Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration

We and others have shown that patients with different severity stages of age-related macular degeneration (AMD) have distinct plasma metabolomic profiles compared to controls. Urine is a biofluid that can be obtained non-invasively and, in other fields, urine metabolomics has been proposed as a feasible alternative to plasma biomarkers. However, no studies have applied urinary mass spectrometry (MS) metabolomics to AMD. This study aimed to assess urinary metabolomic profiles of patients with different stages of AMD and a control group. We included two prospectively designed, multicenter, cross-sectional study cohorts: Boston, US (n = 185) and Coimbra, Portugal (n = 299). We collected fasting urine samples, which were used for metabolomic profiling (Ultrahigh Performance Liquid chromatography-Mass Spectrometry). Multivariable logistic and ordinal logistic regression models were used for analysis, accounting for gender, age, body mass index and use of AREDS supplementation. Results from both cohorts were then meta-analyzed. No significant differences in urine metabolites were seen when comparing patients with AMD and controls. When disease severity was considered as an outcome, six urinary metabolites differed significantly (p < 0.01). In particular, two of the metabolites identified have been previously shown by our group to also differ in the plasma of patients of AMD compared to controls and across severity stages. While there are fewer urinary metabolites associated with AMD than plasma metabolites, this study identified some differences across stages of disease that support previous work performed with plasma, thus highlighting the potential of these metabolites as future biomarkers for AMD

Peripapillary and macular morpho-vascular changes in patients with genetic or clinical diagnosis of autosomal dominant optic atrophy : a case-control study

© Springer-Verlag GmbH Germany, part of Springer Nature 2019.Purpose: To evaluate the macular and peripapillary morpho-vascular changes in ADOA, using optical coherence tomography (OCT) and OCT angiography (OCTA). Methods: Prospectively defined, cross-sectional case-control study. Consecutive patients with a genetic or clinical diagnosis of ADOA along with age- and sex-matched controls were included. The radial peripapillary capillary (RPC) density and vessel density (VD) in the parafoveal superficial and deep capillary plexuses (SCP and DCP, respectively) were evaluated with OCTA. The ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL) thickness were determined using structural OCT. We applied a previously validated customized macro (Fiji, SciJava Consortium) to compute RPC density. The remaining parameters were calculated by the built-in software. Non-parametric methods were used for data analysis. The target α level was 0.05, which was adjusted through Bonferroni's correction when multiple outcomes were tested. Results: Fifty-eight eyes (n = 29 control; n = 29 ADOA) from 30 subjects (mean age 42.43 ± 15.30 years; 37.93% male) were included. Parafoveal SCP VD, GCC thickness, RPC VD in the temporal quadrant, as well as RNFL thickness in the nasal and temporal quadrants were decreased in ADOA eyes (all p < 0.001). When only patients with genetically confirmed diagnosis were included, capillary dropout in the circumpapillary superior and inferior quadrants also became evident (both p < 0.001). The GCC/parafoveal SCP ratio was increased in ADOA, relatively to matched controls. In contrast, none of the circumpapillary morpho-vascular ratios was significantly different in ADOA eyes. Conclusions: The microvascular and structural changes found in ADOA suggest that both the macular and peripapillary regions are involved, although the threshold for damage of the structural and vascular components may be different for each region. Larger series with longitudinal follow-up may validate OCTA biomarkers helpful for disease monitoring.info:eu-repo/semantics/publishedVersio

Real-World Results of Aflibercept versus Ranibizumab for the Treatment of Exudative AMD Using a Fixed Regimen

Intravitreal injections of antivascular endothelial growth factors have been considered a milestone in the treatment of neovascular age-related macular degeneration (nAMD). However, the increasing incidence of AMD and the burden of visits and injections overcharge both the patient and the healthcare systems. Real-world solutions depend on treatment protocols aimed at optimizing the number of clinical visits while guaranteeing good functional outcomes. We performed a retrospective analysis of 72 eyes from 63 naïve patients diagnosed with nAMD that underwent a fixed intravitreal protocol consisting of bimonthly injections after a three-month loading dose, with either Aflibercept or Ranibizumab (no predefined criteria for treatment selection). Best corrected visual acuity (BCVA) and optical coherence tomography were analyzed at baseline and during follow-up clinical visits (months 3, 6, 12, and 18). From the included participants, 42 followed a fixed regimen with Aflibercept and 30 with Ranibizumab. At the 12-month visit, there was not a statistically significant difference in the mean change of BCVA between the two groups (p=0.121); however, the mean difference in the central retinal thickness was significantly superior in the Aflibercept group (-142.2 versus -51.5, p=0.011). The described fixed regimen seems to be efficient in the treatment of nAMD in a clinical practice setting

Macular OCT-angiography parameters to predict the clinical stage of nonproliferative diabetic retinopathy: an exploratory analysis

© The Royal College of Ophthalmologists 2019Background: To test whether a single or a composite set of macular vascular density parameters, evaluated with optical coherence tomography angiography (OCTA), are able to predict nonproliferative diabetic retinopathy (NPDR) staging according to the gold-standard ETDRS-grading scheme. Methods: Prospectively defined, cross-sectional study in which macular structural and vascular parameters of diabetic eyes with nonproliferative DR (up to ETDRS Level 53) were evaluated with OCTA (Avanti RTVue-XR 100, Optovue Inc, Fremont, CA). Seven-field photographs of the fundus were taken for DR staging according to the ETDRS-grading scheme. The vessel density in the superficial and deep capillary plexus (SCP and DCP, respectively), as well as in the choriocapillaris (CC), were calculated using automated software. Univariate and multivariate ordered logistic regression models were used in the analysis. P < 0.05 was considered statistically significant. Results: We included 101 eyes from 56 subjects (mean (SD) age 62.64 (11.74) years; 57.4% were male). On univariate analysis, several OCTA parameters were found to be associated with higher ETDRS level (parafoveal SCP density: OR = 0.87 (95% CI 0.76-0.99), p = 0.039; parafoveal DCP density: OR = 0.79 (95% CI 0.72-0.87), p < 0.001; CC density: OR = 0.89 (95% CI 0.80-0.99)), p = 0.036). In the final model, while also adjusting for relevant clinical features, only parafoveal vessel density in the DCP remained as a significant predictor of NPDR ETDRS level (OR = 0.54 (95% CI 0.32-0.92), p = 0.024). Conclusion: Our results suggest that parafoveal vessel density in the DCP is the parameter most robustly associated with ETDRS level. OCTA analysis may provide objective imaging biomarkers to monitor NPDR clinical progression.info:eu-repo/semantics/publishedVersio

Peripapillary neurovascular coupling in the early stages of diabetic retinopathy

Copyright © 2019, Wolters Kluwer Health. Ophthalmic Communications Society, Inc.Purpose: To study radial peripapillary capillary (RPC) density in the early stages of diabetic retinopathy (DR), using optical coherence tomography angiography. Methods: A cross-sectional evaluation of RPCs was performed using optical coherence tomography angiography (Avanti RTVue-XR 100, Optovue Inc, Fremont, CA). Annular RPC density was the primary outcome. Global density and retinal nerve fiber layer thickness were secondary outcomes. Diabetic eyes were divided into three groups: no DR, mild nonproliferative DR (mild NPDR), and moderate NPDR. Multilevel mixed-effects univariate and multivariate linear regression models were used. Results: We included 155 eyes (n = 42 control; n = 27 no DR; n = 28 mild NPDR; and n = 58 moderate NPDR) from 86 subjects (mean [SD] age 63.39 [10.70] years; 46.45% male). When compared with controls, a significant decrease in annular RPC density was found in all groups of diabetic eyes on multivariate analysis (no DR: β = -2.95, P < 0.001; mild NPDR: β = -1.76, P = 0.017; and moderate NPDR: β = -2.82, P < 0.001). We also detected a significant decrease in retinal nerve fiber layer thickness in diabetic eyes (even in the no DR group). Furthermore, in diabetic eyes, annular RPC density and retinal nerve fiber layer thickness correlated significantly (R = 0.4874, P < 0.001). Conclusion: Peripapillary neurovascular changes occur early in the course of DR. Their significance in the progression of DR warrants further research.info:eu-repo/semantics/publishedVersio

Risk of Second Tumors in Retinoblastoma Survivors after Ionizing Radiation: A Review

Retinoblastoma (RB) is the most common ocular neoplasm in children, whose development depends on two mutational events that occur in both alleles of the retinoblastoma susceptibility gene (RB1). Regarding the nature of these mutational events, RB can be classified as hereditary if the first event is a germline mutation and the second one is a somatic mutation in retina cells or nonhereditary if both mutational events occur in somatic cells. Although the rate of survival of RB is significantly elevated, the incidence of second malignant neoplasms (SMNs) is a concern, since SMNs are the main cause of death in these patients. Effectively, RB patients present a higher risk of SMN incidence compared to other oncology patients. Furthermore, evidence confirms that hereditary RB survivors are at a higher risk for SMNs than nonhereditary RB survivors. Over the decades, some studies have been performed to better understand this subject, evaluating the risk of the development of SMNs in RB patients. Furthermore, this risk seems to increase with the use of ionizing radiation in some therapeutic approaches commonly used in the treatment of RB. This review aims to clarify the effect of ionizing radiation in RB patients and to understand the association between the risk of SMN incidence in patients that underwent radiation therapy, especially in hereditary RB individuals

sj-doc-1-ejo-10.1177_11206721231172534 - Supplemental material for Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus

Supplemental material, sj-doc-1-ejo-10.1177_11206721231172534 for Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus by Rosa L. Pinheiro, Andreia M. Rosa, Tiago Monteiro, João Q. Gil, Ana Esmeralda Costa, Cristina Tavares, Maria João Quadrado and Joaquim N. Murta in European Journal of Ophthalmology</p

sj-doc-3-ejo-10.1177_11206721231172534 - Supplemental material for Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus

Supplemental material, sj-doc-3-ejo-10.1177_11206721231172534 for Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus by Rosa L. Pinheiro, Andreia M. Rosa, Tiago Monteiro, João Q. Gil, Ana Esmeralda Costa, Cristina Tavares, Maria João Quadrado and Joaquim N. Murta in European Journal of Ophthalmology</p

sj-doc-2-ejo-10.1177_11206721231172534 - Supplemental material for Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus

Supplemental material, sj-doc-2-ejo-10.1177_11206721231172534 for Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus by Rosa L. Pinheiro, Andreia M. Rosa, Tiago Monteiro, João Q. Gil, Ana Esmeralda Costa, Cristina Tavares, Maria João Quadrado and Joaquim N. Murta in European Journal of Ophthalmology</p

Human Plasma Metabolomics in Age-Related Macular Degeneration: Meta-Analysis of Two Cohorts

The pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness worldwide, remains only partially understood. This has led to the current lack of accessible and reliable biofluid biomarkers for diagnosis and prognosis, and absence of treatments for dry AMD. This study aimed to assess the plasma metabolomic profiles of AMD and its severity stages with the ultimate goal of contributing to addressing these needs. We recruited two cohorts: Boston, United States (n = 196) and Coimbra, Portugal (n = 295). Fasting blood samples were analyzed using ultra-high performance liquid chromatography mass spectrometry. For each cohort, we compared plasma metabolites of AMD patients versus controls (logistic regression), and across disease stages (permutation-based cumulative logistic regression considering both eyes). Meta-analyses were then used to combine results from the two cohorts. Our results revealed that 28 metabolites differed significantly between AMD patients versus controls (false discovery rate (FDR) q-value: 4.1 × 10-2-1.8 × 10-5), and 67 across disease stages (FDR q-value: 4.5 × 10-2-1.7 × 10-4). Pathway analysis showed significant enrichment of glycerophospholipid, purine, taurine and hypotaurine, and nitrogen metabolism (p-value ≤ 0.04). In conclusion, our findings support that AMD patients present distinct plasma metabolomic profiles, which vary with disease severity. This work contributes to the understanding of AMD pathophysiology, and can be the basis of future biomarkers and precision medicine for this blinding condition