Translational Vision Science & Technology最新文献

Purpose: To explore the usefulness of hierarchical clustering to classify extensive macular atrophy with pseudodrusen-like appearance (EMAP) based on macular and peripheral atrophy extension.

Methods: In this cross-sectional study, all participants underwent best-corrected visual acuity (BCVA) testing, optical coherence tomography (OCT), short-wavelength fundus autofluorescence (SW-AF), and ultra-widefield color fundus photography (UWF-CFP). Peripheral atrophy was quantified in degrees using OptosAdvance software, and macular atrophy area was manually measured. Based on the relative proportion of macular and peripheral atrophy, eyes were clinically classified as having predominantly central, mixed, or predominantly peripheral disease. Hierarchical clustering was performed using macular atrophy area and peripheral angular extension.

Results: Eighty-five eyes from 45 EMAP patients (mean age, 64.0 ± 8.7 years; 26 females, 57.8%) were included. Peripheral pavingstone-like degeneration was observed in 57% of eyes. Four clusters were identified: Cluster 1, minimally atrophic (20%); Cluster 2, predominantly central (20%); Cluster 3, mixed (27%); and Cluster 4, predominantly peripheral (33%). Cluster 2 showed significantly worse BCVA (P = 0.013 vs. Cluster 1; P = 0.007 vs. Cluster 4) and higher prevalence of foveal atrophy (P = 0.004) and fibrosis (P < 0.0001). No significant differences in age or refractive error were found among the groups.

Conclusions: Clinical and clustering-based classifications converged on consistent EMAP subtypes defined by macular and peripheral atrophy distribution. These findings suggest that combining clinical expertise with data-driven methods can help describe disease variability and guide future research.

Translational relevance: Integrating clinical expertise with unsupervised clustering may improve the identification of EMAP subtypes, aiding patient selection and outcome stratification in future trials and longitudinal studies.

Purpose: To identify biometric factors predictive of corneal endothelial contact (CEC) by intracameral implants in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHTN).

Methods: In this prospective observational study, patients with a chart diagnosis of POAG or OHTN without prior cataract or incisional glaucoma surgery were consecutively enrolled between August 2022 and October 2023. Participants underwent anterior segment optical coherence tomography (AS-OCT) imaging along the vertical meridian under dark and light conditions. An intracameral implant was simulated by overlaying a 0.2-mm-diameter circle onto an AS-OCT image of the inferior angle recess to predict CEC, defined as implant contact anterior to Schwalbe's line. Logistic regression models were developed to identify predictors of CEC.

Results: CEC was present in 14 eyes (17.9%) and 11 eyes (14.1%) from 78 eyes of 78 participants in the dark and light conditions, respectively. In univariable analysis, smaller angle opening distance (750 µm; AOD750), shallower anterior chamber depth, greater lens vault and thickness, and iridotrabecular contact were significantly associated with CEC in both environments (P < 0.05). AOD750 was the strongest predictor of CEC (dark AUC = 0.99; light AUC = 0.97), with optimal cutoffs of 0.22 mm (dark) and 0.30 mm (light). Gonioscopy grade was less predictive of CEC (dark AUC = 0.79; light AUC = 0.84).

Conclusions: CEC by a simulated intracameral implant was predicted in a subset of patients with chart diagnosis of POAG or OHTN. AS-OCT biometrics were more strongly predictive of CEC than gonioscopy.

Translational relevance: AS-OCT may enhance preoperative evaluation of intracameral implant candidates by identifying those at higher risk for CEC.

Purpose: This study aimed to compare photopic and mesopic contrast sensitivity (CS) between low-to-moderate myopia (LMM) and high myopia (HM) groups, and to evaluate the associations between CS and chorioretinal structural and vascular parameters.

Methods: In this cross-sectional study, 108 participants were divided into an LMM group (n = 53, mean age = 21.0 years, mean SE = -4.25 diopters [D]) and an HM group (n = 55, mean age = 24.0 years, mean SE = -8.25 D). CS was tested under photopic (85 cd/m²) and mesopic (3 cd/m²) conditions. Chorioretinal parameters were measured using swept-source optical coherence tomography/optical coherence tomography angiography (SS-OCT/OCTA). Associations were assessed using univariate and stepwise multiple linear regression analyses.

Results: The HM group exhibited significantly reduced CS under both photopic (1.07 ± 0.11 vs. 1.19 ± 0.09 in the LMM group, P < 0.001) and mesopic (median = 0.64 vs. 1.04 in the LMM group, P < 0.001) conditions. Compared to the LMM group, the HM group had a significantly thinner choroid and a higher choroidal vascularity index (CVI). Mesopic CS (CSm) demonstrated stronger and more extensive associations with chorioretinal parameters than photopic CS (CSp).

Conclusions: Chorioretinal alterations in high myopia appear to have a more profound impact on visual function under mesopic than photopic conditions. Given its sensitivity to both choroidal and retinal alterations, mesopic CS is a parameter that warrants further investigation for its potential in assessing functional impairment in myopia.

Translational relevance: Measuring mesopic contrast sensitivity offers a superior functional indicator of underlying chorioretinal health in myopia, allowing for earlier and more comprehensive assessment of visual decline in clinical practice.

Purpose: Our previous studies in Royal College of Surgeons (RCS) rats demonstrated that co-administration of MER proto-oncogene tyrosine kinase (MERTK) and its ligand Gas6 effectively protected photoreceptors and improved visual function. To facilitate clinical translation, we developed Gas6-loaded sustained-release liposomes (Gas6 Lips) using liposomes with superior biocompatibility and enhanced release stability as the delivery vehicle, and subsequently evaluated their long-term efficacy and safety in RCS rats and nonhuman primates.

Methods: Gas6 Lips were synthesized using a thin-film hydration method and characterized for morphology, encapsulation efficiency, and release profile. A GMP-grade adeno-associated virus serotype 2 (AAV2)-BEST1-hMERTK vector was constructed. Experimental groups included the AAV-hMERTK group, the combination group with AAV-hMERTK and Gas6 Lips, and the control group. Therapeutic efficacy was assessed in RCS rats using electroretinography (ERG) and histological analysis. Long-term safety was evaluated in cynomolgus monkeys over 12 months.

Results: Gas6 Lips had an average size of 144.1 nm and sustained Gas6 release for over 5 weeks. In RCS rats, the combination group exhibited significantly higher ERG b-wave amplitudes (52.116 ± 9.747 µV vs. 36.186 ± 7.156 µV, P < 0.01) and greater outer nuclear layer preservation (14.47 ± 1.43 µm vs. 10.41 ± 1.19 µm, P < 0.01) compared with the AAV-hMERTK group. These therapeutic effects persisted for over 7 weeks. In primates, no significant changes in retinal structure, ERG, or systemic immune responses were observed, with only transient and reversible mild ocular inflammation in the early post-treatment phase.

Conclusions: Gas6 Lips combined with AAV2-BEST1-hMERTK effectively preserved retinal structure and function in RCS rats and demonstrated long-term safety in primates, supporting its potential for clinical translation.

Translational relevance: This can provide preclinical efficacy and safety data for the clinical translation of Gas6 Lips for the treatment of retinal pigmentosa (RP).

Purpose: Chronic pain is a prevalent condition. Despite overlapping pathophysiological mechanisms, the association between chronic pain and glaucoma remains unclear. This study aimed to investigate their association through a prospective cohort analysis using data from the UK Biobank.

Methods: Chronic pain was assessed at baseline through questionnaire. The patterns analyzed included the number of chronic pain locations and different single-location chronic pain. Participants were followed up until glaucoma diagnosis, death, or censoring. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models, adjusted for covariates.

Results: Compared to individuals without chronic pain, those with chronic pain in three or more locations were at a significantly higher risk of glaucoma, with HRs of 1.20 (95% CI, 1.10-1.30; P < 0.001) for pain in three locations and 1.34 (95% CI, 1.24-1.46; P < 0.001) for pain in four or more locations. However, chronic pain in one or two locations did not show a significant association with glaucoma, and no individual pain location was independently associated with glaucoma risk.

Conclusions: This study highlighted the potential cumulative effect of chronic pain across multiple locations on glaucoma risk.

Translational relevance: These findings highlight the potential need for further investigation into glaucoma screening in populations with chronic pain in multiple locations.

Purpose: Antitubercular therapy (ATT) for tubercular serpiginous-like choroiditis (TB-SLC) is well-established, but not infallible. In this study, we investigated the risk factors underlying persistent inflammation after ATT in TB-SLC patients.

Methods: We retrospectively reviewed consecutive TB-SLC patients, who completed ≥6 months of ATT. The primary outcome measure was persistent inflammation at the completion of ATT. The risk factors for persistent inflammation were analyzed using multivariate logistic regression. Additionally, a categorical network analysis was performed to explore the relationships among key clinical variables. The anti-inflammatory therapy was quantified as total immunosuppressive load (TIL) by scoring systemic and local corticosteroid treatments.

Results: Sixty-five patients, 71% (n = 46) males, with a median age of 33 ± 11.1 years, 45% (n = 29) bilateral, were included. Twelve patients (18.5%; 17 eyes [18.1%]) had ongoing inflammation at the conclusion of ATT. In multivariate regression analysis, the mean TIL at month 1 (adjusted odds ratio, 0.64; 95% confidence interval, 0.43-0.97; P = 0.04) and persistent inflammation at month 3 of ATT (adjusted odds ratio, 13.44; 95% confidence interval, 1.61-111.92; P = 0.02) were risk factors for persistent inflammation after ATT. Network analysis revealed strong mutual associations among low 1-month TIL, persistence at 3 months, paradoxical worsening, and 6-month ATT duration.

Conclusions: Initial immunosuppression offers protection, and ongoing inflammation during therapy increases the risk of persistent inflammation after ATT. Paradoxical worsening and shorter ATT duration may affect these risk factors.

Translational relevance: Persistent inflammation after antitubercular therapy for tubercular serpiginous-like choroiditis is mainly determined by nonmicrobial factors, most notably the level of immunosuppression at the start of antitubercular therapy.

Purpose: RPE65 is a key enzyme in the visual cycle, converting all-trans retinyl esters into 11-cis retinol, a crucial step in regenerating the photopigment necessary for vision. Mutations cause a spectrum of inherited retinal diseases (IRDs), from severe generalized early-onset dystrophies, such as Leber congenital amaurosis, to classical retinitis pigmentosa or mild phenotypes, including congenital stationary night blindness, such as fundus albipunctatus.

Methods: We analyzed two independent patients with mild RPE65-associated IRDs using multimodal diagnostics, including best-corrected visual acuity; Goldman visual field; dark-adapted testing, including scotopic perimetry; full-field electroretinography; and multimodal retinal imaging. Phenotypes were evaluated based on existing literature and predicted variant impact.

Results: Both patients exhibited overall mild IRDs with only slightly impaired rod function and largely preserved cone function. Identified RPE65 missense variants likely allow partial enzyme function, consistent with comparatively mild and slowly progressive disease. Superior rod scotomas and mid-peripheral morphologic changes were identified despite normal or near-normal full-field function.

Conclusions: Functional rod changes in the inferior mid-periphery of the retina, which may be followed by metabolic stress and structural retinal changes, seem to be the hallmark of mild RPE65-associated IRDs and may represent early site-specific pathology. These changes may be linked to an increased susceptibility to UV-induced retinal damage associated with RPE65 mutations. Local rod function assessment is critical for proper disease monitoring and guiding therapeutic decisions.

Translational relevance: Localized multimodal diagnostics help detect early changes in mild RPE65-associated IRDs, supporting precise monitoring and gene therapy counseling.

Purpose: Recombinant adeno-associated virus (rAAV) vectors are promising tools for the treatment of inherited retinal diseases (IRDs) but have a limited carrying capacity for therapeutic cassettes of up to 4.8 kilobase (kb). To circumvent this limitation, multiple vector approaches have been proposed wherein the transgene cassette is split across two or more rAAV vector genomes. In this study, we examine whether rAAV serotype choice has an effect on co-transduction of retinal cells following subretinal delivery and whether co-transduction represents a rate-limiting step preventing successful large transgene delivery.

Methods: The rAAV vector serotypes with known photoreceptor affinity (rAAV2/5, rAAV2/8, and rAAV2/9) packaging fluorescent reporter genes (GFP or mCherry) were co-delivered to C57Bl/6J mice via subretinal injection in all combinations of serotype. Two to 3 weeks following injection, confocal scanning laser ophthalmoscopy (cSLO) imaging and immunohistochemistry was used to visualize the extent of transduction and flow cytometry was utilized to quantify co-transduction of retinal cells.

Results: Fluorescent GFP and mCherry transgene expression was observed by in vivo cSLO imaging in all injected eyes. Flow cytometry showed that the highest rate of co-transduction came from co-administration of rAAV2/8.mCherry and rAAV2/9.GFP (87.43 ± 3.84%) with considerable overlap in the expression observed. The lowest rate of co-transduction resulted from the co-delivery of rAAV2/5.mCherry and rAAV2/8.GFP (36.57 ± 4.79%) with cSLO imaging showing minimal overlap in fluorescent expression.

Conclusions: Utilizing a combination of rAAV capsids with similar cellular tropisms for dual rAAV delivery can result in an increased efficiency of co-transduction but is serotype dependent.

Translational relevance: Identification of bottlenecks in rAAV transduction may improve the efficiency of large transgene delivery.

Purpose: This study aimed to explore the possibility of the clinical application using anterior segment optical coherence tomography angiography (AS-OCTA)-guided laser peripheral iridotomy (LPI).

Methods: AS-OCT/OCTA was performed before LPI and at 1 hour, 1 day, and 1 week post-LPI. All the right eyes of patients with primary angle-closure suspect (PACS) were assigned to the AS-OCTA-guided group, in which the peripheral site with the sparsest iris vasculature on AS-OCTA images was selected for LPI. The left eyes underwent LPI in the slit lamp-guided group, where the site was chosen based on the presence of an iris crypt by clinicians using the slit lamp. The two groups were compared for the incidence of anterior chamber bleeding observed by the LPI operator, anterior chamber particle (ACP) index, mean angle opening distance (AOD750), and anterior chamber depth (ACD) measured from AS-OCT images, as well as the vessel density and perfusion area obtained from AS-OCTA images.

Results: A total of 30 patients with PACS were included in this study. The incidence of anterior chamber bleeding during LPI was 13.33% in the AS-OCTA-guided group, compared with 43.33% in the slit lamp-guided group (P = 0.010). The prominent difference was observed 1 hour after LPI, with the AS-OCTA-guided group showing significantly lower vessel density (P = 0.028), perfusion area (P = 0.003), and ACP (P = 0.004), but a larger AOD750 (P < 0.001) compared with the slit lamp-guided group.

Conclusions: Utilizing AS-OCTA to guide the LPI procedure can significantly decrease the incidence of anterior chamber bleeding and mitigate inflammation.

Translational relevance: This study shows that the AS-OCTA-guided LPI procedure could bridge advanced imaging technology and clinical glaucoma management.

Purpose: Diabetic retinopathy (DR) is a typical complication in patients with diabetes. This study aimed to compare retinal blood flow and vascular resistance between eyes with DR and healthy eyes using laser speckle flowgraphy (LSFG).

Methods: In total, 50 normal eyes and 87 DR eyes were examined at Kagawa University Hospital. LSFG was used to measure the mean blur rate (MBR) and total capillary resistance (TCR) of large vessels in the optic papilla. These values were compared across normal eyes and all eyes with DR, moderate nonproliferative diabetic retinopathy (NPDR), severe NPDR, and proliferative diabetic retinopathy (PDR). A TCR receiver operating characteristic (ROC) curve was plotted, and the diagnostic ability of the TCR for DR was determined using the area under the curve. The TCR cutoff value was determined using the Youden index.

Results: No significant difference in MRB was observed between normal eyes and the other groups. TCR was significantly higher in all groups except the PDR group, compared to normal eyes. The TCR area under the ROC curve was 0.751, indicating moderate diagnostic accuracy for DR. Using the Youden index, the TCR cutoff value was 0.79 (sensitivity, 0.740; specificity, 0.701).

Conclusions: Measuring TCR, in addition to MBR, as diagnostic markers provides more detailed pathological information regarding DR.

Translational relevance: Comparison of values between groups would be useful in predicting DR onset and stage progression.