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The neuroretina is protected by its own defense system, that is microglia and the complement system. Under normal physiological conditions, microglial activation is tightly regulated by the neurons although the underlying mechanism remains elusive. Using published single‐cell RNA sequencing data sets, we found that immune regulatory molecules including CD200, CD47, CX3CL1, TGFβ, and complement inhibitor CD59a are expressed by various retinal neurons. Importantly, we found that photoreceptors express higher levels of CD47 and CD59a, which was further confirmed in cultured 661W cells, WERI‐Rb1 cells, and microdissected photoreceptors from human eyes. The expression of CD59a mRNA in 661W cells was upregulated by TNFα and hypoxia, whereas LPS, hypoxia, and IL‐4 upregulated CD47 mRNA expression in 661W cells. Immunofluorescence staining detected strong CD59a immunoreactivity in the outer nuclear layer, inner/outer segments, and discrete staining in ganglion cell layer (GCL), inner plexiform layer (IPL), and outer plexiform layer. The expression of CD59a in photoreceptors was increased in the detached retina, but decreased in retinas from experimental autoimmune uveoretinitis (EAU) mice. In EAU retina, CD59a was highly expressed by active immune cells. CD47 was detected in GCL, IPL, and inner nuclear layer and some photoreceptors. The expression of CD47 in photoreceptors was also increased in the detached retina but decreased in EAU retina. In a coculture system, 661W enhanced arginase‐1 and reduced IL‐6 mRNA expression in BV2 microglial cells. Our results suggest that photoreceptors express immune regulatory molecules and may have the potential to regulate immune activation in the outer retina/subretinal space under pathophysiological conditions.

Spectral-domain optical coherence tomography (SD-OCT) represents a reliable tool for retinal layer volume and thickness measurement. The aim of this study was to evaluate retinal changes indicating neurodegenerative processes in patients with end-stage renal disease (ESRD) compared to healthy controls. This was a cross-sectional, single-center study comprising 32 ESRD patients and 38 controls. Sectoral retinal nerve fiber layer (RNFL) thickness and retinal layer volumes were obtained by SD-OCT. Age- and gender-adjusted retinal layer volumes such as total retinal volume (p = 0.037), ganglion cell layer volume (GCL, p = 0.003), ganglion cell layer – inner plexiform layer volume (GCL-IPL, p = 0.005) and inner retinal layer volume (IRL, p = 0.042) of the right eye were lower in ESRD patients. Inner plexiform layer volume of both eyes (IPL, right eye: p = 0.017; left eye: 0.044) was reduced, as was RNFL thickness in the temporal superior sector (right eye: p = 0.016). A subgroup analysis excluding patients with diabetes revealed that GCL (p = 0.014) and GCL-IPL volume of the right eye (p = 0.024) and temporal superior sector of the RNFL scan (p = 0.021) in ESRD patients were still significantly thinner. We observed a decrease in several retinal layer volumes and temporal RNFL thickness indicative of retinal neurodegenerative processes in patients with ESRD.

Mouse models of age-related macular degeneration (AMD) such as Ccl2-/- and Ccl2-/-/Cx3cr1-/- have not yet been fully characterized ultrastructurally. Although we have previously shown extranuclear DNA (enDNA) leakage into the cytoplasm and damaged mitochondria in the retinal pigment epithelium (RPE) of these AMD mouse models, little is known about the state of their vascular capillaries of the retina and choroid. Our ultrastructural survey shows that the aberrations were not restricted to the RPE cells, but also extended to the vasculature of the retina and choroid. Their endothelial aberrations included cytoplasmic degeneration, pyknotic DNA, hypertrophic nuclei, and loss of fenestration in addition to duplication of basement membrane and loss of density in Bruch's membrane. Moreover, the state of the vasculature in the mutant mice models suggests that the capillaries could also be active contributors to the pathological findings seen in AMD. The goal of this study is to gain insights into the early events of AMD that may lead to a better understanding of AMD's pathogenesis, improve our preventative measures, and formulate designed therapeutic regimens that are tailored to target the initial pathological events.Abbreviations: AMD: age-related macular degeneration; BM: Bruch's membrane; DPC: degenerate pericyte; EN: endothelial nucleus; enDNA: extranuclear DNA; GCL: ganglion cell layer; HEN: hypertrophic endothelial nucleus; IPL: inner plexiform layer; NFL: nerve fiber layer; OPL: outer plexiform layer; RBC: red blood cell; RPE: retinal pigment epithelium; SNPs: Single nucleotide polymorphisms.

Chemical neuromodulation of the retina using native neurotransmitters to biomimetically activate target retinal neurons through chemical synapses is a promising biomimetic alternative to electrical stimulation for restoring vision in blindness caused by photoreceptor degenerative diseases. Recent research has shown that subretinal chemical stimulation could be advantageous for treating photoreceptor degenerative diseases but many of the parameters for achieving efficacious chemical neuromodulation are yet to be explored. In this paper, we investigated how the depth at which neurotransmitter is injected subretinally affects the success rate, spike rate characteristics (i.e., amplitude, response latency, and time width), and spatial resolution of chemical stimulation in wild-type Long Evans and photoreceptor degenerated S334ter-3 transgenic rat retinas in vitro . We compared the responses to injections of glutamate at the subretinal surface and two subsurface depths near the outer and inner plexiform layers and found that while injections at all depths elicited robust retinal ganglion cell responses, they differed significantly in terms of the spike rate characteristics and spatial resolutions across injection depths. Shallow subsurface injections near the outer plexiform layer evoked the highest spike rate amplitudes and had the highest spatial resolution and success rates, while deep subsurface injections near the inner plexiform layer elicited the shortest latencies and narrowest time widths. Our results suggest that surface injections are suboptimal for subretinal chemical neuromodulation, while shallow subsurface and deep subsurface injections may optimize high spatial and high temporal resolution, respectively. These findings have great significance for the design and development of a potential neurotransmitter-based subretinal prosthesis.

The goal of this study was to analyze wavelet features of topographic thickness maps of the retinal ganglion cell-inner plexiform layer (GCIPL) and evaluate their discrimination ability in patients with multiple sclerosis (MS) and a history of optic neuritis (ON). Twenty-nine patients with relapsing-remitting MS and a history of ON were recruited together with 63 age- and sex-matched controls (HC). There were 33 eyes with a history of ON (MSON), 25 non-ON fellow eyes (MSFE) and 63 HC eyes. Ultrahigh-resolution optical coherence tomography was used to image the macula of each participant, and the volumetric dataset was segmented to yield a topographic thickness map of the GCIPL. The thickness map was analyzed using discrete wavelet transform to extract useful features, which were further analyzed with three machine learning methods, including logistic regression (LR), logistic regression regularized with the elastic net penalty (LR-EN), and support vector machine (SVM), for classification between groups. LR-EN with nested leave-one-out cross-validation resulted in 94% (83%) sensitivity and 100% (97%) specificity in discriminating MSON (MSFE) eyes from HC eyes in the training data and 88% (64%) sensitivity and 94% (94%) specificity in discriminating MSON (MSFE) eyes from HC eyes in the validation data, which were similar to or better than those resulting from LR and SVM. LR-EN improved the sensitivity and specificity of discriminating prior ON and MSFE eyes in patients with MS from HC eyes compared with traditional thickness analysis. It may be promising in facilitating the diagnosis of subclinical ON in patients with MS.

Aim To evaluate the patterns of macular ganglion cell-inner plexiform layer (GCIPL) loss in normal tension glaucoma (NTG) and primary open angle glaucoma (POAG) in a detailed, disease severity-matched way; and to assess the diagnostic capabilities of GCIPL thickness parameters in discriminating NTG or POAG from normal subjects. Methods A total of 157 eyes of 157 subjects, including 57 normal eyes, 51 eyes with POAG and 49 eyes with NTG were enrolled and strictly matched in age, refraction, and disease severity between POAG and NTG groups. The average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal GCIPL thickness, and the average, superior, temporal, inferior, and nasal retinal nerve fiber layer (RNFL) thickness were obtained by Cirrus optical coherence tomography (OCT). The diagnostic capabilities of OCT parameters were assessed by area under receiver operating characteristic (AUROC) curves. Results Among all the OCT thickness parameters, no statistical significant difference between NTG group and POAG group was found (all P>0.05). In discriminating NTG or POAG from normal subjects, the average and inferior RNFL thickness, and the minimum GCIPL thickness had better diagnostic capabilities. There was no significant difference in AUROC curve between the best GCIPL thickness parameter (minimum GCIPL) and the best RNFL thickness parameter in discriminating NTG (inferior RNFL; P=0.076) and indiscriminating POAG (average RNFL; P=0.913) from normal eyes. Conclusion Localized GCIPL loss, especially in the inferior and inferotemporal sectors, is more common in NTG than in POAG. Among all the GCIPL thickness parameters, the minimum GCIPL thickness has the best diagnostic performance in differentiating NTG or POAG from normal subjects, which is comparable to that of the average and inferior RNFL thickness.

Background: Primary open angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGC) and their axons, which results in characteristic excavation of the neuroretinal rim with corresponding visual field (VF) deficits. Optical coherence tomography angiography (OCTA) is a novel imaging modality that can detect vascular flow of the retina and choroid in great detail. The ability to segment OCT angiograms into the different vascular layers may improve understanding of disease pathogenesis. Objective: To evaluate the correlation between Ganglion Cell and Inner Plexiform Layers thickness using optical coherence tomography (OCT) and the macular microvasculature density in different stages of primary open angle glaucoma using optical coherence tomography angiography (OCTA). Subjects and Methods: The study was performed on 80 eyes of 48 subjects including 20 eyes of 11 controls, and 60 eyes of 37 POAG cases which were divided into 3 groups according to Hodapp,Parish,Anderson (H-P-A) classification; Group1: mild glaucoma (20 eyes), Group 2: moderate glaucoma (20 eyes),Group 3: severe glaucoma (20 eyes). Results: In our study, we found that there was a significant reduction in Ganglion Cell - Inner Plexiform Layer (GCIPL) thickness and macular VD in patients with POAG which increased with increasing glaucoma severity, also we found that OCT and OCTA parametrs were significantly differentiate between normal and POAG cases and also between different stages of POAG. Also we found that an OCTA was an important diagnostic tool in diagnosing mild cases of POAG and to differentiate between mild and moderate cases of POAG,in contrast to OCT in which there was no significant differance between mild and moderate cases of POAG. OCTA seems to be a good candidate for diagnosis and follow-up of glaucoma, complementing the results provided by OCT and visual field testing. Conclusion: Significant differences between eyes with POAG and normal eyes in terms of the macular GCIPL thickness and microvasculature density (VD) suggest that the macular GCIPL thickness and the retinal capillary vessel area density may be reliable indicators of glaucoma severity.

Introduction/Objective. The study aims to analyze the thickness of both the ganglion cell layer and the inner plexiform layer (GCL + IPL) among patients suffering from dry and wet form of age-related macular degeneration (AMD). Methods. One hundred ninety-five patients with AMD participated in the study, along with 94 healthy individuals (mean age 75.2 ? 7.8 years; range 55?86). They were divided into three groups: the first group, or group I, included 100 patients suffering from wet AMD; the second group, or group II, included 95 patients afflicted with dry AMD; the final 94 patients made up the control group, group III, of healthy individuals without systemic or ocular diseases. Measurements such as the average macular thickness, the average and minimum GCL + IPL thickness, and the GCL + IPL thickness in all six sectors were obtained by Cirrus spectral-domain optical coherence tomography (SD-OCT, Carl Zeiss Meditec, Inc., Dublin, CA, USA). SPSS version 20.0 was used to analyze the data, while the level of statistical significance was set at p < 0.05. Results. In the case of patients with wet AMD, the average value for GCL + IPL thickness was 43.13 ?m, for patients with dry AMD the value was 66.73 ?m, and the average thickness measured for the control group was 86.23 ?m. There was a statistically significant difference between the average GCL + IPL and minimum GCL + IPL thicknesses between the groups (p < 0.001). Lower values were noted for patients with wet AMD (p < 0.001) than those with dry AMD. In the latter, the average GCL + IPL and the minimum GCL + IPL thicknesses were lower than those of the healthy participants, at a level of statistical significance (p < 0.001). Conclusion. Participants with AMD exhibited thinner GCL + IPL than the healthy participants, as did the participants with wet AMD when compared to the participants with dry AMD.

AIM: To investigate the expression and possible role of the autophagy related protein p62 and LC3 in the retina based on a rat model of acute ocular hypertension. METHODS: Fifty rats were randomized into five groups: control group A, B, C, and D. Groups A to D all received normal saline perfusion into the anterior chamber with pressure of 80 mm Hg for one hour, and retina tissue was obtained at 6, 12, 24 and 48h after perfusion respectively, to investigate the activation of autophagy following ischemia-reperfusion. The distribution and semi-quantification of autophagy related protein p62 and LC3 in the retina were detected using immunohistochemistry technique. The expression level of these two proteins was evaluated using Western blot. RESULTS: The number of retinal ganglion cells (RGCs) decreased with increasing reperfusion time, and significant reduction in the retinal thickness was observed 48h after perfusion. In normal adult rats, LC3 protein was mainly expressed in the ganglion cell layer (GCL), and p62 protein was expressed in the nerve fiber layer (NFL), GCL, inner plexiform layer (IPL), inner nuclear layer (INL) and outer plexiform layer (OPL). In comparison to the control group, the expression level of LC3- II was higher in all the experimental groups (P

Diabetes is expected to accelerate age-related ganglion cell–inner plexiform layer (GC-IPL) loss, but there is limited information on the rate of reduction in GC-IPL thicknesses. We aimed to evaluate the reduction rate of GC-IPL thickness in diabetic patients, and to compare the rates between patients without and with diabetic retinopathy (DR). We included 112 eyes of 112 patients with diabetes [49 eyes without DR (no-DR group) and 63 eyes with mild to moderate non-proliferative DR (NPDR group)] and 63 eyes of 63 normal controls (control group) in this study. Macular GC-IPL thickness in all participants was measured for 3 years at 1-year intervals. The reduction rates of GC-IPL thickness were determined by linear mixed models and compared among the three groups. The estimated reduction rates of the average GC-IPL thickness in the no-DR (−0.627 μm/year) and NPDR (−0.987 μm/year) groups were 2.26-fold (p = 0.010) and 3.56-fold (p = 0.001) faster, respectively, than the control group (−0.277 μm/year). Age, duration of diabetes, and baseline average GC-IPL thickness were associated with longitudinal changes in average GC-IPL thickness. The GC-IPL reduction rate was significantly faster in diabetic patients, with and without DR. Physicians should therefore be aware that GC-IPL damage continues even if there is no DR.

Purpose To report the individual retinal layer thicknesses up to mid-equator in patients with diabetic retinopathy (DR) using Spectralis (Heidelberg Engineering, Heidelberg, Germany) wide-field optical coherence tomography (OCT). Methods Retinal layers were segmented using a custom designed semi-automated algorithm, where reference points were marked by the examiner to enable software to automatically compute the thickness values of each retinal sublayer at an interval of 1 mm from reference points. The values of individual retinal thicknesses in eyes with varying severity of DR were compared with the values of healthy subjects. Generalized estimating equation was performed to compensate for inclusion of both eyes of patients. Results A total of 64 patients (119 eyes) with a mean age of 68.97 ± 10.27 years were included. Overall, ganglion cell layer (GCL)/ inner plexiform layer (IPL) complex (-31.67 microns, p Conclusion Retinal thicknesses vary significantly in patients with diabetic retinopathy and understanding patterns of these changes across different segments of the wide field OCT may help better elucidate the natural progression of the disease in terms of retinal anatomy.

Parasol cells are one of the major types of primate retinal ganglion cells. The goal of this study was to describe the synaptic inputs that shape the light responses of the ON type of parasol cells, which are excited by increments in light intensity. A connectome from central macaque retina was generated by serial blockface scanning electron microscopy. Six neighboring ON parasol cells were reconstructed, and their synaptic inputs were analyzed. On average, they received 21% of their input from bipolar cells, excitatory local circuit neurons receiving input from cones. The majority of their input was from amacrine cells, local circuit neurons of the inner retina that are typically inhibitory. Their contributions to the neural circuit providing input to parasol cells are not well-understood, and the focus of this study was on the presynaptic wide-field amacrine cells, which provided 17% of the input to ON parasol cells. These are GABAergic amacrine cells with long, relatively straight dendrites, and sometimes also axons, that run in a single, narrow stratum of the inner plexiform layer. The presynaptic wide-field amacrine cells were reconstructed, and two types were identified based on their characteristic morphology. One presynaptic amacrine cell was identified as semilunar type 2, a polyaxonal cell that is electrically coupled to ON parasol cells. A second amacrine was identified as wiry type 2, a type known to be sensitive to motion. These inputs likely make ON parasol cells more sensitive to stimuli that are rapidly changing outside their classical receptive fields.

OBJECTIVE Initiation of antihypertensive drug treatment in low-risk individuals with grade 1 hypertension is under debate. The aim of this study was to examine the impact of mildly elevated blood pressure (BP) on early neurodegenerative processes independent of ageing. METHODS Sixty-two individuals were included in this study: 25 young (aged

The morphology of retinal neurons strongly influences their physiological function. Ganglion cell (GC) dendrites ramify in distinct strata of the inner plexiform layer (IPL) so that GCs responding to light increments (ON) or decrements (OFF) receive appropriate excitatory inputs. This vertical stratification prescribes response polarity and ensures consistent connectivity between cell types, whereas the lateral extent of GC dendritic arbors typically dictates receptive field (RF) size. Here, we identify circuitry in mouse retina that contradicts these conventions. AII amacrine cells are interneurons understood to mediate “cross-over” inhibition by relaying excitatory input from the ON layer to inhibitory outputs in the OFF layer. Ultrastructural and physiological analyses show, however, that some AIIs deliver powerful inhibition to OFF GC somas and proximal dendrites in the ON layer, rendering the inhibitory RFs of these GCs smaller than their dendritic arbors. This OFF pathway, avoiding entirely the OFF region of the IPL, challenges several tenets of retinal circuitry. These results also indicate that subcellular synaptic organization can vary within a single population of neurons according to their proximity to potential postsynaptic targets.

CLINICAL RELEVANCE With equivalent inner retinal thickness measurements compared to a more conventional composite optical coherence tomography (OCT) protocol, Widefield optical coherence tomography (WF-OCT) is a clinically viable, time-saving option facilitating detection of ocular pathologies within the central 55° of the retina. PURPOSE To compare ganglion cell-inner plexiform layer (GCIPL) thicknesses obtained using a single WF-OCT scan and standard composite OCT scans acquired in 9 fields of gaze (9F-OCT). METHODS Thirteen healthy participants underwent WF-OCT and 9F-OCT using the Spectralis OCT. The GCIPL was automatically segmented with a manual review for 9F-OCT and was manually segmented for WF-OCT. After registration, differences in GCIPL thicknesses were compared using 95% confidence intervals computed from one-sample t-tests and Bland-Altman analyses. Location-specific differences in B-scan tilt were analysed using Spearman correlations and linear regression models. To determine whether B-scan tilt influences GCIPL measurements, regression models of tilt versus differences between perpendicular and axial GCIPL thickness were applied. RESULTS While scattered locations demonstrated significant GCIPL thickness differences between WF-OCT and 9F-OCT, most differences did not exceed the axial pixel resolution of the instrument of 3.87 µm. Bland-Altman analyses indicated no notable bias using WF-OCT. Moderate correlations indicating significant location-specific differences in B-scan tilt were observed for temporal, central and inferior B-scans (r = -0.62 to 0.72), with linear regression models predicting a maximum difference in the tilt of 4.65°. The quadratic regression model indicated that at tilts greater than 27.3°, perpendicular GCIPL measurements become increasingly thin relative to axial measurements. CONCLUSIONS GCIPL thicknesses and B-scan tilts from WF-OCT are comparable to 9F-OCT, indicating that WF-OCT can be applied clinically to obtain valid inner retinal OCT measurements over 55° of the central retina with relative ease. However, for peripheral locations, B-scan tilt may need to be considered when measuring GCIPL thicknesses.

To increase the understanding of the relationship between structure and function in individuals with damage to the brain from different stages of maturation of the visual system, we examined 16 teenagers and young adults. We used diffusion-weighted magnetic resonance imaging (MRI) and fiber tractography of the optic radiation (OR) and optical coherence tomography (OCT) of the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell layer + inner plexiform layer (GC+IPL) in the macula. Visual field (VF) function was assessed with the Humphrey Field Analyzer (HFA). Injuries to the immature OR were associated with thinning of the pRNFL and GC+IPL, and corresponding VF defects irrespectively of timing of the lesion. However, in cases with bilateral white-matter damage of immaturity (WMDI) we noticed a well preserved central VF despite a very thin GC+IPL. We speculate that this is due to plasticity in the immature visual system. Similar results were not noticed among cases with unilateral damage, acquired pre- or postnatally, in which the central VF was affected in most cases. OCT has proved to be a valuable targeted tool in children with damage to the retro-geniculate visual pathways, and that focal thinning of the GC+IPL predicts VF defects. This brief research report includes a review of four previously published papers. In addition, we present one new case and apply a recently developed classification system for CVI. The classification was applied on cases with bilateral WMDI to investigate its relation to retinal structure.

Neurons in the central nervous system (CNS) are distinguished by the neurotransmitter types they release, their synaptic connections, morphology, and genetic profiles. To fully understand how the CNS works, it is critical to identify all neuronal classes and reveal their synaptic connections. The retina has been extensively used to study neuronal development and circuit formation. Here, we describe a previously unidentified interneuron in mammalian retina. This interneuron shares some morphological, physiological, and molecular features with retinal bipolar cells, such as receiving input from photoreceptors and relaying visual signals to retinal ganglion cells. It also shares some features with amacrine cells (ACs), particularly Aii-ACs, such as their neurite morphology in the inner plexiform layer, the expression of some AC-specific markers, and possibly the release of the inhibitory neurotransmitter glycine. Thus, we unveil an uncommon interneuron, which may play an atypical role in vision.

AimsTo assess the thickness of various retinal layers, and the superficial vessel density (sVD) in the macula of glaucomatous eyes and their associations with axial length (AL) and visual field mean deviation (VFMD) to identify parameters useful for glaucoma management in myopic eyes.Methods248 glaucoma patients (401 eyes) participating in the Diagnostic Innovations in Glaucoma Study observational cohort representing 3 axial myopia groups (non-myopia: n=146 eyes; mild myopia: n=208 eyes; high myopia (AL>26 mm): n=47 eyes) who completed macular OCT and OCT-Angiography imaging were included. The cross-sectional associations of AL and VFMD with the thickness of the ganglion cell inner plexiform layer (GCIPL), macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), sVD and macular choroidal thickness (mCT) were evaluated.ResultsThinner Global GCIPL and GCC were significantly associated with worse VFMD (R2=35.1%; and R2=33.4%; respectively p0.350). Thicker mRNFL showed a weak association with increasing AL (R2=3.4%; p=0.001) and a positive association with VFMD (global R2=20.5%; p2=2.3%; p=0.016) and more strongly associated with more severe glaucoma VFMD (R2=31.8%; p2=17.3% pConclusionsGCIPL and GCC thinned with increasing severity of glaucoma but were not significantly associated with axial length. GCIPL and GCC thickness may be useful clinical parameters to identify glaucoma in myopic eyes.

PurposeTo evaluate the clinical utility of visible light optical coherence tomography (VIS-OCT) and to test whether VIS-OCT reflectivity and spectroscopy of peripapillary retinal nerve fiber layer (pRNFL) are correlated with severity of glaucoma, compared with standard-of-care OCT thickness measurements.DesignCross-sectional study.MethodFifty-four eyes from three groups of subjects (normal, glaucoma suspect, and glaucoma) were scanned by a custom-designed dual-channel device that simultaneously acquired visible (VIS-OCT) and near-infrared OCT (NIR-OCT) images. A 5×5 mm2 scan was taken of the peripapillary nerve fiber layer (pRNFL).The pRNFL reflectivity was calculated for both channels and the spectroscopic marker was quantified by pVN, defined by the ratio of VIS-OCT to NIR-OCT pRNFL reflectivity. The results were compared with ophthalmic exams and clinical Zeiss OCT measurements. Mixed linear model was used to evaluate the association of imaging markers with glaucoma severity.ResultsVIS-OCT pRNFL reflectivity significantly, se uentially declined from normal to suspect to glaucoma (3.42 ± 0.35, 2.58 ± 0.37, 2.16 ± 0.39, mean ± SD), as did NIR-OCT pRNFL reflectivity (2.46 ± 0.24, 2.27 ± 0.24, 1.96 ± 0.25). The pVN also had the same decreasing trend among three groups (1.39 ± 0.08, 1.14 ± 0.08, 1.08 ± 0.10). Normal and suspect eyes were significantly different in VIS-OCT pRNFL reflectivity (p=0.002), pVN (pConclusionVIS-OCT pRNFL reflectivity and pVN was more sensitive in separating suspect eyes from normal ones than clinical OCT thickness measurements. VIS-OCT pRNFL reflectivity and pVN could be a useful metric in early detection of glaucoma upon further longitudinal validation.

The non-classic presentation of paediatric celiac disease (CeD) becomes increasingly common in daily practice, which requires an awareness of eye findings. The purpose of this study was to evaluate eye involvement and effect of gluten-free diet on ocular involvement in paediatric CeD patients by measuring the thicknesses of choroid and ganglion cell complex (GCC) composed of retinal nerve fibre layer, ganglion cell layer and inner plexiform layer using enhanced depth imaging optical coherence tomography.Forty-three CeD patients aged between four and 16 years (mean age: 9.9 ± 4.1, 12 boys and 31 girls) and 48 healthy children (mean age: 11.3 ± 4.1,17 boys and 31 girls) were compared. Following comprehensive eye examinations, thicknesses of choroid at three points and GCC layers (retinal nerve fibre layer at five points, ganglion cell layer and inner plexiform layer) were obtained using enhanced depth imaging optical coherence tomography. Measurement of thicknesses of choroid and GCC layers by a trained optical coherence tomography technician and an ophthalmologist who were not aware about group of children in paediatric CeD patients with 1 year gluten-free diet was carried out.All layers of subfoveal, nasal and temporal choroid were significantly thinner in CeD than in the control group (P .001, all, respectively). No significant difference was observed between the CeD and control groups in terms of GCC thicknesses (P .05, all, respectively).Paediatric CeD caused thinning of subfoveal, nasal and temporal areas of choroid, and this change is apparent even after 1 year gluten-free diet. This eye involvement should be more closely screened at diagnosis, and long-term clinical results of thin choroid should be determined. Thicknesses of GCC layers were not different in CeD group and may reveal the effect of diet or not involvement.

Purpose Retinal alterations in inherited metabolic diseases associated with neurodegeneration are poorly studied. The objective was to study retinal thickness, specifically the components of the ganglion cell complex (GCC)—nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)—using spectral-domain optical coherence tomography (SD-OCT) in two different diseases with potential dopaminergic depletion, phenylketonuria (PKU) and Gaucher disease type 3 (GD3). Methods Retinal layers in 19 patients with PKU, 15 patients with GD3, and 93 healthy individuals were measured using peripapillary ring scan and macular SD-OCT. Linear mixed models were computed including an adjustment for age, sex, and spherical equivalent. We calculated Spearman’s rank correlations between retinal layer measurements and clinical and/or laboratory parameters. Results Thinning of total retinal thickness was found in the macular inner ring (p = 0.002), and outer ring (p = 0.012), sparing the fovea (p = 0.12) in PKU, while in GD3, all subfields were thinned (fovea p p = 0.047, outer ring 0.07). In both conditions, thinning was most evident in the NFL, GCL, and IPL, while OPL (outer plexiform layer) was thickened. Peripapillary retinal nerve fiber layer measurements remained normal. GCL and IPL in PKU correlated with tyrosine serum concentration. Conclusion Thinning of the NFL, GCL, and IPL, with thickened OPL, are both found in PKU and in GD3. Low dopamine concentrations in the retina might promote these effects. However, these data do not give evidence that retinal measurements can be used as a biomarker for disease severity in patients with GD3.

Background There is accumulating evidence to suggest that microRNAs (miRNAs) are associated with the progressive optic neuropathy including glaucoma. Apoptosis of retinal ganglion cells (RGCs) is a hallmark of glaucoma. The present study focused on the effects of miR-145-5p on RGC apoptosis in glaucoma. Methods We established a glaucoma rat model by intraocular injection of N-methyl-D-aspartic acid (NMDA). RGCs were isolated from newborn rats and treated with NMDA. Hematoxylin and eosin staining was performed to detect morphological changes in the retinas of rats. The expression of miR-145-5p and tripartite motif-containing 2 (TRIM2) in RGCs was measured by RT-qPCR. The viability of RGCs was measured by an MTT assay. Flow cytometry analysis and TUNEL assays were conducted to assess the apoptosis of RGCs. The interaction between miR-145-5p and TRIM2 was investigated using a luciferase reporter assay. Results Rats injected with NMDA showed a thinner ganglion cell layer (GCL) and inner plexiform layer (IPL) as well as increased expression of miR-145-5p. Silencing of miR-145-5p significantly increased the GCL and IPL in the glaucoma rat model. Moreover, miR-145-5p expression was upregulated in RGCs ex vivo in response to NMDA. Silencing of miR-145-5p promoted cell viability and suppressed apoptosis in NMDA-treated RGCs. Mechanistically, miR-145-5p targeted the TRIM2 3' untranslated region to suppress its expression. TRIM2 was upregulated in NMDA-treated RGCs and protected RGCs against NMDA-induced apoptosis. Furthermore, miR-145-5p suppressed the PI3K/AKT pathway by downregulating TRIM2 in NMDA-treated RGCs. Conclusions Suppression of miR-145-5p inhibited the apoptosis of RGCs via TRIM2-mediated activation of the PI3K/AKT signaling pathway in NMDA-induced glaucoma.

SummaryIn retinal neurons, morphology strongly influences visual response features. Ganglion cell (GC) dendrites ramify in distinct strata of the inner plexiform layer (IPL) so that GCs responding to light increments (ON) or decrements (OFF) receive appropriate excitatory inputs. This vertical stratification prescribes response polarity and ensures consistent connectivity between cell types, whereas the lateral extent of GC dendritic arbors typically dictates receptive field (RF) size. Here, we identify circuitry in mouse retina that contradicts these conventions. A2 amacrine cells are interneurons understood to mediate “cross-over” inhibition by relaying excitatory input from the ON layer to inhibitory outputs in the OFF layer. Ultrastructural and physiological analyses show, however, that some A2s deliver powerful inhibition to OFF GC somas and proximal dendrites in the ON layer, rendering their inhibitory RFs smaller than their dendritic arbors. This OFF pathway, avoiding entirely the OFF region of the IPL, challenges several tenets of retinal circuitry.

ObjectiveTo investigate the association of combined serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements with future disease activity in patients with early multiple sclerosis (MS).MethodsWe analyzed sNfL by single molecule array technology and performed OCT measurements in a prospective cohort of 78 patients with clinically isolated syndrome and early relapsing-remitting MS with a median (interquartile range) follow-up of 23.9 (23.3–24.7) months. Patients were grouped into those with abnormal or normal sNfL levels, defined as sNfL ≥/ResultsPatients with abnormal baseline sNfL had a higher risk of violating NEDA-3 (hazard ratio [HR] 2.28, 95% CI 1.27–4.09, p = 0.006) and developing a new brain lesion (HR 2.47, 95% CI 1.30–4.69, p = 0.006), but not for a new relapse (HR 2.21, 95% CI 0.97–5.03, p = 0.058). Patients with both abnormal sNfL and thin GCIP had an even higher risk for NEDA-3 violation (HR 3.61, 95% CI 1.77–7.36, p = 4.2e−4), new brain lesion (HR 3.19, 95% CI 1.51–6.76, p = 0.002), and new relapse (HR 5.38, 95% CI 1.61–17.98, p = 0.006) than patients with abnormal sNfL alone.ConclusionsIn patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone.

Signal processing within the retina is generally mediated by graded potentials, whereas output is conveyed by action potentials transmitted along optic nerve axons. Among retinal neurons, amacrine cells seem to be an exception to this general rule, as several types generate voltage-gated Na+ (Nav ) channel-dependent action potentials. The AII, a narrow-field, bistratified axon-less amacrine cell found in mammalian retinas, displays a unique process that resembles an axon initial segment (AIS), with expression of Nav channels colocalized with the cytoskeletal protein ankyrin-G, and generates action potentials. As the role of spiking in AIIs is uncertain, we hypothesized that the morphological properties of the AIS-like process could provide information relevant for its functional importance, including potential pre- and/or postsynaptic connectivity. For morphological analysis, we injected AII amacrine cells in slices with fluorescent dye and immunolabeled the slices for ankyrin-G. Subsequently, this enabled us to reliably identify AII-type processes among ankyrin-G labeled processes in wholemount retina. We systematically analyzed the laminar localization, spatial orientation, and distribution of the AIS-like processes as a function of retinal eccentricity. In the horizontal plane, the processes displayed no preferred orientation and terminal endings were randomly distributed. In the vertical plane, the processes displayed a horizontal preference, but also ascended and descended into the inner nuclear layer and proximal inner plexiform layer, respectively. These results suggest that the AII amacrine AIS-like process is unlikely to take part in conventional synaptic connections, but may instead be adapted to respond to volume neurotransmission by means of extrasynaptic receptors. This article is protected by copyright. All rights reserved.

PurposeWe compared rates of change of macular ganglion cell/inner plexiform (GCIPL) thickness and proportion of worsening and improving rates from 2 optical coherence tomography (OCT) devices in a cohort of eyes with glaucoma.DesignLongitudinal cohort study.MethodsIn a tertiary glaucoma clinic we evaluated 68 glaucoma eyes with ≥2 years of follow-up and ≥4 OCT images. Macular volume scans from 2 OCT devices were exported, coregistered, and segmented. Global and sectoral GCIPL data from the central 4.8×4.0-mm region were extracted. GCIPL rates of change were estimated with linear regression. Permutation analyses were used to control specificity with the 2.5 percentile cutoff point used to define "true" worsening. Main outcome measures included differences in global/sectoral GCIPL rates of change between 2 OCT devices and the proportion of negative vs positive rates of change (P < .05).ResultsAverage (standard deviation) 24-2 visual field mean deviation, median (interquartile range) follow-up time, and number of OCT images were -9.4 (6.1) dB, 3.8 (3.3-4.2) years, and 6 (5-8), respectively. GCIPL rates of thinning from Spectralis OCT were faster (more negative) compared with Cirrus OCT; differences were significant in superonasal (P=.03) and superotemporal (P=.04) sectors. A higher proportion of significant negative rates was observed with Spectralis OCT both globally and in inferotemporal/superotemporal sectors (P < .04). Permutation analyses confirmed the higher proportion of global and sectoral negative rates of change with Spectralis OCT (P < .001).ConclusionsChanges in macular GCIPL were detected more frequently on Spectralis' longitudinal volume scans than those of Cirrus OCT. OCT devices are not interchangeable with regard to detection of macular structural progression.

Purpose: To investigate the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 in human retina. Methods: Human post-mortem eyes from 13 non-diabetic control cases and 11 diabetic retinopathy cases were analyzed for the expression of ACE2. To compare the vascular ACE2 expression between different organs that involve in diabetes, the expression of ACE2 was investigated in renal specimens from nondiabetic and diabetic nephropathy patients. Expression of TMPRSS2, a cell-surface protease that facilitates SARS-CoV-2 entry, was also investigated in human nondiabetic retinas. Primary human retinal endothelial cells (HRECs) and primary human retinal pericytes (HRPCs) were further used to confirm the vascular ACE2 expression in human retina. Results: We found that ACE2 was expressed in multiple nonvascular neuroretinal cells, including the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptor outer segments in both nondiabetic and diabetic retinopathy specimens. Strikingly, we observed significantly more ACE2 positive vessels in the diabetic retinopathy specimens. By contrast, in another end-stage organ affected by diabetes, the kidney, ACE2 in nondiabetic and diabetic nephropathy showed apical expression of ACE2 tubular epithelial cells, but no endothelial expression in glomerular or peritubular capillaries. Western blot analysis of protein lysates from HRECs and HRPCs confirmed expression of ACE2. TMPRSS2 expression was present in multiple retinal neuronal cells, vascular and perivascular cells, and Muller glia. Conclusions: Together, these results indicate that retina expresses ACE2 and TMPRSS2. Moreover, there are increased vascular ACE2 expression in diabetic retinopathy retinas.

Proopiomelanocortin-positive amacrine cells (POMC ACs) were first discovered in adult mouse retinas in 2010; however, the development of POMC-ACs has not been studied. We bred POMC-EGFP mice to label POMC-positive cells and investigated the development of POMC neurons from embryonic to adult stages. We found that POMC neuron development is mainly divided into three stages: the embryonic stage, the closed-eye stage, and the open-eye stage. Each stage has unique characteristics. In the embryonic stage, POMC neurons appeared in the retina at about E13. There was a cell number developmental peak at E15, followed by a steep decline at E16. POMC neurons showed a large soma and increased spine numbers at the closed-eye stage, and two dendritic sublaminas formed in the inner plexiform layer (IPL). The appearance and increased soma size and dendrite numbers did not occur continuously in space. We found that the soma number was asymmetric between the superior and inferior retinas according to the developmental topographic map. Density peaked in the superior retina, which existed persistently in the retinal ganglion cell layer (GCL), but disappeared from the inner nuclear layer (INL) at about P6. At the same time, the soma distribution in the INL was the most regular. At the open-eye stage, the development of POMC neurons was nearly stable only with only an increase in the IPL width, which increased the soma–dendrite distance.

The inner retina has a three-tiered vascular supply, with capillary beds stratifying in the nerve fiber layer/ganglion cell layer, the inner plexiform layer, and the outer plexiform layer (1). While this trilaminar architecture likely functions to serve the metabolic needs of individual retinal layers, we do not know how metabolism and blood flow regulation differ across layers in the healthy retina. In particular, no noninvasive imaging technique with the potential for human translation has yet successfully distinguished the subtle metabolic signals that arise from these thin layers. For the past decade, visible light optical coherence tomography (OCT) (2, 3) has held the promise of imaging retinal oxygenation based on hemoglobin absorption. However, efforts have been largely limited to quantifying oxygenation of large vessels (4), with rare exceptions (5). In their latest work, Pi et al. (6) take a step toward making visible light OCT a tool for studying depth-resolved oxygenation of retinal capillary beds. First, they show that their oximetry method is highly repeatable, a must for any measurement to make it to the clinic. Next, they turn their attention toward accuracy. The closest analog of a retinal capillary saturation measurement is a phosphorescence lifetime-based oxygen tension probe (7) or invasive tissue oxygen electrodes (8). How does one validate a technique for which there is no direct and noninvasive gold standard? The authors propose a creative, albeit indirect, method to gauge accuracy. As noted previously by the authors (9), the superficial vascular plexus supply in Brown Norway rats appears to consist predominantly of arterioles and their higher-order two-dimensional capillary branches that supply the surrounding tissue. In this model vascular bed (Fig. 1 … [↵][1]1To whom correspondence may be addressed. Email: vjsriniv{at}ucdavis.edu. [1]: #xref-corresp-1-1

The present study aimed to determine the main cause of ganglion cell-inner plexiform layer (GCIPL) thinning in long myopic eyes. Optical coherence tomography was performed in 53 subjects with moderate or high myopia (53 eyes; myopia group) and 20 emmetropic subjects (20 eyes; control group). All subjects were over the age of 40 years. Compared groups did not differ in age, sex, and radius of corneal curvature. Spherical equivalent in the myopia group was − 8.2 ± 3.3 D (from − 4.0 to − 22.6 D). A specialized computer program was created to study the effect of the ocular magnification on the average GCIPL thickness. Based on the data of control subjects, a mathematical model was constructed, which showed a very little effect of ocular magnification on GCIPL thickness. It was confirmed by real measurements. After correction by the program, GCIPL thickness in myopes increased only slightly (from 73.9 ± 5.2 to 75.0 ± 5.2 μm, P < 0.000) remaining much lower than in controls (79.7 ± 6.3 μm, P < 0.000). Modeling myopic eye as an ellipsoid showed a significant increase in its surface area compared with emmetropia. Retinal stretching associated with an increase in the surface area of the eyeball explained most of the thinning of GCIPL in myopia. Ocular magnification is responsible for only a minor part of GCIPL thinning in myopia. Stretching of the retina in a long eye is the main cause of the GCIPL thinning. Myopic normative databases should be created to account for the GCIPL thinning in highly myopic eyes.

Purpose To analyse the association between the thickness of the circumpapillary retinal nerve fibre layer (cpRNFL) and the thickness of the inner macular layers with the mean deviation of the visual field (MD) in children with primary congenital glaucoma (PCG). Materials and Methods A total of 41 children with PGC were included in the study. They all had a complete ophthalmological examination, including visual acuity, intraocular pressure, funduscopy, Octopus™ visual field, as well as circumpapillar and macular spectral domain optical coherence tomography (SD-OCT). SD-OCT with automated segmentation was used to measure the thicknesses and volumes of the macular retinal nerve fibre layer (mRNFL), ganglion cell layer (GCL), and inner plexiform layer. Results The mean age was 11.2 ± 3.86 years, and the mean MD was 8.85 ± 6.76 dB. The visual field was classified as normal in 46% of the patients, and 20% of the patients had a concentrical restriction of the visual field. A positive correlation was found between between the cup-to-disc ratio and the MD, r = 0.51 (P = 0.004). The correlation between the MD and the cpRNFL was r = −0.63 (P Conclusions Inner macular layers thickness and cpRNFL thickness show a good correlation with the mean deviation of the visual field in children with primary congenital glaucoma.

Purpose: To investigate the clinical importance of the thicknesses of the retinal nerve fibre (RNFL) and ganglion cell and inner plexiform layer (GCL+) by spectral domain optic coherence to...

PURPOSE To compare retinal thickness between patients with chronic hypertension without retinopathy, hypertensive retinopathy, Keith-Wagener-Barker Grade IV status, and normal controls using spectral domain optical coherence tomography. METHODS In this retrospective study, we analyzed patients who visited our retinal clinic from January 2013 to February 2016. Of those included, 58 eyes of 58 patients were in the healthy control group (Group A), 37 eyes of 37 patients were in the chronic hypertension without retinopathy group (disease duration of at least 10 years; Group B), and 31 eyes of 31 patients with relieved hypertensive retinopathy (Grade IV hypertensive retinopathy a year or more ago but no longer had hypertensive retinopathy at the time of the study; Group C). The thicknesses of the central macula, retinal nerve fiber layer (RNFL), and ganglion cell inner plexiform layer (GCIPL) were measured by spectral domain optical coherence tomography in each group. RESULTS The average thicknesses of the central macula, RNFL, and GCIPL layers were lower in Group B than in Group A (P < 0.001, 0.001, and

To investigate the association between progressive macular ganglion cell/inner plexiform layer (mGCIPL) thinning and change of optical coherence tomography angiography (OCTA)-derived microvascular parameters in early-stage diabetic retinopathy (DR). A retrospective cohort study involved 40 eyes presenting with no DR or mild non-proliferative DR at baseline, and 30 healthy controls were included. All participants underwent spectral-domain OCT and OCTA at baseline and at 6, 12, 18, and 24 months. Change of mGCIPL thickness and OCTA metrics including foveal avascular zone (FAZ) area and FAZ circularity, vessel density (VD), and perfusion index (PI) was measured. Correlations between mGCIPL thickness and OCTA metrics were explored using regression models. Average progressive mGCIPL loss was 0.45 µm per year. Three microvascular parameters were significantly impaired at 24 months compared to baseline (FAZ area: 0.34–0.36 mm2, VD: 18.9–18.5/mm, PI: 0.35–0.34). A strong positive correlation was found between loss of mGCIPL and VD from baseline to 24 months (r = 0.817, p

AimTo determine longitudinal changes of the ganglion cell-inner plexiform layer (GC-IPL) thickness in patients with high myopia.MethodsThe subjects were divided into two groups: a high myopia group (axial length ≥26.0 mm) and a normal control group. Both groups were divided into subgroups based on age (decade): 20s, 30s, 40s and 50s. Twenty eyes were included in each subgroup. After the initial visit, GC-IPL thicknesses were measured three more times with at least a 1-year interval between examinations using spectral domain optical coherence tomography. The average GC-IPL thickness was fitted with linear mixed models.ResultsThe average GC-IPL thickness at the first visit was 78.50 ± 8.79 µm and 84.29 ± 6.12 µm in the high myopia and control groups, respectively. In both groups, the average GC-IPL thickness showed a significant change over time. The rate of GC-IPL reduction in individuals aged in their 50s, 40s, 30s and 20s with high myopia were −0.81 µm/year,–0.51 µm/year, −0.28 µm/year and −0.12 µm/year, respectively, and in controls in their 50s, 40s, 30s and 20s, they were −0.31 µm/year,–0.25 µm/year, −0.12 µm/year and −0.02 µm/year, respectively. Additionally, individuals aged in their 50s showed a statistically significant interaction between group and duration (pConclusionsHighly myopic eyes had thinner GC-IPL and a significantly greater reduction in GC-IPL over 3 years when compared with normal eyes. Additionally, the reduction rate of the GC-IPL thickness was greater in older patients in both groups, which was more prominent in the high myopia group.