Investigative ophthalmology & visual science最新文献

Purpose: The purpose of this study was to define structure-function correlation of geographic atrophy (GA) on optical coherence tomography (OCT) and functional testing on microperimetry (MP) based on deep-learning (DL)-quantified spectral-domain OCT (SD-OCT) biomarkers.

Methods: Patients with GA were prospectively examined by SD-OCT (Spectralis, 97 B-scans) and two microperimetry devices (MP3 and MAIA) in two combined test runs each. DL-algorithms measured the ellipsoid-zone thickness (EZT), ellipsoid-zone loss (EZL), hyper-reflective-foci (HRF) volume, drusen-volume (DV), and retinal-pigment-epithelium loss (RPEL) area. Pointwise co-registration was established between all stimuli and the location on OCT. A multivariable mixed-effect model with variable selection was used to identify pointwise retinal sensitivity (PWS) changes for each biomarker, accounting for age and eccentricity.

Results: Three thousand six hundred stimuli points were collected and correlated with 1940 OCT B-scans in 20 eyes of 20 patients. PWS was significantly lower in stimuli with EZL without RPEL (-2.81, 95% confidence interval [CI] = -3.72 to -1.91 decibel [dB], 0 degrees, P < 0.0001) and in areas with both EZL and RPEL (-10.03, 95% CI = -10.96 to -9.11 dB, 0 degrees, P < 0.0001) compared to areas without any atrophy. Increased EZT had a significant positive effect on PWS (0.34, 95% CI = 0.32 to 0.36 dB/µm, P < 0.0001). Structure-function correlations were consistent throughout all levels of eccentricity with P < 0.001. Drusen and HRF volume, but not age, were associated with reduced PWS.

Conclusions: Functional impairment by MP was associated with defined morphological changes as quantified by DL on OCT. PR degeneration seen as EZL alone impairs the function on MP examinations. The combination of DL-based SD-OCT biomarker assessment and MP appear suited for evaluation of retinal function beyond visual acuity for disease monitoring.

Purpose: Binocular imbalance is known to inhibit stereopsis. This study investigates whether an imbalanced context around stereo stimuli also affects local stereopsis and explores the underlying mechanisms.

Methods: Three experiments were conducted with normally sighted participants. Experiment 1 measured local stereo detection thresholds under three context conditions: binocular balance (0.5 vs. 0.5 contrast), left-eye dominance (0.8 vs. 0.2 contrast), and right-eye dominance (0.2 vs. 0.8 contrast). Experiment 2 assessed the modulation of the imbalance effect by context-target collinearity. Experiment 3 examined the imbalance effect with binocular fusion and rivalry context stimuli.

Results: In experiment 1, the average stereo threshold was 62.4 arcsec in the binocular balance condition, elevated to 111.4 arcsec in the left-eye dominance (P = 0.003), and 114.7 arcsec in the right-eye dominance (P < 0.001), with no significant difference between the two imbalance conditions (P = 0.650). Experiment 2 showed that context-target collinearity modulated the imbalance effect, resulting in a smaller threshold elevation in the non-collinear condition (P = 0.011). Experiment 3 revealed significant main effects of imbalance (P = 0.031) and rivalry (P = 0.004), with no significant interaction (P = 0.966).

Conclusions: Contextual binocular imbalance inhibits local stereopsis, an effect modulated by collinearity and similarly observed in both binocular integrative and suppressive contexts. These findings suggest that lateral connectivity in the primary visual cortex (V1) plays a fundamental role in stereopsis generation, offering novel approaches for clinical interventions aimed at restoring binocular balance and stereopsis.

Purpose: To determine the factors cross-sectionally and longitudinally associated with retinal vessel diameter, total area, and tortuosity in the Canadian Longitudinal Study on Aging (CLSA).

Methods: Of the 30,097 adults between ages 45 and 85 years old in the CLSA Comprehensive Cohort, 26,076 had at least one retinal image gradable by QUARTZ, a deep-learning algorithm that automatically assessed image quality, distinguished between arterioles and venules, and estimated retinal vessel traits over the entire retina. Questions were asked about demographic, lifestyle, and medical factors. Blood pressure, cholesterol, and C-reactive protein were measured. Participants returned for follow-up 3 years later. Multiple linear regression was used to provide adjusted estimates.

Results: Current smoking was strongly associated with wider arteriolar and venular diameters and their widening over 3 years (P < 0.05). Current smoking was also associated with a larger arteriolar and venular area and a 3-year increase in venular area (P < 0.05). Obesity was positively associated with venular diameter, total venular area, 3-year change in total venular area, and venular tortuosity (P < 0.05). Diastolic blood pressure was negatively associated with both arteriolar and venular diameter, area, and tortuosity, both cross-sectionally and longitudinally (P < 0.05). Diabetes was associated with wider arteriolar diameters cross-sectionally, and type 1 diabetes was associated with 3-year widening of arteriolar diameters (P < 0.05).

Conclusions: This work provides comprehensive information on the factors associated with retinal vessel traits and their change. Factors such as smoking, obesity, blood pressure, and diabetes were longitudinally related to retinal vessel traits, which play a role in the development of eye disease.

Purpose: To explore whether there is a difference in postoperative extraocular muscle (EOM) remodeling between 1-month-old and 3-month-old rabbits.

Methods: Recession (n = 16) and resection (n = 16) were performed on the right superior rectus (SR) muscles of 1-month-old and 3-month-old rabbits. SR tissues were harvested 1 and 4 weeks post-surgery (n = 4 for each group), and mid-belly sections were used to assess myosin heavy chain (MyHC) isoform expression (fast 2X, embryonic, and neonatal MyHCs), activated satellite cells (SCs), and centrally nucleated myofibers. Age-matched unoperated rabbits (n = 4) served as controls.

Results: In 1-month-old rabbits, fast 2X-MyHC expression continuously decreased post-recession (all P < 0.01), and embryonic MyHC expression increased both post-recession and post-resection (all P < 0.01), except in the global layer (GL) post-resection. In 3-month-old rabbits, fast 2X-MyHC decreased at 1 week post-recession (in both layers P < 0.01) but returned to preoperative levels by 4 weeks (in both layers P = 1). Embryonic MyHC remained stable (P = 0.239) or increased (in the GL post-recession and in the orbital layer (OL) post-resection, both P < 0.001) at 1 week postoperatively, except in the GL post-resection. It had returned (in the GL post-recession, P = 0.952; in the GL post-resection, P = 0.574) or nearly returned (in the OL post-resection, P = 0.038) to preoperative levels in both layers by 4 weeks. Activated SCs in 1-month-old rabbits continuously increased post-surgery (all P < 0.05), except in the OL post-resection. In 3-month-old rabbits, SCs remained stable at 1 week but decreased by 4 weeks post-surgery (all P < 0.01), except in the OL post-resection. Centrally nucleated myofibers were more prevalent in 1-month-old rabbits by 4 weeks postoperatively.

Conclusions: One-month-old rabbits displayed longer postoperative remodeling and greater plasticity in EOMs than 3-month-old rabbits. The difference in postoperative remodeling may impact strabismus surgery outcomes in patients of different developmental stages.

Purpose: This study aimed to investigate the therapeutic potential of isolated mitochondrial transplantation for the restoration of corneal surface injury in mice after corneal chemical burn.

Methods: Mitochondria were isolated from mesenchymal stem cells via ultracentrifugation, followed by an assessment of their purity and viability. The internalization of mitochondria by human corneal epithelial cells was tracked using a live fluorescence imaging system. Apoptosis-related markers and mitochondrial function were measured by Western blotting and flow cytometry, respectively. Mitochondrial morphology was examined using confocal laser scanning microscopy. The therapeutic effects of subconjunctival administration of isolated mitochondria in vivo were evaluated by fluorescein sodium staining and histopathological examination of the corneas.

Results: Our study demonstrates that corneal epithelial cells possess the capacity to internalize isolated exogenous mitochondria in vitro. Under oxidative stress conditions, recipient cells exhibited an enhanced uptake of exogenous mitochondria. We observed a decrease in apoptosis and a reduction in oxidative stress levels within the recipient cells, as well as a partial restoration of mitochondrial function. Notably, after a single subconjunctival injection, corneal epithelial cells were able to use isolated mitochondria to enhance the repair process in a mouse model of corneal acid burn.

Conclusions: Subconjunctival injection of isolated mitochondria promoted the repair of acute corneal burns in mice. The results of our investigation using injection of isolated mitochondria as a treatment modality for corneal chemical burn offers a novel approach to the treatment of ocular disorders associated with mitochondrial dysfunction.

Purpose: The accurate determination of the etiology and location of lacrimal passage obstruction is key to treatment. However, the main assessments for lacrimal passage are invasive and have limited value. This study aimed to analyze the causes of obstruction of the lacrimal passage and investigate the diagnostic value of magnetic resonance dacryocystography (MRD).

Methods: Fifty-six patients (69 eyes) with lacrimal disease underwent MRD after lacrimal irrigation. The stenotic site and degree were determined. The accuracies of the diagnoses of lesions at different sites based on MRD and routine clinical assessment were determined and compared, and a noninferiority test was used to verify the values obtained via MRD.

Results: The lesion location determined through lacrimal irrigation was inconsistent with that determined through MRD. The overall accuracy of routine clinical assessment was approximately 79.7% (55 of 69) and that of MRD reached 98.6% (68 of 69). For the lesion location, the clinical misdiagnosis rates were 38.9%, 43.8%, and 63.6% for the lacrimal sac, nasolacrimal duct, and perilacrimal passage, respectively. The MRD and surgical pathology results for the lacrimal sac, nasolacrimal duct, and perilacrimal passage were consistent, except for the lacrimal canaliculus. The P value for the noninferiority of MRD to surgical pathology was 0.32.

Conclusions: MRD is noninvasive and has high value for determining the cause, location, and degree of lacrimal stenosis. Its findings are nearly as accurate as those of surgical pathology. MRD should be recommended over other invasive methods for evaluating lacrimal and prelacrimal lesions.

Purpose: To determine pathways in the trigeminal ganglion and corneal epithelium that are targeted by topical naltrexone (NTX) treatment for dry eye.

Methods: NTX drops were administered topically daily for 15 days to the corneal surface of male and female adult type 1 diabetic rats. Schirmer scores and corneal sensitivity were measured at baseline, 5, 10, and 15 days. Trigeminal ganglion and corneal epithelium were processed for immunohistochemistry to detect expression of opioid growth factor receptor (OGFr), Ki67, nerve growth factor, insulin-like growth factor-1, calcitonin gene-related peptide, substance P, and TNF-α. A proteomic study determined protein changes in the cornea.

Results: Corneal sensitivity and tear production in diabetic rats were restored to normal levels within 5 days after topical NTX. Assessment of corneal tissue after 15 days of treatment revealed that defects in OGFr expression, epithelial cell number, and Ki67+ expression were restored to normal by NTX. Inflammation markers (e.g., TNF-α) were reduced in tissue from diabetic rats treated with NTX. Proteomic data suggest diabetes causes dysregulation in inflammatory biological processes. The percentages of calcitonin gene-related peptide-positive neurons, but not substance P-positive neurons, in the trigeminal ganglion were increased after NTX treatment. Diabetic male and female rats responded to NTX in a comparable manner.

Conclusions: Type 1 diabetes results in decreased tear production and altered corneal surface sensitivity. These complications coincide with dysregulated OGFr that maintains ocular homeostasis. Reversal of dry eye and restoration of corneal sensitivity in diabetic male and female rats after 15 days of topical treatment with NTX occur following dual pathways of increased cellular proliferation and reduction of inflammation.

Purpose: Fuchs endothelial corneal dystrophy (FECD) is a progressive corneal disorder characterized by excessive extracellular matrix (ECM) accumulation and corneal endothelial cell death. CTG trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene represents the most significant genetic risk factor. This study aimed to elucidate the role of TCF4 in FECD pathogenesis through comprehensive proteomic analysis.

Methods: Corneal endothelial cells isolated from patients with FECD harboring TCF4 trinucleotide repeat expansion were immortalized to establish an FECD cell model (iFECD). CRISPR/Cas9-mediated genome editing was employed to generate TCF4-knockout iFECD cells. Whole-cell proteome analysis was performed using liquid chromatography-mass spectrometry, followed by pathway enrichment analysis of differentially expressed proteins (DEPs). The effects of TCF4 deletion on TGF-β-mediated protein aggregation and cell death were evaluated using Western blot analysis, flow cytometry, and aggresome detection assays.

Results: Proteomic analysis identified 88 DEPs among 6510 detected proteins. Pathway analysis revealed significant enrichment in ECM-associated pathways, oxidative stress responses, and cellular motility. TCF4 deletion attenuated TGF-β-induced cell death in iFECD cells. Concordantly, Western blot analysis demonstrated that TCF4 deletion suppressed TGF-β2-mediated cleavage of caspase-3 and poly (ADP-ribose) polymerase. Flow cytometric analysis of Annexin V-positive cells confirmed reduced apoptosis in TCF4-deleted cells following TGF-β2 treatment. Additionally, aggresome detection assays revealed that TCF4 deletion diminished TGF-β2-induced protein aggregation.

Conclusions: This study demonstrates a crucial role for TCF4 in FECD pathogenesis, particularly in ECM regulation and protein aggregation-induced cell death.

Purpose: The loss of Dicer in Müller glia (MG) results in severe photoreceptor degeneration, as it occurs in retinitis pigmentosa or age-related macular degeneration; however, the sequence of events leading to this severe degenerative state is unknown. The aim of this study was to conduct a chronological functional and structural characterization of the pathological events in MG-specific Dicer-conditional knockout (cKO) mice in vivo and histologically.

Methods: To delete Dicer and mature microRNAs (miRNAs) in MG, two conditional Dicer1 knockout mouse strains (Rlbp-CreER:tdTomato:Dicer-cKOMG and Glast-CreER:tdTomato:Dicer-cKOMG) were created. Optical coherence tomography (OCT), electroretinograms (ERGs), and histological analyses were conducted to investigate structural and functional changes up to 6 months after Dicer deletion.

Results: Dicer/miRNA loss in MG leads to (1) impairments of the area spanning from the external limiting membrane (ELM) to the retinal pigment epithelium (RPE), (2) cone photoreceptor dysfunction, and (3) retinal remodeling and functional loss of the inner retina at 1, 3, and 6 months after Dicer loss, respectively, in both of the knockout mouse strains. Furthermore, in the Rlbp-CreER:tdTomato:Dicer-cKOMG strain, rod photoreceptor impairment was found 4 months after Dicer depletion (4) accompanied by alteration of RPE integrity (5).

Conclusions: MG Dicer loss in the adult mouse retina impacts cone function prior to any measurable changes in rod function, suggesting a pivotal role for MG Dicer and miRNAs in supporting cone health. A partially impaired RPE, however, seems to accelerate rod degeneration and overall degenerative events.