Ophthalmology. 2020 Mar 29.
Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study).
Glassman AR, Wells JA 3rd, Josic K, Maguire MG, Antoszyk AN, Baker C, Beaulieu WT, Elman MJ, Jampol LM, Sun JK.
PURPOSE: Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial.
DESIGN: Multicenter cohort study.
PARTICIPANTS: Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion).
METHODS: Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit.
MAIN OUTCOME MEASURES: Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST).
RESULTS: Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 μm (95% CI, 142-166) and was stable between 2 and 5 years (-1 μm; 95% CI, -12 to 9).
CONCLUSIONS: Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.
PMID: 32402554 DOI: 10.1016/j.ophtha.2020.03.021
Graefes Arch Clin Exp Ophthalmol. 2020 May 12.
Beneficial switch from aflibercept to ranibizumab for the treatment of refractory neovascular age-related macular degeneration.
Marquis LM, Mantel I.
PURPOSE: The aim of this study was to evaluate the effects of switching to ranibizumab in patients with neovascular age-related macular degeneration (nAMD) refractory to aflibercept treatment and to identify predictive factors for switch response.
METHODS: A retrospective chart review was conducted including 32 eyes from 26 patients with refractory nAMD, who switched from monthly intravitreal aflibercept treatment (≥ 6 months) to ranibizumab. Outcome measures included changes in visual acuity (VA), intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), and central retinal thickness (CRT), evaluated at 6 months before switch (T1), at the time of switch (T2), and 3 months post-switch (T3).
RESULTS: There was an increase in CRT from T1 to T2, which decreased after switch from T2 to T3. Regression analysis of the changes per month observed between time points showed significant differences in PED height (p = 0.02), SRF (p = 0.01), and neuroretinal thickness as a measure for IRF (p = 0.03). No significant change was found for VA. Predictive factors for better switch response included an exacerbation between T1 and T2, thicker measurements at T2, male sex, shorter treatment duration before switch, and fewer preceding injections. No association with preceding switch was found.
CONCLUSION: Patients with nAMD refractory to aflibercept benefit from switching to ranibizumab, particularly those whose condition worsened prior to the switch. This may be explained by drug tolerance to aflibercept. Our findings may facilitate making appropriate treatment decisions, potentially improving patient outcomes.
PMID: 32399582 DOI: 10.1007/s00417-020-04730-8
Drugs Today (Barc). 2020 May;56(5):311-320.
An update on conbercept to treat wet age-related macular degeneration.
Ferro Desideri L, Traverso CE, Nicolò M.
Wet age-related macular degeneration (w-AMD) represents the main cause of vision loss in the elderly in the western countries. The important role displayed by vascular endothelial growth factor (VEGF) in the pathogenesis of this disease has been largely demonstrated. For this reason, anti-VEGF drugs have been developed and currently are considered as the first-line treatment options in the management of w-AMD. Among the novel anti-VEGF agents studied, conbercept is a fusion protein composed of the combination between VEGF receptor domains with the Fc fragment of human immunoglobulin. It was already approved in China in 2014 for treating w-AMD. In this regard, the phase III PHOENIX trial has reported a good clinical efficacy and safety profile of conbercept for w-AMD, also by adopting a quarterly regimen. In this review, we will discuss its pharmacokinetics, pharmacodynamics, clinical efficacy, without neglecting also its safety and tolerability profile.
PMID: 32406878 DOI: 10.1358/dot.2020.56.5.3137164
Ophthalmol Retina. 2020 Feb 27.
Timing of Peak Vision Gains in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab.
Khurana RN, Chang L, Day BM, Ghanekar A, Stoilov I.
PURPOSE: To investigate whether time to peak best-corrected visual acuity (BCVA) was predictive of magnitude of BCVA changes at study end in patients with neovascular age-related macular degeneration (nAMD) who received ranibizumab and assess whether patient baseline characteristics and on-study events were predictive of time to peak BCVA.
DESIGN: Exploratory analysis of data from HARBOR (ClinicalTrials.gov identifier, NCT00891735).
PARTICIPANTS: Treatment-naïve patients 50 years of age or older with subfoveal nAMD.
METHODS: Data by ranibizumab dose were pooled; data by dosing schedule (pro re nata [PRN] and monthly) were evaluated separately. Time to peak BCVA was the monthly evaluation at which the patient's greatest gain in Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline was achieved. Early peakers achieved peak BCVA between day 7 and month 6; late peakers achieved peak BCVA between months 7 and 12, months 13 and 18, and months 19 and 24. Variables evaluated for effect of time to peak BCVA included baseline demographic and clinical characteristics, presence of persistent subretinal fluid (SRF) or intraretinal fluid (IRF), and on-study events (atrophy status, fibrosis, retinal pigment epithelium tears).
MAIN OUTCOME MEASURES: Time to peak BCVA and its predictive value for magnitude of BCVA changes and BCVA at month 24 (study end).
RESULTS: Most patients reached peak BCVA after more than 6 months of treatment: 64% in the PRN group (301/474) and 70% in the monthly groups (327/469). Thirty-six percent and 30% of patients, respectively, peaked early, and 64% and 70%, respectively, peaked late. At month 24, early peakers on average lost vision (PRN, -1.6 ETDRS letters; monthly, -1.9 ETDRS letters). By contrast, late peakers achieved significantly better vision gains from baseline (PRN, 8.5-17.7 ETDRS letters; monthly, 10.1-18.7 ETDRS letters). No differences were found in patient characteristics, persistent SRF or IRF, or on-study events to account for the observed different outcomes between early and late peakers.
CONCLUSIONS: In most treatment-naïve patients with nAMD, vision gains were achieved at a slower rate (>6 months), and a slower response was associated with better vision outcomes after 24 months of ranibizumab. These findings suggest that continued treatment may result in greater vision improvements when consistent anti-vascular endothelial growth factor therapy is maintained over a longer period.
PMID: 32387055 DOI: 10.1016/j.oret.2020.02.011
DIAGNOSIS & IMAGING
Ophthalmology. 2020 Apr 2.
Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration.
Sadda SR, Abdelfattah NS, Lei J, Shi Y, Marion KM, Morgenthien E, Gune S, Balasubramanian S.
PURPOSE: To identify baseline risk factors for macular atrophy (MA) development in HARBOR via a longitudinal assessment of monthly spectral-domain (SD)-OCT scans. Previous analyses of MA in HARBOR examined data from color fundus photography (CFP) and fluorescein angiography (FA).
DESIGN: Retrospective, post hoc analysis of SD-OCT images from HARBOR (ClinicalTrials.gov identifier, NCT00891735), a phase 3, multicenter, prospective, randomized, double-blind, active treatment-controlled clinical trial.
PARTICIPANTS: Patients (N = 1097) with subfoveal choroidal neovascularization secondary to neovascular age-related macular degeneration (nAMD) treated with intravitreal ranibizumab 0.5 mg monthly (n = 275), 0.5 mg pro re nata (PRN) after 3 loading doses (n = 275), 2.0 mg monthly (n = 274), or 2.0 mg PRN (n = 273).
METHODS: Evaluable SD-OCT macular cube scans from patients with 24 months of follow-up (N = 941) were examined monthly from baseline to month 24 by masked reading center-trained graders. Atrophy diagnosis criteria were consistent with those proposed by the Classification of Atrophy Meetings (CAM) group: hypertransmission of light into the choroid, loss of retinal pigment epithelium, and loss of outer retinal layers. Multivariable proportional hazards regression was performed for time to atrophy development.
MAIN OUTCOME MEASURES: Risk factors for MA as determined by time to MA development over 24 months of treatment.
RESULTS: Baseline risk factors for MA were confirmed from prior analyses that used CFP and FA data: absence of subretinal fluid, presence of intraretinal cysts, presence of Type 3 neovascularization, and presence of atrophy in the fellow eye. This analysis of SD-OCT data identified new baseline risk factors for MA: higher central drusen volume, lower choroidal thickness, presence of nascent atrophy, presence of reticular pseudodrusen, and increased central foveal thickness. Ranibizumab treatment regimen and dose level were not found to be risk factors for MA development.
CONCLUSIONS: In this analysis of a major nAMD trial using CAM atrophy criteria, new baseline risk factors for MA development were identified using an SD-OCT dataset. Risk factors for MA development identified by prior analyses were confirmed. Monthly treatment with ranibizumab 0.5 mg was not found to be a risk factor for MA development over 24 months.
PMID: 32402555 DOI: 10.1016/j.ophtha.2020.03.031
Ophthalmol Retina. 2020 May 7.
Hyperreflective foci and specks are associated with delayed rod-mediated dark adaptation in non-neovascular age-related macular degeneration.
Echols BS, Clark ME, Swain TA, Chen L, Kar D, Zhang Y, Sloan KR, McGwin G Jr, Singireddy R, Mays C, Kilpatrick D, Crosson JN, Owsley C, Curcio CA.
PURPOSE: Hyperreflective foci (HRF) are optical coherence tomography (OCT) biomarkers for progression of non-neovascular age-related macular degeneration (AMD) attributed to anteriorly migrated retinal pigment epithelial (RPE) cells. We examined associations between rod- and cone-mediated vision and HRF plus smaller hyperreflective specks (HRS); we sought a histologic candidate for HRS.
DESIGN: cross-sectional study; histologic survey
PARTICIPANTS: Patients with normal maculas (n=34), early AMD (N=26), and intermediate AMD (N=41)
METHODS: AMD severity was determined via the 9-step Age-Related Eye Disease Study scale. In OCT scans HRF and HRS were manually counted. Vision tests probed cones (best corrected visual acuity (VA), contrast sensitivity), mixed cones and rods (low luminance VA, low luminance deficit, mesopic light sensitivity), or rods (scotopic light sensitivity, rod-mediated dark adaptation (RMDA)). An online AMD histopathology resource was reviewed.
MAIN OUTCOME MEASURES: Vision in eyes assessed for HRF and HRS; candidate histology for HRS.
RESULTS: In 101 eyes of 101 patients, HRF and HRS were identified in 25 and 95 eyes, respectively, with good intra- and inter-rater reliability. HRF were present but sparse in normal eyes, infrequent in early AMD eyes, and frequent but highly variable among intermediate AMD eyes (number per eye, 0.1±0.2, 0.2±0.5, 1.9 ± 3.4; normal, early, intermediate, respectively). HRS outnumbered HRF in all groups (4.5 ± 3.2; 6.3±5.8; 19.4 ± 22.4). Delayed RMDA was strongly associated with more HRF and HRS (both p<0.0001). HRF were also associated with worse low luminance VA (p=0.0117). HRS were associated with worse contrast sensitivity (p=0.0278), low luminance VA (p=0.0010), low luminance deficit (p=0.0031), and mesopic (p=0.0018) and scotopic sensitivity (p<0.0001). By histology, cone lipofuscin was found in inner segments, and the outer nuclear and Henle fiber layers of 25% of normal aged eyes.
CONCLUSIONS: HRF and HRS are markers of cellular activity associated with visual dysfunction, especially delayed RMDA, an AMD risk indicator assessing efficiency of retinoid re-supply. HRS may represent lipofuscin granules translocating inwardly within cone photoreceptors. Visible and quantifiable on SD-OCT, HRF and HRS may serve as structural endpoints in clinical trials targeting AMD stages earlier than atrophy expansion. These results should be confirmed in a larger sample.
PMID: 32389889 DOI: 10.1016/j.oret.2020.05.001
J Ophthalmol. 2020 Jan 13;2020:7493419.
Multimodal Retinal Image Analysis via Deep Learning for the Diagnosis of Intermediate Dry Age-Related Macular Degeneration: A Feasibility Study.
Vaghefi E, Hill S, Kersten HM, Squirrell D.
RESULTS: The CNN trained using OCT alone showed a diagnostic accuracy of 94%, whilst the OCT-A trained CNN resulted in an accuracy of 91%. When multiple modalities were combined, the CNN accuracy increased to 96% in the AMD cohort.
CONCLUSIONS: Here we demonstrate that superior diagnostic accuracy can be achieved when deep learning is combined with multimodal image analysis.
PMID: 32411434 PMCID: PMC7201607 DOI: 10.1155/2020/7493419
Graefes Arch Clin Exp Ophthalmol. 2020 May 14.
Dimple in vascularized serous pigment epithelial detachment secondary to neovascular age-related macular degeneration.
Capuano V, Sacconi R, Borrelli E, Miere A, Gelormini F, Farci R, Bandello F, Souied EH, Querques G.
BACKGROUND: To describe the "dimple," a previously unreported structural optical coherence tomography (OCT) finding in vascularized serous pigment epithelial detachment (PED) secondary to neovascular age-related macular degeneration (AMD).
METHODS: Retrospective, longitudinal, case series study. Clinical charts and multimodal imaging including OCT (structural and angiography) and dye-based angiography (fluorescein and indocyanine green) examinations of patients with dimple-defined as a localized invagination of the vascularized serous PED-were analyzed in 2 high-volume referral centers.
RESULTS: Nineteen eyes of 18 patients were included. Mean follow-up was at 64.1 ± 35.8 months. The greater basal and height diameters of the vascularized serous PED were respectively 3425.8 ± 1049.6 μm and 667.1 ± 279.9 μm at baseline and 3076.2 ± 1649.9 μm (p = 0.8) and 368.3 ± 295.1 at last follow-up (p = 0.0006). OCT analysis identified 2 phenotypes of dimple: type 1 or ("top denting") (9 eyes) and type 2 (or "side denting") (10 eyes). Both phenotypes are associated with hyper-reflective holding sub-retinal pigment epithelium (RPE) band encompassing the posterior face of the RPE and extending to the Bruch's membrane. Hyper-reflective holding band is not correlated with angiographic signs of neovascular tissue in all cases. During follow-up, no case of RPE tear was observed.
CONCLUSIONS: We describe the characteristics of the dimple and its association with hyper-reflective holding sub-RPE bands in the context of large vascularized serous PED in neovascular AMD. The presence of a dimple does not seem to be an additional risk factor for the development of RPE tearing in high-risk PED secondary to neovascular AMD.
PMID: 32409980 DOI: 10.1007/s00417-020-04732-6
Eye (Lond). 2020 May 12.
Predictive factors for exudation of quiescent choroidal neovessels detected by OCT angiography in the fellow eyes of eyes treated for a neovascular age-related macular degeneration.
Solecki L, Loganadane P, Gauthier AS, Simonin M, Puyraveau M, Delbosc B, Saleh M.
BACKGROUND: To identify predictive factors for exudation for quiescent choroidal neovessels (qCNV) in the fellow eyes of eyes treated for a neovascular age-related macular degeneration (AMD).
METHODS: Prospective observational study. One hundred and forty-four contralateral eyes of 144 patients treated for wet AMD were analysed. At a baseline visit, multimodal imaging including dye angiographies and optical coherence tomography angiography (OCT-A) was performed in order to detect qCNV. Patients were followed up for 12 months with a monthly assessment. The manifestation of any type of exudation (either intra- or subretinal fluid or hyperreflective subretinal material) was monitored.
RESULTS: The prevalence of qCNV in the treatment-naive eyes was 15.9% with an incidence over a 12-month period of 2.8%. In total, 40.7% of the overall neovessels remained stable with no sign of exudation, while 59.3% presented some fluid during the follow-up. A statistically significant relationship was established for the following variables preceding the exudation: increase in central macular thickness (OR = 116; 95% CI [4.74; 50530] p = 0.038), increase in pigment epithelial detachment height (OR = 1.76; 95% CI [1.17; 3.18] p = 0.021) and width (OR = 1.53; 95% CI [1.12; 2.62] p = 0.042), increase in neovessels' surface on OCT-A (OR = 6.32; 95% CI [1.62; 51.0] p = 0.033), emergence of a branching pattern (OR = 7.50; 95% CI[1.37; 61.5] p = 0.032) and appearance of a hypointense halo surrounding the lesion (OR = 10.00; 95% CI [1.41; 206] p = 0.048).
CONCLUSIONS: The risk of exudation in the treatment-naive fellow eyes of eyes treated for neovascular AMD was notably increased in the presence of qCNV. The biomarkers identified will help to detect their activation in order to ensure prompt antiangiogenic therapy.
PMID: 32398845 DOI: 10.1038/s41433-020-0936-7
Invest Ophthalmol Vis Sci. 2020 May 11;61(5):11.
Macular Functional and Morphological Changes in Intermediate Age-Related Maculopathy.
Parisi V, Ziccardi L, Costanzo E, Tedeschi M, Barbano L, Manca D, Di Renzo A, Giorno P, Varano M, Parravano M.
PURPOSE: The purpose of this study was to evaluate macular preganglionic function and to verify its relationship with retinal and choroidal morphology in patients with intermediate age-related macular degeneration (iAMD) patients.
METHODS: All included patients performed multifocal electroretinogram (mfERG) for investigating on macular function from the central 15° of foveal eccentricity, spectral domain optical coherence tomography (SD-OCT) for studying retinal structure, enhanced depth imaging OCT (EDI-OCT) for the measure of choroidal vascularity index (CVI), and OCT-angiography (OCTA) for the evaluation of vessel density (VD) in the superficial and deep capillary plexus, and choriocapillaris (CC) layer.
RESULTS: Twenty-seven patients with iAMD and 20 age-matched control eyes were analyzed. Significantly (P < 0.01) delayed and reduced mfERG responses in the central 0 to 2.5°, paracentral 2.5 to 5°, and overall 0 to 5° areas, as well as increased CVI values in both foveal (1 mm centered to the fovea) and fovea + parafovea areas (3 mm centered to the fovea), increased foveal and parafoveal (annular area of 1-3 mm centered to the fovea) retinal pigment epithelium thickness, and volume and parafoveal outer retinal volume were found in iAMD eyes as compared to controls. Moreover, iAMD eyes showed significantly (P < 0.01) reduced foveal and parafoveal OCTA-VD values in the CC layer when compared to controls. In the iAMD group, not significant (P > 0.01) correlations were found between morphological and functional parameters.
CONCLUSIONS: Our findings support a dysfunction of photoreceptors and bipolar cells in both foveal and parafoveal areas in the presence of outer retina, CC, and choroidal structural changes, however, not significantly correlated. The observed enlargement of luminal choroidal area (measured by CVI) is possibly compensatory to CC vascular insufficiency.
PMID: 32396630 DOI: 10.1167/iovs.61.5.11
Invest Ophthalmol Vis Sci. 2020 May 11;61(5):19.
Functional Evaluation of AMD-Associated Risk Variants of Complement Factor B.
Pilotti C, Greenwood J, Moss SE.
PURPOSE: The 32W and 32Q variants of complement factor B (CFB) are associated with reduced risk of developing neovascular age-related macular degeneration (AMD) compared with the common 32R allele. The objective of this study was to determine if the most protective R32Q variant affects the neovascular process in a manner consistent with the reported reduced disease association.
METHODS: The 32R, 32W, and 32Q human CFB variants were expressed in human embryonic kidney 293T cells and purified from culture supernatant. The ex vivo mouse fetal metatarsal explant model was used to investigate the effect of these three human CFB variants on angiogenesis. Metatarsal bones were isolated from mouse embryos and cultured in the presence of the three CFB variants, and angiogenesis was measured following immunostaining of fixed samples. ELISAs were used to quantify C3 and VEGF protein levels in metatarsal culture and quantitative PCR to measure Cfb, C3, and Vegf expression.
RESULTS: We show here that the three CFB variants have different biological activities in the mouse metatarsal assay, with CFBR32 exhibiting significantly greater angiogenic activity than CFBQ32 or CFBW32, which were broadly similar. We also observed differences in macrophage phenotype with these two variants that may contribute to their activities in this experimental model.
CONCLUSIONS: We have demonstrated that the biological activities of CFBR32, CFBW32, and CFBQ32 are consistent with their AMD risk association, and we provide functional evidence of roles for these variants in angiogenesis that may be relevant to the pathogenesis of the neovascular form of AMD.
PMID: 32407521 DOI: 10.1167/iovs.61.5.19
Ophthalmic Genet. 2020 May 14:1-7.
Association of combined complement factor H Y402H and ARMS2/LOC387715 A69S polymorphisms with age-related macular degeneration: an updated meta-analysis.
Jabbarpoor Bonyadi MH, Yaseri M, Soheilian M.
Background: Complement factor H (CFH) Y402 H (rs1061170) and age-related maculopathy susceptibility2 (ARMS2)/LOC387715 A69 S (rs10490924) polymorphisms shown to have significant association with AMD. In this meta-analysis, we updated and pooled the results of available association studies between combined ARMS2/LOC387715A69 S-CFHY402 H genotypes and AMD to estimate the synergistic effects.
Methods: Heterogeneity of studies was evaluated using Cochran Q-test and I-square index. To modify the heterogeneity in the variables we used random effects model. Meta-analysis was performed using STATA. To estimate the additive or supra-additive effects we calculated RERI (relative excess risk due to interaction), AP (attributable proportion due to interaction), S (synergy index) and V (multiplicative index).
Results: We included 12 studies with 4668 AMD patients and 4936 control subjects. Considering the GGTT genotypes as reference line, the pooled AMD odds ratios for stratified combined genotypes was 2.13 (95% CI 1.64-2.78) for GGnonTT, 2.17 (95% CI 1.63-2.89) for nonGGTT and 7.23 (95% CI 4.95-10.55) for nonGGnonTT. Pooled synergy analysis revealed RERI = 3.90 (95% CI 0.58-10.03), AP = .53 (95% CI 0.09-0.69), S = 2.57 (95% CI 1.27-5.22) and V = 1.47 (95% CI 1.21-1.80).
Conclusion: This updated analysis showed a strong synergistic and positive multiplicative effect of these two genes indicating that there is common pathway of ARMS2/LOC387715 A69 S and CFH Y402 H in AMD pathogenesis which may be complement system pathway.
PMID: 32406777 DOI: 10.1080/13816810.2020.1765396
Cells. 2020 May 11;9(5).
Genome-Wide Transcriptomic Analysis Identifies Pathways Regulated by Sterculic Acid in Retinal Pigmented Epithelium Cells.
Pariente A, Pérez-Sala Á, Ochoa R, Peláez R, Larráyoz IM.
In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment of various diseases. Sterculic acid (SA) is a cyclopropene fatty acid with numerous biological activities, generally attributed to its Stearoyl-CoA desaturase (SCD) inhibitory properties. Additional effects exerted by SA, independently of SCD inhibition, may be mediating anti-inflammatory and protective roles in retinal diseases such as age-related macular degeneration (AMD), but the mechanisms involved are poorly understood. In order to provide insights into those mechanisms, genome-wide transcriptomic analyses were carried out in mRPE cells exposed to SA for 24 h. Integrative functional enrichment analysis of genome-wide expression data provided biological insight about the protective mechanisms induced by SA. On the one hand, pivotal genes related to fatty acid biosynthesis, steroid biosynthesis, cell death, actin-cytoskeleton reorganization and extracellular matrix-receptor interaction were significantly downregulated by exposition to SA. On the other hand, genes related to fatty acid degradation and beta-oxidation were significantly upregulated. In conclusion, SA administration to RPE cells regulates crucial pathways related to cell proliferation, inflammation and cell death that may be of interest for the treatment of ocular diseases.
PMID: 32403229 DOI: 10.3390/cells9051187
Exp Eye Res. 2020 May 6;196:108061.
CXCR5/NRF2 double knockout mice develop retinal degeneration phenotype at early adult age.
Huang H, Lennikov A.
The objective of this study is to characterize the retinal degeneration (RD) phenotype of CXCR5/NRF2 double knockout (DKO) mice at the early adult age. CXCR5 KO mice and NRF2 KO mice were bred to create CXCR5/NRF2 DKO mice. The assessment of RD features included fundus and optical coherence tomography (OCT) imaging, periodic acid-Schiff (PAS), and immunofluorescence staining of retinal pigment epithelium (RPE)-choroid flatmounts. Stained samples were imaged with fluorescent microscopy, and Western blots were used to monitor protein expression changes. The staining of cleaved caspase-3 and PNA-lectin was performed to assess the presence of photoreceptor cell apoptosis. Quantification and statistical analyses were performed with Image J and Graphpad software. The young adult (2-6 months) DKO mice exhibited increased hypopigmented spots on fundus and sub-RPE abnormalities on OCT as compared to the CXCR5-KO mice, and C57BL6 WT controls. PAS-stained sections demonstrated aberrant RPE/sub-RPE depositions. The DKO mice had increased sub-RPE depositions of IgG and AMD-associated proteins (β-amyloid, Apolipoprotein-E, C5b-9, and αB-crystallin). The protein expression of AMD-associated proteins and microglia marker (TMEM119) were upregulated at the RPE/BM/choroid complex of DKO mice. The adult DKO mice underwent photoreceptor cell apoptosis compared to the single CXCR5 and NRF2 KO and the WT mice at an early adult age. Mechanistically increased expression of CXCL13 and N-cadherin was observed as a sign of epithelial-mesenchymal transition. The data suggest that the CXCR5/NRF2-DKO mice develop RD characteristics at an early age and may serve as a valuable animal model of RD.
PMID: 32387618 DOI: 10.1016/j.exer.2020.108061
Nutrients. 2020 May 7;12(5).
Why is Zeaxanthin the Most Concentrated Xanthophyll in the Central Fovea?
Widomska J, SanGiovanni JP, Subczynski WK.
Diet-based xanthophylls (zeaxanthin and lutein) are conditionally essential polar carotenoids preferentially accreted in high concentrations (1 mM) to the central retina, where they have the capacity to impart unique physiologically significant biophysical biochemical properties implicated in cell function, rescue, and survival. Macular xanthophylls interact with membrane-bound proteins and lipids to absorb/attenuate light energy, modulate oxidative stress and redox balance, and influence signal transduction cascades implicated in the pathophysiology of age-related macular degeneration. There is exclusive transport, sequestration, and appreciable bioamplification of macular xanthophylls from the circulating carotenoid pool to the retina and within the retina to regions required for high-resolution sensory processing. The distribution of diet-based macular xanthophylls and the lutein metabolite meso-zeaxanthin varies considerably by retinal eccentricity. Zeaxanthin concentrations are 2.5-fold higher than lutein in the cone-dense central fovea. This is an ~20-fold increase in the molar ratio relative to eccentric retinal regions with biochemically detectable macular xanthophylls. In this review, we discuss how the differences in the specific properties of lutein and zeaxanthin could help explain the preferential accumulation of zeaxanthin in the most vulnerable region of the macula.
PMID: 32392888 DOI: 10.3390/nu12051333
Ophthalmic Genet. 2020 May 13:1-4.
Cystoid macular edema precipitated by altitude in a patient with X-linked retinitis pigmentosa.
Zhao PY, Hovland PG, Fahim AT.
Background: X-linked retinitis pigmentosa (XLRP) is a hereditary retinopathy that may present with cystoid macular edema (CME). The exact cause of CME in XLRP is unknown. We describe a case report of new-onset CME precipitated by travel to high altitude in an adult with XLRP, but no known prior history of CME.
Case Description: A 38-year-old man with XLRP caused by a hemizygous pathogenic variant in RPGR (c.372del; p.Glu125fs) reported sudden onset bilateral blurry vision 4 days after ascending to an altitude of 3,700 m. He sought local ophthalmic care and was found to have severe bilateral CME. He was treated with topical and oral carbonic anhydrase inhibition and instructed to return to normal altitude. Follow-up imaging at normal altitude revealed that the CME was nearly completely resolved 4 days after initial presentation, and completely resolved 2 weeks after initial presentation.
Conclusion: Vascular and metabolic changes caused by retinal degeneration in XLRP may predispose to the development of CME under the hypoxic conditions experienced at high altitudes. We advise that retinal specialists treating patients with RP should caution them on traveling to high altitudes that could precipitate or exacerbate CME.
PMID: 32400255 DOI: 10.1080/13816810.2020.1762901