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    Research Update 579


    Prediction of Diabetic Retinopathy Severity Using a Combination of Retinal Neurodegeneration and Capillary Nonperfusion on OCT Angiography.

    Retina ( Philadelphia, Pa.) 2023 Apr 27.

    Kim K, Kim ES, Yu SY.

    Purpose: To generate a prediction model of diabetic retinopathy (DR) severity stages based on retinal neurodegeneration and capillary nonperfusion area (NPA) detected using optical coherence tomography (OCT) and OCT angiography (OCTA).

    Methods: A total of 155 treatment-naïve eyes were retrospectively included. Macular ganglion cell/inner plexiform layer (mGCIPL) thickness in six macular regions was measured. A custom algorithm was used to calculate capillary NPA from 3×3 mm2 and 12×12 mm2 field OCTA images. The region of interest was selected as circular areas of 3 mm and 12 mm diameter and divided into six subsections. Classification and regression tree analysis identified the best predictors to discriminate between the five DR stages.

    Results: Inferotemporal sector showed the largest mean NPA, and the inferior hemispheric NPA was significantly larger compared with the superior hemisphere. The mean mGCIPL thickness was significantly correlated with NPA of 12×12 mm2 field in participants with early stage DR. Inferior hemispheric NPA of 12×12 mm2 field and mean mGCIPL thickness were the two best variables to discriminate no DR versus mild nonproliferative DR (NPDR) and mild versus moderate NPDR (accuracy: 88.8% and 93.5%). Meanwhile, a combination of NPA of 12×12 mm2 and 3×3 mm2 fields was the best prediction model to discriminate moderate versus severe NPDR and severe NPDR versus PDR (accuracy: 91.8% and 94.1%).

    Conclusion: A combination model of capillary NPA and mGCIPL thickness may be a novel biomarker for predicting DR severity. Capillary nonperfusion seems to initially occurs in midperipheral retina with macular neurodegeneration and progress posteriorly.

    DOI: 10.1097/IAE.0000000000003820


    Insights Into PROM1-Macular Disease Using Multimodal Imaging.

    Investigative ophthalmology & visual science. 2023 Apr 3;

    Paavo M, Lee W, Parmann R, Lima de Carvalho JR Jr, Zernant J, Tsang SH, Allikmets , Sparrow JR.

    Purpose: To describe the features of genetically confirmed PROM1-macular dystrophy in multimodal images.

    Methods: Thirty-six (36) eyes of 18 patients (5-66 years; mean age, 42.4 years) were prospectively studied by clinical examination and multimodal imaging. Short-wavelength autofluorescence (SW-AF) and quantitative fundus autofluorescence (qAF) images were acquired with a scanning laser ophthalmoscope (HRA+OCT, Heidelberg Engineering) modified by insertion of an internal autofluorescent reference. Further clinical testing included near-infrared autofluorescence (NIR-AF; HRA2, Heidelberg Engineering) with semiquantitative analysis, spectral domain-optical coherence tomography (HRA+OCT) and full-field electroretinography. All patients were genetically confirmed by exome sequencing.

    Results: All 18 patients presented with varying degrees of maculopathy. One family with individuals affected across two generations exhibited granular fleck-like deposits across the posterior pole. Areas of granular deposition in SW-AF and NIR-AF corresponded to intermittent loss of the ellipsoid zone, whereas discrete regions of hypoautofluorescence corresponded with a loss of outer retinal layers in spectral-domain optical coherence tomography scans. For 18 of the 20 eyes, qAF levels within the macula were within the 95% confidence intervals of healthy age-matched individuals; nor was the mean NIR-AF signal increased relative to healthy eyes.

    Conclusions: Although PROM1-macular dystrophy (Stargardt disease 4) can exhibit phenotypic overlap with recessive Stargardt disease, significantly increased SW-AF levels were not detected. As such, elevated bisretinoid lipofuscin may not be a feature of the pathophysiology of PROM1 disease. The qAF approach could serve as a method of early differential diagnosis and may help to identify appropriate disease targets as therapeutics become available to treat inherited retinal disease.

    DOI: 10.1167/iovs.64.4.27

    Performance of a Smart Device over 12-Months for Home Monitoring of Patients with Intermediate Age-Related Macular Degeneration.

    Journal of clinical medicine 2023 Mar 27;

    Prea S, Guymer R, Kong G, Vingrys A.

    Background: To determine the 12-month compliance with and retention of home monitoring (HM) with Melbourne Rapid Fields (MRFh) for patients with intermediate age-related macular degeneration (iAMD) and compare visual acuity (VA) and retinal sensitivity (RS) results to clinical measures.

    Methods: Participants were recruited to a 12-month HM study with weekly testing of vision with MRFh. Inclusion criteria were a diagnosis of iAMD, understand English instructions, VA ≥ 20/40, and access to an iPad. Supervised in-clinic testing of high contrast VA (HVA, ETDRS), low-luminance VA (LLVA, ETDRS with ND2 filter), and RS (Macular Integrity Assessment, MAIA, and MRF in-clinic, MRFc) was conducted every 6-months.

    Results: A total of 54 participants (67 ± 6.8 years) were enrolled. Compliance to weekly HM was 61% and study retention at 12-months was 50% of those with uptake (n = 46). No difference was observed between MRFc and MRFh across all RS and VA outcomes (p > 0.05). MRFh RS was higher than MAIA (29.1 vs. 27.1 dB, p < 0.001). MRFh HVA was not different from ETDRS (p = 0.08), but LLVA was 9 letters better (81.5 vs. 72.4 letters, p < 0.001).

    Conclusions: Over 12-months, MRFh yields a moderate level of compliance with (61%) and retention (50%) of weekly testing. Further studies are required to assess the ability of MRFh to detect early progression to nAMD.

    DOI: 10.3390/jcm12072530


    Retinal Aging Transcriptome and Cellular Landscape in Association with the Progression of Age-Related Macular Degeneration.

    Investigative ophthalmology & visual science. 2023 Apr 3;

    Wang JH, Wong RCB, Liu GS

    Purpose: Age is the main risk factor for age-related macular degeneration (AMD), a leading cause of blindness in the elderly, with limited therapeutic options.

    Methods: Here, we analyze the transcriptomic characteristics and cellular landscape of the aging retinas from controls and patients with AMD.

    Results: We identify the aging genes in the neural retina, which are associated with innate immune response and inflammation. Deconvolution analysis reveals that the estimated proportions of M2 macrophages are significantly increased with both age and AMD severity. Moreover, we find that proportions of Müller glia are significantly increased only with age but not with AMD severity. Several genes associated with both age and AMD severity, particularly C1s and MR1, are strong positively correlated with the proportions of Müller glia.

    Conclusions: Our studies expand the genetic and cellular landscape of AMD and provide avenues for further studies on the relationship between age and AMD.

    DOI: 10.1167/iovs.64.4.32

    Gene-level association analysis of bivariate ordinal traits with functional regressions.

    Genetic epidemiology. 2023 Apr 26.

    Wang S, Chiu CY, Wilson AF, Bailey-Wilson JE, Agron E, Chew EY, Ahn , Xiong M, Fan R.

    In genetic studies, many phenotypes have multiple naturally ordered discrete values. The phenotypes can be correlated with each other. If multiple correlated ordinal traits are analyzed simultaneously, the power of analysis may increase significantly while the false positives can be controlled well. In this study, we propose bivariate functional ordinal linear regression (BFOLR) models using latent regressions with cumulative logit link or probit link to perform a gene-based analysis for bivariate ordinal traits and sequencing data. In the proposed BFOLR models, genetic variant data are viewed as stochastic functions of physical positions, and the genetic effects are treated as a function of physical positions. The BFOLR models take the correlation of the two ordinal traits into account via latent variables. The BFOLR models are built upon functional data analysis which can be revised to analyze the bivariate ordinal traits and high-dimension genetic data. The methods are flexible and can analyze three types of genetic data: (1) rare variants only, (2) common variants only, and (3) a combination of rare and common variants. Extensive simulation studies show that the likelihood ratio tests of the BFOLR models control type I errors well and have good power performance. The BFOLR models are applied to analyze Age-Related Eye Disease Study data, in which two genes, CFH and ARMS2, are found to strongly associate with eye drusen size, drusen area, age-related macular degeneration (AMD) categories, and AMD severity scale.

    DOI: 10.1002/gepi.22524


    Modifications in Macular Perfusion and Neuronal Loss After Acute Traumatic Brain Injury.

    Investigative ophthalmology & visual science. 2023 Apr 3;

    Hepschke JL, Laws E, Bin Saliman NH, Juncu S, Courtie E, Belli A, Blanch RJ.

    Purpose: Traumatic brain injury (TBI) causes structural damage and functional impairment in the visual system, often with retinal ganglion cell (RGC) degeneration occurring without visual symptoms. RGC degeneration is associated with reduced retinal blood-flow, however, it is not known whether reductions in perfusion precede or are secondary to neurodegeneration.

    Methods: We conducted a prospective observational single-center case series. Patients were included if they were admitted to the hospital after acute TBI and underwent ophthalmic clinical examination, including optical coherence tomography (OCT) and OCT angiography (OCTA) acutely and at follow-up. Ganglion cell layer thickness (GCL) thickness, vascular density in the superficial vascular plexus (SVP), and intermediate capillary plexus (ICP) were quantified.

    Results: Twenty-one patients aged 20 to 65 years (mean = 38 years) including 16 men and 5 women were examined less than 14 days after moderate to severe TBI, and again after 2 to 6 months. Macular structure and perfusion were normal at baseline in all patients. Visual function was abnormal at baseline in three patients and subsequent neurodegeneration and loss of perfusion corresponded to baseline visual function abnormalities. Nine patients (43%) had reduced macular GCL thickness at follow up. Perfusion in the SVP strongly associated with local GCL thickness. The strongest association of the SVP metrics was the sum of vessel density (P < 0.0001).

    Conclusions: In cases of reduced visual function after TBI, macular perfusion remained normal until reductions in GCL thickness occurred, indicating that perfusion changes were secondary to local GCL loss.

    DOI: 10.1167/iovs.64.4.35

    Alterations of the intestinal microbiota in age-related macular degeneration.

    Frontiers in microbiology. 2023 Apr 5;

    Zhang Y, Wang T, Wan Z, Bai J, Xue Y, Dai R, Wang M, Peng Q.

    Purpose: Age-related macular degeneration (AMD) is the leading cause of vision loss in those over the age of 50. Recently, intestinal microbiota has been reported to be involved in the pathogenesis of ocular diseases. The purpose of this study was to discover more about the involvement of the intestinal microbiota in AMD patients.

    Methods: Fecal samples from 30 patients with AMD (AMD group) and 17 age- and sex-matched healthy controls (control group) without any fundus disease were collected. DNA extraction, PCR amplification, and 16S rRNA gene sequencing of the samples were performed to identify intestinal microbial alterations. Further, we used BugBase for phenotypic prediction and PICRUSt2 for KEGG Orthology (KO) as well as metabolic feature prediction.

    Results: The intestinal microbiota was found to be significantly altered in the AMD group. The AMD group had a significantly lower level of Firmicutes and relatively higher levels of Proteobacteria and Bacteroidota compared to those in the control group. At the genus level, the AMD patient group showed a considerably higher proportion of Escherichia-Shigella and lower proportions of Blautia and Anaerostipes compared with those in the control group. Phenotypic prediction revealed obvious differences in the four phenotypes between the two groups. PICRUSt2 analysis revealed KOs and pathways associated with altered intestinal microbiota. The abundance of the top eight KOs in the AMD group was higher than that in the control group. These KOs were mainly involved in lipopolysaccharide biosynthesis.

    Conclusion: The findings of this study indicated that AMD patients had different gut microbiota compared with healthy controls, and that AMD pathophysiology might be linked to changes in gut-related metabolic pathways. Therefore, intestinal microbiota might serve as non-invasive indicators for AMD clinical diagnosis and possibly also as AMD treatment targets.

    DOI: 10.3389/fmicb.2023.1069325


    Self-rated eyesight among healthy older Australians: Baseline results of the ASPREE Longitudinal Study of Older Persons.

    Clinical & experimental ophthalmology. 2023 Apr 28

    McGuinness MB, Robman LD, McNeil JJ, Tran C, Woods RL, Owen AJ, Pham T, Guymer RH.

    We aimed to describe the self-reported level of eyesight amongst a cohort of relatively healthy older Australian adults, and to investigate associations between poorer self-rated eyesight and demographic, health, and functional characteristics METHODS: The ASPirin in Reducing Events in the Elderly (ASPREE) Longitudinal Study of Older Persons (ALSOP) study was embedded in a multisite trial which recruited independently living Australians from general practices (2010-2014). Self-rated eyesight was recorded on a paper-based questionnaire as Excellent, Good, Fair, Poor, Very poor, or Completely blind at the baseline study wave RESULTS: Data from 14 592 participants (aged 70-95 years, 54.61% female) were included in this cross-sectional analysis. Eighty percent of participants reported excellent or good eyesight (n = 11 677). People with complete blindness were precluded from enrolling but 299 participants (2.0%) reported poor or very poor eyesight, and 2616 rated their eyesight as fair (17.9%). Lower levels of eyesight were associated with being older, female, fewer years of formal education, a primary language other than English, smoking, and self-reported macular degeneration, glaucoma, retinopathy, cataracts, and hearing problems (each p ≤ 0.021). People with lower levels of eyesight had a higher number of falls, frailty characteristics, and depressive symptoms, and lower mental and physical health functioning scores (each p < 0.001)

    Conclusions: Whilst most of these healthy older Australians reported good or excellent eyesight, a notable minority reported poor or very poor eyesight, and this was associated with a range of poorer health measures. These findings support the need for additional resources to prevent vision loss and associated sequelae.

    DOI: 10.1111/ceo.14233


    Age-Related Macular Degeneration With Visual Disability Is Associated With Cardiovascular Disease Risk in the Korean Nationwide Cohort.

    Journal of the Americal Heart Association. 2023 Apr 29:

    Jung W, Han K, Kim B, Hwang S, Yoon JM, Park J, Lim DH, Shin DW.

    Background: Age-related macular degeneration (AMD) is the leading cause of visual disability. AMD shares some risk factors with the pathogenesis of cardiovascular disease (CVD). However, previous studies examining the association between AMD and the risk of CVD provide conflicting results. Hence, we investigated the association between AMD, visual disability, and the risk of CVD.

    Methods and Results: This is a nationwide cohort study using data from the Korean National Health Insurance System database (2009-2019) on subjects who underwent a national health screening program in 2009. A total of 3 789 963 subjects were categorized by the presence of AMD and visual disability. Visual disability was defined as a best-corrected visual acuity of ≤20/100 by validated documentation from a specialist physician. Cox regression hazard model was used to examine the hazard ratios (HRs) of CVD, including myocardial infarction and ischemic stroke, after adjusting for potential confounders. During a mean 9.77 years of follow-up, AMD was associated with a 5% higher risk of myocardial infarction (adjusted HR [aHR], 1.05 [95% CI, 1.01-1.10]) but not associated with increased risk of overall CVD (aHR, 1.02 [95% CI, 1.00-1.05]) or ischemic stroke (aHR, 1.02 [95% CI, 0.98-1.06]). However, when AMD was accompanied by visual disability, there was increased risk of CVD (aHR, 1.17 [95% CI, 1.06-1.29]), myocardial infarction (aHR, 1.18 [95% CI, 1.01-1.37]), and ischemic stroke (aHR, 1.20 [95% CI, 1.06-1.35]). These trends were more evident in women and subjects with cardiometabolic comorbidities.

    Conclusions: AMD with visual disability, but not all AMD, was associated with an increased risk of CVD. Patients with AMD who have visual disability should be targeted for CVD prevention.

    DOI: 10.1161/JAHA.122.028027


    Pathways of Fluid Leakage in Age Related Macular Degeneration.

    Retina (Philadelphia, Pa.)2023 Mar 28.

    Fouad YA, Santina A, Bousquet E, Sadda SR, Sarraf D.

    Age related macular degeneration is the most common cause of blindness in the western world and the development of intravitreal pharmacotherapies for the treatment of the neovascular complications of this disorder is considered a revolution in the care of this devastating disease. Anti-vascular endothelial growth factor (VEGF) agents such as ranibizumab and aflibercept can prevent blindness by reducing or resolving fluid in AMD and therefore the detection of these biomarkers (e.g. intraretinal and subretinal fluid) with high resolution, depth resolved tools such as optical coherence tomography (OCT) is a critical process in the successful management of this condition. However, there is growing evidence to indicate that fluid is not always the result of neovascular pathways and therefore the obligatory administration of anti-VEGF therapy in response to the observation of fluid on OCT may be flawed. Non-neovascular mechanisms of fluid leakage (e.g. retinal pigment epithelium pump impairment) should also be considered and in these circumstances anti-VEGF injection should be deferred. This editorial will review the neovascular and non-neovascular pathways of fluid leakage in AMD and will provide more informed guidance for the overall evaluation and management of exudation in AMD, including an observe and extend regimen in the context of non-neovascular fluid.

    DOI: 10.1097/IAE.0000000000003798