The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population.

OBJECTIVE: Excessive dietary sodium intake has known adverse effects on intravascular fluid volume and systemic blood pressure, which may influence intraocular pressure (IOP) and glaucoma risk. This study aimed to assess the association of urinary sodium excretion, a biomarker of dietary intake, with glaucoma and related traits, and to determine whether this relationship is modified by genetic susceptibility to disease. DESIGN: Cross-sectional observational and gene-environment interaction analyses in the population-based UK Biobank study. PARTICIPANTS: Up to 103 634 individuals (mean age 57 years, 51% women) with complete urinary, ocular, and covariable data. METHODS: Urine sodium:creatinine ratio (UNa:Cr; mmol:mmol) was calculated from a midstream urine sample. Ocular parameters were measured as part of a comprehensive eye examination and glaucoma case ascertainment was through a combination of self-report and linked national hospital records. Genetic susceptibility to glaucoma was calculated based on a glaucoma polygenic risk score (PRS) comprising 2 673 common genetic variants. Multivariable linear and logistic regression, adjusted for key sociodemographic, medical, anthropometric, and lifestyle factors, were used to model associations and gene-environment interactions. MAIN OUTCOME MEASURES: Corneal-compensated IOP, optical coherence tomography derived macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness, and prevalent glaucoma. RESULTS: In maximally adjusted regression models, a one standard deviation increase in UNa:Cr was associated with higher IOP (0.14mmHg; 95% CI, 0.12 to 0.17; P<0.001) and greater prevalence of glaucoma (OR, 1.11; 95% CI, 1.07 to 1.14; P<0.001), but not mRNFL or GCIPL thickness. Compared to those with UNa:Cr in the lowest quintile, those in the highest quintile had significantly higher IOP (0.45mmHg; 95% CI, 0.36 to 0.53, P<0.001) and prevalence of glaucoma (OR, 1.30; 95% CI, 1.17 to 1.45; P<0.001). Stronger associations with glaucoma (P interaction=0.001) were noted in participants with a higher glaucoma PRS. CONCLUSIONS: Urinary sodium excretion, a biomarker of dietary intake, may represent an important modifiable risk factor for glaucoma, especially in individuals at high underlying genetic risk. These findings warrant further investigation as they may have important clinical and public health implications.

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.

Survival of medical treatment success in primary open-angle glaucoma and ocular hypertension.

BACKGROUND/AIMS: Topical agents to lower intraocular pressure (IOP) are the most common initial therapeutic measure in glaucoma prevention. This study aims to assess treatment success duration among patients initiating or intensifying topical glaucoma medication. METHODS: Medical records (2013‒2018) for adults initiating/intensifying topical glaucoma medication were extracted from five secondary-care and tertiary-care UK ophthalmology centres. Main study outcomes were time from treatment initiation/intensification to treatment failure (<20% IOP reduction or IOP >21 mm Hg at consecutive clinic visits, or intensification of glaucoma treatment) and time from treatment change to subsequent treatment intensification. RESULTS: Study eyes (n=6587) underwent treatment intensification 0-to-1 glaucoma drop (5358 events), 1-to-2 drops (1469 events) and 2-to-3 drops (857 events) during the observation period. Median time to treatment failure was 1.60 (95% CI 1.57 to 1.65), 1.00 (95% CI 0.94 to 1.07) and 0.92 (95% CI 0.81 to 1.02) years following escalation 0-to-1, 1-to-2 and 2-to-3 drops, respectively. Median time to treatment intensification (non-IOP-based criterion) was 4.68 (95% CI 4.50 to 5.08) years for treatment initiators, 3.83 (95% CI 3.36 to 4.08) years on escalation 1-to-2 drops and 4.35 (95% CI 3.82 to 4.88) years on escalation 2-to-3 drops. On multivariable regression, significant risk factors for both treatment failure and intensification were lower baseline visual field mean deviation, primary open-angle glaucoma and lower eyedrop count in the fellow eye; lower baseline IOP was associated with treatment failure, higher baseline IOP with treatment intensification. CONCLUSION: Large-scale survival analyses provide the expected duration of treatment success from topical glaucoma medication.

Periodontitis and Outer Retinal Thickness: a Cross-Sectional Analysis of the United Kingdom Biobank Cohort.

Purpose: Periodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone, can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration (AMD), in individuals with no eye disease. Design: Cross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank. Participants: Sixty-seven thousand three hundred eleven UK residents aged 40 to 70 years recruited between 2006 and 2010 underwent retinal imaging. Methods: Macular-centered OCT images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses, adjusting for age, sex, ethnicity, socioeconomic status, alcohol consumption, smoking status, diabetes mellitus, hypertension, refractive error, and previous cataract surgery. Main Outcome Measures: Photoreceptor layer (PRL) and retinal pigment epithelium-Bruch's membrane (RPE-BM) thicknesses. Results: Among 36 897 participants included in the analysis, 1571 (4.3%) reported very severe periodontitis. Affected individuals were older, lived in areas of greater socioeconomic deprivation, and were more likely to be hypertensive, diabetic, and current smokers (all P < 0.001). On average, those with very severe periodontitis were hyperopic (0.05 ± 2.27 diopters) while those unaffected were myopic (-0.29 ± 2.40 diopters, P < 0.001). Following adjusted analysis, very severe periodontitis was associated with thinner PRL (-0.55 µm, 95% confidence interval [CI], -0.97 to -0.12; P = 0.022) but there was no difference in RPE-BM thickness (0.00 µm, 95% CI, -0.12 to 0.13; P = 0.97). The association between PRL thickness and very severe periodontitis was modified by age (P < 0.001). Stratifying individuals by age, thinner PRL was seen among those aged 60 to 69 years with disease (-1.19 µm, 95% CI, -1.85 to -0.53; P < 0.001) but not among those aged < 60 years. Conclusions: Among those with no known eye disease, very severe periodontitis is statistically associated with a thinner PRL, consistent with incipient AMD. Optimizing oral hygiene may hold additional relevance for people at risk of degenerative retinal disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Additional Guidance on the Use of the PRESERFLO™ MicroShunt in the Treatment of Glaucoma: Insights from a Second Delphi Consensus Panel.

INTRODUCTION: The PRESERFLO™ MicroShunt (PMS) has been proven to significantly lower intraocular pressure (IOP) in patients with glaucoma and has been available for use since 2019. With increasing published evidence and growing experience of glaucoma surgeons, the aim of this modified Delphi panel was to build on the findings of a previous Delphi panel conducted in 2021 and provide further guidance on the role of the PMS to treat patients with glaucoma in Europe. METHODS: Thirteen European glaucoma surgeons experienced in the PMS procedure participated in a 3-round modified Delphi panel. A targeted literature review and expert steering committee guided Round 1 questionnaire development. Consensus was pre-defined at a threshold of ≥ 70% of panellists selecting 'strongly agree'/'agree' or 'strongly disagree'/'disagree' for 6-point Likert scale questions or ≥ 70% selecting the same option for multiple or single-choice questions. Questions not reaching consensus were restated/revised for the next round, following guidance from free-text responses/scoping questions. RESULTS: In total, 28% (n = 9/32), 52% (n = 16/31) and 91% (n = 10/11) of statements reached consensus in Rounds 1, 2 and 3, respectively. There was agreement that the PMS may be used in patients with pigmentary, post-trauma or post-vitrectomy glaucoma and for patients with uveitic glaucoma without active inflammation. The PMS may be more suitable for patients with contact lenses than other subconjunctival filtering surgeries, without eliminating bleb-associated risks. Consensus was reached that combining PMS implantation and phacoemulsification may be as safe as standalone PMS surgery, but further efficacy data are required. Following a late rise in IOP ≥ 4 months post-surgery, topical aqueous suppressant drops or bleb revision may be suitable management options. CONCLUSIONS: This Delphi panel builds on the considerations explored in the 2021 Delphi panel and provides further detailed guidance for glaucoma surgeons on the use of the PMS, reflecting the availability of novel evidence and surgical experience. Videos are available for this article.

Utilizing multimodal AI to improve genetic analyses of cardiovascular traits.

Electronic health records, biobanks, and wearable biosensors contain multiple high-dimensional clinical data (HDCD) modalities (e.g., ECG, Photoplethysmography (PPG), and MRI) for each individual. Access to multimodal HDCD provides a unique opportunity for genetic studies of complex traits because different modalities relevant to a single physiological system (e.g., circulatory system) encode complementary and overlapping information. We propose a novel multimodal deep learning method, M-REGLE, for discovering genetic associations from a joint representation of multiple complementary HDCD modalities. We showcase the effectiveness of this model by applying it to several cardiovascular modalities. M-REGLE jointly learns a lower representation (i.e., latent factors) of multimodal HDCD using a convolutional variational autoencoder, performs genome wide association studies (GWAS) on each latent factor, then combines the results to study the genetics of the underlying system. To validate the advantages of M-REGLE and multimodal learning, we apply it to common cardiovascular modalities (PPG and ECG), and compare its results to unimodal learning methods in which representations are learned from each data modality separately, but the downstream genetic analyses are performed on the combined unimodal representations. M-REGLE identifies 19.3% more loci on the 12-lead ECG dataset, 13.0% more loci on the ECG lead I + PPG dataset, and its genetic risk score significantly outperforms the unimodal risk score at predicting cardiac phenotypes, such as atrial fibrillation (Afib), in multiple biobanks.

Relationship between Oral Health and Glaucoma Traits in the United Kingdom.

PRECIS: In this cross-sectional analysis of UK Biobank participants, we find no adverse association between self-reported oral health conditions and either glaucoma or elevated intraocular pressures. PURPOSE: Poor oral health may cause inflammation that accelerates the progression of neurodegenerative diseases. We investigated the relationship between oral health and glaucoma. PATIENTS: United Kingdom (UK) Biobank participants. METHODS: This is a cross-sectional analysis of participants categorized by self-reported oral health status. Multivariable linear and logistic regression models were employed. Primary analysis examined the association with glaucoma prevalence. Secondary analyses examined associations with IOP, macular retinal nerve fiber layer (mRNFL), and ganglion cell inner plexiform layer (mGCIPL) thicknesses, and interaction terms with multi-trait glaucoma polygenic risk scores (MTAG PRS) or intraocular pressure (IOP) PRS. RESULTS: 170,815 participants (34.3%) reported current oral health problems, including painful or bleeding gums, toothache, loose teeth, and/or denture wear. 33,059, 33,004, 14,652, and 14,613 participants were available for analysis of glaucoma, IOP, mRNFL, and mGCIPL, respectively. No association between oral health and glaucoma was identified (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.95, 1.14). IOPs were slightly lower among those with oral disease (-0.08 mmHg, 95% CI: -0.15, -0.009); specifically, among those with loose teeth (P=0.03) and denture-wearers (P<0.0001). mRNFL measurements were lower among those with oral health conditions (-0.14 microns, 95% CI: -0.27, -0.0009), but mGCIPL measurements (P=0.96) were not significantly different. A PRS for IOP or glaucoma did not modify relations between oral health and IOP nor glaucoma (P-for-interactions0.17). CONCLUSIONS: Self-reported oral health was not associated with elevated IOP nor increased risk of glaucoma. Future studies should confirm the null association between clinically diagnosed oral health conditions and glaucoma.

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma.

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Smoking, Corneal Biomechanics, and Glaucoma: Results From Two Large Population-Based Cohorts.

Purpose: Smoking may influence measured IOP through an effect on corneal biomechanics, but it is unclear whether this factor translates into an increased risk for glaucoma. This study aimed to examine the association of cigarette smoking with corneal biomechanical properties and glaucoma-related traits, and to probe potential causal effects using Mendelian randomization (MR). Methods: Cross-sectional analyses within the UK Biobank (UKB) and Canadian Longitudinal Study on Aging (CLSA) cohorts. Multivariable linear and logistic regression models were used to assess associations of smoking (status, intensity, and duration) with corneal hysteresis (CH), corneal resistance factor, IOP, inner retinal thicknesses, and glaucoma. Two-sample MR analyses were performed. Results: Overall, 68,738 UKB (mean age, 56.7 years; 54.7% women) and 22 845 CLSA (mean age, 62.7 years; 49.1% women) participants were included. Compared with nonsmokers, smokers had a higher CH (UKB, +0.48 mm Hg; CLSA, +0.57 mm Hg; P < 0.001) and corneal resistance factor (UKB, +0.47 mm Hg; CLSA, +0.60 mm Hg; P < 0.001) with evidence of a dose-response effect in both studies. Differential associations with Goldmann-correlated IOP (UKB, +0.25 mm Hg; CLSA, +0.36 mm Hg; P < 0.001) and corneal-compensated IOP (UKB, -0.28 mm Hg; CLSA, -0.32 mm Hg; P ≤ 0.001) were observed. Smoking was not associated with inner retinal thicknesses or glaucoma status in either study. MR provided evidence for a causal effect of smoking on corneal biomechanics, especially higher CH. Conclusions: Cigarette smoking seems to increase corneal biomechanical resistance to deformation, but there was little evidence to support a relationship with glaucoma. This outcome may result in an artefactual association with measured IOP and could account for discordant results with glaucoma in previous epidemiological studies.

Associations of inner retinal layers with risk of incident dementia: An individual participant data analysis of four prospective cohort studies.

INTRODUCTION: Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all-cause dementia and Alzheimer's disease (AD). METHODS: We performed an individual participant data meta-analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all-cause dementia; n = 520 cases incident AD; follow-up time median [interquartile range] 11.3 [8.8-11.5] years). RESULTS: General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all-cause dementia and AD, respectively. Lower baseline macular ganglion cell-inner plexiform layer thickness was not significantly associated with these outcomes. DISCUSSION: These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia.

Lessons From The Glaucoma Foundation Think Tank 2023: A Patient-Centric Approach to Glaucoma.

PRCIS: The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease. PURPOSE: To summarize the main topics discussed during the 28th Annual Glaucoma Foundation Think Tank Meeting "A Patient-Centric Approach to Glaucoma" held in New York on June 9 and 10, 2023. METHODS: The highlights of the sessions on BIG DATA, genetics, modifiable lifestyle risk factors, female sex hormones, and neuroprotection in the field of primary open angle glaucoma (POAG) were summarized. RESULTS: The researchers discussed the importance of BIG DATA repositories available at national and international levels for POAG research, including the United Kingdom Biobank. Combining genotyped large cohorts worldwide, facilitated by artificial intelligence (AI) and machine-learning approaches, led to the milestone discovery of 312 genome-wide significant disease loci for POAG. While these loci could be combined into a polygenic risk score with clinical utility, Think Tank meeting participants also provided analytical epidemiological evidence that behavioral risk factors modify POAG polygenetic risk, citing specific examples related to caffeine and alcohol use. The impact of female sex hormones on POAG pathophysiology was discussed, as was neuroprotection and the potential use of AI to help mitigate specific challenges faced in clinical trials and speed approval of neuroprotective agents. CONCLUSIONS: The experts agreed on the importance of genetics in defining individual POAG risk and highlighted the additional crucial role of lifestyle, gender, blood pressure, and vascular risk factors. The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease.

WITHDRAWN: Genome-wide risk prediction of primary open-angle glaucoma across multiple ancestries.

This manuscript has been withdrawn by medRxiv following a formal request by the QIMR Berghofer Medical Research Institute Research Integrity Office owing to lack of author consent.

TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study.

BACKGROUND: In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm's canal (SC) is a hybrid vascular and lymphatic vessel that mediates aqueous humour drainage from the anterior ocular chamber. Animal studies support the importance of SC endothelial angiopoietin-TEK signalling, and more recently TIE1 signalling, in maintaining normal IOP. However, human genetic support for a causal role of TIE1 and TEK signalling in lowering IOP is currently lacking. METHODS: GWAS summary statistics were obtained for plasma soluble TIE1 (sTIE1) protein levels (N = 35,559), soluble TEK (sTEK) protein levels (N = 35,559), IOP (N = 139,555) and POAG (Ncases = 16,677, Ncontrols = 199,580). Mendelian randomization (MR) was performed to estimate the association of genetically proxied TIE1 and TEK protein levels with IOP and POAG liability. Where significant MR estimates were obtained, genetic colocalization was performed to assess the probability of a shared causal variant (PPshared) versus distinct (PPdistinct) causal variants underlying TIE1/TEK signalling and the outcome. Publicly available single-nucleus RNA-sequencing data were leveraged to investigate differential expression of TIE1 and TEK in the human ocular anterior segment. RESULTS: Increased genetically proxied TIE1 signalling and TEK signalling associated with a reduction in IOP (- 0.21 mmHg per SD increase in sTIE1, 95% CI = - 0.09 to - 0.33 mmHg, P = 6.57 × 10-4, and - 0.14 mmHg per SD decrease in sTEK, 95% CI = - 0.03 to - 0.25 mmHg, P = 0.011), but not with POAG liability. Colocalization analysis found that the probability of a shared causal variant was greater for TIE1 and IOP than for TEK and IOP (PPshared/(PPdistinct + PPshared) = 0.98 for TIE1 and 0.30 for TEK). In the anterior segment, TIE1 and TEK were preferentially expressed in SC, lymphatic, and vascular endothelium. CONCLUSIONS: This study provides novel human genetic support for a causal role of both TIE1 and TEK signalling in regulating IOP. Here, combined evidence from cis-MR and colocalization analyses provide stronger support for TIE1 than TEK as a potential IOP-lowering therapeutic target.

Genomics enabling personalised glaucoma care.

Glaucoma is a leading cause of visual impairment and a significant public health concern, but despite ongoing advances in our understanding of the disease, several important clinical challenges remain. With the number of affected people projected to increase substantially over coming decades, novel approaches to screening, risk stratification, therapy and glaucoma research are essential to deal with this expanding burden in an efficient and cost-effective manner. Genomics may hold the key to unlocking further biological insights and enabling precision medicine, in which glaucoma care is tailored to the individual patient, based on their unique profile for disease. Here, we provide an overview of how genomics may enable cost-effective targeted population screening and personalised predictions of risk, response to treatment and effective lifestyle advice. Given rapid advances in genetic testing technology and a move towards population-level genotyping, these early results have several important implications that promise to revolutionise the way in which glaucoma is detected and managed in years to come.

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.

Association Between Retinal Nerve Fiber Layer Thickness and Incident Dementia in the European Prospective Investigation into Cancer in Norfolk Cohort.

BACKGROUND: Retinal nerve fiber layer (RNFL) thickness may reflect cerebral status. OBJECTIVE: This study assessed the relationship between RNFL thickness and incident all-cause dementia in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) Eye Study. METHODS: Glaucoma detection with variable corneal compensation (GDx-VCC) and Heidelberg Retinal Tomograph II (HRT II) derived global mean RNFL thickness from dementia-free participants at baseline within the EPIC-Norfolk Eye Study were analyzed. Incident dementia was identified through linkage to electronic medical records. Cox proportional hazard mixed-effects regression models adjusted for key confounders were used to examine the associations between RNFL thickness and incident dementia in four separate models. RESULTS: 6,239 participants were included with 322 cases of incident dementia and mean age of 67.5-years old, with 49.7% women (median follow-up 13.2-years, interquartile range (11.7 to 14.6 years). Greater RNFL thickness (GDx-VCC) was not significantly associated with a lower risk of incident dementia in the full adjusted model [HR per quartile increase 0.95; 95% CI 0.82-1.10]. Similarly, RNFL thickness assessed with HRT II was also not associated with incident dementia in any model (full adjusted model; HR per quartile increase: 1.06; [95% CI 0.93-1.19]. Gender did not modify any associations under study. CONCLUSION: GDx-VCC and HRT II derived RNFL thickness are unlikely to be useful predictors of incident dementia. Higher resolution optical imaging technologies may clarify whether there are useful relationships between neuro-retinal morphology and brain measures.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease.

BACKGROUND AND OBJECTIVES: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. METHODS: This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.

Metabolite and Lipid Biomarkers Associated With Intraocular Pressure and Inner Retinal Morphology: 1H NMR Spectroscopy Results From the UK Biobank.

Purpose: The purpose of this study was to assess metabolites associated with intraocular pressure (IOP) and inner retina structure. Methods: We cross-sectionally assessed 168 non-fasting plasma metabolites measured by nuclear magnetic resonance (NMR) spectroscopy with IOP (n = 28,195), macular retinal nerve fiber layer thickness (mRNFL; n = 10,584), and macular ganglion cell inner plexiform layer thickness (mGCIPL; n = 10,554) in the UK Biobank. We used multiple linear regression models adjusting for various covariates with probit-transformed metabolite levels as predictors for each outcome. Each estimate represents the difference in outcome variable per standard deviation increase in the probit-transformed metabolite values. We used the number of effective (NEF) tests and false discovery rate (FDR) to adjust for multiple comparisons for metabolites and metabolite classes, respectively. Results: In individual metabolite analysis, multiple amino acids, especially branched-chain amino acids, were associated with lower IOP (-0.12 mm Hg; 95% confidence interval = -0.16 to -0.07; NEF = 2.7E-05). Albumin, 3 hydroxybutyrate, lactate, and several lipids were associated with higher IOP (range = 0.07 to 0.18 mm Hg, NEF = ≤ 0.039). In IOP-adjusted analyses, five HDL-related metabolites were associated with thinner mRNFL (-0.15 microns for all metabolites, NEF = ≤ 0.027), whereas five LDL-related metabolites were associated with thicker mGCIPL (range = 0.17 to 0.20 microns; NEF = ≤ 0.044). In metabolite class analysis, the lipid components of lipoproteins (cholesterol, triglycerides, etc.) were not associated with our outcomes (FDR > 0.2 for all); yet multiple lipoproteins were significantly (FDR < 0.05) associated with all outcomes. Conclusions: Branched-chain amino acids were associated with lower IOP, HDL metabolites were associated with thinner mRNFL, and LDL metabolites were associated with thicker mGCIPL.

Towards modifying the genetic predisposition for glaucoma: An overview of the contribution and interaction of genetic and environmental factors.

Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of large-scale, population-based cohorts and biobanks, combining genotyping and detailed phenotyping, has greatly accelerated research into the aetiology of glaucoma in recent years. Hypothesis-free genome-wide association studies have furthered our understanding of the complex genetic architecture underpinning the disease, while epidemiological studies have provided advances in the identification and characterisation of environmental risk factors. It is increasingly recognised that the combined effects of genetic and environmental factors may confer a disease risk that reflects a departure from the simple additive effect of the two. These gene-environment interactions have been implicated in a host of complex human diseases, including glaucoma, and have several important diagnostic and therapeutic implications for future clinical practice. Importantly, the ability to modify the risk associated with a particular genetic makeup promises to lead to personalised recommendations for glaucoma prevention, as well as novel treatment approaches in years to come. Here we provide an overview of genetic and environmental risk factors for glaucoma, as well as reviewing the evidence and discussing the implications of gene-environment interactions for the disease.