Background & aimsInflammation is involved in the pathogenesis of cataract, age-related macular degeneration (AMD), and possibly open-angle glaucoma (OAG). We assessed whether the inflammatory... Show moreBackground & aimsInflammation is involved in the pathogenesis of cataract, age-related macular degeneration (AMD), and possibly open-angle glaucoma (OAG). We assessed whether the inflammatory potential of diet (quantified using the dietary inflammatory index; DII) affects the incidence of these common blinding age-related eye diseases. Serum inflammation markers were investigated as possible mediators.MethodsParticipants aged >45 years were selected from the prospective, population-based Rotterdam Study. From 1991 onwards, every 4–5 years, participants underwent extensive eye examinations. At baseline, blood samples and dietary data (using food frequency questionnaires) were collected. The DII was adapted based on the data available. Of the 7436 participants free of eye diseases at baseline, 4036 developed incident eye diseases during follow-up (cataract = 2895, early-intermediate AMD = 891, late AMD = 81, OAG = 169).ResultsThe adapted DII (aDII) ranged from −4.26 (i.e., anti-inflammatory) to 4.53 (i.e., pro-inflammatory). A higher aDII was significantly associated with increased inflammation. A higher neutrophil-lymphocyte ratio (NLR) was associated with an increased risk of cataract and AMD. Additionally, complement component 3c (C3c) and systemic immune-inflammation index (SII) were associated with increased risks of cataract and late AMD, respectively. Every point increase in the aDII was associated with a 9% increased risk of cataract (Odds ratio [95% confidence interval]: 1.09 [1.04–1.14]). The NLR and C3c partly mediated this association. We also identified associations of the aDII with risk of AMD (early-intermediate AMD, OR [95% CI]: 1.11 [1.03–1.19]; late AMD, OR [95% CI]: 1.24 [1.02–1.53]). The NLR partly mediated these associations. The aDII was not associated with OAG.ConclusionsA pro-inflammatory diet was associated with increased risks of cataract and AMD. Particularly the NLR, a marker of subclinical inflammation, appears to be implicated. These findings are relevant for patients with AMD and substantiate the current recommendations to strive for a healthy lifestyle to prevent blindness. Show less
Purpose: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies.Methods: A longitudinal questionnaire study included 22 patients... Show morePurpose: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies.Methods: A longitudinal questionnaire study included 22 patients with pathogenic CRB1 variants. The National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year follow-up, and 4-year follow-up. Classical test theory was performed to obtain subdomain scores and in particular 'near activities' and 'total composite' scores. The Rasch analysis based on previous calibrations of the NEI VFQ-25 was applied to create visual functioning and socio-emotional subscales.Results: In total, 22 patients with pathogenic CRB1 variants were included, with a median age of 25.0 years (IQR: 13-31 years) at baseline and mean followup of 4.0 +/- 0.3 years. A significant decline at 4 years was observed for 'near activities' (51.0 +/- 23.8 vs 35.4 +/- 14.7, p = 0.004) and 'total composite' (63.0 +/- 13.1 vs 52.0 +/- 12.1, p = 0.001) subdomain scores. For the Rasch-scaled scores, the 'visual functioning' scale significantly decreased after 4 years (- 0.89 logits; p = 0.012), but not at 4-year follow-up (+0.01 logits; p = 0.975). The 'socio- emotional' scale also showed a significant decline after 2 years (-0.78 logits, p = 0.033) and 4 years (- 0.83 logits, p = 0.021).Conclusion: In the absence of an intervention, a decline in vision-related quality of life is present in patients with pathogenic CRB1 variants at 4-year follow-up. Patient-reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy. Show less
IMPORTANCE Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients.OBJECTIVE To identify the genes and pathways associated with... Show moreIMPORTANCE Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients.OBJECTIVE To identify the genes and pathways associated with idiopathic MFC.DESIGN, SETTING, AND PARTICIPANTS This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022.MAIN OUTCOMES AND MEASURES Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients.RESULTS This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 x 10(-9)). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P =.002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 x 10(-8)). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 x 10(-3)) and proteins involved in platelet activation and the complement cascade.CONCLUSIONS AND RELEVANCE Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC. Show less
Uveal melanomas (UM) are detected earlier. Consequently, tumors are smaller, allowing for novel eye-preserving treatments. This reduces tumor tissue available for genomic profiling. Additionally,... Show moreUveal melanomas (UM) are detected earlier. Consequently, tumors are smaller, allowing for novel eye-preserving treatments. This reduces tumor tissue available for genomic profiling. Additionally, these small tumors can be hard to differentiate from nevi, creating the need for minimally invasive detection and prognostication. Metabolites show promise as minimally invasive detection by resembling the biological phenotype. In this pilot study, we determined metabolite patterns in the peripheral blood of UM patients (n = 113) and controls (n = 46) using untargeted metabolomics. Using a random forest classifier (RFC) and leave-one-out cross-validation, we confirmed discriminatory metabolite patterns in UM patients compared to controls with an area under the curve of the receiver operating characteristic of 0.99 in both positive and negative ion modes. The RFC and leave-one-out cross-validation did not reveal discriminatory metabolite patterns in high-risk versus low-risk of metastasizing in UM patients. Ten-time repeated analyses of the RFC and LOOCV using 50% randomly distributed samples showed similar results for UM patients versus controls and prognostic groups. Pathway analysis using annotated metabolites indicated dysregulation of several processes associated with malignancies. Consequently, minimally invasive metabolomics could potentially allow for screening as it distinguishes metabolite patterns that are putatively associated with oncogenic processes in the peripheral blood plasma of UM patients from controls at the time of diagnosis. Show less
Age-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for... Show moreAge-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for clinical management include recommendations for a healthy lifestyle and antioxidant supplementation. However, many ophthalmologists do not inform their patients of this AMD-beneficial lifestyle. An important reason is the lack of trust that transition of lifestyle will be feasible in persons of advanced age and lack of methodology to measure lifestyle or its biological effects. To address these issues, we set up the lifestyle intervention study AMD-Life. It aims to investigate whether personalized risk-profiling (including genetic testing) and/or additional coaching can motivate patients to change their lifestyle. It also explores which biomarkers best reflect lifestyle change beneficial for AMD. The first year is a three-arm, self-contained open-label randomized clinical trial. A total of 150 AMD patients aged 55-85 years were randomized into three arms: (A) merely standard recommendations; (B) A conditions plus personalized risk profiling based on genetics and lifestyle, (C) B conditions plus coaching. The second year tests sustainability of lifestyle changes without active intervention. AMD-Life can provide further insight into the relevance of these interventions for the clinical management of AMD. Show less
Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient... Show moreObjective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials.Design: International, multicenter, retrospective cohort study.Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral -domain OCT [SD-OCT], fundus autofluorescence).Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 0.712, P < 0.001, respectively) in those with CORD.Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long pres-ervation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Show less
Purpose: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS).Design: Retrospective cohort study.Participants: Three hundred forty patients with... Show morePurpose: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS).Design: Retrospective cohort study.Participants: Three hundred forty patients with XLRS from 178 presumably unrelated families.Methods: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence).Main Outcome Measures: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings.Results: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's rho = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G -> A (p.(G1u72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]).Conclusions: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found. (C) 2021 by the American Academy of Ophthalmology. Show less
Purpose To investigate the retinal structure and function in patients with CRB1-associated retinal dystrophies (RD) and to explore potential clinical endpoints.Methods In this prospective cross... Show morePurpose To investigate the retinal structure and function in patients with CRB1-associated retinal dystrophies (RD) and to explore potential clinical endpoints.Methods In this prospective cross-sectional study, 22 patients with genetically confirmed CRB1-RD (aged 6-74 years), and who had a decimal best-corrected visual acuity (BCVA) >= 0.05 at the last visit, were studied clinically with ETDRS BCVA, corneal topography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, Goldmann visual field (VF), microperimetry, full-field electroretinography (ERG) and full-field stimulus testing (FST). Ten patients were from a genetic isolate (GI).Results Patients had retinitis pigmentosa (n = 19; GI and non-GI), cone-rod dystrophy (n = 2; GI) or macular dystrophy (n = 1; non-GI). Median age at first symptom onset was 3 years (range 0.8-49). Median decimal BCVA in the better and worse-seeing eye was 0.18 (range 0.05-0.83) and 0.08 (range light perception-0.72), respectively. Spectral-domain optical coherence tomography (SD-OCT) showed cystoid maculopathy in 8 subjects; inner retinal thickening (n = 20), a well-preserved (para)foveal outer retina (n = 7) or severe (para)foveal outer retinal atrophy (n = 14). All retinal layers were discernible in 13/21 patients (62%), with mild to moderate laminar disorganization in the others. Nanophthalmos was observed in 8 patients (36%). Full-field stimulus testing (FST) provided a subjective outcome measure for retinal sensitivity in eyes with (nearly) extinguished ERG amplitudes.Conclusions Despite the generally severe course of CRB1-RDs, symptom onset and central visual function are variable, even at advanced ages. Phenotypes may vary within the same family. Imaging and functional studies in a prospective longitudinal setting should clarify which endpoints may be most appropriate in a clinical trial. Show less
Nguyen, X.T.A.; Talib, M.; Cauwenbergh, C. van; Schooneveld, M.J. van; Fiocco, M.; Wijnholds, J.; ... ; Boon, C.J.F. 2021
Purpose: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). Methods: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP.... Show morePurpose: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). Methods: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. Results: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20 degrees) and blindness (central visual field <10 degrees), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 <= BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's rho = 0.733; P < 0.001). Conclusion: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies. Show less
Purpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as... Show morePurpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways.Design: Case-control association analysis of metabolomics data.Participants: Five European cohorts consisting of 2267 AMD patients and 4266 control participants.Methods: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. MetabolomeeAMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression.Main Outcome Measures: Metabolites associated with AMD.Results: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high- density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation.Conclusions: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD. (C) 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license Show less
