Glaucoma is a leading cause of permanent blindness, affecting 80 million people worldwide. Recent studies have emphasized the importance of neuroinflammation in the early stages of glaucoma, involving immune and glial cells. To investigate this further, we used the GSE27276 dataset from the GEO (Gene Expression Omnibus) database and neuroinflammation genes from the GeneCards database to identify differentially expressed neuroinflammation-related genes associated with primary open-angle glaucoma (POAG). Subsequently, these genes were submitted to Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes for pathway enrichment analyses. Hub genes were picked out through protein-protein interaction networks and further validated using the external datasets (GSE13534 and GSE9944) and real-time PCR analysis. The gene-miRNA regulatory network, receiver operating characteristic (ROC) curve, genome-wide association study (GWAS), and regional expression analysis were performed to further validate the involvement of hub genes in glaucoma. A total of 179 differentially expressed genes were identified, comprising 60 upregulated and 119 downregulated genes. Among them, 18 differentially expressed neuroinflammation-related genes were found to overlap between the differentially expressed genes and neuroinflammation-related genes, with six genes (SERPINA3, LCN2, MMP3, S100A9, IL1RN, and HP) identified as potential hub genes. These genes were related to the IL-17 signaling pathway and tyrosine metabolism. The gene-miRNA regulatory network showed that these hub genes were regulated by 118 miRNAs. Notably, GWAS data analysis successfully identified significant single nucleotide polymorphisms (SNPs) corresponding to these six hub genes. ROC curve analysis indicated that our genes showed significant accuracy in POAG. The expression of these genes was further confirmed in microglia, Müller cells, astrocytes, and retinal ganglion cells in the Spectacle database. Moreover, three hub genes, SERPINA3, IL1R1, and LCN2, were validated as potential diagnostic biomarkers for high-risk glaucoma patients, showing increased expression in the OGD/R-induced glaucoma model. This study suggests that the identified hub genes may influence the development of POAG by regulation of neuroinflammation, and it may offer novel insights into the management of POAG.

OBJECTIVE: Our study aimed to investigate the relationship between vascular endothelial growth factor (VEGF), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory complex, erythropoietin (EPO) levels, and ocular hemodynamics in patients diagnosed with primary open-angle glaucoma (POAG).
METHODS: This is a prospective observational study. Patients diagnosed with POAG at The Sixth Hospital of Wuhan hospital between November 2022 and February 2023were enrolled.The patients were categorized into three groups based on the average visual field defect (mean deviation, MD) value: severe injury group (MD > 12 dB, 93 cases), moderate injury group (7 ≤ MD ≤ 12 dB, 89 cases), and mild injury group (MD < 7 dB, 85 cases). The levels of VEGF, NLRP3 inflammatory complex, EPO, and ocular hemodynamics were compared among the groups. Furthermore, the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG was analyzed using Pearson correlation analysis. After adjusting for confounding factors such as age and gender, multivariate Logistic regression analysis was performed with the ocular hemodynamics indexes being used as dependent variables, and VEGF, NLRP3, ASC, Caspase-1, and EPO being used as independent variables.
RESULTS: A total of267 patients with POAG were enrolled. There were no significant differences in sex, age, body mass index, systolic blood pressure, diastolic blood pressure, smoking, alcohol consumption, and blood glucose between the two groups (P > 0.05). The levels of NLRP3, ASC, Caspase-1, and EPO in the severe and moderate injury groups were higher than those in the mild injury group, whereas the VEGF levels were lower in the severe and moderate groups compared to the mild group, showing significant differences (P < 0.05). The severe group exhibited higher levels of NLRP3, ASC, Caspase-1, and EPO than the moderate group, while the VEGF levels were lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). The peak systolic velocity(PSV) and resistance index (RI) were higher in the severe and moderate groups than in the mild group, whereas the EDV was significantly lower in the severe and moderate groups compared to the mild group (P < 0.05). The severe group exhibited higher PSV and RI values compared to the moderate group, while the EDV was lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). Pearson correlation analysis was performed to examine the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG. VEGF, NLRP3, ASC, Caspase-1, and EPO showed positive correlations with PSV and RI, and negative correlations with EDV in patients with POAG. Regression analysis showed that VEGF, NLRP3, ASC, Caspase-1 and EPO were significantly correlated with ocular hemodynamics in POAG (all P < 0.001).
CONCLUSIONS: We demonstrated that the levels of VEGF, NLRP3 inflammatory complex, and EPO were highly associated with ocular hemodynamics in patients diagnosed with POAG.

Background/Objectives: To investigate macular vascular biomarkers for the detection of primary open-angle glaucoma (POAG). Methods: A total of 56 POAG patients and 94 non-glaucomatous controls underwent optical coherence tomography angiography (OCTA) assessment of macular vessel density (VD) in the superficial (SCP), and deep (DCP) capillary plexus, foveal avascular zone (FAZ) area, perimeter, VD, choriocapillaris and outer retina flow area. POAG patients were classified for severity based on the Glaucoma Staging System 2 of Brusini. ANCOVA comparisons adjusted for age, sex, race, hypertension, diabetes, and areas under the receiver operating characteristic curves (AUCs) for POAG/control differentiation were compared using the DeLong method. Results: Global, hemispheric, and quadrant SCP VD was significantly lower in POAG patients in the whole image, parafovea, and perifovea (p < 0.001). No significant differences were found between POAG and controls for DCP VD, FAZ parameters, and the retinal and choriocapillaris flow area (p > 0.05). SCP VD in the whole image and perifovea were significantly lower in POAG patients in stage 2 than stage 0 (p < 0.001). The AUCs of SCP VD in the whole image (0.86) and perifovea (0.84) were significantly higher than the AUCs of all DCP VD (p < 0.05), FAZ parameters (p < 0.001), and retinal (p < 0.001) and choriocapillaris flow areas (p < 0.05). Whole image SCP VD was similar to the AUC of the global retinal nerve fiber layer (RNFL) (AUC = 0.89, p = 0.53) and ganglion cell complex (GCC) thickness (AUC = 0.83, p = 0.42). Conclusions: SCP VD is lower with increasing functional damage in POAG patients. The AUC for SCP VD was similar to RNFL and GCC using clinical diagnosis as the reference standard.

The eye is vulnerable to the adverse effects of air pollution. Previous experimental study found that fine particulate matter (PM2.5) had a direct toxic effect on intraocular tissues. However, clinical evidence for the impact of air pollutants exposure on functional and structural changes in glaucoma remains scarce. A total of 120 patients with primary open-angle glaucoma (POAG) who met the inclusion criteria were included in this retrospective study. The standardized ophthalmic examination, such as intraocular pressure (IOP), visual field, optical coherence tomography, and comprehensive physical examination, were performed. The air pollution data, including PM2.5 concentration and air quality index (AQI), were collected. PM2.5 and AQI for the day of the medical examination, as well as one month, and three months before the medical examination date, were investigated. In our results, higher average exposure levels for one-month and three-month, were associated with increased IOP (r=0.229, P=0.013; r=0.204, P=0.028, respectively) and decreased visual field mean sensitivity (MS) (r=-0.212, P=0.037; r=-0.305, P=0.002, respectively). PM2.5 concentrations for the day of the medical examination was not significantly associated with ocular parameters. In multiple linear regression analysis adjusted for demographic and clinical factors, higher PM2.5 exposure for one month was associated with elevated IOP (P=0.040, β=0.173, 95 %CI=0.008-0.337). We also found an association between PM2.5 and MS (one-month exposure: β=-0.160, P=0.029; three-month exposure: β=-0.238, P=0.002). The logistic regression analysis found that three-month average PM2.5 exposure level was significantly associated with the disease severity (β=0.043, P=0.025, 95 %CI=1.005-1.084). In conclusion, this study is the first to investigate the relationship between air pollution and detailed ocular parameters of POAG patients in Shanghai over a three-year period, and to explore the effects of different exposure times of PM2.5 on glaucoma. This study found that PM2.5 exposure was correlated with elevated IOP and decreased MS. The one-month PM2.5 exposure level had the most significant effects on IOP. The three-month PM2.5 exposure level was an independent risk factor for POAG severity. Current evidence suggests there may be an association between PM2.5 exposure and POAG.

OBJECTIVE: Loss to follow-up (LTFU) in primary open-angle glaucoma (POAG) can lead to undertreatment, disease progression, and irreversible vision loss. Patients who become LTFU either eventually re-establish glaucoma care after a lapse or never return to the clinic. The purpose of this study is to examine a large population of POAG patients who became LTFU to determine the proportion that return to care and to identify demographic and clinical factors associated with non-return after LTFU.
METHODS: Retrospective longitudinal cohort study PARTICIPANTS: Patients with a diagnosis of POAG with a clinical encounter in 2014 in the IRIS® Registry (Intelligent Research in Sight) METHODS: We examined follow-up patterns for 553,663 patients with POAG who had an encounter in the IRIS Registry in 2014 by following their documented clinic visits through 2019. LTFU was defined as exceeding one calendar year without an encounter. Within the LTFU group, patients were classified as returning after a lapse in care (return after LTFU) or not (non-return after LTFU).
METHODS: Proportion of patients with non-return after LTFU and baseline demographic and clinical characteristics associated with non-return among LTFU POAG patients.
RESULTS: Among 553,663 POAG patients, 277,019 (50%) had at least one episode of LTFU over the 6-year study period. Within the LTFU group, 33% (92,471) returned to care and 67% (184,548) did not return to care. Compared to those who returned to care, LTFU patients with non-return were more likely to be older (age >80 years; RR=1.48; 95% CI: 1.47-1.50), to have unknown/missing insurance (RR=1.31; 95% CI: 1.30-1.33), and to have severe-stage POAG (RR=1.13; 95% CI: 1.11-1.15). Greater POAG severity and visual impairment were associated with non-return with a dose-dependent relationship in the adjusted model that accounted for demographic characteristics. Among those with return after LTFU, almost all returned within 2 years of last appointment (82,201; 89%) rather than 2 or more years later.
CONCLUSIONS: Half of POAG patients in the IRIS Registry had at least one period of LTFU, and two-thirds of LTFU POAG patients did not return to care. More effort is warranted to re-engage the vulnerable POAG patients who become LTFU.

OBJECTIVE: To examine the associations between open-angle glaucoma (OAG) subtypes and dementia in 2019 California (CA) Medicare beneficiaries.
METHODS: Retrospective cross-sectional study.
METHODS: OAG diagnosis was determined by the International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes in Part B claims, including the following OAG subtypes: primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), pseudoexfoliative glaucoma (PXG), and pigmentary glaucoma (PG). Diagnoses of any dementia, Alzheimer\'s dementia (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD) were identified by ICD-10 diagnosis codes. Covariates included: demographics, systemic diseases, depression, hearing loss, obesity, smoking and alcohol-related disorders, and long-term aspirin, anticoagulant, and antithrombotic or antiplatelet use. Univariate and multivariable logistic regression models were used to assess the associations between OAG and dementia, adjusting for all covariates. Age-stratified analysis was also performed for beneficiaries aged 65-74 years, 75-84 years, and 85+ years.
RESULTS: Among 2,431,150 CA Medicare beneficiaries included in this study, 104,873 (4.3%) had POAG, 9,199 (0.4%) had NTG, 4,045 (0.2%) had PXG and 1,267 (0.05%) had PG. The overall prevalence of any dementia was 3.2% (n=79,009). In adjusted analyses, the odds of any dementia were lower for beneficiaries with all OAG subtypes compared to beneficiaries without glaucoma (odds ratio [OR]=0.74 for POAG, OR=0.74 for PXG, OR=0.60 for NTG, and OR=0.38 for PG; p<0.01). In age-stratified analyses, beneficiaries with PXG had greater odds of VD (OR: 2.84, p=0.006, [aOR]: 2.18, p=0.04) in the youngest age stratum (65-74 years) compared to patients with no glaucoma. The odds for any dementia were lower for beneficiaries with all OAG subtypes compared to beneficiaries without glaucoma in the oldest, but not in the youngest age stratum.
CONCLUSIONS: In the 2019 CA Medicare population, PXG is associated with an increased likelihood of VD in beneficiaries 65-74 years old, while other subtypes of POAG are associated with a decreased likelihood of any dementia. These findings may suggest selection bias since older adults who continue to follow up with glaucoma care may be more cognitively intact. Further studies are needed to better understand the complex relationship between glaucoma, dementia, and their subtypes.

OBJECTIVE: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals.
METHODS: Cross-sectional analysis.
METHODS: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study).
METHODS: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements.
METHODS: Proportion of patients with POAG after stratification according to the GRS.
RESULTS: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35-8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79-9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10-4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10-6).
CONCLUSIONS: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: This study aimed to investigate and compare the anterior scleral thickness (AST) among high myopia (HM), primary open-angle glaucoma (POAG), and POAG with HM (HMPOAG) groups.
UNASSIGNED: Thirty-two HM eyes, 30 POAG eyes, and 31 HMPOAG eyes were included. The Schlemm\'s canal (SC) area, trabecular meshwork (TM) thickness, scleral spur (SS) length, and AST were measured using swept-source optical coherence tomography. AST was measured at 0 mm (AST0), 1 mm (AST1), 2 mm (AST2), and 3 mm (AST3) from SS.
UNASSIGNED: The HMPOAG group had significantly thinner AST, SS length, and TM thickness than the HM and POAG groups (all p < 0.05). In addition, the SC area of the HMPOAG group was also significantly smaller than that of the HM group (p < 0.001).
UNASSIGNED: The HMPOAG group had the thinnest AST, shortest SS, thinnest TM, and smallest SC. The thinnest AST might contribute to the shortest SS, and further to the thinnest TM and smallest SC in the HMPOAG group. AST might be a novel clinical indicator in the prediction and evaluation of POAG.

Glaucoma is the leading cause of irreversible blindness worldwide. Previous observational studies have suggested a relationship between central corneal thickness (CCT) and glaucoma; however, the results are inconsistent. This study aimed to investigate whether CCT is associated with a risk for developing open-angle glaucoma (OAG). We employed two-sample Mendelian randomization to assess the relationship between CCT and OAG, namely, primary open-angle glaucoma (POAG) and suspected glaucoma. Genetic instruments composed of variants associated with CCT at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies from Iglesias et al. for discovery and Bonnemaijer et al. for replication. Summary-level statistics for these instruments for the OAG were obtained from the FinnGen Project (Release 10). Inverse-variance-weighted regression of genetic susceptibility predicted that increased CCT was positively associated with an increased risk for POAG (odds ratio [OR], 1.005; 95% confidence interval [CI], 1.002-1.008; P = 0.001) and suspected glaucoma (OR, 1.006; 95% CI, 1.003-1.009; P < 0.001). In the replication sample of CCT, increased CCT was also positively associated with an increased risk for POAG (OR, 1.004; 95% CI, 1.000-1.008; P = 0.029) and suspected glaucoma (OR, 1.005; 95% CI, 1.001-1.008; P = 0.013). We found genetic evidence supporting a potential causal association between increased CCT and the risk of POAG and suspected glaucoma in the European population. This findings indicates the clinical significance of CCT in the diagnosis and treatment of glaucoma. Further studies are needed to elucidate the underlying mechanisms of this causal relationship.

Interactions between trabecular meshwork (TM) cells and their extracellular matrix (ECM) are critical for normal outflow function in the healthy eye. Multifactorial dysregulation of the TM is the principal cause of elevated intraocular pressure that is strongly associated with glaucomatous vision loss. Key characteristics of the diseased TM are pathologic contraction and actin stress fiber assembly, contributing to overall tissue stiffening. Among first-line glaucoma medications, the Rho-associated kinase inhibitor (ROCKi) netarsudil is known to directly target the stiffened TM to improve outflow function via tissue relaxation involving focal adhesion and actin stress fiber disassembly. Yet, no in vitro studies have explored the effect of netarsudil on human TM (HTM) cell contractility and actin remodeling in a 3D ECM environment. Here, we use our bioengineered HTM cell-encapsulated ECM hydrogel to investigate the efficacy of different netarsudil-family ROCKi compounds on reversing pathologic contraction and actin stress fibers. Netarsudil and all related experimental ROCKi compounds exhibited significant ROCK1/2 inhibitory and focal adhesion disruption activities. Furthermore, all ROCKi compounds displayed potent contraction-reversing effects on HTM hydrogels upon glaucomatous induction in a dose-dependent manner, relatively consistent with their biochemical/cellular inhibitory activities. At their tailored EC50 levels, netarsudil-family ROCKi compounds exhibited distinct effect signatures of reversing pathologic HTM hydrogel contraction and actin stress fibers, independent of the cell strain used. Netarsudil outperformed the experimental ROCKi compounds in support of its clinical status. In contrast, at uniform EC50-levels using netarsudil as reference, all ROCKi compounds performed similarly. Collectively, our data suggest that netarsudil exhibits high potency to rescue HTM cell pathobiology in a tissue-mimetic 3D ECM microenvironment, solidifying the utility of our bioengineered hydrogel model as a viable screening platform to further our understanding of TM pathophysiology in glaucoma.