Structural correlations between brain magnetic resonance image-derived phenotypes and retinal neuroanatomy.

BACKGROUND AND PURPOSE: The eye is a well-established model of brain structure and function, yet region-specific structural correlations between the retina and the brain remain underexplored. Therefore, we aim to explore and describe the relationships between the retinal layer thicknesses and brain magnetic resonance image (MRI)-derived phenotypes in UK Biobank. METHODS: Participants with both quality-controlled optical coherence tomography (OCT) and brain MRI were included in this study. Retinal sublayer thicknesses and total macular thickness were derived from OCT scans. Brain image-derived phenotypes (IDPs) of 153 cortical and subcortical regions were processed from MRI scans. We utilized multivariable linear regression models to examine the association between retinal thickness and brain regional volumes. All analyses were corrected for multiple testing and adjusted for confounders. RESULTS: Data from 6446 participants were included in this study. We identified significant associations between volumetric brain MRI measures of subregions in the occipital lobe (intracalcarine cortex), parietal lobe (postcentral gyrus), cerebellum (lobules VI, VIIb, VIIIa, VIIIb, and IX), and deep brain structures (thalamus, hippocampus, caudate, putamen, pallidum, and accumbens) and the thickness of the innermost retinal sublayers and total macular thickness (all p < 3.3 × 10-5). We did not observe statistically significant associations between brain IDPs and the thickness of the outer retinal sublayers. CONCLUSIONS: Thinner inner and total retinal thicknesses are associated with smaller volumes of specific brain regions. Notably, these relationships extend beyond anatomically established retina-brain connections.

Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: Two-Year Results from a Randomized, Multicenter Study.

PURPOSE: To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). DESIGN: Prospective, randomized, multicenter trial conducted in the United States and Europe. PARTICIPANTS: Adult patients (aged 40-85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg. METHODS: Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes. MAIN OUTCOME MEASURES: The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions. RESULTS: At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. CONCLUSION: At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants.

Importance: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. Objective: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. Design, Setting, and Participants: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. Exposure: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. Main Outcomes and Measures: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. Results: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 µm [95% CI, -0.54 to -0.15 µm]; P = .001) and mRNFL (-0.16 µm [95% CI, -0.30 to -0.02 µm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). Conclusions and Relevance: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care.

Cell-Based Therapies for Glaucoma.

Glaucomatous optic neuropathy (GON) is the major cause of irreversible visual loss worldwide and can result from a range of disease etiologies. The defining features of GON are retinal ganglion cell (RGC) degeneration and characteristic cupping of the optic nerve head (ONH) due to tissue remodeling, while intraocular pressure remains the only modifiable GON risk factor currently targeted by approved clinical treatment strategies. Efforts to understand the mechanisms that allow species such as the zebrafish to regenerate their retinal cells have greatly increased our understanding of regenerative signaling pathways. However, proper integration within the retina and projection to the brain by the newly regenerated neuronal cells remain major hurdles. Meanwhile, a range of methods for in vitro differentiation have been developed to derive retinal cells from a variety of cell sources, including embryonic and induced pluripotent stem cells. More recently, there has been growing interest in the implantation of glial cells as well as cell-derived products, including neurotrophins, microRNA, and extracellular vesicles, to provide functional support to vulnerable structures such as RGC axons and the ONH. These approaches offer the advantage of not relying upon the replacement of degenerated cells and potentially targeting earlier stages of disease pathogenesis. In order to translate these techniques into clinical practice, appropriate cell sourcing, robust differentiation protocols, and accurate implantation methods are crucial to the success of cell-based therapy in glaucoma. Translational Relevance: Cell-based therapies for glaucoma currently under active development include the induction of endogenous regeneration, implantation of exogenously derived retinal cells, and utilization of cell-derived products to provide functional support.

Transcriptomics of CD29+/CD44+ cells isolated from hPSC retinal organoids reveals a single cell population with retinal progenitor and Müller glia characteristics.

Müller glia play very important and diverse roles in retinal homeostasis and disease. Although much is known of the physiological and morphological properties of mammalian Müller glia, there is still the need to further understand the profile of these cells during human retinal development. Using human embryonic stem cell-derived retinal organoids, we investigated the transcriptomic profiles of CD29+/CD44+ cells isolated from early and late stages of organoid development. Data showed that these cells express classic markers of retinal progenitors and Müller glia, including NFIX, RAX, PAX6, VSX2, HES1, WNT2B, SOX, NR2F1/2, ASCL1 and VIM, as early as days 10-20 after initiation of retinal differentiation. Expression of genes upregulated in CD29+/CD44+ cells isolated at later stages of organoid development (days 50-90), including NEUROG1, VSX2 and ASCL1 were gradually increased as retinal organoid maturation progressed. Based on the current observations that CD24+/CD44+ cells share the characteristics of early and late-stage retinal progenitors as well as of mature Müller glia, we propose that these cells constitute a single cell population that upon exposure to developmental cues regulates its gene expression to adapt to functions exerted by Müller glia in the postnatal and mature retina.

Glaucoma Drainage Device Surgery Outcomes in Children With Uveitic Glaucoma.

PURPOSE: To evaluate outcomes of glaucoma drainage device (GDD) implantation children with uveitic glaucoma. DESIGN: Retrospective interventional case series. METHODS: Success was defined as intraocular pressure (IOP) ≥5 and ≤21 mm Hg. Failure was defined at final follow-up when the IOP was outside the success criterion, and visual function was no perception of light or if further glaucoma surgery (excluding removal of intraluminal stent suture or needling) was required. RESULTS: Fifty eyes of 36 children with uveitic glaucoma underwent GDD implantation. Mean age at surgery was 10.1±3.1 years (range 5-17) with a mean follow-up of 113±61 months (range 8-228). Mean cumulative probabilities of success (95% CI) were 0.98 (0.86-1.00) at 1 year, 0.87 (0.73-0.94) at 5 years, and 0.59 (0.32-0.78) at 15 years. Fourteen tubes were classified as failed, with 12 due to uncontrolled IOP (11 eyes required a second GDD); 1 eye, removal of the tube due to plate exposure; and 1 eye, lost light perception. Postoperative complications occurred in 36% of patients and included hypotony (22%), tube exposure (6%), tube obstruction (4%), corneal decompensation (2%), and cystoid macular edema (2%). Visual acuity remained stable (preoperation 0.35±0.42 vs postoperation 0.45±0.67, P = .49). IOP was significantly reduced from 31.4±7.5 mm Hg to 14.4±5.1 mm Hg (P < .0001) as were the number of glaucoma medications 3.5±1.0 vs 1.1±1.3 (P < .0001). CONCLUSIONS: Refractory pediatric uveitic glaucoma can be treated successfully by GDD implantation. Further interventions to manage consequences of glaucoma or the underlying disease are common, and visual function is maintained in the majority of cases.

MicroRNA profile of extracellular vesicles released by Müller glial cells.

Introduction: As with any other radial glia in the central nervous system, Müller glia derive from the same neuroepithelial precursors, perform similar functions, and exhibit neurogenic properties as radial glia in the brain. Müller glial cells retain progenitor-like characteristics in the adult human eye and can partially restore visual function upon intravitreal transplantation into animal models of glaucoma. Recently, it has been demonstrated that intracellular communication is possible via the secretion of nano-sized membrane-bound extracellular vesicles (EV), which contain bioactive molecules like microRNA (miRNA) and proteins that induce phenotypic changes when internalised by recipient cells. Methods: We conducted high-throughput sequencing to profile the microRNA signature of EV populations secreted by Müller glia in culture and used bioinformatics tools to evaluate their potential role in the neuroprotective signalling attributed to these cells. Results: Sequencing of miRNA within Müller EV suggested enrichment with species associated with stem cells such as miR-21 and miR-16, as well as with miRNA previously found to play a role in diverse Müller cell functions in the retina: miR-9, miR-125b, and the let-7 family. A total of 51 miRNAs were found to be differentially enriched in EV compared to the whole cells from which EV originated. Bioinformatics analyses also indicated that preferential enrichment of species was demonstrated to regulate genes involved in cell proliferation and survival, including PTEN, the master inhibitor of the PI3K/AKT pathway. Discussion: The results suggest that the release by Müller cells of miRNA-enriched EV abundant in species that regulate anti-apoptotic signalling networks is likely to represent a significant proportion of the neuroprotective effect observed after the transplantation of these cells into animal models of retinal ganglion cell (RGC) depletion. Future studies will seek to evaluate the modulation of putative genes as well as the activation of these pathways in in vitro and in vivo models following the internalisation of Müller-EV by target retinal neurons.

The economics of vision impairment and its leading causes: A systematic review.

Vision impairment (VI) can have wide ranging economic impact on individuals, households, and health systems. The aim of this systematic review was to describe and summarise the costs associated with VI and its major causes. We searched MEDLINE (16 November 2019), National Health Service Economic Evaluation Database, the Database of Abstracts of Reviews of Effects and the Health Technology Assessment database (12 December 2019) for partial or full economic evaluation studies, published between 1 January 2000 and the search dates, reporting cost data for participants with VI due to an unspecified cause or one of the seven leading causes globally: cataract, uncorrected refractive error, diabetic retinopathy, glaucoma, age-related macular degeneration, corneal opacity, trachoma. The search was repeated on 20 January 2022 to identify studies published since our initial search. Included studies were quality appraised using the British Medical Journal Checklist for economic submissions adapted for cost of illness studies. Results were synthesized in a structured narrative. Of the 138 included studies, 38 reported cost estimates for VI due to an unspecified cause and 100 reported costs for one of the leading causes. These 138 studies provided 155 regional cost estimates. Fourteen studies reported global data; 103/155 (66%) regional estimates were from high-income countries. Costs were most commonly reported using a societal (n = 48) or healthcare system perspective (n = 25). Most studies included only a limited number of cost components. Large variations in methodology and reporting across studies meant cost estimates varied considerably. The average quality assessment score was 78% (range 35-100%); the most common weaknesses were the lack of sensitivity analysis and insufficient disaggregation of costs. There was substantial variation across studies in average treatment costs per patient for most conditions, including refractive error correction (range $12-$201 ppp), cataract surgery (range $54-$3654 ppp), glaucoma (range $351-$1354 ppp) and AMD (range $2209-$7524 ppp). Future cost estimates of the economic burden of VI and its major causes will be improved by the development and adoption of a reference case for eye health. This could then be used in regular studies, particularly in countries with data gaps, including low- and middle-income countries in Asia, Eastern Europe, Oceania, Latin America and sub-Saharan Africa.

Corneal Endothelial Cell Density Loss after Glaucoma Surgery Alone or in Combination with Cataract Surgery: A Systematic Review and Meta-analysis.

TOPIC: Corneal endothelial cell density (ECD) loss after glaucoma surgery with or without cataract surgery. CLINICAL RELEVANCE: Corneal ECD loss may occur as the result of intraoperative surgical trauma in glaucoma surgery or postoperatively with chronic endothelial cell trauma or irritation. METHODS: Glaucoma filtration surgery or microinvasive glaucoma surgery (MIGS) in participants with ocular hypertension, primary and secondary open-angle glaucoma, normal-tension glaucoma, and angle-closure glaucoma were included. Electronic databases searched in December 2021 included MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the International Prospective Register of Systematic Reviews, Food and Drug Administration (FDA) Premarket Approval, and FDA 510(k). RESULTS: A total of 39 studies were included in quantitative synthesis. Twelve months after suprachoroidal MIGS, mean ECD loss was 282 cells/mm2 (95% confidence interval [CI], 220-345; P < 0.00001; chi-square = 0.06; I2 = 0%; 2 studies; very low certainty). Mean ECD loss after Schlemm's canal implantable devices was 338 cells/mm2 (95% CI, 185-491; P < 0.0001; chi-square = 0.08; I2 = 0%; 2 studies; low certainty) at 12 months. Mean ECD loss was 64 cells/mm2 (95% CI, 21-107; P = 0.004; chi-square = 4.55; I2 = 0%; 6 studies; low certainty) after Schlemm's canal procedures (without implantable devices) at 12 months. At 12 months, the mean ECD loss after trabeculectomy was 33 cells/mm2 (95% CI, -38 to 105, P = 0.36, chi-square = 1.17; I2 = 0%; moderate certainty). At 12 months, mean ECD loss was 121 cells/mm2 (95% CI, 53-189; P = 0.0005; chi-square = 3.00; I2 = 0%; 5 studies; low certainty) after Express (Alcon) implantation. When compared with the control fellow eye, aqueous shunt surgery reduced ECD by 5.75% (95% CI, -0.93 to 12.43; P = 0.09, chi-square = 1.32; I2 = 0%; low certainty) and 8.11% ECD loss (95% CI, 0.06-16.16 P = 0.05; chi-square = 1.93; I2 = 48%) at 12 and 24 months, respectively. CONCLUSIONS: Overall, there is low certainty evidence to suggest that glaucoma surgery involving long-term implants has a greater extent of ECD loss than glaucoma filtration surgeries without the use of implants. The results of this review support follow-up beyond 36 months to assess ECD loss and corneal decompensation after implantation of glaucoma drainage implants.

Grand Challenges in global eye health: a global prioritisation process using Delphi method.

BACKGROUND: We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. METHODS: Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. FINDINGS: Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. INTERPRETATION: This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenges. FUNDING: The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research Moorfields Biomedical Research Centre, Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The Seva Foundation, British Council for the Prevention of Blindness, and Christian Blind Mission. TRANSLATIONS: For the French, Spanish, Chinese, Portuguese, Arabic and Persian translations of the abstract see Supplementary Materials section.

Association of ambient air pollution with age-related macular degeneration and retinal thickness in UK Biobank.

AIM: To examine the associations of air pollution with both self-reported age-related macular degeneration (AMD), and in vivo measures of retinal sublayer thicknesses. METHODS: We included 115 954 UK Biobank participants aged 40-69 years old in this cross-sectional study. Ambient air pollution measures included particulate matter, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Participants with self-reported ocular conditions, high refractive error (< -6 or > +6 diopters) and poor spectral-domain optical coherence tomography (SD-OCT) image were excluded. Self-reported AMD was used to identify overt disease. SD-OCT imaging derived photoreceptor sublayer thickness and retinal pigment epithelium (RPE) layer thickness were used as structural biomarkers of AMD for 52 602 participants. We examined the associations of ambient air pollution with self-reported AMD and both photoreceptor sublayers and RPE layer thicknesses. RESULTS: After adjusting for covariates, people who were exposed to higher fine ambient particulate matter with an aerodynamic diameter <2.5 µm (PM2.5, per IQR increase) had higher odds of self-reported AMD (OR=1.08, p=0.036), thinner photoreceptor synaptic region (ß=-0.16 µm, p=2.0 × 10-5), thicker photoreceptor inner segment layer (ß=0.04 µm, p=0.001) and thinner RPE (ß=-0.13 µm, p=0.002). Higher levels of PM2.5 absorbance and NO2 were associated with thicker photoreceptor inner and outer segment layers, and a thinner RPE layer. Higher levels of PM10 (PM with an aerodynamic diameter <10 µm) was associated with thicker photoreceptor outer segment and thinner RPE, while higher exposure to NOx was associated with thinner photoreceptor synaptic region. CONCLUSION: Greater exposure to PM2.5 was associated with self-reported AMD, while PM2.5, PM2.5 absorbance, PM10, NO2 and NOx were all associated with differences in retinal layer thickness.

The Association of Ambient Air Pollution With Cataract Surgery in UK Biobank Participants: Prospective Cohort Study.

Purpose: Air pollution is associated with chronic diseases of later life. Cataract is the most common cause of blindess globally. It is biologically plausible that cataract risk is increased by pollution exposure. Therefore, the relationship between air pollution and incident cataract surgery was examined. Methods: This was a prospective, observational study involving 433,727 UK Biobank participants. Ambient air pollution measures included particulates, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Outdoor air pollution was estimated based on land use regression models. Participants undergoing cataract surgery in either eye were ascertained via data linkage to the National Health Service procedure statistics. Those undergoing cataract surgery within 1 year of baseline assessment and those reporting cataract at baseline were excluded. Cox proportional hazards models were used to examine the associations between air pollutants and incident cataract surgery, adjusting for sociodemographic and lifestyle factors. Results: There were 16,307 incident cases of cataract surgery. Higher exposure to PM2.5 was associated with a 5% increased risk of incident cataract surgery (per interquartile range [IQR] increase). Compared to the lowest quartile, participants with exposures to PM2.5, NO2, and NOx in the highest quartile were 14%, 11%, and 9% more likely to undergo cataract surgery, respectively. A continuous exposure-response relationship was observed, with the likelihood of undergoing cataract surgery being progressively higher with greater levels of PM2.5, NO2, and NOx (P for trend P < 0.001). Conclusions: Although the results of our study showed a 5% increased risk of future cataract surgery following an exposure to PM2.5, NO2, and NOx, the effect estimates were relatively small. Further research is required to determine if the associations identified are causal.

Correction: Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Alcohol Consumption and Incident Cataract Surgery in Two Large UK Cohorts.

PURPOSE: To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in 2 large cohorts. DESIGN: Longitudinal, observational study. PARTICIPANTS: We included 469 387 participants of UK Biobank with a mean age of 56 years and 23 162 participants of European Prospective Investigation of Cancer (EPIC)-Norfolk with a mean age of 59 years. METHODS: Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics. We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index (BMI), smoking, and diabetes status. MAIN OUTCOME MEASURES: Incident cataract surgery. RESULTS: There were 19 011 (mean cohort follow-up of 95 months) and 4573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively. Compared with nondrinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.93) and EPIC-Norfolk (HR, 0.90; 95% CI, 0.84-0.97) after adjusting for covariables. Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P < 0.001), whereas a U-shaped association was observed in the UK Biobank. Compared with nondrinkers, subgroup analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively. CONCLUSIONS: Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding, and further studies are required to determine whether this association is causal in nature.

Strain Specific Responses in a Microbead Rat Model of Experimental Glaucoma.

PURPOSE: A major challenge in glaucoma research is the lack of reproducible animal models of RGC and optic nerve damage, the characteristic features of this condition. We therefore examined the glaucomatous responses of two different rat strains, the Brown Norway (BN) and Lister Hooded (LH) rats, to high intraocular pressure (IOP) induced by injection of magnetic beads into the anterior chamber. METHODS: Magnetic microsphere suspensions (20 µl of 5-20 mg/ml) were injected into the anterior chamber of BN (n = 9) or LH (N = 15) rats. Animals from each strain were divided into three groups, each receiving a different dose of microspheres. IOP was measured over 4 weeks using a rebound tonometer. Retinal ganglion cell (RGC) damage and function were assessed using scotopic electroretinograms (ERGs), retinal flatmounts and optic nerve histology. ANOVA and Student's t-tests were used to analyse the data. RESULTS: A significant elevation in IOP was observed in BN rats receiving injections of 20 mg (37.18 ± 12.28 mmHg) or 10 mg microspheres/ml (36.95 ± 13.63 mmHg) when compared with controls (19.63 ± 4.29 mmHg) (p < .001) over 2 weeks. This correlated with a significant impairment of RGC function, as determined by scotopic ERG (p < .001), reduction in axon number (p < .05) and lower RGC density (P < .05) in animals receiving 20 mg or 10 mg microspheres/ml as compared with controls. LH rats receiving similar microsphere doses showed reduced scotopic ERG function (p < .001) after 2 weeks. No changes in IOP was seen in this strain, although a reduction in axon density was observed in optic nerve cross-sections (p < .05). Initial changes in IOP and ERG responses observed in BN rats remained unchanged for a duration of 7 weeks. In LH animals, ERG responses were decreased at 1-2 weeks and returned to control levels after 5 weeks. CONCLUSIONS: Although this model was easily reproducible in BN rats, the phenotype of injury observed in LH rats was very different from that observed in BN animals. We suggest that differences in the glaucomatous response observed in these two strains may be ascribed to anatomical and physiological differences and merits further investigation.

Retinal asymmetry in multiple sclerosis.

The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72 120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229-0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67-0.76) and IEAD (0.71, 95% CI 0.67-0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59-0.69, P = 0.0017); IEAD AUROC curve (0.63, 95% CI 0.58-0.68, P < 0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54-0.63, P < 0.0001); IEAD AUROC curve (0.55, 95% CI 0.50-0.59, P < 0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 µm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ω2 > 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed.

Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort.

BACKGROUND AND PURPOSE: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image-derived phenotypes (IDPs) in a large cohort of healthy older people. METHODS: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. RESULTS: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. CONCLUSIONS: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults.

Dual-acting therapeutic proteins for intraocular use.

Intravitreally injected antibody-based medicines have revolutionised the treatment of retinal disease. Bispecific and dual-functional antibodies and therapeutic proteins have the potential to further increase the efficacy of intraocular medicines.