Participation des facteurs nutritionnels et environnementaux au vieillissement de la rétine et aux rétinopathies liées à l'âge

Chez l Homme, le vieillissement de la rétine peut aboutir à des pathologies telles que la dégénérescence maculaire liée à l âge (DMLA) ou la rétinopathie diabétique (RD). Il semble qu une alimentation riche en acides gras polyinsaturés à longue chaîne (AGPI-LC), notamment en oméga-3 comme l EPA et le DHA, soit potentiellement protecteur vis-à-vis du développement de la DMLA et de l insulinorésistance (IR), principal facteur de risque de la RD. Dans ce contexte, nous avons tenter d évalué 1- l impact de facteurs endogènes et environnementaux générateurs de stress oxydatif, de produits terminaux de glycation (PTG) ou d insulinorésistance sur la fonction et le vieillissement de la rétine, et 2- l adaptation de la rétine à un régime riche en AGPI-LC oméga-3 dans modèle murin de vieillissement de la rétine humaine, la souris ApoB100,LDLR-/-.Les animaux soumis à un stress oxydatif et à des PTG présentent une altération de la fonction rétinienne associée à une accumulation de cellules microgliales et/ou macrophages dans la rétine externe. L IR induit une modulation de gènes impliqués dans le métabolisme des lipides, l inflammation et dans la synthèse de facteurs nucléaires. Une alimentation riche en AGPI-LC oméga-3 induit une amélioration de l incorporation d acides gras oméga-3 dans la rétine et la modulation du gène codant le récepteur aux LDL dans la rétine neurosensorielle.En conclusion, nos travaux montrent une adaptation de la rétine d une part à des conditions propices au vieillissement de la rétine et l insulinorésistance, et d autre part à un régime alimentaire riche en acides gras oméga-3 et pauvre en oméga-6, reconnu comme protecteur du vieillissement de la rétineWith advanced age, aging of the human retina can evolve into pathological forms, age-related macular degeneration (AMD) or diabetic retinopathy (DR). Meanwhile, epidemiological studies suggest that a diet rich in long-chain omega-3 polyunsaturated fatty acids (LC-PUFA) such as EPA and DHA, potentially protects against the development of AMD and insulin resistance, the main risk factor for DR. Within this context, our research objectives were to assess: 1 - the impact of endogen and environmental factors, known to trigger oxidative stress, advanced glycation end-products (AGEs) or insulin resistance, on the function and aging of the retina, and 2 - the response of the retina to a omega-3 LC-PUFA-enriched diet in a murine model of aging of the human retina, the ApoB100,LDLR-/- mouse.The animals exposed to oxidative stress and AGEs showed an alteration of the retinal function associated with an accumulation of microglial cells and/or macrophages in the outer retina. The insulin resistance induced a modulation of the expression of genes coding proteins involved in lipid metabolism, inflammation and nuclear factors. An omega-3 LC-PUFA-enriched diet improved the incorporation of omega-3 LC-PUFA in the retina and modulated the expression of the LDL-receptor gene in the neurosensory retina.In conclusion, our works reported the adaptive response of the retina to environmental and endogenous factors known to promote aging of the retina. It included the impairment of the retinal function, and the modulation of gene expression. Our data also gave a better understanding of the effects of omega-3 LC-PUFA against aging of the retinaDIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Involvement of plasmalogens in post-natal retinal vascular development

Objective: Proper development of retinal blood vessels is essential to ensure sufficient oxygen and nutrient supplies to the retina. It was shown that polyunsaturated fatty acids (PUFAs) could modulate factors involved in tissue vascularization. A congenital deficiency in ether-phospholipids, also termed "plasmalogens'', was shown to lead to abnormal ocular vascularization. Because plasmalogens are considered to be reservoirs of PUFAs, we wished to improve our understanding of the mechanisms by which plasmalogens regulate retinal vascular development and whether the release of PUFAs by calcium-independent phospholipase A2 (iPLA2) could be involved. [br/]Methods and Results: By characterizing the cellular and molecular steps of retinal vascular development in a mouse model of plasmalogen deficiency, we demonstrated that plasmalogens modulate angiogenic processes during the early phases of retinal vascularization. They influence glial activity and primary astrocyte template formation, endothelial cell proliferation and retinal vessel outgrowth, and impact the expression of the genes involved in angiogenesis in the retina. These early defects led to a disorganized and dysfunctional retinal vascular network at adult age. By comparing these data to those obtained on a mouse model of retinal iPLA2 inhibition, we suggest that these processes may be mediated by PUFAs released from plasmalogens and further signalling through the angiopoietin/tie pathways. [br/]Conclusions: These data suggest that plasmalogens play a crucial role in retinal vascularization processes

Incidence, Risk Factors, and Outcomes of Rhegmatogenous Retinal Detachment after Intravitreal Injections of Anti-VEGF for Retinal Diseases: Data from the Fight Retinal Blindness! Registry

PURPOSE To report the estimated incidence, probability, risk factors, and 1-year outcomes of rhegmatogenous retinal detachment (RRD) in eyes receiving intravitreal injections (IVTs) of VEGF inhibitors for various retinal conditions in routine clinical practice. DESIGN Retrospective analysis of data from a prospectively designed observational outcomes registry: the Fight Retinal Blindness! PROJECT PARTICIPANTS Eyes of patients starting IVTs of VEGF inhibitors (ranibizumab, aflibercept, or bevacizumab) for neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion from January 1, 2006, to December 31, 2020. All eyes that developed RRD within 90 days of IVTs were defined as cases with RRD and were matched with control eyes. METHODS Estimated incidence, probability, and hazard ratios (HRs) of RRD were measured using Poisson regression, Kaplan-Meier survival curve, and Cox proportional hazards models. Locally weighted scatterplot smoothing curves were used to compare visual acuity (VA) between cases and matched controls. MAIN OUTCOME MEASURES Estimated incidence of RRD. RESULTS We identified 16 915 eyes of 13 792 patients who collectively received 265 781 IVTs over 14 years. Thirty-six eyes were reported to develop RRD over the study period. The estimated incidence (95% confidence interval [CI]) per year per 1000 patients and per 10 000 injections was 0.77 (0.54-1.07) and 1.36 (0.95-1.89), respectively. The probability of RRD did not significantly increase at each successive injection (P = 0.95) with the time of follow-up. Older patients (HR [95% CI] = 1.81 [1.21-3.62] for every decade increase in age, P < 0.01) were at a higher risk of RRD, whereas patients with good presenting VA (HR [95% CI] = 0.85 [0.70-0.98] for every 10-letter increase in VA, P = 0.02) were at a lower risk. Neither the type of retinal disease (P = 0.52) nor the VEGF inhibitor (P = 0.09) was significantly associated with RRD risk. Cases with RRD lost 3 lines of vision on average compared with the prior RRD VA and had significantly fewer injections than matched controls over the year after the RRD. CONCLUSIONS Rhegmatogenous retinal detachment is a rare complication of VEGF inhibitor IVT in routine clinical practice with poor visual outcomes at 1 year

Primary open-angle glaucoma: association with cholesterol 24S-hydroxylase (CYP46A1) gene polymorphism and plasma 24-hydroxycholesterol levels

Purpose. Genetics has made significant contributions to the study of glaucoma over the past few decades. Cholesterol-24S-hydroxylase (CYP46A1) is a cholesterol-metabolizing enzyme that is especially expressed in retinal ganglion cells. CYP46A1 and its metabolic product, 24S-hydroxycholesterol, have been linked to neurodegeneration. A single-nucleotide polymorphism (SNP) in the CYP46A1 gene, designated as rs754203 and associated with Alzheimer disease, was evaluated as a genetic risk factor for primary open-angle glaucoma (POAG), as well as plasma 24S-hydroxycholesterol levels. Methods. The frequency of the CYP46*C and CYP46*T alleles was analyzed in 150 patients with POAG and 118 control subjects. Plasma 24S-hydroxycholesterol levels were quantified. Sex, age, alleles, and genotype frequencies between patients with POAG and control subjects were compared by using the {chi}2 and Student's t-tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression to assess the relative association between disease and age, sex, and genotypes. Results. The frequency of the TT genotype was significantly higher in patients with POAG than in control subjects (61.3% versus 48.3%, respectively, OR = 1.26; 95% CI = 1.006–1.574, P < 0.05). Plasma 24S-hydroxycholesterol levels did not differ between control subjects and patients with POAG. The ratio of estimated brain weight to liver volume as an estimate of the capacity of the human body to synthesize and metabolize 24S-hydroxycholesterol was found to correlate to plasma 24S-hydroxycholesterol in control subjects and patients with POAG. Conclusions. The rs754203 SNP in CYP46A1 was associated with a risk for POAG. This polymorphism was not associated with changes in plasma 24S-hydroxycholesterol, highlighting that despite its retinal origin, 24S-hydroxycholesterol cannot be used as a biomarker for POAG

Erythrocyte phospholipid and polyunsaturated fatty acid composition in diabetic retinopathy

Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans. Methodology and Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids. Conclusions and Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines

Nutrition in ophthalmology – Clinical application to age-related macular degeneration

« Let food be your medicine. » This contribution from Hippocrates is still timely addressed, especially in the field of ophthalmology. Observational epidemiology reports close associations between food habits and the risk or prevention of several ocular pathologies such as cataract or Age-related Macular Degeneration (AMD). Anti-oxidant vitamins, minerals and lipids are the nutrients that have been the most widely studied. Interventional epidemiology and experimental works partially corroborated these findings. Unexpectedly, the benefit of long chain omega 3 polyunsaturated fatty acids in the prevention of late AMD was not firmly established in Age-Related Eye Disease Study 2 (AREDS2). Nevertheless, one should not omit to refer to well established data in this field. Still, further works are needed and warranted, especially for better delineating the role of, not only nutrients but also dietary habits, and gene-nutrients interactions.« Que ton aliment soit ta seule médecine ». Cette citation d'Hippocrate est d'actualité aujourd'hui, plus encore qu'hier et particulièrement en ophtalmologie. L'épidémiologie observationnelle rapporte des associations solides entre alimentation et risque ou prévention de certaines pathologies oculaires, comme la cataracte ou la Dégénérescence Maculaire Liée à l'Âge (DMLA). Vitamines anti-oxydantes, minéraux et lipides sont les nutriments qui ont été les plus étudiés. L'épidémiologie interventionnelle et la recherche expérimentale ont permis de corroborer un certain nombre de ces observations. De façon plus inattendue, le bénéfice d'une supplémentation en acides gras oméga 3 à longue chaîne dans la prévention de l'évolution de la DMLA vers ses formes avancées n'a pas été retrouvé dans l'étude AREDS2 (Age-Related Eye Disease Study 2). Sans vouer aux gémonies plusieurs décennies de travaux dans ce domaine, les problématiques de la nutrition en ophtalmologie sont encore porteuses de découvertes et d'espoirs, en particulier lorsque l'on considère le cadre plus large de l'alimentation et des relations gènes-nutriments

Three-year treatment outcomes of Aflibercept versus Ranibizumab for diabetic macular edema:: Data from the Fight Retinal Blindness! Registry

PURPOSE Compare the 3-year outcomes of ranibizumab versus aflibercept in eyes with diabetic macular edema in daily practice. METHODS This was a retrospective analysis of naive diabetic macular edema eyes starting intravitreal injections of ranibizumab (0.5 mg) or aflibercept (2 mg) from January 1, 2013 to December 31, 2017 that were collected in the Fight Retinal Blindness! Registry. RESULTS We identified 534 eyes (ranibizumab-267 and aflibercept-267) of 402 patients. The adjusted mean (95% confidence interval) visual acuity change of +1.3 (-0.1 to 4.2) letters in the ranibizumab group and +2.4 (-0.2 to 5.1) letters (P = 0.001) in the aflibercept group at 3 years was not clinically different. However, the adjusted mean CST change seemed to remain significantly different throughout the 3-year period with higher reductions in favor of aflibercept (-87.8 [-108.3 to -67.4] µm for ranibizumab vs. -114.4 [-134.4 to -94.3] for aflibercept; P < 0.01). When baseline visual impairment was moderate (visual acuity ≤68 Early Treatment Diabetic Retinopathy Study letters), we found a faster improvement in visual acuity in eyes treated with aflibercept up until 18 months of treatment than eyes treated with ranibizumab, which then stayed similar until 36 months of treatment, whereas there was no apparent difference when baseline visual impairment was mild (visual acuity ≥69 Early Treatment Diabetic Retinopathy Study letters). The rate of serious adverse events was low. CONCLUSION Aflibercept and ranibizumab were both effective and safe for diabetic macular edema over 3 years

Incidence, risk factors and outcomes of submacular haemorrhage with loss of vision in neovascular age-related macular degeneration in daily clinical practice: data from the FRB! registry

PURPOSE The main purpose of the study was to report the estimated incidence, cumulative rate, risk factors and outcomes of submacular haemorrhage (SMH) with loss of vision in neovascular age-related macular degeneration (nAMD) receiving intravitreal injections (IVT) of vascular endothelial growth factor (VEGF) inhibitor in routine clinical practice. METHODS Retrospective analysis of treatment-naïve eyes receiving IVTs of VEGF inhibitors (ranibizumab, aflibercept or bevacizumab) for nAMD from 1 January 2010 to 31 December 2020 that were tracked the Fight Retinal Blindness! registry. Estimated incidence, cumulative rate and hazard ratios (HR) of SMH with loss of vision during treatment were measured using the Poisson regression, Kaplan-Meier survival curves and Cox proportional hazard models. RESULTS We identified 7642 eyes (6425 patients) with a total of 135 095 IVT over a 10-year period. One hundred five eyes developed SMH with loss of vision with a rate of 1 per 1283 injections (0.08% 95% confidence interval [95% CI] [0.06; 0.09]). The estimated incidence [95% CI] was 4.6 [3.8; 5.7] SMH with loss of vision per year per 1000 treated patients during the study. The cumulative [95% CI] rate of SMH per patient did not increase significantly with each successive injection (p = 0.947). SMH cases had a mean VA drop of around 6 lines at diagnosis, which then improved moderately to a 4-line loss at 1 year. CONCLUSIONS Submacular haemorrhage (SMH) with loss of vision is an uncommon complication that can occur at any time in eyes treated for nAMD in routine clinical practice, with only limited recovery of vision 1 year later

Vascular endothelial growth factor inhibitors for predominantly Caucasian myopic choroidal neovascularization: 2-year treatment outcomes in clinical practice: data from the Fight Retinal Blindness! Registry

Purpose: To report the 24-month outcomes of vascular endothelial growth factor (VEGF) inhibitors for myopic choroidal neovascularization (mCNV) in predominantly Caucasian eyes in routine clinical practice. Methods: Retrospective analysis of treatment-na¿ıve eyes starting intravitreal injection of VEGF inhibitors of either bevacizumab (1.25 mg) or ranibizumab (0.5 mg) for mCNV from 1 January 2006 to 31 May 2018 that were tracked in the Fight Retinal Blindness! registry. Results: We identified 203 eyes (bevacizumab-85 and ranibizumab-118) of 189 patients. The estimated mean (95% CI) change in VA over 24 months for all eyes using longitudinal models was +8 (5, 11) letters with a median (Q1, Q3) of 3 (2, 5) injections given mostly during the first year. The estimated mean change in VA at 24 months was similar between bevacizumab and ranibizumab [+9 (5, 13) letters for bevacizumab versus +9 (6, 13) letters for ranibizumab; p = 0.37]. Both agents were also similar in the mCNV activity outcomes, treatment frequency and visit frequency. Conclusions: The 24-month treatment outcomes of VEGF inhibitors for mCNV were favourable in this largest series yet reported of predominantly Caucasian eyes in routine clinical practice,with approximately two lines of visual gain and amedian of three injections given mostly during the first year. These outcomes are similar to those reported for predominantly Asian eyes.Bevacizumab appeared to be as safeandeffective as ranibizumab. Key words: anti-VEGF therapy - Caucasian - high myopia - myopia - myopic choroidal neovascularization - optical coherence tomography - pathologic myopia - VEGF inhibitor

Conjunctival Proinflammatory and Proapoptotic Effects of Latanoprost and Preserved and Unpreserved Timolol: An Ex Vivo and In Vitro Study

PURPOSE. To compare the toxicity of latanoprost and preserved and unpreserved timolol on conjunctival cells. Expression of inflammatory markers and MUC5AC-related mucin production were evaluated by impression cytology in a case-control ex vivo study. The proapoptotic effect of the same drugs was also evaluated in vitro in a conjunctival cell line and compared with that of benzalkonium chloride (BAC). METHODS. Impression cytology (IC) specimens were obtained from a series of normal subjects and from patients with glaucoma treated for at least 1 year with latanoprost eye drops or preserved or unpreserved timolol. All groups were comparable in age and duration of treatment. Expression of HLA-DR, intercellular adhesion molecule (ICAM)-1, and mucin was evaluated in a masked manner by flow cytometry. For the in vitro study, a human conjunctiva-derived cell line was treated with 0.02% BAC-containing latanoprost or timolol, unpreserved timolol, or 0.02% BAC alone for 15 minutes, followed or not by 4 or 24 hours of cell recovery in normal medium. Cell viability and chromatin condensation were evaluated using microplate cold light cytofluorometry with the neutral red and the Hoechst 33342 tests, respectively. The Hoechst-neutral red ratio was defined for the apoptosis assay, and cytoskeleton changes were assessed by confocal microscopy. RESULTS. No difference was found between normal eyes and those receiving unpreserved timolol. Preserved latanoprost and timolol significantly increased the inflammatory marker expression and decreased MUC5AC expression, but to a significantly higher extent in the preserved timolol group compared with latanoprost. In vitro, 0.02% BAC-containing timolol and latanoprost triggered conjunctival cell apoptosis-however, to a significantly lesser extent than did 0.02% BAC alone. Unpreserved timolol did not cause any cell toxicity. CONCLUSIONS. These ex vivo and in vitro studies demonstrate that BAC-containing latanoprost and timolol exhibit higher proinflammatory and proapoptotic effects on conjunctival cells than does unpreserved timolol. Latanoprost caused less toxicity, however, than preserved timolol, and both drugs were less toxic than BAC alone. These results suggest a potential protective effect of the prostaglandin analogue and to a lesser extent of timolol against the toxicity of BAC in conjunctival cells. (Invest Ophthalmol Vis Sci