A unilateral lesion in a post-geniculate section of the retino-geniculo-striate pathway (hereafter: optic pathway) leads to binocular vision loss in the contralateral visual hemifield. The extent of additional damage following such a lesion is not fully understood. Although degeneration of the ipsilesional optic tract and both retinas has been reported, potential degeneration in the contralesional post-chiasmal optic pathway has largely been overlooked. We aimed to investigate the presence and extent of contralesional degeneration in individuals with post-geniculate optic pathway lesions. In this case-control study, we examined the optic pathways of study cohorts with 10 (dataset 1) and 22 (dataset 2) individuals with unilateral post-geniculate lesions and 12 (dataset 1) and 17 (dataset 2) neurologically healthy controls. For both datasets, we applied a higher-order analysis framework, i.e. fixel-based analysis, to diffusion-weighted imaging data to evaluate the white matter of optic pathway tracts. Fixel-based analysis showed reduced fibre density and fibre-bundle cross-section in the ipsi- and contralesional optic pathways. Post-hoc analysis and observations further demonstrated reduced fibre density and fibre-bundle cross-section in the forceps major. In individuals with unilateral post-geniculate optic pathway lesions, degeneration extends beyond their primary site to the optic pathway tracts, including contralesional ones. This pattern of widespread transhemispheric degeneration suggests that it spreads more extensively than previously recognized and highlights the need for understanding its implications for visual function.

Purpose:The purpose of this study was to investigate the association between serum uric acid (UA) levels and primary open-angle glaucoma (POAG), and to explore potential genetic links and causal relationships using large population-based cohorts. Methods:We analyzed data from 7443 participants in the LifeLines cohort and 90,107 participants in the UK Biobank, all aged ≥55 years. Glaucoma status was determined based on questionnaires and International Classification of Diseases (ICD) codes. Logistic regression was used to assess the association between serum UA levels and glaucoma, adjusting for demographic, clinical, and lifestyle covariates. Meta-analysis was performed to combine results across cohorts. Genetic correlation, polygenic risk score (PRS), and two-sample Mendelian randomization (MR) analyses were conducted to evaluate shared genetic architecture and causality. Results:Higher serum UA levels were significantly associated with increased odds of glaucoma in the UK Biobank (per 0.1 mM increase, odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.02-1.11, P = 0.007 in the fully adjusted model), with consistent findings in meta-analysis. No association was observed in the LifeLines cohort. Genetic analyses revealed no evidence of shared genetic correlation or causality between UA and glaucoma. The UA PRS was not associated with glaucoma odds, and the glaucoma PRS showed no association with serum UA levels. Conclusions:Elevated serum UA levels were phenotypically associated with glaucoma, but genetic analyses did not support a causal link. UA may reflect systemic oxidative stress rather than directly contribute to glaucoma pathogenesis. Further studies are needed to clarify underlying mechanisms and clinical relevance.

Early detection of glaucoma prevents blindness but its low population-based prevalence impedes cost-effective screening. We investigated whether genetic pre-screening could increase the prior probability. Design, methods, and primary analysis were pre-specified and published previously. In this prospective study, we invited 1829 participants aged 55 + from the Dutch Lifelines cohort, selecting from either the highest or lowest 20

PURPOSE. Binocular visual field (VF) loss affects vision-related quality of life (VR-QoL) but the relationship between specific VF loss patterns and difficulties with specific tasks remains poorly understood. Archetypal analysis offers a promising method to elucidate spatial patterns of VF loss. In this study, we aimed to develop archetypes for binocular VF loss and assess their relationship with VR-QoL. METHODS. We included 7305 pairs of reliable standard automated perimetry (24-2 SITA fast and standard) test results of patients from 5 glaucoma clinics in England from a Healthcare Quality Improvement Partnership-funded audit. We executed an archetypal analysis on the corresponding integrated VFs (estimates of the binocular VFs from pairs of monocular VFs) to identify the best-fitting set of archetypes from our dataset. Then, we used these archetypes to deconstruct the binocular VF of 269 patients with glaucoma from the Netherlands that had completed 4 different VR-QoL questionnaires. Finally, relationships between each of the archetypes and different aspects of VR-QoL were analyzed. RESULTS. The archetypal analysis demonstrated that a solution comprising 12 archetypes provides the best-fitting model. Our analysis of the 269 patients' with glaucoma data showed various significant and plausible relationships between the different archetypes and various aspects of VR-QoL. CONCLUSIONS. Our results demonstrate how archetypes can elucidate relationships between the location of a VF defect and different aspects of VR-QoL in glaucoma. This may help clinicians and patients better understand the impact of different types of VF defects.

BackgroundIndividuals with an abnormal birth are at risk of having ophthalmic complications and visual impairment. The aim of this study was to understand the relationship between birth-related characteristics and vision-related quality of life (VR-QoL) in adults in the general population.MethodsWe used data from Lifelines, a population-based cohort study from the North of Netherlands (n = 167,000). We included individuals with National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25) data (n = 29,840; 18-55 years). Included birth-related characteristics were gestation length, birth weight, mode of delivery, and the presence of birth defects. We used ordinal regression with the NEI-VFQ-25 items as dependent variable and the birth-related characteristics as independent variables. Analyses were adjusted for age and gender, and corrected for multiple hypothesis testing using false discovery rate (FDR).ResultsParticipants with birth defects directly related to eye or brain development showed a poor VR-QoL in 9/10 subscales (FDR-corrected P value q < 0.001 to 0.05) with the most pronounced effect for difficulties performing peripheral vision-related activities. Individuals with birth defects not directly related to eye or brain development showed a poor VR-QoL in 4/10 subscales (q = 0.02 to 0.05). Early preterm birth was related to the general vision (q = 0.02) and vision specific social functioning (q = 0.05) subscales. High birth weight (>4500 g) contributed to general vision problems (q = 0.05), and vacuum or forceps mode of delivery was associated with difficulties performing activities under low luminance conditions (q = 0.02).ConclusionAt the level of the general population, birth-related characteristics are related to VR-QoL. To elucidate the underlying mechanisms, future studies could add visual function to the questionnaire outcomes.

Purpose:Chronic kidney disease (CKD) and glaucoma are major health burdens, yet their phenotypic and genotypic relationships remain poorly understood. This population-based study aims to explore the phenotypic and genotypic relationship between CKD and glaucoma. Methods:In this cross-sectional study, European-descended individuals aged 55 years + from the Lifelines Cohort (n = 21,475; 906 CKD cases) and UK Biobank (n = 90,133; 3323 CKD cases) were analyzed. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m². In Lifelines, glaucoma was defined using a previously established algorithm, which integrated self-reported glaucoma diagnosis and treatment with NEI-VFQ-25 scores. In the UK Biobank, primary open angle glaucoma cases were identified using a combination of self-reported diagnoses, treatment history, and International Classification of Diseases (ICD) codes. Logistic regression assessed the phenotypic association of CKD and eGFR with glaucoma, adjusting for demographic and clinical factors. Genetic analysis included linkage disequilibrium score regression (LDSR), polygenic risk scores (PRS), and Mendelian randomization (MR). Results:The prevalence of glaucoma was 8.2% in Lifelines and 5.5% in the UK Biobank. In Lifelines, no association between eGFR and glaucoma was found, but eGFR quintile 5 showed increased odds of glaucoma when excluding possible cases (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.07-2.23, P = 0.02). In the UK Biobank, per 10 mL/min/1.73 m² eGFR increase was associated with higher odds of glaucoma (OR = 1.04, 95% CI = 1.02-1.07, P = 0.001), and quintile 5 exhibited increased odds regardless of whether all cases were included (OR = 1.14, 95% CI = 1.03-1.25, P = 0.01) or possible cases were excluded (OR = 1.13, 95% CI = 1.02-1.25, P = 0.02). No significant associations were found between CKD and glaucoma. LDSR showed no genetic correlations, but PRS indicated a significant association between glaucoma PRS and higher eGFR. MR revealed no causal relationship between eGFR and glaucoma. Conclusions:No association was found between CKD and glaucoma, but higher eGFR was associated with increased odds of glaucoma. These findings challenge the assumed link between low eGFR and glaucoma and highlight the need for further research into the underlying mechanisms and potential clinical implications of this association.

PURPOSE: Primary open angle glaucoma (POAG, hereafter referred to as glaucoma) is a neuro-ophthalmic disease characterized by progressive degeneration of the retinal ganglion cells and nerve fibers. However, the exact pathogenesis of this disease remains unresolved, notably including its effect on the neural circuits of the visual pathway and cortex. METHODS: We used both resting state (RS) and stimulus-driven functional MRI and applied a novel analysis technique (Bayesian Connective Field Modelling) to investigate the intra-cortical functional connective organization of the early visual cortex of patients with POAG. Analogous to population receptive field modelling for stimulus-driven activity, our connective field approach models how the activity in one cortical area (e.g. V2) can be explained based on that of another (e.g. V1). RESULTS: We compared the CF parameters obtained for the early visual cortical areas in glaucoma to those of control participants. Our results show that in both RS and stimulus-driven conditions, CF sizes in early visual areas are smaller in glaucoma compared to control participants. To assess if these differences could be related to the ocular damage altering the visual input to the visual cortex, the control participants also observed the visual stimuli with a simulated scotoma (SS), designed to match the visual sensitivity of a participant affected by glaucoma as assessed using standard automated perimetry (SAP). In this condition, no differences in CF size were observed. Moreover, we found that CF size did not correlate with glaucoma severity, as assessed using both SAP and optical coherence tomography (OCT). CONCLUSION: The observed differences in CF metrics may be the result of local reorganization or neurodegeneration of the early visual cortex that must have developed already at an early disease stage. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement AI and JC were supported by the European Union s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 661883 (EGRET) and No. 641805 (NextGenVis). AI and JC received additional funding from the Graduate School of Medical Sciences (GSMS), University of Groningen, The Netherlands. The funding organizations had no role in the design, conduct, analysis, or publication of this research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study procedures followed the Declaration of Helsinki and were approved by the ethics board of the University Medical Center Groningen (UMCG) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Peripheral crowding is the difficulty in recognizing objects in cluttered peripheral vision, affecting tasks like reading, visual search, and driving. The luminance of the environment also plays a significant role in these tasks. However, the potential interaction between crowding and luminance is still not clear. This study examined peripheral crowding (10 deg) by measuring its magnitude and critical spacing across a wide range of luminance levels, spanning from scotopic to photopic conditions. Ten participants binocularly identified the orientation of a target presented alone or flanked by four flankers. Responses were made by adjusting a central reference stimulus. Luminance was manipulated using neutral-density filter goggles (0.02-200 cd/m2). The distribution of differences between reported and actual target orientations was obtained, and the standard deviation of these distributions was taken as the perceptual error for each condition. Crowding magnitude was calculated by dividing perceptual error in the flanked condition by that in the isolated condition. Critical spacing was defined as the maximum separation between target and flanker for crowding to occur. It was calculated by fitting a hinged-line to the perceptual errors as a function of target-flanker-distance. Crowding magnitude and critical spacing were both measured for flankers with either no gap, a gap with a size matching each individual's luminance-specific acuity threshold, or a suprathreshold (200 % of worst-acuity) gap. Results showed that both crowding magnitude and critical spacing were similar under all luminance and gap conditions. Our findings suggest that the same peripheral crowding mechanisms operate under scotopic and photopic conditions.

In clinical care, glaucoma patients are often assumed to have normal vision as long as each point of visual space is seen normally by at least one eye. Recent studies have challenged this assumption. In glaucoma, visual perception of spatially fragmented binocular input may be altered by long-term neural adaptation and by acute sensory effects. These two components cannot be disentangled easily in glaucoma patients, but the latter component can be isolated with simulated visual field defects in healthy subjects. Therefore, the aim of this study was to find out if simulated non-overlapping visual field defects (NOVFDs) can hamper certain aspects of visual perception in healthy subjects. We included 10 healthy subjects in this cross-sectional, observational study. Subjects underwent psychophysical experiments targeting contrast sensitivity, motion perception (line motion and coherent dot motion), and shape recognition. Experiments were done in three different viewing conditions using a stereoscope: (1) binocularly, (2) with simulated NOVFDs, and (3) monocularly. The NOVFDs viewing condition resulted in a decreased performance across all tested aspects of visual perception, when compared to the binocular viewing condition. The NOVFDs viewing condition resulted in a poorer performance in shape recognition compared to the monocular viewing condition. No other differences were observed between these two viewing conditions. Our results show that simulated NOVFDs impair certain visual functions. This contributes to the basic understanding of visual perception in healthy subjects and acts as a first step in the understanding of the relationship between disease stage and the visual problems that glaucoma patients may experience.

Purpose: Continuous visual stimulus tracking could be used as an easy alternative to standard automated perimetry (SAP) for visual function screening. With continuous visual stimulus tracking, we simplified the perimetric task to following a moving dot on a screen with the eyes. Here, we determined whether tracking performance (the agreement between gaze and stimulus position) enables the detection and quantification of glaucomatous visual function loss (in terms of SAP), and whether it shows a learning effect. Methods: We evaluated the tracking performance of 36 cases with early, moderate, or severe glaucoma (median with interquar tile range [IQR] age = 70 [67-74] years) and 36 controls (median = 70, IQR = 67-72 years). All participants monocularly tracked a moving stimulus (Goldmann size III) at 3 Weber contrast levels: 40, 160, and 640%, while their eye movements were recorded. Results: Glaucoma decreased the tracking performance, with the most severe reduction in the severe glaucoma cases. A distinction between groups was possible, but depended on the contrast level: tracking performance of early glaucoma cases was significantly different from controls only at 40% contrast. Within the cases, glaucomatous visual function loss (SAP Mean Sensitivity [MS]) was best correlated with tracking performance when using 160% contrast. There was no significant learning effect. Conclusions: Overall, the data indicate that it is possible to detect and quantify glaucomatous visual function loss with continuous visual stimulus tracking. Translational Relevance: Continuous visual stimulus tracking is an easy, fast, and intuitive technique that has the potential for diagnostic applications in detection of new glaucoma cases and monitoring of previously diagnosed cases.

Purpose: Glaucoma screening potentially prevents blindness but is currently considered not cost effective due to insufficient screening test specificity given a low disease prevalence in the general population. Genetic pre‐screening could increase the prior probability (higher prevalence in a selected population). The aim of this study was to identify the relative risk of glaucoma in a subgroup of the general population with a high compared to one with a low genetic glaucoma risk. Methods: The study protocol has been published previously (PMID: 33413217). We invited 1600 participants from the European Lifelines cohort ( n = 165 000) aged 55+. Participants belonged to either the highest or lowest 20% of a GWAS‐based genetic risk score distribution; subgroups had similar age and gender. Researchers and participants were blinded regarding subgroup allocation. All participants underwent frequency doubling perimetry (FDT), optical coherence tomography (OCT) of the peripapillary retinal nerve fibre layer, and fundus photography to assess the optic nerve head (ONH). Any abnormal test result resulted in an ophthalmic exam including gonioscopy. Participants were classified as definite (abnormal FDT and either abnormal OCT or ONH), probable (either abnormal FDT or abnormal OCT and ONH), or possible (normal FDT with either abnormal OCT or ONH) open‐angle glaucoma (OAG), or as healthy. We obtained the relative risk of combined definite and probable OAG compared to healthy, excluding possible OAG. Results: A total of 1031 participants responded (65%; 493 with high versus 538 with low risk). Of those, 31 (29 versus 2) were classified as definite and 28 (21 versus 7) as probable OAG. The prevalence of combined definite and probable OAG was 5.7%. The relative risk was 6.3 (95% CI 3.1–12.9). Conclusions: Genetic pre‐screening seems a promising way to increase the prior probability of glaucoma and thus make glaucoma screening more cost‐effective.

PURPOSE:Glaucoma patients may be considered to have normal vision as long as each point of visual space is perceived by at least 1 eye, that is, with an intact binocular visual field (VF). We aimed to investigate the effect of nonoverlapping VF defects on vision-related quality of life (VR-QoL) in glaucoma. DESIGN:Cross-sectional study. SUBJECTS AND CONTROLS:Two hundred sixty-nine glaucoma patients and 113 controls. METHODS:We evaluated VR-QoL of glaucoma patients (n = 269) and controls (n = 113) using 4 different questionnaires (National Eye Institute visual function questionnaire [NEI-VFQ-25], NEI-VFQ neuro-ophthalmology supplement, Glaucoma Quality of Life-15, and a luminance-specific questionnaire). We defined "differential VF" (DVF) as a measure of location-specific differences in the VFs of both eyes. Within the group of glaucoma patients, we analyzed the relationship between different aspects of VR-QoL and DVF using ordinal multiple regression analysis. Analyses were adjusted for age, sex, integrated VF (IVF; an estimate of the binocular VF from the monocular VFs), and higher visual acuity of both eyes, and corrected for multiple hypothesis testing. MAIN OUTCOME MEASURES:Vision-related quality of life. RESULTS:Glaucoma patients had lower VR-QoL than controls. Among the glaucoma patients, DVF was significantly associated with general vision (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.54-0.89), peripheral vision (OR, 0.68; 95% CI, 0.54-0.86), walking on uneven ground (OR, 0.73; 95% CI, 0.58-0.93), crossing the street (OR, 0.61; 95% CI, 0.46-0.83), seeing other road users coming from the side (OR, 0.67; 95% CI, 0.52-0.85), cycling during the day (OR, 0.64; 95% CI, 0.46-0.89) and seeing outside on a sunny day (OR, 0.73; 95% CI, 0.57-0.94). In general, IVF was a stronger predictor of VR-QoL than DVF. CONCLUSIONS:Nonoverlapping VF defects affect VR-QoL. Although IVF is strongly associated with VR-QoL, basing clinical decisions only on IVF leads to overlooking vision problems that patients may have. FINANCIAL DISCLOSURE(S):The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Aims/Purpose: To investigate the effect of the orthostatic hypotension test on the macular and disc capillaries, in subjects with different blood pressure (BP) status. Methods: We prospectively recruited ophthalmologically healthy subjects (age 50–65) from a large‐scale population‐based Dutch cohort. We allocated participants to four groups: low BP, normal BP, treated high BP, and untreated high BP. We obtained two 6x6 mm macular and two 6x6 mm disc OCTA scans of the superficial capillaries. After lying for 5 min, participants stood up for 3 min, following which third scans were obtained from both regions. We quantified vessel density (VD) using customized software. We used linear mixed models to compare VD among groups before and after the orthostatic hypotension test. Results: We included 98 eyes from 98 subjects for the macular scans and 95 for the disc scans. Parafoveal VD was similar between groups ( p = 0.65) and increased following the orthostatic hypotension test (40.4%, 40.6% pre‐test and 40.7% post‐test; p = 0.002). Post hoc analysis revealed that this difference was only significant between the first and third scan ( p = 0.001). Peripapillary VD remained unchanged pre‐ and post‐test ( p = 0.61), but differed between groups (low BP: 44.0%, normal BP: 45.0%, treated high BP: 44.1%, untreated high BP: 44.5%; p = 0.022). Post hoc analysis revealed that these differences were significant between normotensives and subjects with low BP ( p = 0.028) and borderline between normotensives and subjects with treated high BP ( p = 0.072). Conclusions: We observed an autoregulatory response of macular, but not disc, capillaries, following BP drop due to the orthostatic hypotension test.

Primary open -angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta -analysis across 15 biobanks (of the Global Biobank Meta -analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multiancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene -enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.

PurposeTo evaluate abnormalities in serum and aqueous humor uric acid (UA) levels in primary angle closure glaucoma (PACG).MethodsPatients with PACG and age-similar and gender-similar controls (patients scheduled for cataract extraction) were enrolled prospectively. Serum UA levels were determined by enzymatic colorimetry; aqueous humor UA levels by Enzyme-Linked ImmunoSorbent Assay. A t-test was used to compare UA levels between PACG patients and controls, with one-way ANOVA used to compare levels across PACG subgroups with differing disease severity. Comparisons between PACG patients and controls were adjusted for systemic and ocular confounding factors using binary logistic regression.ResultsIn all, 131 PACG patients and 112 controls were included. The serum UA level was 266 ± 69 μmol/L in the PACG group and 269 ± 73 μmol/L in the control group (p = 0.71). The aqueous humor UA level was 35.4 ± 8.2 μmol/L in the PACG group and 53.9 ± 18.6 μmol/L in the control group (p < 0.001). This difference remained significant after adjusting for age, gender, systolic blood pressure, diastolic blood pressure, body mass index, axial length, central corneal thickness, anterior chamber depth, lens thickness, white-to-white distance, corneal endothelial cell density, and serum UA level (odds ratio: 0.88, 95% confidence interval: 0.83–0.93, p < 0.001).ConclusionAqueous humor UA levels differ between PACG patients and controls, but serum UA levels do not. This indicates that local UA plays a role in the pathogenesis of PACG, but systemic UA does not.