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PURPOSE: This study analyzes the effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration (nAMD) in real clinical practice. MATERIAL AND METHODS: The study included patients with nAMD who received brolucizumab treatment and evaluated the changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume, as well as the number of injections and adverse events. RESULT: The group of previously treated patients included 28 subjects (28 eyes) that were switched to brolucizumab with a loading phase. By 12 months, BCVA changed from 0.43±0.29 to 0.33±0.27 LogMAR (p=0.11), CRT decreased from 281.5±58.2 to 239.9±45.6 µm (p=0.02). The group of previously untreated patients included 29 subjects (29 eyes). By 12 months, BCVA changed from 0.47±0.32 to 0.40±0.30 LogMAR (p=0.09), CRT decreased from 333.2±77.3 to 226.2±49.6 µm (p<0.001). Patients received 6.3±0.7 injections. In this group, baseline choroidal thickness showed a statistically significant correlation with final visual acuity (r=0.54; p<0.05) and CRT (r= -0.5; p<0.05). The group of previously treated patients switched without a loading phase included 18 patients (18 eyes). By 6 months, BCVA changed from 0.42±0.2 to 0.37±0.26 LogMAR (p=0.42). CRT remained stable at 285.6±56.9 µm (p=0.97). No adverse events related to intraocular inflammation were reported during the course of 385 injections. CONCLUSION: Brolucizumab therapy helps achieve significant anatomical and functional improvements in real clinical practice both in patients switched from previous treatments and in treatment-naïve patients. Greater baseline choroidal thickness may be associated with better anatomical and functional outcomes with brolucizumab treatment.
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Inhibidores de la Angiogénesis , Anticuerpos Monoclonales Humanizados , Inyecciones Intravítreas , Agudeza Visual , Humanos , Masculino , Femenino , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado del Tratamiento , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Tomografía de Coherencia Óptica/métodos , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/diagnóstico , Degeneración Macular/fisiopatología , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatologíaRESUMEN
Purpose: The purpose of this study was to develop a deep learning algorithm for detecting and quantifying incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) in optical coherence tomography (OCT) that generalizes well to data from different devices and to validate in an intermediate age-related macular degeneration (iAMD) cohort. Methods: The algorithm comprised a domain adaptation (DA) model, promoting generalization across devices, and a segmentation model for detecting granular biomarkers defining iRORA/cRORA, which are combined into iRORA/cRORA segmentations. Manual annotations of iRORA/cRORA in OCTs from different devices in the MACUSTAR study (168 patients with iAMD) were compared to the algorithm's output. Eye level classification metrics included sensitivity, specificity, and quadratic weighted Cohen's κ score (κw). Segmentation performance was assessed quantitatively using Bland-Altman plots and qualitatively. Results: For ZEISS OCTs, sensitivity and specificity for iRORA/cRORA classification were 38.5% and 93.1%, respectively, and 60.0% and 96.4% for cRORA. For Spectralis OCTs, these were 84.0% and 93.7% for iRORA/cRORA, and 62.5% and 97.4% for cRORA. The κw scores for 3-way classification (none, iRORA, and cRORA) were 0.37 and 0.73 for ZEISS and Spectralis, respectively. Removing DA reduced κw from 0.73 to 0.63 for Spectralis. Conclusions: The DA-enabled iRORA/cRORA segmentation algorithm showed superior consistency compared to human annotations, and good generalization across OCT devices. Translational Relevance: The application of this algorithm may help toward precise and automated tracking of iAMD-related lesion changes, which is crucial in clinical settings and multicenter longitudinal studies on iAMD.
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Aprendizaje Profundo , Degeneración Macular , Epitelio Pigmentado de la Retina , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Femenino , Degeneración Macular/patología , Degeneración Macular/diagnóstico , Degeneración Macular/diagnóstico por imagen , Masculino , Anciano , Atrofia/patología , Algoritmos , Anciano de 80 o más AñosRESUMEN
Purpose: To develop a novel classification of highly myopic eyes using artificial intelligence (AI) and investigate its relationship with contrast sensitivity function (CSF) and fundus features. Methods: We enrolled 616 highly myopic eyes of 616 patients. CSF was measured using the quantitative CSF method. Myopic macular degeneration (MMD) was graded according to the International META-PM Classification. Thickness of the macula and peripapillary retinal nerve fiber layer (p-RNFL) were assessed by fundus photography and optical coherence tomography, respectively. Classification was performed by combining CSF and fundus features with principal component analysis and k-means clustering. Results: With 83.35% total variance explained, highly myopic eyes were classified into four AI categories. The percentages of AI categories 1 to 4 were 14.9%, 37.5%, 36.2%, and 11.4%, respectively. Contrast acuity of the eyes in AI category 1 was the highest, which decreased by half in AI category 2. For AI categories 2 to 4, every increase in category led to a decrease of 0.23 logarithm of the minimum angle of resolution in contrast acuity. Compared with those in AI category 1, eyes in AI category 2 presented a higher percentage of MMD2 and thinner temporal p-RNFL. Eyes in AI categories 3 and 4 presented significantly higher percentage of MMD ≥ 3, thinner nasal macular thickness and p-RNFL (P < 0.05). Multivariate regression showed AI category 4 had higher MMD grades and thinner macular compared with AI category 3. Conclusions: We proposed an AI-based classification of highly myopic eyes with clear relevance to visual function and fundus features. Translational Relevance: This classification helps to discover the early hidden visual deficits of highly myopic patients, becoming a useful tool to evaluate the disease comprehensively.
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Inteligencia Artificial , Sensibilidad de Contraste , Fondo de Ojo , Tomografía de Coherencia Óptica , Humanos , Femenino , Masculino , Persona de Mediana Edad , Tomografía de Coherencia Óptica/métodos , Anciano , Sensibilidad de Contraste/fisiología , Agudeza Visual/fisiología , Adulto , Miopía Degenerativa/fisiopatología , Miopía Degenerativa/diagnóstico por imagen , Miopía Degenerativa/diagnóstico , Miopía Degenerativa/clasificación , Miopía Degenerativa/patología , Degeneración Macular/clasificación , Degeneración Macular/fisiopatología , Degeneración Macular/diagnóstico , Degeneración Macular/patología , Degeneración Macular/diagnóstico por imagen , Mácula Lútea/patología , Mácula Lútea/diagnóstico por imagen , Mácula Lútea/fisiopatología , Fibras Nerviosas/patologíaRESUMEN
The aim of this study was to evaluate the impact of COVID-19 on ocular diseases and changes in risk factors before and after the COVID-19 pandemic. This study was conducted using data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2015-2021, a national cross-sectional health examination and survey. Associations between ocular diseases and risk factors were determined using the chi-squared test and logistic regression analysis. Bivariable adjusted logistic regression analysis was performed to examine the odds ratio (OR) and 95% confidence interval (CI) to evaluate of the impact of COVID-19 on ocular diseases. Individuals were divided into two age groups (< 60 and ≥ 60 years). A total of 50,158 people were diagnosed, of whom 7270 were diagnosed with cataract, 921 with glaucoma, and 439 with age-related macular degeneration (AMD). Risk factors for cataract were COVID-19 pandemic (OR 1.161), hypertension (OR 1.608), diabetes (OR 1.573), dyslipidemia (OR 1.167), stroke (OR 1.272), and depression (OR 1.567). Risk factors for AMD were COVID-19 pandemic (OR 1.600), dyslipidemia (OR 1.610), and depression (OR 1.466). Risk factors for glaucoma were hypertension (OR 1.234), dyslipidemia (OR 1.529), diabetes (OR 1.323), and depression (OR 1.830). The COVID-19 pandemic was a risk factor for cataracts and AMD, but not for glaucoma. Cataracts and AMD may be more influenced by the acquired health conditions or the environment.
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COVID-19 , Catarata , Oftalmopatías , Glaucoma , Degeneración Macular , Humanos , COVID-19/epidemiología , Persona de Mediana Edad , Masculino , Femenino , República de Corea/epidemiología , Factores de Riesgo , Estudios Transversales , Anciano , Catarata/epidemiología , Oftalmopatías/epidemiología , Degeneración Macular/epidemiología , Adulto , Glaucoma/epidemiología , Encuestas Nutricionales , SARS-CoV-2/aislamiento & purificación , Pandemias , Anciano de 80 o más AñosRESUMEN
Subretinal injection (SR injection) is a commonly used method of ocular drug delivery and has been mainly applied for the treatment of neovascular age-associated macular degeneration (nAMD) and sub-macular hemorrhage (SMH) caused by nAMD, as well as various types of hereditary retinopathies (IRD) such as Stargardt's disease (STGD), retinitis pigmentosa (RP), and a series of fundus diseases such as Leber's congenital dark haze (LCA), choroidal defects, etc. The commonly used carriers of SR injection are mainly divided into viral and non-viral vectors. Leber's congenital amaurosis (LCA), choroidal agenesis, and a series of other fundus diseases are also commonly treated using SR injection. The commonly used vectors for SR injection are divided into two categories: viral vectors and non-viral vectors. Viral vectors are a traditional class of SR injection drug carriers that have been extensively studied in clinical treatment, but they still have many limitations that cannot be ignored, such as poor reproduction efficiency, small loading genes, and triggering of immune reactions. With the rapid development of nanotechnology in the treatment of ocular diseases, nanovectors have become a research hotspot in the field of non-viral vectors. Nanocarriers have numerous attractive properties such as low immunogenicity, robust loading capacity, stable structure, and easy modification. These valuable features imply greater safety, improved therapeutic efficacy, longer duration, and more flexible indications. In recent years, there has been a growing interest in nanocarriers, which has led to significant advancements in the treatment of ocular diseases. Nanocarriers have not only successfully addressed clinical problems that viral vectors have failed to overcome but have also introduced new therapeutic possibilities for certain classical disease types. Nanocarriers offer undeniable advantages over viral vectors. This review discusses the advantages of subretinal (SR) injection, the current status of research, and the research hotspots of gene therapy with viral vectors. It focuses on the latest progress of nanocarriers in SR injection and enumerates the limitations and future perspectives of nanocarriers in the treatment of fundus lesions. Furthermore, this review also covers the research progress of nanocarriers in the field of subretinal injection and highlights the value of nanocarrier-mediated SR injection in the treatment of fundus disorders. Overall, it provides a theoretical basis for the application of nanocarriers in SR injection.
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Portadores de Fármacos , Humanos , Animales , Portadores de Fármacos/química , Inyecciones Intraoculares , Retina , Enfermedades de la Retina/terapia , Enfermedades de la Retina/tratamiento farmacológico , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Degeneración Macular/terapiaRESUMEN
Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr-/- mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGFß2 induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGFß receptor I/II complex by interacting with unglycosylated TGFß receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFß2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.
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Carnitina O-Palmitoiltransferasa , Fibrosis , Degeneración Macular , Mitocondrias , Receptores de LDL , Epitelio Pigmentado de la Retina , Factor de Crecimiento Transformador beta2 , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Animales , Degeneración Macular/metabolismo , Degeneración Macular/patología , Degeneración Macular/genética , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/deficiencia , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta2/genética , Receptores de LDL/metabolismo , Receptores de LDL/genética , Receptores de LDL/deficiencia , Humanos , Ratones Noqueados , Transición Epitelial-Mesenquimal , Metabolismo Energético , Ratones Endogámicos C57BLRESUMEN
With the approval of the first two substances for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), a standardized monitoring of patients treated with complement inhibitors in clinical practice is needed. Optical coherence tomography (OCT) provides high-resolution access to the retinal pigment epithelium (RPE) and neurosensory layers, such as the ellipsoid zone (EZ), which further enhances the understanding of disease progression and therapeutic effects in GA compared to conventional fundus autofluorescence (FAF). In addition, artificial intelligence-based methodology allows the identification and quantification of GA-related pathology on OCT in an objective and standardized manner. The purpose of this study was to comprehensively evaluate automated OCT monitoring for GA compared to reading center-based manual FAF measurements in the largest successful phase 3 clinical trial data of complement inhibitor therapy to date. Automated OCT analysis of RPE loss showed a high and consistent correlation to manual GA measurements on conventional FAF. EZ loss on OCT was generally larger than areas of RPE loss, supporting the hypothesis that EZ loss exceeds underlying RPE loss as a fundamental pathophysiology in GA progression. Automated OCT analysis is well suited to monitor disease progression in GA patients treated in clinical practice and clinical trials.
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Atrofia Geográfica , Epitelio Pigmentado de la Retina , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Atrofia Geográfica/diagnóstico por imagen , Atrofia Geográfica/tratamiento farmacológico , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Anciano , Femenino , Masculino , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/patología , Progresión de la Enfermedad , Angiografía con Fluoresceína/métodos , Anciano de 80 o más Años , Fragmentos Fab de InmunoglobulinasRESUMEN
Mitochondrial malfunction, excessive production of reactive oxygen species (ROS), deficient autophagy/mitophagy, and chronic inflammation are hallmarks of age-related macular degeneration (AMD). Metformin has been shown to activate mitophagy, alleviate inflammation, and lower the odds of developing AMD. Here, we explored the ability of metformin to activate mitophagy and alleviate inflammation in retinal pigment epithelium (RPE) cells. Human ARPE-19 cells were pre-treated with metformin for 1 h prior to exposure to antimycin A (10 µM), which induced mitochondrial damage. Cell viability, ROS production, and inflammatory cytokine production were measured, while autophagy/mitophagy proteins were studied using Western blotting and immunocytochemistry. Metformin pre-treatment reduced the levels of proinflammatory cytokines IL-6 and IL-8 to 42% and 65% compared to ARPE-19 cells exposed to antimycin A alone. Metformin reduced the accumulation of the autophagy substrate SQSTM1/p62 (43.9%) and the levels of LC3 I and II (51.6% and 48.6%, respectively) after antimycin A exposure. Metformin also increased the colocalization of LC3 with TOM20 1.5-fold, suggesting active mitophagy. Antimycin A exposure increased the production of mitochondrial ROS (226%), which was reduced by the metformin pre-treatment (84.5%). Collectively, metformin showed anti-inflammatory and antioxidative potential with mitophagy induction in human RPE cells suffering from mitochondrial damage.
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Inflamación , Metformina , Mitocondrias , Mitofagia , Especies Reactivas de Oxígeno , Epitelio Pigmentado de la Retina , Metformina/farmacología , Humanos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Mitofagia/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Inflamación/patología , Inflamación/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Antimicina A/farmacología , Autofagia/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Degeneración Macular/patología , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismoRESUMEN
Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This study investigates the genetic factors associated with susceptibility to AMD and response to treatment, focusing on key polymorphisms in the ARMS2 (rs10490924), IL1B1 (rs1143623), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), VEGFA (rs3024997), ARMS2, IL1B1, TNFRSF1B, TNFRSF1A, and VEGFA serum levels in AMD development and treatment efficacy. This study examined the associations of specific genetic polymorphisms and serum protein levels with exudative and early AMD and the response to anti-VEGF treatment. The AA genotype of VEGFA (rs3024997) was significantly associated with a 20-fold reduction in the odds of exudative AMD compared to the GG + GA genotypes. Conversely, the TT genotype of ARMS2 (rs10490924) was linked to a 4.2-fold increase in the odds of exudative AMD compared to GG + GT genotypes. In females, each T allele of ARMS2 increased the odds by 2.3-fold, while in males, the TT genotype was associated with a 5-fold increase. Lower serum IL1B levels were observed in the exudative AMD group compared to the controls. Early AMD patients had higher serum TNFRSF1B levels than controls, particularly those with the GG genotype of TNFRSF1B rs1061622. Exudative AMD patients with the CC genotype of TNFRSF1A rs4149576 had lower serum TNFRSF1A levels compared to the controls. Visual acuity (VA) analysis showed that non-responders had better baseline VA than responders but experienced decreased VA after treatment, whereas responders showed improvement. Central retinal thickness (CRT) reduced significantly in responders after treatment and was lower in responders compared to non-responders after treatment. The T allele of TNFRSF1B rs1061622 was associated with a better response to anti-VEGF treatment under both dominant and additive genetic models. These findings highlight significant genetic and biochemical markers associated with AMD and treatment response. This study found that the VEGFA rs3024997 AA genotype reduces the odds of exudative AMD, while the ARMS2 rs10490924 TT genotype increases it. Lower serum IL1B levels and variations in TNFRSF1B and TNFRSF1A levels were linked to AMD. The TNFRSF1B rs1061622 T allele was associated with better anti-VEGF treatment response. These markers could potentially guide risk assessment and personalized treatment for AMD.
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Interleucina-1beta , Degeneración Macular , Polimorfismo de Nucleótido Simple , Receptores Tipo I de Factores de Necrosis Tumoral , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/sangre , Masculino , Femenino , Degeneración Macular/genética , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/sangre , Degeneración Macular/patología , Anciano , Interleucina-1beta/genética , Interleucina-1beta/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Anciano de 80 o más Años , Predisposición Genética a la Enfermedad , Persona de Mediana Edad , Genotipo , Alelos , Proteínas , Receptores Tipo II del Factor de Necrosis TumoralRESUMEN
Previous studies on the association between age-related macular degeneration (AMD) and rheumatoid arthritis (RA) have shown conflicting results. We sought to assess the association between AMD with/without visual disability (VD) and the risk of RA using National Health Insurance data in South Korea. In total, 3,537,293 individuals who underwent health checkups in 2009 were included and followed until 2019. Participants with VD were defined as those with loss of vision or a visual field defect as certified by the Ministry of Health and Welfare of Korea. Using multivariable adjusted Cox regression analysis, RA hazard ratios were estimated for control and AMD with/without VD groups. In total, 43,772 participants (1.24%) were diagnosed with RA. Individuals with AMD were at higher risk of RA compared to controls, regardless of the presence of VD (aHR 1.11; 95% CI 1.02-1.21). Among individuals with AMD, different risk levels of RA were observed between those without VD (aHR 1.13; 95% CI 1.03-1.21) and those with VD (aHR 0.90; 95% CI 0.64-1.27). AMD was associated with a higher risk of RA, which remained significant as a trend even after adjusting for lifestyle factors and comorbidities.
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Artritis Reumatoide , Degeneración Macular , Humanos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/complicaciones , Femenino , Degeneración Macular/epidemiología , Masculino , Persona de Mediana Edad , Estudios Longitudinales , Anciano , República de Corea/epidemiología , Factores de Riesgo , Comorbilidad , Modelos de Riesgos Proporcionales , AdultoRESUMEN
Oxidative damage to human retinal pigment epithelial (RPE) cells is the main cause of age-related macular degeneration (AMD), in our previous work, we showed that ghrelin has an antioxidative effect on human lens epithelium (HLE) cells, however, the studies of using ghrelin in treating the degenerative diseases of the retina have rarely been reported. In this article, we assessed the effect of ghrelin on preventing oxidative stress induced by hydrogen peroxide (H2O2) in ARPE-19 cells and its mechanism. We observed that pretreatment with ghrelin protected ARPE-19 cells from H2O2-induced cell oxidative injuries and apoptosis responses. Furthermore, an oxidative stress-induced mouse model of AMD was established via injection of sodium iodate (NaIO3) to tail veins, and treatment with ghrelin preserved retinal function, and protected photoreceptors.
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Apoptosis , Modelos Animales de Enfermedad , Ghrelina , Peróxido de Hidrógeno , Degeneración Macular , Estrés Oxidativo , Epitelio Pigmentado de la Retina , Estrés Oxidativo/efectos de los fármacos , Degeneración Macular/etiología , Degeneración Macular/metabolismo , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/prevención & control , Animales , Ghrelina/farmacología , Ghrelina/metabolismo , Humanos , Ratones , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/efectos de los fármacos , Línea Celular , Apoptosis/efectos de los fármacos , Yodatos , Antioxidantes/farmacología , Ratones Endogámicos C57BL , MasculinoRESUMEN
OBJECTIVES: Despite global research on early detection of age-related macular degeneration (AMD), not enough is being done for large-scale screening. Automated analysis of retinal images captured via smartphone presents a potential solution; however, to our knowledge, such an artificial intelligence (AI) system has not been evaluated. The study aimed to assess the performance of an AI algorithm in detecting referable AMD on images captured on a portable fundus camera. DESIGN, SETTING: A retrospective image database from the Age-Related Eye Disease Study (AREDS) and target device was used. PARTICIPANTS: The algorithm was trained on two distinct data sets with macula-centric images: initially on 108,251 images (55% referable AMD) from AREDS and then fine-tuned on 1108 images (33% referable AMD) captured on Asian eyes using the target device. The model was designed to indicate the presence of referable AMD (intermediate and advanced AMD). Following the first training step, the test set consisted of 909 images (49% referable AMD). For the fine-tuning step, the test set consisted of 238 (34% referable AMD) images. The reference standard for the AREDS data set was fundus image grading by the central reading centre, and for the target device, it was consensus image grading by specialists. OUTCOME MEASURES: Area under receiver operating curve (AUC), sensitivity and specificity of algorithm. RESULTS: Before fine-tuning, the deep learning (DL) algorithm exhibited a test set (from AREDS) sensitivity of 93.48% (95% CI: 90.8% to 95.6%), specificity of 82.33% (95% CI: 78.6% to 85.7%) and AUC of 0.965 (95% CI:0.95 to 0.98). After fine-tuning, the DL algorithm displayed a test set (from the target device) sensitivity of 91.25% (95% CI: 82.8% to 96.4%), specificity of 84.18% (95% CI: 77.5% to 89.5%) and AUC 0.947 (95% CI: 0.911 to 0.982). CONCLUSION: The DL algorithm shows promising results in detecting referable AMD from a portable smartphone-based imaging system. This approach can potentially bring effective and affordable AMD screening to underserved areas.
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Algoritmos , Aprendizaje Profundo , Degeneración Macular , Teléfono Inteligente , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/diagnóstico por imagen , Estudios Retrospectivos , Anciano , Fondo de Ojo , Femenino , Sensibilidad y Especificidad , Fotograbar/instrumentación , Masculino , Curva ROC , Persona de Mediana Edad , Tamizaje Masivo/métodos , Tamizaje Masivo/instrumentaciónRESUMEN
Purpose: To investigate the intraocular concentration profiles of stem cell factor (SCF)/c-KIT, galectin-1 (GAL-1), and vascular endothelial growth factor (VEGF)-A with regard to retinal disease and treatment response. Methods: The study group included 13 patients with dry age-related macular degeneration (AMD), 196 with neovascular AMD (nAMD), 21 with diabetic macular edema (DME), 10 with retinal vein occlusion (RVO), and 34 normal subjects with cataracts. Aqueous humor levels of SCF, c-KIT, GAL-1, and VEGF-A were analyzed by immunoassay according to disease group and treatment response. Results: Increased aqueous levels of SCF, c-KIT, and GAL-1 were observed in eyes with nAMD (2.67 ± 3.66, 296.84 ± 359.56, and 3945.61 ± 5976.2 pg/mL, respectively), DME (1.64 ± 0.89, 238.80 ± 265.54, and 3701.23 ± 4340.54 pg/mL, respectively), and RVO (4.62 ± 8.76, 509.63 ± 647.58, and 9079.60 ± 11909.20 pg/mL, respectively) compared with controls (1.13 ± 0.24, 60.00 ± 0.00, and 613.27 ± 1595.12 pg/mL, respectively). In the eyes of nAMD, the levels of all three cytokines correlated positively with VEGF-A levels. After intravitreal injections of anti-VEGF agents, the levels of GAL-1 and VEGF-A decreased significantly, whereas those of SCF and c-Kit showed no significant change. Eyes of nAMD patients with improved vision after treatment had significantly lower levels of c-KIT, GAL-1, and VEGF-A at baseline. Conclusions: The intraocular levels of cytokines were significantly elevated in eyes with nAMD, DME, and RVO compared to the controls and they showed different response to anti-VEGF treatment. With this result and their known association with angiogenesis, these cytokines may be potential therapeutic targets for future research.
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Galectina 1 , Proteínas Proto-Oncogénicas c-kit , Factor de Células Madre , Factor A de Crecimiento Endotelial Vascular , Humanos , Galectina 1/metabolismo , Factor de Células Madre/metabolismo , Masculino , Anciano , Femenino , Proteínas Proto-Oncogénicas c-kit/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Persona de Mediana Edad , Humor Acuoso/metabolismo , Anciano de 80 o más Años , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/tratamiento farmacológico , Edema Macular/metabolismo , Edema Macular/tratamiento farmacológico , Oclusión de la Vena Retiniana/metabolismo , Oclusión de la Vena Retiniana/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Degeneración Macular/metabolismo , Degeneración Macular/tratamiento farmacológico , Inyecciones IntravítreasRESUMEN
Age-related macular degeneration (AMD) is a leading cause of blindness. It is associated with peripheral drusen which has not been categorized. We investigated peripheral drusen to validate an image grading system and to understand possible associations between peripheral drusen and AMD. We collated clinical data, ultra-widefield (UWF) pseudocolor fundus images and Spectral-Domain Optical Coherence Tomography (SD-OCT) scans from consecutive retinal patients. SD-OCT scans were used to determine AMD stage. A masked retinal specialist recorded the types of peripheral drusen observed in UWF images. Eyes whose UWF images did not pass quality screening and those without AMD and peripheral drusen were excluded from the study. Statistical tests were utilized to determine the validity of our grading system and associations of peripheral drusen with AMD. A total of 481 eyes (283 subjects) were included in the study (mean age 73.1 ± 1.2years, 64.3% female). Interobserver and test-retest statistical analyses to evaluate the UWF image grading system resulted in Cohen's Kappa 0.649 (p < 0.001) and 0.922 (p < 0.001) respectively. A total of 284 (59.0%), 28 (5.8%), 15 (3.1%), 22 (4.6%), 4 (0.8%), 39 (8.1%), and 32 (6.7%) eyes had hard, soft, reticular, cuticular, atrophic, mixed drusen, and mixed drusen and atrophy respectively in at least one peripheral retinal quadrant. Hard peripheral drusen was significantly associated with the presence of AMD (p = 0.010). Peripheral drusen types were variably seen in retinal patients with and without AMD. We validated a peripheral drusen grading system and provided an image library to assist in the identification of peripheral drusen. Our study found an association between peripheral hard drusen and an AMD diagnosis but did not find a link between peripheral drusen and severity of AMD.
Asunto(s)
Degeneración Macular , Drusas Retinianas , Tomografía de Coherencia Óptica , Humanos , Femenino , Masculino , Drusas Retinianas/diagnóstico por imagen , Drusas Retinianas/patología , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/patología , Degeneración Macular/complicaciones , Anciano , Tomografía de Coherencia Óptica/métodos , Anciano de 80 o más Años , Retina/diagnóstico por imagen , Retina/patología , Índice de Severidad de la EnfermedadRESUMEN
Stargardt disease, one of the most common forms of inherited retinal diseases, affects individuals worldwide. The primary cause is mutations in the ABCA4 gene, leading to the accumulation of toxic byproducts in the retinal pigment epithelium (RPE) and subsequent photoreceptor cell degeneration. Over the past few years, research on Stargardt disease has advanced significantly, focusing on clinical and molecular genetics. Recent studies have explored various innovative therapeutic approaches, including gene therapy, stem cell therapy, and pharmacological interventions. Gene therapy has shown promise, particularly with adeno-associated viral (AAV) vectors capable of delivering the ABCA4 gene to retinal cells. However, challenges remain due to the gene's large size. Stem cell therapy aims to replace degenerated RPE and photoreceptor cells, with several clinical trials demonstrating safety and preliminary efficacy. Pharmacological approaches focus on reducing toxic byproduct accumulation and modulating the visual cycle. Precision medicine, targeting specific genetic mutations and pathways, is becoming increasingly important. Novel techniques such as clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 offer potential for directly correcting genetic defects. This review aims to synthesize recent advancements in understanding and treating Stargardt disease. By highlighting breakthroughs in genetic therapies, stem cell treatments, and novel pharmacological strategies, it provides a comprehensive overview of emerging therapeutic options.
Asunto(s)
Transportadoras de Casetes de Unión a ATP , Terapia Genética , Enfermedad de Stargardt , Enfermedad de Stargardt/genética , Humanos , Terapia Genética/métodos , Transportadoras de Casetes de Unión a ATP/genética , Mutación , Trasplante de Células Madre/métodos , Animales , Degeneración Macular/terapia , Degeneración Macular/genética , Degeneración Macular/congénito , Epitelio Pigmentado de la Retina/metabolismo , Sistemas CRISPR-CasRESUMEN
Glaucoma and age-related macular degeneration (AMD) are progressive retinal diseases characterized by increased oxidative stress, inflammation, and mitochondrial dysfunction. This review investigates the potential therapeutic benefits of NAD+ and niacin supplementation in managing glaucoma and AMD. A literature search was conducted encompassing keywords such as "niacin", "NAD", "glaucoma", "AMD", and "therapeutics". NAD+ depletion is associated with increased oxidative stress and mitochondrial dysfunction in glaucoma and AMD. Niacin, a precursor to NAD+, has shown promise in replenishing NAD+ levels, improving choroidal blood flow, and reducing oxidative damage. Animal studies in glaucoma models indicate that nicotinamide (NAM) supplementation preserves RGC density and function. Large-scale population-based studies indicate an inverse correlation between niacin intake and glaucoma prevalence, suggesting a preventative role. Randomized controlled trials assessing niacin supplementation showed significant improvements in visual field sensitivity and inner retinal function, with a dose-dependent relationship. In AMD, nicotinamide supplementation may improve rod cell function and protect against oxidative stress-induced damage. Cross-sectional studies reveal that individuals with AMD have a lower dietary intake of niacin. Further studies suggest niacin's role in improving choroidal blood flow and dilating retinal arterioles, potentially mitigating ischemic damage and oxidative stress in AMD. Beyond current management strategies, NAD+ and niacin supplementation may offer novel therapeutic avenues for glaucoma and AMD. Further research is warranted to elucidate their efficacy and safety in clinical settings.
Asunto(s)
Suplementos Dietéticos , Glaucoma , Degeneración Macular , NAD , Niacina , Estrés Oxidativo , Humanos , Niacina/administración & dosificación , Niacina/uso terapéutico , Niacina/farmacología , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/prevención & control , NAD/metabolismo , Glaucoma/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , AnimalesRESUMEN
Deep learning has potential to automate screening, monitoring and grading of disease in medical images. Pretraining with contrastive learning enables models to extract robust and generalisable features from natural image datasets, facilitating label-efficient downstream image analysis. However, the direct application of conventional contrastive methods to medical datasets introduces two domain-specific issues. Firstly, several image transformations which have been shown to be crucial for effective contrastive learning do not translate from the natural image to the medical image domain. Secondly, the assumption made by conventional methods, that any two images are dissimilar, is systematically misleading in medical datasets depicting the same anatomy and disease. This is exacerbated in longitudinal image datasets that repeatedly image the same patient cohort to monitor their disease progression over time. In this paper we tackle these issues by extending conventional contrastive frameworks with a novel metadata-enhanced strategy. Our approach employs widely available patient metadata to approximate the true set of inter-image contrastive relationships. To this end we employ records for patient identity, eye position (i.e. left or right) and time series information. In experiments using two large longitudinal datasets containing 170,427 retinal optical coherence tomography (OCT) images of 7912 patients with age-related macular degeneration (AMD), we evaluate the utility of using metadata to incorporate the temporal dynamics of disease progression into pretraining. Our metadata-enhanced approach outperforms both standard contrastive methods and a retinal image foundation model in five out of six image-level downstream tasks related to AMD. We find benefits in both a low-data and high-data regime across tasks ranging from AMD stage and type classification to prediction of visual acuity. Due to its modularity, our method can be quickly and cost-effectively tested to establish the potential benefits of including available metadata in contrastive pretraining.
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Aprendizaje Profundo , Metadatos , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Degeneración Macular/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Retina/diagnóstico por imagenRESUMEN
Purpose: Homozygous hypomorphic variants of the RP1 gene, including c.5797C>T, p.Arg1933Ter, have traditionally been considered non-pathogenic. This study aimed to elucidate the clinical manifestations of late-onset, slowly progressive cone/macular dystrophy in patients homozygous for p.Arg1933Ter in the RP1 gene. Methods: Five patients with biallelic p.Arg1933Ter in RP1 were retrospectively recruited, and their clinical profiles were analyzed. Copy number variation analysis and Alu insertion assessment of genes associated with inherited retinal diseases were conducted. The results of comprehensive ophthalmological examinations, multimodal imaging, and full-field electroretinogram tests were analyzed. Results: No specific sequencing errors or structural variations associated with the clinical phenotypes were identified. Alu element insertion in RP1 was not detected. The mean ± SD age at the first visit was 62.2 ± 9.8 years, with symptoms typically starting between 45 and 50 years of age. Two patients exhibited a mild form of cone/macular dystrophy, characterized by a relatively preserved fundus appearance and blurring of the ellipsoid zone on optical coherence tomography. Three patients had late-onset cone/macular dystrophy with significant atrophy. Conclusions: To our knowledge, this study is the first to report that a homozygous hypomorphic variant of RP1, previously considered non-pathogenic, leads to cone/macular dystrophy. Translational Relevance: The study introduces novel possibilities suggesting that the homozygous hypomorphic variant of RP1 may be linked to variant pathogenicity.
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Electrorretinografía , Proteínas del Ojo , Tomografía de Coherencia Óptica , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Proteínas del Ojo/genética , Agudeza Visual , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Distrofia del Cono/genética , Distrofia del Cono/diagnóstico por imagen , Degeneración Macular/genética , Degeneración Macular/patología , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/congénito , Linaje , Homocigoto , Fenotipo , Mutación , Adulto , Edad de Inicio , Proteínas Asociadas a MicrotúbulosRESUMEN
Purpose: To determine the reliability of a nine-point summary scale for grading intermediate age-related macular degeneration (AMD) image morphologic features based on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Methods: Two trained graders independently divided spectral domain-optical coherence tomography (SD-OCT) scans into nine subfields and then graded each subfield for the presence of intraretinal hyperreflective foci (HRF), reticular pseudodrusen (RPD), and incomplete or complete retinal pigment epithelium and outer retinal atrophy (iRORA or cRORA). Grading results were assessed by summing the subfield grades into a nine-point summary score and also by using an eye-level binary grade for presence of the finding in any subfield. Gwet's first-order agreement coefficient (AC1) was calculated to assess intergrader agreement. Results: Images of 79 eyes from 52 patients were evaluated. Intergrader agreement was higher when the OCT grades were summarized with a nine-point summary score (Gwet's AC1 0.92, 0.89, 0.99, and 0.99 for HRF, RPD, iRORA, and cRORA, respectively) compared with the eye-level binary grade (Gwet's AC1 0.75, 0.76, 0.97, and 0.96 for HRF, RPD, iRORA, and cRORA, respectively), with significant differences detected for HRF and RPD. Conclusions: The use of a nine-point summary score showed higher reliability in grading when compared to the binary subfield- and eye-level data, and thus may offer more precise estimation of AMD disease staging. Translational Relevance: These findings suggest that a nine-point summary score could be a useful means of disease staging by using findings on OCT in clinical studies of AMD.
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Degeneración Macular , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Anciano , Femenino , Masculino , Reproducibilidad de los Resultados , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/patología , Variaciones Dependientes del Observador , Persona de Mediana Edad , Anciano de 80 o más Años , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Drusas Retinianas/diagnóstico por imagen , Drusas Retinianas/patología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Occult Macular Dystrophy (OMD), primarily caused by retinitis pigmentosa 1-like 1 (RP1L1) variants, is a complex retinal disease characterised by progressive vision loss and a normal fundus appearance. This study aims to investigate the diverse phenotypic expressions and genotypic correlations of OMD in Chinese patients, including a rare case of Vitelliform Macular Dystrophy (VMD) associated with RP1L1. METHODS: We analysed seven OMD patients and one VMD patient, all with heterozygous pathogenic RP1L1 variants. Clinical assessments included Best Corrected Visual Acuity (BCVA), visual field testing, Spectral Domain Optical Coherence Tomography (SD-OCT), multifocal Electroretinograms (mfERGs), and microperimetry. Next-generation sequencing was utilised for genetic analysis. RESULTS: The OMD patients displayed a range of phenotypic variability. Most (5 out of 7) had the RP1L1 variant c.133 C > T; p.R45W, associated with central vision loss and specific patterns in SD-OCT and mfERG. Two patients exhibited different RP1L1 variants (c.3599G > T; p.G1200V and c.2880G > C; p.W960C), presenting milder phenotypes. SD-OCT revealed photoreceptor layer changes, with most patients showing decreased mfERG responses in the central rings. Interestingly, a unique case of VMD linked to the RP1L1 variant was observed, distinct from traditional OMD presentations. CONCLUSIONS: This study highlights the phenotypic diversity within OMD and the broader spectrum of RP1L1-associated macular dystrophies, including a novel association with VMD. The findings emphasise the complexity of RP1L1 variants in determining clinical manifestations, underscoring the need for comprehensive genetic and clinical evaluations in macular dystrophies.