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BioRxiv : the Preprint Server For... Nov 2023In age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD), lipid-rich deposits known as drusen accumulate under the retinal pigment epithelium (RPE)....
PURPOSE
In age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD), lipid-rich deposits known as drusen accumulate under the retinal pigment epithelium (RPE). Drusen may contribute to photoreceptor and RPE degeneration in AMD and SFD. We hypothesize that stimulating β-oxidation in RPE will reduce drusen accumulation. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate β-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, limits the accumulation of lipid deposits in cultured RPE cells.
METHODS
We probed metabolism and cellular function in mouse RPE-choroid, human fetal- derived RPE cells, and induced pluripotent stem cell-derived RPE cells. We used C6-glucose and C16-palmitate to determine the effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism. C labeling of metabolites in these pathways were analyzed using gas chromatography-linked mass spectrometry. We quantified ApoE and VEGF release using enzyme-linked immunosorbent assays. Immunostaining of sectioned RPE was used to visualize ApoE deposits. RPE function was assessed by measuring the trans-epithelial electrical resistance (TEER).
RESULTS
ACC inhibition with Firsocostat increases fatty acid oxidation and remodels lipid composition, glycolytic metabolism, lipoprotein release, and enhances TEER. When human serum is used to induce sub-RPE lipoprotein accumulation, fewer lipoproteins accumulate with Firsocostat. In a culture model of Sorsby's fundus dystrophy, Firsocostat also stimulates fatty acid oxidation, improves morphology, and increases TEER.
CONCLUSIONS
Firsocostat remodels intracellular metabolism and improves RPE resilience to serum-induced lipid deposition. This effect of ACC inhibition suggests that it could be an effective strategy for diminishing drusen accumulation in the eyes of patients with AMD.
PubMed: 37986876
DOI: 10.1101/2023.11.07.566117 -
Acta Ophthalmologica Dec 2023Globally age-related macular degeneration (AMD) is a leading cause of blindness with a significant impact on quality of life. Geographic atrophy (GA) is the atrophic... (Review)
Review
Globally age-related macular degeneration (AMD) is a leading cause of blindness with a significant impact on quality of life. Geographic atrophy (GA) is the atrophic late form of AMD and its prevalence increases markedly with age with around 1 in 5 persons aged 85 and above having GA in at least one eye. Bilateral GA leads to severe visual impairment thus posing a significant burden on patients, careers and health providers. The incidence and prevalence of GA varies across different geographic regions, with the highest rates in those of European ancestry. Although heterogeneity in definitions of GA and reporting strategy can explain some of the discrepancies, the data overall are consistent in showing a lower prevalence in other ethnicities such as those of Asian heritage. This is at present unexplained but thought to be due to the existence of protective factors such as differences in eye pigmentation, diet, environmental exposures and genetic variability. This review covers key aspects of the prevalence and incidence of the ocular precursor features of GA (large drusen, pigmentary abnormalities and reticular pseudo-drusen), the late stage of GA and factors that have been known to be associated with modifying risk including systemic, demographic, environment, genetic and ocular. Understanding the global epidemiology scenario is crucial for the prevention of and management of patients with GA.
Topics: Humans; Geographic Atrophy; Retinal Drusen; Quality of Life; Macular Degeneration; Retina
PubMed: 37933608
DOI: 10.1111/aos.15767 -
Clinical Ophthalmology (Auckland, N.Z.) 2023Prior studies have validated ultra-widefield imaging as a remote screening tool for diabetic retinopathy. The aim of this study was to determine its use in screening for...
BACKGROUND
Prior studies have validated ultra-widefield imaging as a remote screening tool for diabetic retinopathy. The aim of this study was to determine its use in screening for any fundus pathology in a routine patient population.
METHODS
In this prospective randomized study, patients underwent both slit lamp indirect ophthalmoscopy and ultra-widefield imaging. Ultra-widefield images were independently reviewed by two optometrists, and discrepancies were adjudicated by a retina specialist. Clinical findings from slit-lamp examiners and image-reviewers were coded into themes and clinically meaningful findings were extracted. Cohen's kappa was used to estimate agreement for these findings between the two image-reviewers and between the image-reviewers and slit-lamp examiners.
RESULTS
Nine-hundred eyes of 450 patients were examined and imaged, of which 616 eyes were analyzed. At least one abnormal fundus finding was present on ophthalmoscopy in 71 eyes (11%) and on adjudicated image interpretation in 166 eyes (27%). Agreement between the two image-reviewers was moderate to substantial for most clinically meaningful findings, including optic disc hemorrhage (κ = 0.8), macular exudates (κ = 0.7), and macular pigmentary changes (κ = 0.7). Agreement between examiners and image-reviewers was moderate to substantial for optic disc hemorrhage (κ = 1), indistinct optic disc margins (κ = 0.5), drusen (κ = 0.4), pigmentary changes (κ = 0.4), and hemorrhage (κ = 0.8). A total of 187 findings were detected by imaging but not examination, compared with 42 that were detected on examination but not imaging.
CONCLUSION
In a routine patient population, ultra-widefield imaging agreed with standard-of-care slit-lamp examinations and detected more fundus findings.
PubMed: 37927576
DOI: 10.2147/OPTH.S433864 -
Retina (Philadelphia, Pa.) Mar 2024The aim of this literature review was to summarize novel optical coherence tomography (OCT) imaging biomarkers that have recently been described in the literature and... (Review)
Review
PURPOSE
The aim of this literature review was to summarize novel optical coherence tomography (OCT) imaging biomarkers that have recently been described in the literature and are frequently encountered clinically.
METHODS
The literature was reviewed to identify novel OCT biomarkers reported to date. A descriptive summary of all terms and representative illustrations were provided to highlight the most relevant features.
RESULTS
Thirty-seven OCT terminologies were identified. The vitreomacular interface disorder group included the four stages of epiretinal membrane, macular pseudohole, tractional lamellar hole (LH), degenerative LH, cotton ball sign, and foveal crack sign. The age-related macular degeneration group included outer retinal tubulation, multilayered pigment epithelial detachment, prechoroidal cleft, onion sign, double-layer sign, complete outer retinal atrophy, complete retinal pigment epithelium and outer retinal atrophy, and reticular pseudodrusen. The uveitic disorder group consisted of bacillary layer detachment, syphilis placoid, rain-cloud sign, and pitchfork sign. The disorders relating to the toxicity group included flying saucer sign and mitogen-activated protein kinase (MEK) inhibitor-associated retinopathy. The disorders associated with the systemic condition group included choroidal nodules and needle sign. The pachychoroid spectrum group included pachychoroid and brush border pattern. The vascular disorder group included pearl necklace sign, diffuse retinal thickening, disorganization of retinal inner layers, inner nuclear layer microcysts, hyperreflective retinal spots, paracentral acute middle maculopathy, and acute macular neuroretinopathy. The miscellaneous group included omega sign (ω), macular telangiectasia (type 2), and omega sign (Ω).
CONCLUSIONS
Thirty-seven OCT terminologies were summarized, and detailed illustrations consolidating the features of each biomarker were included. A nuanced understanding of OCT biomarkers and their clinical significance is essential because of their predictive and prognostic value.
Topics: Humans; Tomography, Optical Coherence; Epiretinal Membrane; Uveitis; Retinal Drusen; Biomarkers; Atrophy; Retrospective Studies
PubMed: 37903455
DOI: 10.1097/IAE.0000000000003974 -
Case Reports in Ophthalmology 2023We present a case of reticular pseudodrusen (RPD) regression on multimodal retinal imaging following a rhegmatogenous retinal detachment. Two mechanisms of action can be...
We present a case of reticular pseudodrusen (RPD) regression on multimodal retinal imaging following a rhegmatogenous retinal detachment. Two mechanisms of action can be postulated. The subretinal deposits dissolve due to voluminous subretinal fluid during retinal separation from the retinal pigment epithelium and are in turn mechanically cleared during retinal re-attachment surgery. Alternatively, an RPD clearance is facilitated by enhanced phagocytic activity of macrophages and microglial cells as a response to acute retinal stress.
PubMed: 37901649
DOI: 10.1159/000531676 -
Survey of Ophthalmology 2024There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently,... (Meta-Analysis)
Meta-Analysis Review
There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.
Topics: Humans; Prognosis; Angiogenesis Inhibitors; Disease Progression; Visual Acuity; Vascular Endothelial Growth Factor A; Wet Macular Degeneration; Retinal Drusen
PubMed: 37890677
DOI: 10.1016/j.survophthal.2023.10.010 -
Journal of Imaging Oct 2023Optical Coherence Tomography (OCT) is an imperative symptomatic tool empowering the diagnosis of retinal diseases and anomalies. The manual decision towards those...
Optical Coherence Tomography (OCT) is an imperative symptomatic tool empowering the diagnosis of retinal diseases and anomalies. The manual decision towards those anomalies by specialists is the norm, but its labor-intensive nature calls for more proficient strategies. Consequently, the study recommends employing a Convolutional Neural Network (CNN) for the classification of OCT images derived from the OCT dataset into distinct categories, including Choroidal NeoVascularization (CNV), Diabetic Macular Edema (DME), Drusen, and Normal. The average k-fold (k = 10) training accuracy, test accuracy, validation accuracy, training loss, test loss, and validation loss values of the proposed model are 96.33%, 94.29%, 94.12%, 0.1073, 0.2002, and 0.1927, respectively. Fast Gradient Sign Method (FGSM) is employed to introduce non-random noise aligned with the cost function's data gradient, with varying epsilon values scaling the noise, and the model correctly handles all noise levels below 0.1 epsilon. Explainable AI algorithms: Local Interpretable Model-Agnostic Explanations (LIME) and SHapley Additive exPlanations (SHAP) are utilized to provide human interpretable explanations approximating the behaviour of the model within the region of a particular retinal image. Additionally, two supplementary datasets, namely, COVID-19 and Kidney Stone, are assimilated to enhance the model's robustness and versatility, resulting in a level of precision comparable to state-of-the-art methodologies. Incorporating a lightweight CNN model with 983,716 parameters, 2.37×108 floating point operations per second (FLOPs) and leveraging explainable AI strategies, this study contributes to efficient OCT-based diagnosis, underscores its potential in advancing medical diagnostics, and offers assistance in the Internet-of-Medical-Things.
PubMed: 37888326
DOI: 10.3390/jimaging9100219 -
Investigative Ophthalmology & Visual... Oct 2023Proteopathy is believed to contribute to age-related macular degeneration (AMD). Much research indicates that AMD begins in the retinal pigment epithelium (RPE), which...
PURPOSE
Proteopathy is believed to contribute to age-related macular degeneration (AMD). Much research indicates that AMD begins in the retinal pigment epithelium (RPE), which is associated with formation of extracellular drusen, a clinical hallmark of AMD. Human RPE produces a drusen-associated abnormal protein, the exon Ⅵ-skipping splice isoform of retinal G protein-coupled receptor (RGR-d). In this study, we investigate the detrimental effects of RGR-d on cultured cells and mouse retina.
METHODS
ARPE-19 cells were stably infected by lentivirus overexpressing RGR or RGR-d and were treated with MG132, sometimes combined with or without endoplasmic reticulum (ER) stress inducer, tunicamycin. RGR and RGR-d protein expression, degeneration pathway, and potential cytotoxicity were explored. Homozygous RGR-d mice aged 8 or 14 months were fed with a high-fat diet for 3 months and then subjected to ocular examination and histopathology experiments.
RESULTS
We confirm that RGR-d is proteotoxic under various conditions. In ARPE-19 cells, RGR-d is misfolded and almost completely degraded via the ubiquitin-proteasome system. Unlike normal RGR, RGR-d increases ER stress, triggers the unfolded protein response, and exerts potent cytotoxicity. Aged RGR-d mice manifest disrupted RPE cell integrity, apoptotic photoreceptors, choroidal deposition of complement C3, and CD86+CD32+ proinflammatory cell infiltration into retina and RPE-choroid. Furthermore, the AMD-like phenotype of RGR-d mice can be aggravated by a high-fat diet.
CONCLUSIONS
Our study confirmed the pathogenicity of the RGR splice isoform and corroborated a significant role of proteopathy in AMD. These findings may contribute to greater comprehension of the multifactorial causes of AMD.
Topics: Animals; Humans; Mice; Exons; Macular Degeneration; Opsins; Protein Isoforms; Retina; Receptors, G-Protein-Coupled; Eye Proteins
PubMed: 37883094
DOI: 10.1167/iovs.64.13.41 -
Turkish Journal of Ophthalmology Oct 2023To investigate the presence and prevalence of reticular pseudodrusen (RPD) in patients with age-related macular degeneration using multiple imaging modalities and to...
OBJECTIVES
To investigate the presence and prevalence of reticular pseudodrusen (RPD) in patients with age-related macular degeneration using multiple imaging modalities and to compare the sensitivity and specificity of these modalities in the detection of RPD.
MATERIALS AND METHODS
Images from a total of 198 consecutive patients were analyzed prospectively. Color fundus photography, red-free imaging, spectral domain optical coherence tomography (SD-OCT), infrared and blue reflectance (BR) imaging, fundus autofluorescence (FAF), enhanced-depth imaging OCT (EDI-OCT), fundus fluorescein angiography (FFA) and indocyanine green angiography were performed. RPD was diagnosed in the presence of relevant findings in at least two of the imaging methods used.
RESULTS
RPD were detected in 149 eyes (37.6%). In the detection of RPD, color fundus photography, red-free photography, SD-OCT, infrared, FAF, BR, and FFA imaging had sensitivity values of 50%, 57.7%, 91.6%, 95%, 74.6%, 65.7%, and 28.2% and specificity values of 99.6%, 100%, 98.4%, 94.6%, 100%, 99.6%, and 69.8%, respectively.
CONCLUSION
Infrared imaging had the highest sensitivity. SD-OCT combined with infrared imaging was the most sensitive imaging technique for detecting RPD. The high specificity of FAF, red-free, and BR imaging may be useful to confirm a diagnosis of RPD.
Topics: Humans; Ophthalmoscopy; Retinal Drusen; Macular Degeneration; Fluorescein Angiography; Multimodal Imaging
PubMed: 37867466
DOI: 10.4274/tjo.galenos.2023.85616 -
Frontiers in Bioengineering and... 2023Cell monolayers that form a barrier between two structures play an important role for the maintenance of tissue functionality. In the anterior portion of the eye, the... (Review)
Review
Cell monolayers that form a barrier between two structures play an important role for the maintenance of tissue functionality. In the anterior portion of the eye, the corneal endothelium forms a barrier that controls fluid exchange between the aqueous humor of the anterior chamber and the corneal stroma. This monolayer is central in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD). FECD is a common corneal disease, in which corneal endothelial cells deposit extracellular matrix that increases the thickness of its basal membrane (Descemet's membrane), and forms excrescences (guttae). With time, there is a decrease in endothelial cell density that generates vision loss. Transplantation of a monolayer of healthy corneal endothelial cells on a Descemet membrane substitute could become an interesting alternative for the treatment of this pathology. In the back of the eye, the retinal pigment epithelium (RPE) forms the blood-retinal barrier, controlling fluid exchange between the choriocapillaris and the photoreceptors of the outer retina. In the retinal disease dry age-related macular degeneration (dry AMD), deposits (drusen) form between the RPE and its basal membrane (Bruch's membrane). These deposits hinder fluid exchange, resulting in progressive RPE cell death, which in turn generates photoreceptor cell death, and vision loss. Transplantation of a RPE monolayer on a Bruch's membrane/choroidal stromal substitute to replace the RPE before photoreceptor cell death could become a treatment alternative for this eye disease. This review will present the different biomaterials that are proposed for the engineering of a monolayer of corneal endothelium for the treatment of FECD, and a RPE monolayer for the treatment of dry AMD.
PubMed: 37840667
DOI: 10.3389/fbioe.2023.1269385