Identification of Retinal Amyloid-Beta in Ex-Vivo Human Glaucoma Eyes Using a Novel Ocular Tracer.

PURPOSE: To characterize the presence of amyloid-beta (Aß) in human glaucoma retina and to test identification of retinal Aß using a novel fluorescent Aß-binding small molecule (AMDX-2011). METHODS: Post-mortem human eyes with (n=4) and without (n=4) glaucoma were acquired from an eye bank. Retinas were dissected, flat-mounted, and fixed. Using the flat-mounts, immunofluorescence was performed against Aß, AMDX-2011 staining was conducted, and images were acquired using fluorescence microscopy. RESULTS: Fluorescence microscopy demonstrated presence of Aß signal that co-localized with AMDX-2011 staining in glaucoma retina. Co-labeled puncta appeared in all quadrants of the retina, including retina temporal to the optic nerve. The puncta were mainly located within the inner layers of the retina. Glaucoma retinas had more co-labeled puncta than control retinas in all locations (P = 0.002-0.02). Co-labeled puncta were also larger in the superior quadrant of glaucoma compared to control retinas (P = 0.02). CONCLUSIONS: Aß was detected in human glaucomatous retina, and its distribution was mapped. AMDX-2011 identification of Aß may lead to future diagnostic tests aimed at detecting Aß in glaucoma patients.

Rates of Visual Field Progression Before and After the Onset of Atrial Fibrillation.

PRECIS: This case-control study investigated the effect of atrial fibrillation (AF) on the progression of glaucoma. The presence of AF and related microvascular damage were associated with a slightly faster visual field loss in glaucoma patients. PURPOSE: To investigate the effect of atrial fibrillation (AF) on glaucoma progression. METHODS: In this longitudinal case-control study, a total of 144 eyes from 105 patients with primary open angle glaucoma were included. 48 eyes of case developed AF during the follow-up followed for 15.6 years. 96 eyes of control that did not have AF at baseline or during follow-up matched for age, baseline glaucoma severity and follow-up period were followed for an average of 14.7 years. Mixed-effects linear models were used to calculate the difference in the VF MD slopes before and after the AF. CHADS2 and CHA2DS2-VASc scores were used to evaluate the risk of thrombosis event, and related microvascular damage was assessed based on these scores. RESULTS: The rate of VF MD change was -0.20 (-0.42 to 0.02) dB/y before AF and -0.28 (-0.47 to -0.09) dB/y after AF for the patients with AF, and -0.21 (-0.25 to -0.17) dB/y for the control. In the multivariable models, the VF slope difference before and after the onset of AF (-0.10 (-0.14 to -0.05) dB/y, P<0.001), higher CHADS2 score (-0.07 (-0.13 to 0.00) dB/y per 1 unit, P=0.040), and higher CHA2DS2-VASc score (-0.05 (-0.10 to 0.00) dB/y per 1 unit, P=0.039) were associated with faster VF MD loss. CONCLUSIONS: The presence of atrial fibrillation and related microvascular damage might accelerate visual field loss. This underscores the need for a comprehensive medical history and management of cardiovascular risk factors to mitigate increase VF loss in glaucoma.

Reference Database for a Novel Binocular Visual Function Perimeter: A Randomized Clinical Trial.

Purpose: To construct a comprehensive reference database (RDB) for a novel binocular automated perimeter. Design: A four-site prospective randomized clinical trial. Subjects and Controls: Three hundred fifty-six healthy subjects without ocular conditions that might affect visual function were categorized into 7 age groups. Methods: Subjects underwent comprehensive ocular examination of both eyes before enrollment. Using the TEMPO/IMOvifa automated perimeter (Topcon Healthcare/CREWT Medical Systems), each subject completed 4 binocular threshold visual field (VF) tests during a single visit: First, practice 24-2 and 10-2 tests were obtained from both eyes. Next, study 24-2 and 10-2 tests were obtained from both eyes. Test order of each sequence was randomized, and the tests were conducted under standard automated perimetry testing conditions: Goldmann stimulus size III, 3183 cd/m2 maximum stimulus intensity, and background intensity of 10 cd/m2, using AIZE-Rapid test strategy. Standard VF reliability indices were assessed. For each subject, 24-2 and 10-2 test results from 1 randomly selected eye were analyzed. Main Outcome Measures: Perimetric threshold sensitivity and reference limits for each test analysis parameter. Results: The ages of the study cohort were widely distributed, with a mean age (standard deviation [SD]) of 52.3 (18.5) years. Sex assignment was 44.0% male and 56.0% female. The majority of subjects self-identified as White (67.4%), followed by Black or African American (13.5%) and Asian (8.7%), with 14.6% self-identified as Hispanic or Latino ethnicity. Mean sensitivity (SD) was 29.1 (1.3) decibels (dB) for the 24-2 and 32.4 (1.0) dB for the 10-2 test. For the 24-2 and 10-2, mean sensitivity (SD) age-related changes averaged -0.06 (0.01) dB and -0.05 (0.01) dB per year, respectively. The normal range of pointwise threshold sensitivity increased with eccentricity and showed asymmetry around the mean, particularly notable in the 24-2 test. Mean (SD) binocular test duration was 3.18 (0.38) minutes (1 minute 35 seconds per eye) for the 24-2 test and 3.58 (0.43) minutes (1 minute 47 seconds per eye) for the 10-2 test. Conclusions: An RDB for the TEMPO/IMOvifa perimeter was established, highlighting the significance of considering both age and stimulus eccentricity in interpreting threshold VF test results. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association between Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists Exposure and Intraocular Pressure Change: GLP-1 Receptor Agonists and Intraocular Pressure Change.

OBJECTIVE: This study aims to provide data on the effects of glucagon-like peptide 1 receptor (GLP-1R) agonists on intraocular pressure (IOP). DESIGN: Retrospective clinical cohort study. SETTING: Multicenter. STUDY POPULATION: 1247 glaucoma surgery and treatment naïve eyes of 626 patients who were initiated on GLP-1R agonists compared to 1083 glaucoma surgery and treatment naïve eyes of 547 patients who were initiated on other oral antidiabetics. OBSERVATION PROCEDURES: The University of California Health Data Warehouse was queried for patients exposed to GLP-1R agonists or other oral antidiabetics. Index date was defined as the date of first exposure to the medication. Eyes with at least one pre-exposure and one post-exposure tonometry record within 365 days of the index date were included in the analysis. Clinical and laboratory data elements were extracted from the database. Eyes were censored from the analysis upon exposure to glaucoma hypotensive medication or glaucoma surgery. ∆IOP was analyzed using a paired t-test. Regression analysis was conducted using generalized estimating equations (GEE) accounting for inter-eye correlation. Sensitivity analyses were performed to assess the robustness of the findings. MAIN OUTCOME MEASURES: Primary outcome measure was ∆IOP after exposure to the medication. RESULTS: The median age of all included subjects was 66.2 years [IQR=18.3]; 607 (51.7%) were female, and 667 (56.9%) were Caucasian. Median pre-exposure IOP, HbA1c, and BMI were 15.2 mmHg [IQR=3.8], 7.5 [IQR=2.4], and 29.8 [IQR=9.4], respectively. 776 individuals (66.1%) had diabetes, with the median number of active oral antidiabetics being 1.0 [IQR=1.0], and 441 (37.5%) being insulin users. Several pre-exposure characteristics significantly differed between the GLP-1R agonist and the control group. The mean ∆IOP was -0.4±2.8 mmHg (paired t-test p<0.001) and -0.2±3.3 mmHg (paired t-test p = 0.297) in the GLP-1R agonist and other antidiabetics groups, respectively. Pre-exposure IOP was the only independent predictor of ΔIOP in multivariable GEE. Sensitivity analyses yielded similar results. CONCLUSIONS: Although GLP-1R agonists were significantly associated with a decrease in IOP in the paired analysis, they were not associated with ΔIOP in multivariable GEE. Moreover, the difference between the ΔIOP in the two groups was small. Future prospective studies following a standardized dose and delivery method may provide further insights.

Time to Glaucoma Progression Detection by Optical Coherence Tomography and Visual Field in Glaucoma Individuals of African Descent.

PURPOSE: To examine the time to glaucoma progression detection by retinal nerve fiber layer thickness (RNFLT) and visual field (VF) among individuals of African descent (AD). DESIGN: Retrospective cohort study. METHODS: This multicenter study included eyes with glaucoma from individuals of AD from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study with ≥2 years/5 visits of optic nerve head RNFLT and 24-2 VF examinations. INTERVENTION OR OBSERVATION PROCEDURE: Rates of VF mean deviation (MD) and RNFLT worsening were analyzed using linear mixed-effects models, and longitudinal data were simulated using the variability estimates. MAIN OUTCOME MEASURE: The simulated time to detect trend-based glaucoma progression was assessed with assumed rates of VF MD and RNFLT change derived from the cohort (25th, 50th, and 75th percentile [as p25, median, and p75] slopes and mean slopes). Severity-stratified analyses were also performed. RESULTS: We included 184 eyes from 128 subjects of AD (mean baseline age 63.4 years; VF MD -4.2 dB; RNFLT 80.2 µm). The p25, median, mean, and p75 rates of change were -0.43, -1.01, -1.15, and -1.64 µm per year for RNFLT, and 0.00, -0.21, -0.30, and -0.51 dB per year for VF MD, respectively. Compared with VF MD, RNFLT showed an overall shorter mean time to progression detection (time difference 0.4-1.7 years), with the mean rates showing the largest difference (RNFLT 5.2 years vs VF MD 6.9 years). Similarly, we found an overall shorter time to detect RNFLT progression, compared with that of VF MD progression, in eyes with mild glaucoma (≥1 year earlier) and in eyes with moderate to advanced glaucoma (∼0.5 year earlier). CONCLUSIONS: Computer simulation showed a potentially shorter time to detect RNFLT progression than VF MD progression in eyes from individuals of AD. Our findings support the importance of using RNFLT to detect progressive glaucoma in individuals of AD.

Relationship Between Retinal Oxygen Saturation and the Severity of Visual Field Damage in Glaucoma.

PRCIS: Increased oxygen saturation (StO 2 ) was significantly associated with the severity of visual field (VF) damage in patients with glaucoma. OBJECTIVE: To investigate the association between retinal StO 2 percentage and the severity of VF loss in glaucoma. METHODS: A total of 198 eyes from 131 patients with glaucoma were included in this cross-sectional study. Participants underwent imaging using ocular oximetry (Zilia) and 24-2 Swedish Interactive Threshold Algorithm standard VF (Carl Zeiss-Meditec). StO 2 (%) was measured at 2 locations of the peripapillary optic nerve head (superotemporal, and inferotemporal). Measurements were reported as the mean of at least 5 measurements in each location. Associations between the severity of VF loss, reported as mean deviation, and StO 2 (%) were calculated. RESULTS: A total of 198 eyes of 131 patients (mean (95% CI) age, 71.1 (68.9,73.3) years, 68 females (51.9%), and 63 males (48.1%) were analyzed. In univariable analysis, higher StO 2 -0.06 (-0.12, 0.00) was associated with severity in all hemifields ( P = 0.047). Multivariate regression analysis showed that each 1% increase in StO 2 was associated with -0.06 (-0.12, -0.00) dB loss in mean deviation in all hemifields ( P = 0.043). In multivariate regression analysis in the superior hemifields, higher StO 2 -0.07 (-0.16, 0.01) tended to be associated with superior hemifield severity ( P = 0.09). CONCLUSIONS: Retinal oximetry enabled the continuous quantitative measurement of retinal StO 2. Increased StO 2 was significantly associated with the severity of VF damage in patients with glaucoma.

Suspicious eyes - Elvis's glaucoma battle.

Elvis Presley (1935-1977) is an iconic figure in modern pop culture. Although many of his medical conditions have been the subject of extensive speculation, less is known about his ophthalmological problems, including steroid-induced glaucoma caused by a life-long use of steroids, both prescribed and self-administered, and secondary angle closure glaucoma most likely due to anterior uveitis. Further, he had an episode of acute angle closure glaucoma in 1971 that was treated with a subconjunctival injection of a mydriatic agent or, less likely, a paracentesis combined with an iridotomy. David Meyer, MD, was Presley's main ophthalmologist from 1971 until the latter's death in 1977.

Detection of glaucoma progression on longitudinal series of en-face macular optical coherence tomography angiography images with a deep learning model.

BACKGROUND/AIMS: To design a deep learning (DL) model for the detection of glaucoma progression with a longitudinal series of macular optical coherence tomography angiography (OCTA) images. METHODS: 202 eyes of 134 patients with open-angle glaucoma with ≥4 OCTA visits were followed for an average of 3.5 years. Glaucoma progression was defined as having a statistically significant negative 24-2 visual field (VF) mean deviation (MD) rate. The baseline and final macular OCTA images were aligned according to centre of fovea avascular zone automatically, by checking the highest value of correlation between the two images. A customised convolutional neural network (CNN) was designed for classification. A comparison of the CNN to logistic regression model for whole image vessel density (wiVD) loss on detection of glaucoma progression was performed. The performance of the model was defined based on the confusion matrix of the validation dataset and the area under receiver operating characteristics (AUC). RESULTS: The average (95% CI) baseline VF MD was -3.4 (-4.1 to -2.7) dB. 28 (14%) eyes demonstrated glaucoma progression. The AUC (95% CI) of the DL model for the detection of glaucoma progression was 0.81 (0.59 to 0.93). The sensitivity, specificity and accuracy (95% CI) of DL model were 67% (34% to 78%), 83% (42% to 97%) and 80% (52% to 95%), respectively. The AUC (95% CI) for the detection of glaucoma progression based on the logistic regression model was lower than the DL model (0.69 (0.50 to 0.88)). CONCLUSION: The optimised DL model detected glaucoma progression based on longitudinal macular OCTA images showed good performance. With external validation, it could enhance detection of glaucoma progression. TRIAL REGISTRATION NUMBER: NCT00221897.

Screening of Glaucoma: Consensus and Directions.

PURPOSE: Glaucoma is a leading public health concern globally. This summary discusses barriers to glaucoma screening and novel strategies for a cost-effective glaucoma screening. METHODS/RESULTS: We discuss barriers to glaucoma screening and recent advancements in glaucoma detection and care, including targeted screening approach as well as telemedicine, genetic testing, and artificial intelligence (AI). A major barrier to glaucoma screening is the cost-effectiveness of case finding resulting from the low prevalence of the disease and the complexity of the diagnosis. Targeted-screening, as well as multi-level screening, can reduce the false positive rate and increase the cost-effectiveness of the program. Telemedicine, availability of genetic testing and polygenic risk scores, and AI provide the opportunity for novel glaucoma screening programs in primary care, portable, and home-based settings and will be helpful for lowering the costs, identifying patients in need of urgent treatment and enabling timely diagnosis and early intervention. CONCLUSIONS: Screening of glaucoma is challenging and changing. Recent advancements in digital technology and genetics have led to the development of tools that are promising for novel screening methodologies. Clinical trials are needed to demonstrate the long-term effect of targeted screening on the burden of glaucoma worldwide.

Gap Analysis of Glaucoma Examination Concept Representations within Standard SNOMED Clinical Terms.

PURPOSE: Standardization of eye care data is important for clinical interoperability and research . We aimed to address gaps in the representations of glaucoma examination concepts within Systemized Nomenclature of Medicine - Clinical Terms (SNOMED-CT), the preferred terminology of the American Academy of Ophthalmology. DESIGN: Study of data elements. METHODS: Structured eye exam data fields from two electronic health records (EHR) systems (Epic Systems and Medisoft) were compared against existing SNOMED-CT codes for concepts representing glaucoma examination findings3. Glaucoma specialists from multiple institutions were surveyed to identify high-priority gaps in representation, which were discussed among the SNOMED International Eye Care Clinical Reference Group. Proposals for new codes to address the gaps were formulated and submitted for inclusion in SNOMED-CT. MAIN OUTCOME MEASURES: Gaps in SNOMED-CT glaucoma examination concept representations RESULTS: We identified several gaps in SNOMED-CT regarding glaucoma examination concepts. A survey of glaucoma specialists identified high-priority data elements within the categories of tonometry and gonioscopy. For tonometry, there was consensus that we need to define new codes related to maximum intraocular pressure (IOP) and target IOP, and to delineate all methods of measuring IOP. These new codes were proposed and successfully added to SNOMED-CT for future use. Regarding gonioscopy, the current terminology did not include the ability to denote the gonioscopic grading system used (e.g., Shaffer or Spaeth), degree of angle pigmentation, iris configuration (except for plateau iris), and iris approach. There was also no ability to specify eye laterality or angle quadrant for gonioscopic findings. We proposed a framework for representing gonioscopic findings as observable entities in SNOMED-CT. DISCUSSION: There are existing gaps in the standardized representation of findings related to tonometry and gonioscopy within SNOMED-CT. These are important areas for evaluating clinical outcomes and enabling secondary use of EHR data for glaucoma research. This international, multi-institutional collaborative process enabled identification of gaps, prioritization, and development of data standards to address these gaps. CONCLUSION: Addressing these gaps and augmenting SNOMED-CT coverage of glaucoma examination findings could enhance clinical documentation and future research efforts related to glaucoma.

Federated Learning in Glaucoma: A Comprehensive Review and Future Perspectives.

Current approaches to developing artificial intelligence (AI) models for widespread glaucoma screening have encountered several obstacles. First, glaucoma is a complex condition with a wide range of morphological and clinical presentations. There exists no consensus definition of glaucoma or glaucomatous optic neuropathy. Further, training effective deep learning algorithms poses numerous challenges, including susceptibility to overfitting and lack of generalizability on external data. Therefore, training data should ideally be sourced from large, well-curated, multi-client cohorts to ensure diversity in patient populations, disease presentations, and imaging protocols. However, the construction of centralized repositories for multimodal data faces hurdles such as concerns regarding data sharing, re-identification, storage, regulations, patient privacy, and intellectual property. Federated learning (FL) has emerged as a proposed solution to address some of these concerns by enabling data to remain locally hosted while facilitating distributed model training. This article aims to provide a comprehensive review of the existing literature on FL in the context of its applications for AI tasks related to glaucoma.

Assessment of Missing Data on Glaucoma Severity among Participants in the NIH All of Us Research Program of the United States.

PRECIS: There were statistically significant differences across multiple socioeconomic characteristics and self-reported barriers to care among primary glaucoma patients with severity staging data versus those missing this data in the NIH All of Us database. PURPOSE: To characterize missing data among glaucoma patients within All of Us. PATIENTS AND METHODS: We used diagnosis codes to define cohorts of primary glaucoma patients with and without severity staging specified. Descriptive analyses were conducted by presence of disease severity stage. Analysis of missing data was conducted using a set intersection plot and Little's Test of Missing Completely at Random. T-tests were performed to evaluate differences. RESULTS: Of 2982 participants, 1714 (57%) did not have glaucoma severity stage specified, and 11 of 23 analyzed variables had missing data. Little's Test indicated data was not missing completely at random (P<0.001). Significant differences existed between the two cohorts with respect to age, age of first glaucoma diagnosis, gender, ethnicity, education, income, insurance, history of glaucoma surgery and medication use, and answers regarding ability to afford eyeglasses and having seen an eye care provider in the last 12 months (all P values≤0.01). CONCLUSION: There were significant differences between glaucoma participants with glaucoma severity stage specified versus those with unstaged disease across multiple socioeconomic characteristics and self-reported barriers to care. Glaucoma severity staging data was not missing completely at random. The unstaged cohort included higher rates of multiple underrepresented communities, which may potentially contribute to bias in ophthalmology research as participants from vulnerable populations may be disproportionately excluded from electronic health records or claims data studies where diagnosis codes with severity/staging levels are used to examine risk factors for disease, progression, and treatment efficacy.

Wide-Field Optical Coherence Tomography Imaging Improves Rate of Change Detection in Progressing Glaucomatous Eyes Compared With Standard-Field Imaging.

Purpose: To compare rates of retinal nerve fiber layer change over time in healthy, eyes with nonprogressing glaucoma and eyes with progressing glaucoma using single wide-field (SWF) and optic nerve head (ONH) cube scan optical coherence tomography (OCT) images. Methods: Forty-five eyes of 25 healthy individuals and 263 eyes of 161 glaucoma patients from the Diagnostic Innovations in Glaucoma Study were included. All eyes underwent 24-2 visual field testing and OCT (Spectralis SD-OCT) ONH and macular imaging. SWF images (up to 43° × 28°) were created by stitching together ONH cube scans centered on the optic disc and macular cube scans centered on the fovea. Visual field progression was defined as guided progression analysis likely progression and/or a significant (P < 0.01) mean deviation slope of less than -1.0 dB/year. Mixed effects models were used to compare rates of change. Highly myopic eyes were included. Results: Thirty glaucomatous eyes were classified as progressing. In eyes with glaucoma, mean global rate of change was -1.22 µm/year (P < 0.001) using SWF images and -0.83 µm/year (P = 0.003) using ONH cube scans. Rate of change was significantly greater in eyes with progressing glaucoma compared with eyes with nonprogressing glaucoma (-1.51 µm/year vs. -1.24 µm/year; P = 0.002) using SWF images and was similar using ONH cube scans (P = 0.27). Conclusions: In this cohort that includes eyes with and without high axial myopia, the mean rate of retinal nerve fiber layer thinning measured using SWF images was faster in eyes with progressing glaucoma than in eyes with nonprogressing glaucoma. Wide-field OCT images including the ONH and macula can be effective for monitoring glaucomatous progression in patients with and without high myopia.

Social Factors Associated with the Risk of Glaucoma Suspect Conversion to Glaucoma: Analysis of the Nationwide All of Us Program.

PURPOSE: To examine social factors associated with the 5-year risk of glaucoma suspects (GS) converting to open-angle glaucoma (OAG). DESIGN: Retrospective cohort analysis. SUBJECTS: We screened for participants diagnosed with GS in the All of Us database. Cases that converted to OAG within 5 years of GS diagnosis (the "conversion group") were compared with control cases that did not convert. METHODS: Demographic, socioeconomic and health-care utilization data of the cases were extracted and compared between the conversion group and the control group. Multivariable Cox proportional hazards modeling was used to identify potential factors associated with the risk of conversion. MAIN OUTCOME MEASURES: Hazard ratios (HRs) of significant factors associated with the risk of conversion. RESULTS: A total of 5274 GS participants were identified, and 786 (15%) cases converted to OAG within 5-year follow-up. The 2 groups showed significant differences in age, race, gender, employment status, income/education level, history of intraocular surgery, and health-care utilization patterns. In the multivariable model, African American/Black race (HR : 1.70 [95% confidence interval (CI) 1.44-2.00]), older age at GS diagnosis (1.17 [95% CI 1.09-1.25]), male gender (1.30 [95% CI 1.13-1.50], no history of recreational drug use (1.23 [1.07-1.42]), history of intraocular surgery (1.60 [95% CI 1.02-1.53]), and having more reasons for delayed health-care access (2.27 [95% CI 1.23-4.18]) were associated with a greater hazard of conversion, while being employed (0.71 [95% CI 0.60-0.86]) was associated with a smaller hazard of conversion (P < 0.05 for all). CONCLUSIONS: Several social factors were associated with the conversion from GS to OAG, which may help to identify patients at higher risk of disease progression. Future studies are needed to examine the basis for these findings and the potential interventions that could address them. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Rates of Choriocapillaris Microvascular Dropout and Macular Structural Changes in Glaucomatous Optic Neuropathy With and Without Myopia.

PURPOSE: To evaluate the association between rates of juxtapapillary choriocapillaris microvasculature dropout (MvD) change and rates of ganglion cell inner plexiform layer (GCIPL) loss in primary open-angle glaucoma (POAG) and glaucoma suspect eyes with and without myopia. DESIGN: Cohort study from clinical trial data. METHODS: 238 eyes from 155 POAG and glaucoma suspect patients were stratified into no-myopia (axial length (AL) ≤ 24 mm; n = 78 eyes), mild myopia (24 mm < AL ≤ 26 mm; n = 114 eyes), and high myopia (AL > 26 mm; n = 46 eyes). Eyes with a minimum of 3 visits and 1.5 years of follow-up with both optical coherence tomography angiography (OCT-A) and OCT macula scans were included. Presence, area, and angular circumference of juxtapapillary MvD were evaluated on en face choroidal images and horizontal B-scans obtained from OCT-A imaging. RESULTS: Over the mean follow-up of 4.4 years, the mean MvD area rates of change (95% CI) were largest in high and mild myopia group (0.04 [0.03, 0.05] mm2/year in both groups), followed by the no-myopia group (0.03 [0.02, 0.04] mm2/year). The mean MvD angular circumference rates of change (95% CI) were highest in mild myopia group (8.7° [6.9°, 10.5°]/year) followed by the high myopia and no-myopia groups (8.1° [5.3°, 10.9°]/year, and 7.4° [5.3°, 9.6°]/year, respectively). While the mean global GCIPL thinning rates between eyes with MvD at baseline compared to eyes without were similar in all myopia groups, the rates of MvD area change were significantly faster in all myopia groups with baseline MvD (all p ≤ 0.004). Significant faster rates of MvD angular circumference change were found in the mild myopia group with baseline MvD (P < .001) only. In multivariable models, the rates of GCIPL thinning over time were significantly associated with rates of MvD angular circumference change and MvD area change (R2 = 0.33, P < .001 and R2 = 0.32, P = .006, respectively). CONCLUSIONS: Rates of GCIPL thinning were associated with rates of MvD area and angular circumference change over time in myopic POAG eyes. Utilizing OCT-A to detect MvD may provide an additional tool for monitoring macular structural changes in glaucomatous eyes with myopia.

Long-Term Systemic Use of Calcium Channel Blockers and Incidence of Primary Open-Angle Glaucoma.

PURPOSE: To evaluate the association between the systemic use of calcium channel blockers (CCBs) and primary open-angle glaucoma (POAG) using a diverse nationwide dataset. DESIGN: Retrospective cohort study. SUBJECTS: 213 424 individuals aged 40 years and older in the National Institutes of Health All of Us dataset, notable for its demographic, geographic, and medical diversity and inclusion of historically underrepresented populations. Patients with a diagnosis of POAG prior to use of any kind of antihypertensive medication were excluded. METHODS: Bivariate and multivariable regression analyses were performed to evaluate associations between CCB use and POAG. Calcium channel blocker use was further divided into exposure to dihydropyridine CCBs and nondihydropyridine CCBs, and subgroup analyses were performed using chi-square and Fisher tests. MAIN OUTCOME MEASURES: Diagnosis of POAG. RESULTS: Within our cohort, 2772 participants (1.3%) acquired a diagnosis of POAG, while 210 652 (98.7%) did not. Among patients who developed POAG, the mean age was 73.3 years, 52.5% were female, and 48.2% identified as White. Among patients with POAG, 32.6% used 1 or more CCB, 28.2% used a dihydropyridine CCB, and 2.2% used a nondihydropyridine CCB. In bivariate analysis, use of any CCBs was associated with an increased risk of POAG (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.27-1.31, P < 0.001). In multivariable analysis adjusting for age, gender, race, ethnicity, and comorbidities such as diabetes, hyperlipidemia, and hypertension, use of any CCBs remained associated with an increased risk of developing POAG (OR: 1.52, 95% CI: 1.33-1.74, P < 0.001). When stratified by type of CCB, the use of dihydropyridine CCBs (OR: 1.31, 95% CI: 1.14-1.50, P < 0.001) was associated with increased POAG risk. CONCLUSIONS: Use of dihydropyridine CCBs was associated with a significantly higher risk of developing POAG, both before and while adjusting for demographic factors and comorbid medical conditions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association between metformin use with circumpapillary retinal nerve fibre layer thickness and capillary vessel density in glaucoma.

BACKGROUND/AIMS: To investigate the association between use of metformin and circumpapillary retinal nerve fibre layer (cpRNFL) thickness, as well as whole image capillary density (wiCD), in patients with glaucoma. METHODS: This cross-sectional study included patients with glaucoma suspect or primary open-angle glaucoma (POAG) underwent optical coherence tomography angiography imaging. Use and duration of antidiabetic medications were assessed at the time of imaging. Multivariable linear mixed-effect modelling was used to estimate the effect of diabetes medication on wiCD and cpRNFL while controlling for covariates including age, race, body mass index, diagnosis, 24-2 visual field mean deviation, and intraocular pressure, average signal strength index as well as any variables that showed a p <0.1 in the univariable analysis. RESULTS: A total of 577 eyes (330 POAG and 247 glaucoma suspect) of 346 patients were included. Sixty-five patients (23%) had diabetes, of whom 55 (78.5%) used metformin, and 17 (26.2%) used insulin. After adjusting for covariates, the association between metformin use and wiCD (1.56 (95% CI 0.40 to 2.71); p=0.008), duration of metformin use and wiCD (0.12 (95% CI 0.02 to 0.22) per 1 year longer; p=0.037), and metformin use and cpRNFL thickness (5.17 (95% CI 1.24 to 9.10) µm; p=0.010) had statistically significant associations in each model. CONCLUSIONS: Metformin use was associated with higher wiCD and thicker cpRNFL. These findings indicate a potential association, underscoring the need for longitudinal studies to determine if metformin plays a role in the retinal conditions of patients with glaucoma. TRIAL REGISTRATION NUMBER: NCT00221897.

Administration of Bicarbonate Protects Mitochondria, Rescues Retinal Ganglion Cells, and Ameliorates Visual Dysfunction Caused by Oxidative Stress.

Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is a key regulator of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which is known to protect mitochondria and promote RGC survival. However, the precise molecular mechanisms connecting the sAC-mediated signaling pathway with mitochondrial protection in RGCs against oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress induced by ischemic injury and paraquat administration, we found that administration of bicarbonate, as an activator of sAC, protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death. Notably, the administration of bicarbonate ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

Association between Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists Exposure and Intraocular Pressure Change.

Objective: This study aims to provide data on the effects of glucagon-like peptide 1 receptor (GLP-1R) agonists on intraocular pressure (IOP). Design: Retrospective cohort study. Subjects Participants and/or Controls: 1247 glaucoma surgery and treatment naïve eyes of 626 patients who were initiated on GLP-1R agonists compared to 1083 glaucoma surgery and treatment naïve eyes of 547 patients who were initiated on other oral antidiabetics. Methods Intervention or Testing: The University of California Health Data Warehouse was queried for patients exposed to GLP-1R agonists or other oral antidiabetics. Index date was defined as the date of first exposure to the medication. Eyes with at least one pre-exposure and one post-exposure tonometry record within 365 days of the index date were included in the analysis. Clinical and laboratory data elements were extracted from the database. Eyes were censored from the analysis upon exposure to glaucoma hypotensive medication or glaucoma surgery. ΔIOP was analyzed using a paired t-test. Regression analysis was conducted using generalized estimating equations (GEE) accounting for inter-eye correlation. Sensitivity analyses were performed to assess the robustness of the findings. Main Outcome Measures: Primary outcome measure was ΔIOP after exposure to the medication. Results: The median age of all included subjects was 66.2 years [IQR=18.3]; 607 (51.7%) were female, and 667 (56.9%) were Caucasian. Median pre-exposure IOP, HbA1c, and BMI were 15.2 mmHg [IQR=3.8], 7.5 [IQR=2.4], and 29.8 [IQR=9.4], respectively. 776 individuals (66.1%) had diabetes, with the median number of active oral antidiabetics being 1.0 [IQR=1.0], and 441 (37.5%) being insulin users. Several pre-exposure characteristics significantly differed between the GLP-1R agonist and the control group. The mean ΔIOP was -0.4±2.8 mmHg (paired t-test p<0.001) and -0.2±3.3 mmHg (paired t-test p = 0.297) in the GLP-1R agonist and other antidiabetics groups, respectively. Pre-exposure IOP was the only independent predictor of ΔIOP in multivariable GEE. Sensitivity analyses yielded similar results. Conclusions: Although GLP-1R agonists were significantly associated with a decrease in IOP in the paired analysis, they were not associated with ΔIOP in multivariable GEE. Moreover, the difference between the ΔIOP in the two groups was small. Future prospective studies following a standardized dose and delivery method may provide further insights.