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Inner Retinal Changes in Primary Open-Angle Glaucoma Revealed Through Adaptive Optics-Optical Coherence Tomography
摘要： To examine the microstructural changes in the inner nuclear layer (INL) and ganglion cell layer (GCL) in a primary open-angle glaucoma (POAG) subject at 2 timepoints, 4 months apart. This case-control study (1 POAG subject and 1 normal control) used the single cell, 3-dimensional volumetric imaging capability of an adaptive optics-optical coherence tomography-scanning laser ophthalmoscopy system to examine the inner retina. At the area of greatest glaucomatous change in the POAG subject [3-degrees temporal (T), 3-degrees inferior (I), right eye], the GCL was greatly thinned at both timepoints, yet retinal ganglion cell soma remained visible amid a meshwork of capillaries. Microcystic lesions in the INL were visible at both timepoints, ranging in diameter from 8 to 43 μm on day 1 to 11 to 64 μm at 4 months, with an average diameter increase of ～124%. Small hyperre?ective features (not seen in the contralateral eye or control subject) at a depth midway through the INL seemed correlated to the development of microcysts. We demonstrate the ability to image microcystic lesions early in their development and have quanti?ed longitudinal changes. The presence of small hyperre?ective structures at a layer midway through the INL seems to be a precursor to their formation and is a potential biomarker for assessing POAG severity and progression. The adaptive optics imaging system is also able to visualize retinal ganglion cells in this subject, despite severe thinning of the GCL.
关键词： optical coherence tomography,adaptive optics,retinal ganglion cells,microcysts,primary open-angle glaucoma
更新于2025-09-16 10:30:52
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Assessment of macular ganglion cell complex using optical coherence tomography: Impact of a paediatric reference database in clinical practice
摘要： Importance: Optical coherence tomography software classifies abnormality of macular ganglion cell-inner plexiform layer thickness and macular retinal nerve fibre layer thickness based on adult series. Background: We assessed the impact of using paediatric reference macular ganglion cell complex values instead of adult reference values. Design: Cross-sectional study. Primary and tertiary health-care setting. Participants: Out of 140 healthy participants aged 5 to 18 years, 90% were eligible. Methods: Following a dilated eye examination and cycloplegic refraction, participants underwent optical coherence tomography ganglion cell scans (Topcon 3D OCT-2000; Topcon Corporation, Tokyo, Japan). Right eye measurements for superior, inferior, and total layer thickness and spherical equivalent were reported, together with age, sex and origin. Main Outcome Measures: Paediatric reference values by age and spherical equivalent were produced, and the specific agreement between paediatric and adult to percentile 5 was ganglion cell complex reference values below or equal estimated. Results: The multivariate analysis confirmed a positive association between spherical equivalent and macular ganglion cell-inner plexiform layer thickness, and between age and macular retinal nerve fibre layer (five out of six regression coefficients P values were (cid:1) 0.03). Specific agreement was 25% for ganglion cell-inner plexiform layer thickness and > 80% for macular retinal nerve fibre layer. Adult-based software identified low ganglion cell values in one in seven children compared to paediatric reference values (0.8% vs 5.5%, P = 0.031). Conclusions and Relevance: The availability of optical coherence tomography ganglion cell complex reference values for paediatric age and spherical equivalent groups can be used to improve detection of children with low cell layer thickness.
关键词： macular ganglion cell-inner plexiform layer,childhood,optical coherence tomography,children reference database,retinal ganglion cells,macular retinal nerve fibre layer,ganglion cell complex
更新于2025-09-10 09:29:36
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The Post-Illumination Pupil Response (PIPR)
摘要： The post-illumination pupil response (PIPR) has been quantified using four metrics, but the spectral sensitivity of only one is known; here we determine the other three. To optimize the human PIPR measurement, we determine the protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. METHODS. The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer. Experiment 1: Spectral sensitivity of four PIPR metrics (plateau, 6 seconds, area under curve early and late recovery) was determined from a criterion PIPR to a 1-second pulse and fitted with vitamin A1 nomogram (kmax ? 482 nm). Experiment 2: The PLR was measured as a function of three stimulus durations (1 second, 10 seconds, 30 seconds), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8–14.8 log quanta.cm(cid:2)2.s(cid:2)1), and two wavelengths, one with high (465 nm) and one with low (637 nm) melanopsin excitation. Intra- and interindividual coefficients of variation (CV) were calculated. RESULTS. The melanopsin (opn4) photopigment nomogram adequately describes the spectral sensitivity of all four PIPR metrics. The PIPR amplitude was largest with 1-second short-wavelength pulses (?12.8 log quanta.cm(cid:2)2.s(cid:2)1). The plateau and 6-second PIPR showed the least intra- and interindividual CV ((cid:3)0.2). The maximum duration of the sustained PIPR was 83.0 6 48.0 seconds (mean 6 SD) for 1-second pulses and 180.1 6 106.2 seconds for 30-second pulses (465 nm; 14.8 log quanta.cm(cid:2)2.s(cid:2)1). CONCLUSIONS. All current PIPR metrics provide a direct measure of the intrinsic melanopsin photoresponse. To measure progressive changes in melanopsin function in disease, we recommend that the PIPR be measured using short-duration pulses (e.g., (cid:3)1 second) with high melanopsin excitation and analyzed with plateau and/or 6-second metrics. Our PIPR interstimulus intervals between duration data provide a baseline for the selection of consecutive pupil testing sequences.
关键词： pupil light reflex,intrinsically photosensitive retinal ganglion cells (ipRGCs),melanopsin,post-illumination pupil response
更新于2025-09-09 09:28:46
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Melanopsin-Mediated Post-Illumination Pupil Response in Early Age-Related Macular Degeneration
摘要： PURPOSE. To determine whether melanopsin-expressing intrinsically photosensitive retinal ganglion cell (ipRGC) inputs to the pupil light re?ex (PLR) are affected in early age-related macular degeneration (AMD). METHODS. The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 seconds duration, 35.68 diameter) were presented to the study eye and the consensual pupil response was measured to lights with high melanopsin excitation (464 nm [blue]) and with low melanopsin excitation (638 nm [red]) that biased activation to the outer retina. Two melanopsin PLR metrics were quanti?ed: the phase amplitude percentage (PAP) during the sinusoidal stimulus presentation and the post-illumination pupil response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, the transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves. RESULTS. The blue PIPR was signi?cantly less sustained in the early AMD group (P < 0.001). The red PIPR was not signi?cantly different between groups (P > 0.05). The PAP and blue stimulus constriction amplitude were signi?cantly lower in the early AMD group (P < 0.05). There was no signi?cant difference between groups in the latency or transient amplitude for both stimuli (P > 0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (area under the curve > 0.9). CONCLUSIONS. This is the initial report that the melanopsin-controlled PIPR is dysfunctional in early AMD. The noninvasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD.
关键词： illumination pupil response,pupil light re?ex,intrinsically photosensitive retinal ganglion cells,post-illumination pupil response,ipRGCs,melanopsin
更新于2025-09-09 09:28:46
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Transplantation of retinal progenitor cells from optic cup-like structures differentiated from human embryonic stem cells in vitro and in vivo generation of retinal ganglion-like cells
摘要： Human embryonic stem cells (hESCs) have the potential to differentiate along the retinal lineage. We have efficiently differentiated human pluripotent stem cells (hPSCs) into optic cup-like structures by using a novel retinal differentiation medium (RDM).The purpose of this study was to determine whether the retinal progenitor cells (RPCs) derived from hESCs can integrate into the host retina and differentiate into retinal ganglion cells (RGCs) in vivo. In the present study, hESCs (H9-GFP) were induced to differentiate into optic cup-like structures by using our novel differentiation system. The RPCs extracted from the optic cup-like structures were transplanted into the vitreous cavity of N-Methyl-D-aspartic acid (NMDA)-treated mice. Sham-treated eyes received the same amount of retinal differentiation medium (RDM). The host retinas were analyzed by triple immunofluorescence on the 4th and 5th weeks after transplantation. The optic cup-like structures were efficiently differentiated from hESCs by using our novel differentiation system in vitro for 6-8 weeks. The RPCs extracted from the optic cup-like structures migrated and integrated into the GCL of the host retina. Furthermore, the remaining transplanted cells were spread over the GCL and had a complementary distribution with host residual RGCs in the GCL of the mouse retina. Surprisingly, some of the transplanted cells expressed the RGC-specific marker Brn3a. These findings demonstrated that the RPCs derived from hESCs could integrate into the host GCL and differentiate into retinal ganglion-like cells in vivo, suggesting that RPCs can be used as an ideal source in supplying countless RGC and ESC-based replacement therapies may be a promising treatment to restore vision in patients with degenerative retinal diseases.
关键词： retinal ganglion cells,human embryonic stem cells,transplantation,optic cup-like structures,retinal progenitor cells
更新于2025-09-04 15:30:14
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Macular Inner Retinal Layer Thickness in Relation to Photopic and Mesopic Contrast Sensitivity in Healthy Young and Older Subjects
摘要： PURPOSE. To examine relationships between the thicknesses of ganglion cell (GC)-related macular layers and central photopic or mesopic contrast sensitivity (CS) in healthy eyes. METHODS. Measurements were made in 38 young and 38 older healthy individuals. Total, inner, layer (IRL) thicknesses were measured in the macula region through and outer retinal spectral-domain optical coherence tomography (SD-OCT) across three sub?elds, or rings, centered at the fovea: central foveal, pericentral, and peripheral. Ganglion cell complex and circumpapillary retinal nerve ?ber layer thicknesses were also measured. Low-spatial-frequency CS for gratings presented at the central 108 visual ?eld were measured through computerized psychophysical tests under photopic and mesopic conditions. Relationships were examined by uni- and multivariate regression analysis. RESULTS. Peripheral IRL thickness emerged as the only independent predictor of photopic CS (P ? 0.001) in the young group and of photopic (P ? 0.026) and mesopic CS (P ? 0.001) in the older group. The slopes of regression lines used to predict CS from peripheral IRL thickness were signi?cantly different for pair-wise comparisons of both photopic CS and age group (P ? 0.0001) and mesopic CS (P ? 0.0001) and age group. These models explained 37% of the variability in photopic CS and 36% of the variability in mesopic CS. CONCLUSIONS. Macular IRL thinning likely due to GC loss was related to reduced photopic and mesopic CS in older healthy eyes. In contrast, in the young eyes, a thicker macular IRL, possibly indicating transient gliosis, was associated with reduced CS.
关键词： contrast sensitivity,optical coherence tomography,retinal ganglion cells,macular inner retinal layer thickness,mesopic vision,glial cells
更新于2025-09-04 15:30:14
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Optic nerve head width and retinal nerve fiber layer changes are good indexes for validating the successful induction of experimental anterior ischemic optic neuropathy
摘要： Reproducible skills are essential for successful induction of a rat model of anterior ischemic optic neuropathy (rAION). We established an in vivo validation index by measuring the natural course of optic nerve head (ONH) width and retinal nerve fiber layer (RNFL) thickness in the rAION model using optical coherence tomography (OCT). The rAION model was induced by photodynamic operations. We measured the ONH width and RNFL thickness in the acute stage (<3 days), subacute stage (day 7 and day 14) and later stage (day 28) post-infarct by OCT. RNFL were measured by hematoxylin and eosin stain (HE) to confirm the OCT findings. The RGCs survival rate was determined by retrograde Fluoro-gold labeling, and the visual function was assessed with flash visual-evoked potentials (FVEPs) 4 weeks post-infarct. The ONH showed significant swelling in the acute stage, which also correlated with RNFL swelling. The swelling was reduced to normal within one-week post-infarct. The rAION group (0.51± 0.12 mm2) showed a significant RNFL thinning when compared with sham groups (0.92±0.15 mm2, p<0.05) on day-28 post-infarct. And HE-stained retina cross sections also showed RNFL thinning, which further confirmed our OCT Findings. The RGC density and P1-N2 amplitude were significantly reduced in rAION. Swelling, reduction of swelling, and atrophy of RNFL in acute, sub-acute, and later stage, respectively, are important events for confirming the successful induction of rAION. They suggest that the longitudinal OCT data provides a reliable index for validating the reproducibility and correct order of rAION.
关键词： optic nerve head (ONH),retinal ganglion cells (RGCs),optical coherence tomography (OCT),anterior ischemic optic neuropathy in rats (rAION),retina nerve fiber layer (RNFL)
更新于2025-09-04 15:30:14
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Influence of <i>Opa1</i> Mutation on Survival and Function of Retinal Ganglion Cells
摘要： PURPOSE. Mutations in the OPA1 gene cause autosomal dominant optic atrophy (ADOA), a visual disorder associated with degeneration of retinal ganglion cells (RGCs). Here, we characterized the disease progression in a homologous mouse model B6;C3-Opa1329-355del and asked whether the pronounced cell death affects certain RGC types more than others. METHODS. The in?uence of the Opa1 mutation was assessed by morphologic (retina and optic nerve histology) and functional (multielectrode array) methods. RESULTS. The RGC loss of approximately 50% within 18 months was signi?cantly more pronounced in RGCs with small-caliber axons. Small-caliber axon RGCs comprise a variety of functional RGC types. Accordingly, electrophysiological analyses of RGCs did not show a dropout of distinct functional RGC subgroups. However, the response properties of RGCs were affected signi?cantly by the mutation. Surprisingly, these functional changes were different under different luminance conditions (scotopic, mesopic, and photopic). Finally, melanopsin cells are known to be less susceptible to retinal insults. We found that these cells are also spared in the Opa1 mouse model, and demonstrated for the ?rst time that this resistance persisted even when the melanopsin gene had been knocked-out. CONCLUSIONS. Small-caliber axons show a higher vulnerability to the Opa1 mutation in our mouse model for ADOA. Luminance-dependent functional changes suggest an in?uence of the Opa1 mutation on the retinal circuitry upstream of RGCs. Photoresponsive RGCs are protected against cell death due to the Opa1 mutation, but not by melanopsin expression itself.
关键词： retinal ganglion cells,optic nerve,melanopsin,MEA recordings,optic neuropathy
更新于2025-09-04 15:30:14
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Spatiotemporal Expression Changes of PACAP and Its Receptors in Retinal Ganglion Cells After Optic Nerve Crush
摘要： Pituitary adenylate cyclase-activating polypeptide (PACAP) has been demonstrated to play a crucial part in protecting retinal ganglion cells (RGCs) from apoptosis in various retinal injury animal models. PACAP has two basic groups of receptors: PACAP receptor type 1 (PAC1R) and vasoactive intestinal polypeptide/PACAP receptors (VPAC1R and VPAC2R). However, few studies illustrated the spatial and temporal expression changes of endogenous PACAP and its receptors in a rodent optic nerve crush (ONC) model. In this study, a significant upregulation of PACAP and PAC1R in the retina after ONC was observed in both protein and RNA levels. The peak level of PACAP and PAC1R expression could be found on the fifth day following ONC. In addition, immunofluorescent labeling indicated that PACAP and PAC1R were localized mainly in RGCs. On the contrary, VPAC1R and VPAC2R were hardly detected in the retina. Collectively, the spatiotemporal expression of PACAP and its high-affinity receptor PAC1R were remarkably changed after ONC, and mainly expressed in the ganglion cell layer of the retina. This suggested that the upregulation of PACAP and PAC1R may play a vital role in RGC death after ONC.
关键词： PACAP,Receptors,Rat,Retinal ganglion cells,Optic nerve crush
更新于2025-09-04 15:30:14
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The Role of Endogenous Neuroprotective Mechanisms in the Prevention of Retinal Ganglion Cells Degeneration
摘要： Retinal neurons are not able to undergo spontaneous regeneration in response to damage. A variety of stressors, i.e., UV radiation, high temperature, ischemia, allergens, and others, induce reactive oxygen species production, resulting in consecutive alteration of stress-response gene expression and finally can lead to cell apoptosis. Neurons have developed their own endogenous cellular protective systems. Some of them are preventing cell death and others are allowing functional recovery after injury. The high efficiency of these mechanisms is crucial for cell survival. In this review we focus on the contribution of the most recently studied endogenous neuroprotective factors involved in retinal ganglion cell (RGC) survival, among which, neurotrophic factors and their signaling pathways, processes regulating the redox status, and different pathways regulating cell death are the most important. Additionally, we summarize currently ongoing clinical trials for therapies for RGC degeneration and optic neuropathies, including glaucoma. Knowledge of the endogenous cellular protective mechanisms may help in the development of effective therapies and potential novel therapeutic targets in order to achieve progress in the treatment of retinal and optic nerve diseases.
关键词： endogenous neuroprotection,optic neuropathy,retinal ganglion cells,cell survival,stress-response
更新于2025-09-04 15:30:14