthly intervals up over a 36-month follow-up period. The presence of RPD per eye was determined based on either a combined MMI criterion, or each individual imaging modality, and their extent measured on combined OCT and NIR imaging. The association between the presence of RPD on different imaging modalities, and their extent, with the development of late AMD (including OCT-defined atrophy) was evaluated. RESULTS: The presence of RPD on MMI, or any of its individual modalities, at baseline was not significantly associated with an increased rate of developing late AMD, with or without adjusting for risk factors for AMD progression (age, drusen volume on OCT, and pigmentary abnormalities on CFP; all P ≥ 0.205). The extent of RPD present was also not significantly associated with an increased rate of developing late AMD, with or without adjustment for risk factors for AMD progression (both P ≥ 0.522). CONCLUSIONS: In this cohort with bilateral large drusen, the presence of RPD was not significantly associated with an increased risk of developing late AMD. Additional longitudinal studies in all stages of AMD are needed to understand the implications of RPD on vision loss in this condition.
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    P2X7-mediated alteration of membrane fluidity is associated with the late stages of age-related macular degeneration
    Drysdale, C ; Park, K ; Vessey, KA ; Huang, X ; Caruso, E ; Li, Y ; Wong, J ; Wiley, JS ; Fletcher, E ; Guymer, RH ; Gu, BJ (SPRINGER, 2022-12)
    We have shown deficits in monocyte phagocytosis from patients with age-related macular degeneration (AMD). Cell membrane fluidity is known to affect phagocytic capacity and leucocyte functionality more generally. Therefore, we examined membrane fluidity of peripheral blood leucocytes in human patients with AMD and in the P2X7 null mouse model of AMD using flow cytometry with a fluorescent probe for fluidity, TMA-DPH. The results showed that membrane fluidity was decreased in all leucocyte types of late AMD relative to healthy controls (HC) including monocytes, neutrophils and lymphocytes but this was not apparent in earlier stages of AMD. Further analysis of factors contributing to membrane fluidity indicated that pre-treatment of monocytes and lymphocytes with ATP greatly increased membrane fluidity in humans and mice. Evidence from P2X7 null mice and P2X7 antagonists confirmed that these ATP-driven increases in membrane fluidity were mediated by P2X7 but were not associated with the classic P2X7 functions of pore formation or phagocytosis. Analysis of P2X7 expression indicated that receptor levels were elevated in classic monocytes of late AMD patients, further suggesting the P2X7 may contribute to altered plasma membrane properties. Our findings identified a novel biological function of P2X7 in modulating membrane fluidity of leucocytes and demonstrated reduced membrane fluidity in cellular changes associated with the late stage of AMD.