Drug combination of topical ripasudil and brimonidine enhances neuroprotection in a mouse model of optic nerve injury.

PURPOSE: To determine whether combination of topical ripasudil and brimonidine has more effective neuroprotection on retinal ganglion cells (RGCs) following injury to axons composing the optic nerve. METHODS: Topical ripasudil, brimonidine, or mixture of both drugs were administered to adult mice after optic nerve injury (ONI). The influence of drug conditions on RGC health were evaluated by the quantifications of surviving RGCs, phosphorylated p38 mitogen-activated protein kinase (phospho-p38), and expressions of trophic factors and proinflammatory mediators in the retina. RESULTS: Topical ripasudil and brimonidine suppressed ONI-induced RGC death respectively, and mixture of both drugs further stimulated RGC survival. Topical ripasudil and brimonidine suppressed ONI-induced phospho-p38 in the whole retina. In addition, topical ripasudil suppressed expression levels of TNFα, IL-1ß and monocyte chemotactic protein-1 (MCP-1), whereas topical brimonidine increased the expression level of basic fibroblast growth factor (bFGF). CONCLUSIONS: Combination of topical ripasudil and brimonidine may enhance RGC protection by modulating multiple signaling pathways in the retina.

TrkB Signaling in Retinal Glia Stimulates Neuroprotection after Optic Nerve Injury.

Brain-derived neurotrophic factor (BDNF) regulates neural cell survival mainly by activating TrkB receptors. Several lines of evidence support a key role for BDNF-TrkB signaling in survival of adult retinal ganglion cells in animal models of optic nerve injury (ONI), but the neuroprotective effect of exogenous BDNF is transient. Glial cells have recently attracted considerable attention as mediators of neural cell survival, and TrkB expression in retinal glia suggests its role in neuroprotection. To elucidate this point directly, we examined the effect of ONI on TrkB(flox/flox):glial fibrillary acidic protein (GFAP)-Cre+ (TrkB(GFAP)) knockout (KO) mice, in which TrkB is deleted in retinal glial cells. ONI markedly increased mRNA expression levels of basic fibroblast growth factor (bFGF) in wild-type (WT) mice but not in TrkB(GFAP) KO mice. Immunohistochemical analysis at 7 days after ONI (d7) revealed bFGF up-regulation mainly occurred in Müller glia. ONI-induced retinal ganglion cell loss in WT mice was consistently mild compared with TrkB(GFAP) KO mice at d7. On the other hand, ONI severely decreased TrkB expression in both WT and TrkB(GFAP) KO mice after d7, and the severity of retinal degeneration was comparable with TrkB(GFAP) KO mice at d14. Our data provide direct evidence that glial TrkB signaling plays an important role in the early stage of neural protection after traumatic injury.

Valproic acid prevents NMDA-induced retinal ganglion cell death via stimulation of neuronal TrkB receptor signaling.

Valproic acid (VPA) is widely prescribed for treatment of epilepsy, mood disorders, migraines, and neuropathic pain. It exerts its therapeutic benefits through multiple mechanisms, including enhancement of GABAergic activity, activation of prosurvival protein kinases, and inhibition of histone deacetylase. Increasing evidence suggests that VPA possesses neuroprotective properties. We examined neuroprotective effects of VPA in an N-methyl-d-aspartate (NMDA) excitotoxicity model, which mimics some of the pathological features of glaucoma. In vivo retinal imaging using optical coherence tomography revealed that NMDA-induced retinal degeneration was suppressed in the VPA-treated retina, and histological analyses confirmed that VPA reduced retinal ganglion cell death. In vivo electrophysiological analyses demonstrated that visual impairment was prevented in the VPA-treated retina, clearly establishing both histological and functional effects of VPA. Brain-derived neurotrophic factor (BDNF) expression was up-regulated in Müller glial cells, and neuroprotective effects of VPA on retinal ganglion cells were significantly reduced in a conditional knockout mouse strain with deletion of tropomyosin receptor kinase B (TrkB), a receptor for BDNF from retinal ganglion cells. The results show that VPA stimulates BDNF up-regulation in Müller glial cells and provides direct evidence that neuronal TrkB is important in VPA-mediated neuroprotection. Also, VPA suppresses oxidative stress induced by NMDA in the retina. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be useful for treatment of glaucoma.

[Correlation of intraocular pressure variation after visual field examination with 24-hour intraocular pressure variations in primary open-angle glaucoma].

OBJECTIVES: We retrospectively examined intraocular pressure variations after visual field examination in primary open angle glaucoma (POAG), together with its influencing factors and its association with 24-hour intraocular pressure variations. SUBJECTS AND METHODS: Subjects were 94 eyes (52 POAG patients) subjected to measurements of 24-hour intraocular pressure and of changes in intraocular pressure after visual field examination using a Humphrey Visual Field Analyzer. Subjects were classified into three groups according to the magnitude of variation (large, intermediate and small), and 24-hour intraocular pressure variations were compared among the three groups. Factors influencing intraocular pressure variations after visual field examination and those associated with the large variation group were investigated. RESULTS: Average intraocular pressure variation after visual field examination was -0.28 ± 1.90 (range - 6.0(-) + 5.0) mmHg. No significant influencing factors were identified. The intraocular pressure at 3 a.m. was significantly higher in the large variation group than other two groups (p < 0.001). Central corneal thickness was correlated with the large variation group (odds ratio = 1.04; 95% confidence interval, 1.01-1.07 ; p = 0.02). CONCLUSION: No particular tendencies in intraocular pressure variations were found after visual field examination. Increases in intraocular pressure during the night might be associated with large intraocular pressure variations after visual field examination.

Correlation of Binocular Perimetry Screening using imo, a Portable Head Mounted Perimeter with 10-2 Standard Automated Perimetry for Early Glaucoma with Central Visual Field Defects.

PRCIS: The screening program using imo strongly correlates with 10-2 Standard automated perimetry in detecting central visual field defects in early glaucoma, highlighting its potential as a valuable tool for efficient screening and severity quantification. PURPOSE: To investigate the correlation between abnormalities within the central 10° of the screening program using imo, a portable head-mounted perimeter, and 10-2 standard automated perimetry in early-stage glaucoma with central visual field defects. METHODS: This retrospective study included early glaucoma with (26 eyes) and without (38 eyes) central visual field defects. The correlation between the numbers of abnormal points within the central 10° of the imo screening program and those in the probability plot of 10-2, and mean total deviation and pattern deviation, were analyzed. RESULTS: The imo screening program demonstrated sensitivity (80%) and specificity (98.7%) in detecting abnormalities, with a 91.6% agreement rate of 10-2. The mean number of anomalies in the 10-2 plot (pattern deviation) with P<1% was 0.85, 7.75, and 9.69 (95% confidence interval: 0.18-1.51, 5.38-10.1, and 6.89-12.5, respectively) for no, one, and two anomalies in the imo screening program, respectively. The number of anomalies with P<1% was significantly higher when the imo screening program detected one anomaly versus none (P<0.01), and two versus one (P<0.05). Mean total deviation values were -1.15, -7.5, and -15.2 (95% confidence interval: -2.32 to 0.03, -11.21 to -3.78, and -19.7 to -10.6, respectively), while mean pattern deviation values were -1.57, -9.0, and -16.0 (95% confidence interval: -2.57 to -0.57, -12.5 to -5.49, and -21.4 to -10.7, respectively), for no, one, and two anomalies in the imo screening program, respectively. CONCLUSIONS: The imo portable head-mounted perimeter was found to correlate with 10-2 standard automated perimetry in glaucoma patients with central visual field defects and has the potential to shorten visual field testing times.

Membrane-anchored intracellular insulin receptor or insulin-like growth factor-1 receptor elicits ligand-independent downstream signaling.

Neurodegenerative diseases including glaucoma affect insulin signaling, and insulin treatment has been shown to reverse the neurodegenerative loss of dendritic complexity in retinal ganglion cells. Therefore, strategies for enhancing or maintaining insulin signaling are worth pursuing to establish new therapies for these diseases. In the present study, we generated constitutively active insulin receptor (F-iIR) and insulin-like growth factor-1 receptor (F-iIGF1R) using a system that forces membrane localization of the intracellular domains of these receptors by farnesylation. Immunohistochemistry and Western blot analysis revealed that F-iIR and F-iIGF1R caused the activation of ERK and AKT in the absence of ligands in vitro. Our results suggest that in vivo effects of F-iIR and F-iIGF1R on the progression of neurodegenerative diseases should be investigated in the future.

Association Between Days of the Week and Intraocular Pressure: Japan Ningen Dock Study.

PRCIS: The analysis of intraocular pressure (IOP) by day of the week using the mega database showed a periodic weekly pattern with the highest value on Monday. PURPOSE: To evaluate IOP by the day of the week. PATIENTS AND METHODS: Annual health checkup examinees between April 2014 and March 2015 were cross-sectionally evaluated. As a result, 655,818 participants [51.5±10.5 (range: 20-96) years, 40.1% women] from 103 medical centers were included. IOP was measured using a noncontact tonometer. The mean IOPs of each day of the week were compared using multiple comparison test and multiple linear regression analysis. Wednesday was set as the reference. Moreover, weekly IOP variations stratified by sex and age were also evaluated. RESULTS: Mean IOPs from Monday to Sunday were 13.19±2.97, 13.06±2.92, 13.05±2.91, 13.05±2.92, 13.12±2.94, 13.10±2.96, and 13.16±2.78 mm Hg. IOP was significantly higher on Monday, Friday, and Saturday than those on Wednesday ( P <0.001, <0.001, 0.002). After adjusting for factors affecting IOP, the IOPs on Monday and Saturday were higher than those on Wednesday [ß=0.097 (95% CI: 0.074-0.121), P <0.001; ß=0.032 (95% CI: 0.005-0.059), P =0.019]. Men had significantly higher IOPs on Monday and Saturday than on Wednesday [ß=0.142 (95% CI: 0.110-0.173), P <0.001; ß=0.053 (95% CI: 0.017-0.089), P =0.004], whereas women did not have a significant trend. Participants aged below 65 years had higher IOPs on Monday ( P <0.001 in under 60 years; P =0.003 in 60-64 years), while those aged 65 years or older did not ( P =0.856). CONCLUSION: IOP values may have a periodic weekly pattern. The high IOP on Monday was more pronounced in men aged less than 65 years.

Comparison of Glaucoma Detection Performance of Binocular Perimetry Screening Program Using imo Perimetry With Frequency Doubling Technology.

Purpose: We aimed to preliminarily compare the glaucoma detection accuracy of a head-mounted binocular visual perimeter "imo" screening program (ISP) with that of frequency doubling technology (FDT). Methods: This multicenter, diagnostic accuracy study based on prospectively collected data included 76 non-glaucoma (including pre-perimetric glaucoma) eyes and 92 glaucomatous eyes from patients visiting two hospitals. Patients underwent ISP and FDT (C-20-1 screening program) on the same day. Diagnostic efficacy was evaluated using receiver operating characteristic curves and areas under the curve (AUCs). In addition, we compared the ISP and FDT testing times. Results: AUC values for ISP versus FDT were as follows: (1) mild-stage glaucoma (mean deviation [MD] > -6 dB), 0.82 (95% confidence interval [CI], 0.75-0.88) versus 0.76 (95% CI, 0.68-0.83); moderate-stage glaucoma (-6 dB ≥ MD ≥ -12 dB), 0.98 (95% CI, 0.95-1.00) versus 0.96 (95% CI, 0.93-1.00); and advanced-stage glaucoma (-12 dB > MD), 1.00 (95% CI, 1.00-1.00) versus 0.99 (95% CI, 0.98-1.00). In addition, mild-stage glaucoma was classified into two stages (MD > -3 D) and (-3 D ≥ MD > -6 D). AUC values were 0.81 (95% CI, 0.73-0.88) versus 0.76 (95% CI, 0.68-0.84) for MD > -3 D and 0.86 (95% CI, 0.77-0.94) versus 0.73 (95% CI, 0.61-0.86) for -3 D ≥ MD > -6 D. The testing time for the ISP was significantly shorter than that of FDT for all glaucoma stages (P < 0.001). Conclusions: The ISP demonstrates non-inferiority in detecting glaucoma and has a shorter testing time compared with FDT. These findings provide evidence for applied further studies on large-scale population-based glaucoma screening. Translational Relevance: Our study provides a non-inferior and quicker glaucoma screening than existing tools.

Comparative Analysis of 24-2C, 24-2, and 10-2 Visual Field Tests for Detecting Mild-Stage Glaucoma With Central Visual field Defects.

PURPOSE: This study sought to identify the most effective testing program for detecting visual-field defects in mild-stage glaucoma with central visual-field defects. DESIGN: A multicenter, retrospective diagnostic testing evaluation. PARTICIPANTS: The study involved 93 eyes (83 patients) with mild-stage glaucoma (median mean deviation [interquartile range]: -1.79 [2.16] dB) with central visual-field defects and 69 eyes (63 patients; median mean deviation, -1.38 [2.31] dB) with mild-stage glaucoma without central visual-field defects, from Jikei University School of Medicine and Tajimi Iwase Eye Clinic. METHODS: Patients underwent 10-2 Swedish Interactive Thresholding Algorithm (SITA) Standard, 24-2 SITA Standard, and 24-2C SITA Faster tests. Central visual-field defects were defined using 10-2 SITA Standard and optical coherence tomography (OCT). A detection power of 4 points in the 24-2 that coincided with 10-2 (Center4), 12 points that lie within 10° (24-2-12), and 22 points that lie within 10° of 24-2C (24-2C-22) were analyzed using receiver operating characteristic (ROC) curves based on logistic regression analysis, using total deviation (TD) and pattern deviation (PD) probability plots. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC) of the Center4, 24-2-12, and 24-2C-22 tests. RESULTS: In the upper-central visual field, AUCs of the TD plot were 0.50 (0.40-0.58) for the Center4, 0.75 (0.67-0.83) for 24-2-12, and 0.85 (0.78-0.91) for 24-2C-22, with 24-2C-22 AUC significantly exceeding 24-2-12 AUC. For the PD plot, AUCs were 0.53 (0.44-0.63), 0.81 (0.74-0.89), and 0.84 (0.77-0.90), respectively. In the lower-central visual field, using a total plot, AUCs were 0.27 (0.18-0.36), 0.57 (0.47-0.69), and 0.57 (0.46-0.68) for the Center4, 24-2-12, and 24-2C-22, respectively. Using the PD plot in the upper field, AUCs were 0.27 (0.19-0.36), 0.64 (0.53-0.75), and 0.81 (0.72-0.90), respectively, with the AUC of the 24-2C-22 significantly exceeding that of 24-2-12. The 24-2C test was significantly faster than both the 24-2 and 10-2 tests, reducing testing duration by 46% and 52%, respectively. CONCLUSIONS: The 24-2C SITA Faster test is highly effective and efficient for detecting mild-stage glaucoma with central visual-field defects. This, and its reduced duration, makes it a valuable tool in clinical settings.

A Novel Visual Field Screening Program for Glaucoma With a Head-Mounted Perimeter.

PRCIS: A novel visual field screening program with a head-mounted perimeter 'imo' could detect glaucoma at all stages in a short time with high accuracy. PURPOSE: The present study aimed to examine the accuracy and availability of a novel glaucoma visual field screening program using a head-mounted visual perimeter 'imo.' PARTICIPANTS AND METHODS: Eyes of 76 non-glaucoma participants and 92 glaucoma patients were examined. All patients underwent visual field tests using the Humphrey Visual Field Analyzer (30-2 or 24-2 Swedish Interactive Thresholding Algorithm standard program) and imo (the visual field screening program). We evaluated five visual field screening program indicators: sensitivity, specificity, positive predictive value, negative predictive value, and testing time. We also evaluated the ability of this visual field screening program to differentiate between glaucoma patients and normal controls using the receiver operating characteristic curves and areas under the receiver operating characteristic curves. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of the visual field screening program were 76%-100%, 91%-100%, 86%-89%, and 79%-100%, respectively. The visual field screening program test time was 46±13 seconds for normal controls and 61±18, 82±21, and 105±16 econds, respectively for mild, moderate, and advanced-stage patients. The areas under the receiver operating characteristic curves were 0.77, 0.97, and 1.0 in the mild, moderate, and advanced stages, respectively. CONCLUSIONS: Visual field screening using a head-mounted perimeter 'imo' detected glaucoma at all stages in a short time with high accuracy.

Personality Traits Associated with Treatment Choice with an Explicit Statistical Prediction After an Explanation in a Negative Context: A Study in Patients with Glaucoma.

Purpose: Over 50% of patients with early-stage glaucoma discontinue topical therapy within the first 6 months of treatment initiation. This risk of discontinuation could be reduced by how the ophthalmologist explains the treatment plan. Ophthalmologists can explain the treatment plan to patients in either positive or negative contexts. Although explanations in a negative context can be selected depending on the medical situation, identification of patients who will choose the treatment with explicit statistical prediction after an explanation in a negative context is important; personality traits are related to these emotional decisions. Therefore, in the present study, we examined the personality traits associated with choice of treatment with explicit statistical prediction after an explanation in a negative context. Patients and Methods: A total of 147 patients with glaucoma were recruited for this study. The questionnaire booklets used contained positively framed or negatively framed versions of an "Asian disease problem" to enable examination of the influence of the way in which a problem is framed (framing effect) on the participants' decision-making. The Japanese version of the Ten-Item Personality Inventory was used to estimate the personality traits of the participants. Results: Low conscientiousness was identified as the only variable that was strongly predictive of the choice of treatment with explicit statistical prediction (ß = -0.44, z = 2.19, p = 0.03). In addition, while the association was not statistically significant, low neuroticism was found to be weakly predictive of the choice of uncertain treatment (ß = -0.37, z = 1.73, p = 0.08). Conclusion: In conclusion, we showed that low levels of conscientiousness predict the choice of treatment with explicit statistical prediction (ie, topical treatment) for glaucoma after an explanation in a negative context.

Age-Related Changes in Intraocular Pressure: Japan Ningen Dock Study.

PRCIS: The analysis of intraocular pressure by age using a mega database showed a consistent age-related intraocular pressure decrease. PURPOSE: To clarify the association between age and intraocular pressure (IOP), the IOP value by age was assessed using a large IOP database. MATERIALS AND METHODS: This cross-sectional study was conducted among 103 health checkup institutions registered to the Japan Society of Ningen Dock, and included participants who underwent annual health checkups between April 2014 and March 2015. The inclusion criteria were as follows: complete data for IOP in eyes, body mass index, waist circumference, blood pressure, hemoglobin A1c, and a self-administered health questionnaire. A total of 655,818 participants were enrolled. The mean age was 51.5±10.5 years (range, 20-96 y), and 40.1% were women. IOP was measured using a noncontact tonometer. Multiple linear regression analysis was conducted to explore factors associated with IOP, including age, and analyses stratified by age group: <40, 40-69, and ≥70 years. RESULTS: A consistent negative association between IOP and age [ß=-0.353 (95% confidence interval: -0.360--0.346)] was observed. In the age groups of <40 and ≥70 years, the age-related IOP decline was more pronounced [ß=-0.502 (95% CI: -0.566 to -0.439); ß=-0.674 (95% CI: -0.753 to -0.595)], with it being 14.21±2.95 and 11.18±2.52 mm Hg in the 20-24 and 90-96 year age groups, respectively. The middle-aged (aged 40-69 y) population showed gradual decline [ß=-0.313 (95% CI: -0.323 to -0.303)]. CONCLUSION: Age was strongly and negatively associated with IOP. The magnitude of IOP decline across lifespans was ∼3 mmHg. Age-related decreases in IOP were nonlinear and phasic.

Association between personality traits and experience of adverse periocular reactions to topical prostaglandin analogues.

BACKGROUND: Aesthetically unappealing adverse periocular reactions to prostaglandin (PG) eye-drops are a major challenge in glaucoma treatment. This study analysed the personality traits of patients with glaucoma based on a five-factor model and examined the associations between these factors and adverse periocular reactions. METHODS: One hundred and forty-seven patients with glaucoma were surveyed anonymously regarding their personality traits and how often adverse periocular reactions were experienced. RESULTS: The analysis included 117 valid responses (71 men and 46 women, age: 61.9±11.5 years). Patients who experienced hypertrichosis of the eyelashes scored significantly higher on extraversion (p<0.05), with no significant differences in the other four personality traits. Patients who experienced eyelid hyperpigmentation and deepening of the upper eyelid sulcus showed no significant differences in any of the personality traits. Younger patients scored significantly higher on hypertrichosis (p<0.05). CONCLUSION: The experience of adverse reactions differed according to patient age and personality traits. Therefore, eye-drops should be chosen based on these factors. TRIAL REGISTRATION NUMBER: UMIN000035155.

Elk-1 regulates retinal ganglion cell axon regeneration after injury.

Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strongly pro-regenerative factors to discover genes that regulate survival and regeneration. We used advanced bioinformatic analysis to identify the top transcriptional regulators of upstream genes and cross-referenced these with the regulators upstream of genes differentially expressed between embryonic RGCs that exhibit robust axon growth vs. postnatal RGCs where this potential has been lost. We established the transcriptional activator Elk-1 as the top regulator of RGC gene expression associated with axon outgrowth in both models. We demonstrate that Elk-1 is necessary and sufficient to promote RGC neuroprotection and regeneration in vivo, and is enhanced by manipulating specific phosphorylation sites. Finally, we co-manipulated Elk-1, PTEN, and REST, another transcription factor discovered in our analysis, and found Elk-1 to be downstream of PTEN and inhibited by REST in the survival and axon regenerative pathway in RGCs. These results uncover the basic mechanisms of regulation of survival and axon growth and reveal a novel, potent therapeutic strategy to promote neuroprotection and regeneration in the adult CNS.

Real-Time Risk Score for Glaucoma Mass Screening by Spectral Domain Optical Coherence Tomography: Development and Validation.

Purpose: To develop and validate a risk score assessable in real-time using only retinal thickness-related values measured by spectral domain optical coherence tomography alone for use in population-based glaucoma mass screenings. Methods: A total of 7572 participants (aged 35-74 years) underwent spectral domain optical coherence tomography examination annually between 2016 to 2021 in a population-based setting. We selected 284 glaucoma cases and 284 controls, matched by age and sex, from 11,487 scans in 2016. We conducted multivariable logistic regression with backward stepwise selection of retinal thickness-related variables to develop the diagnostic models. The developed risk scores were applied to all participants in 2018 (9720 eyes), and we randomly selected 723 scans for validation. Additional validation using the Humphrey field analyzer was conducted on 129 eyes in 2020. We assessed the models using sensitivity, specificity, the area under the receiver operating characteristic curve and positive and negative predictive values. Results: The best-predicting model achieved an area under the receiver operating characteristic curve of 0.97 (95% confidence interval, 0.96-0.98) with a sensitivity of 0.93 and specificity of 0.91. The validation dataset showed a positive predictive value of 90.8% for high-risk scorers, corresponding to 6.2% of the population, and negative predictive value of 88.2% for low-risk scorers, corresponding to 85.2%. Sensitivity and specificity for glaucoma diagnosis were 0.85 and 0.91, when we set the risk score cut-off at 90 points out of 100. Conclusions: This risk score could be used as a valid index for glaucoma screening in a population-based setting. Translational Relevance: The score is feasible by installing a simple computer application on an existing spectral domain optical coherence tomography and will help to improve the accuracy and efficiency of glaucoma screening.

Seasonal Fluctuation in Intraocular Pressure and Retinal Nerve Fiber Layer Thinning in Primary Open-Angle Glaucoma.

PURPOSE: To detect seasonal fluctuations in intraocular pressure (IOP) in healthy eyes and eyes with primary open-angle glaucoma (POAG) and to evaluate whether these seasonal fluctuations affect retinal nerve fiber layer (RNFL) thinning in eyes with POAG. DESIGN: Observational, retrospective cohort study. PARTICIPANTS: Healthy population who underwent a comprehensive health check-up and patients with POAG using only topical medications were enrolled. METHODS: Kaplan-Meier survival analysis was used to compare the cumulative incidence probabilities of RNFL thinning between different seasonal IOP fluctuation groups. A Cox proportional hazards model, with adjustments for potential confounding factors, was used to evaluate the association between seasonal fluctuations in IOP and RNFL thinning. MAIN OUTCOME MEASURES: Intraocular pressure fluctuation rate calculated from winter and summer IOPs and RNFL thinning as determined by event-based analysis with high-definition OCT. RESULTS: A total of 12 686 healthy eyes and 179 eyes of 179 POAG patients showed a significantly higher IOP in winter than in summer (healthy, 13.2 ± 3.0 mmHg vs. 12.5 ± 2.9 mmHg [P < 0.001]; POAG, 13.1 ± 2.7 mmHg vs. 11.8 ± 2.3 mmHg [P < 0.001]). In POAG patients, the mean age at initial OCT and follow-up duration were 55.1 ± 11.7 years and 98.4 ± 26.4 months, respectively. The mean deviation (MD) at first visit, MD slope, and RNFL thinning rate were -2.2 ± 3.4 dB, -0.07 ± 0.44 dB/year, and -0.44 ± 0.88 µm/year, respectively. During the study period, 85 eyes (47.5%) showed RNFL thinning progression. Kaplan-Meier analysis showed that a high seasonal IOP fluctuation rate significantly suppressed RNFL thinning (P < 0.05, log-rank test). After adjusting for confounders in the Cox analysis, the seasonal IOP fluctuation rate still showed a significantly negative association with RNFL thinning (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99; P = 0.005). CONCLUSIONS: Winter IOP was higher than summer IOP in both healthy and POAG eyes. The temporary IOP decline in summer, rather than a constant IOP throughout the year, may prevent glaucoma progression.

Seasonal fluctuation in intraocular pressure and its associated factors in primary open-angle glaucoma.

BACKGROUND/OBJECTIVES: To evaluate seasonal fluctuations in intraocular pressure (IOP) in primary open-angle glaucoma (POAG) and its associated factors. SUBJECTS/METHODS: POAG patients treated only with glaucoma eye drops were enroled. Winter and summer IOPs were evaluated. The Seasonal fluctuation rate of IOP was defined as follows: (mean winter IOP-mean summer IOP)/mean IOP in all seasons. Multiple linear regression analysis was used to explore factors associated with the seasonal IOP fluctuation rate including: age, gender, family history of glaucoma, type of glaucoma, number of eye drops, type of eye drops, mean deviation (MD) value, MD slope, disc haemorrhage, central corneal thickness and spherical equivalent. RESULTS: Winter IOP was higher than summer IOP in 204 POAG eyes of 204 patients, including 162 eyes with normal tension glaucoma (NTG) (13.2 ± 2.7 vs. 12.0 ± 2.3 mmHg, P < 0.001). The mean age and follow-up duration were 63.3 ± 11.4 years and 140.0 ± 66.9 months. Initial MD and MD slope were -2.1 ± 3.4 dB and -0.07 ± 0.50 dB/year, respectively. POAG was positively associated with the rate of seasonal IOP fluctuations compared to NTG (ß = 5.29, P = 0.013). Family history, and timolol and carteolol use were also factors associated with the IOP fluctuation rate (ß = -6.27, P = 0.007; ß = 4.94, P = 0.030; and ß = 4.51, P = 0.042, respectively). CONCLUSIONS: We confirmed seasonal IOP fluctuations in POAG. Type of glaucoma, family history of glaucoma, and ß-blocker use might influence IOP fluctuations.

Posttranslational Modification of Sox11 Regulates RGC Survival and Axon Regeneration.

The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury but exacerbates the death of a subset of retinal ganglion cells (RGCs), α-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent SUMOylation at lysine 91 (K91) increased Sox11 nuclear localization and RGC differentiation in vitro Here, we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro, we found that non-SUMOylatable Sox11K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in vivo in the adult mouse. RNA sequence (RNA-seq) data showed that Sox11 and Sox11K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated Spp1 and Opn4 expression in RGC cultures, consistent with negatively regulating the survival of α-RGCs and ipRGCs. Thus, Sox11 and its SUMOylation site at K91 regulate gene expression, survival and axon growth in RGCs, and may be explored further as potential regenerative therapies for optic neuropathy.

Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma.

Glaucoma is a neurodegenerative disease of the eye, which involves degeneration of retinal ganglion cells (RGCs): the output neurons of the retina to the brain, which with their axons comprise the optic nerve. Recent studies have shown the possible involvement of oxidative stress in the pathogenesis of glaucoma, especially in the subtype of normal tension glaucoma. Basic experiments utilizing rodent and primate models of glaucoma revealed that antioxidants protect RGCs under various pathological conditions including glutamate neurotoxicity and optic nerve injury. These results suggested that existing drugs and food factors may be useful for prevention and hence therapy of glaucoma. In this review, we highlight some therapeutic candidates, particularly those with antioxidant properties, and discuss the therapeutic potential of RGC protection by modulating gene expressions that prevent and ameliorate glaucoma.

Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury.

Optic nerve injury induces optic nerve degeneration and retinal ganglion cell (RGC) death that lead to visual disturbance. In this study, we examined if topical ripasudil has therapeutic potential in adult mice after optic nerve crush (ONC). Topical ripasudil suppressed ONC-induced phosphorylation of p38 mitogen-activated protein kinase and ameliorated RGC death. In addition, topical ripasudil significantly suppressed the phosphorylation of collapsin response mediator protein 2 and cofilin, and promoted optic nerve regeneration. These results suggest that topical ripasudil promotes RGC protection and optic nerve regeneration by modulating multiple signaling pathways associated with neural cell death, microtubule assembly and actin polymerization.