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Leber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial disorder that presents with severe bilateral sequential vision loss, due to the selective degeneration of retinal ganglion cells (RGCs). Since the mitochondrial genetic basis for LHON was uncovered in 1988, considerable progress has been made in understanding the pathogenetic mechanisms driving RGC loss, which has enabled the development of therapeutic approaches aimed at mitigating the underlying mitochondrial dysfunction. In this review, we explore the genetics of LHON, from bench to bedside, focusing on the pathogenetic mechanisms and how these have informed the development of different gene therapy approaches, in particular the technique of allotopic expression with adeno-associated viral vectors. Finally, we provide an overview of the recent gene therapy clinical trials and consider the unanswered questions, challenges, and future prospects.

ImportanceGanglion cell analysis (GCA) of ocular coherence tomography (OCT) imaging is routinely used to detect and monitor glaucomatous damage of the ganglion cell complex in the macula. The GCA printout provides qualitative and quantitative data about the macular ganglion cell–inner plexiform layer and a single B-scan of the retina through the fovea. However, the full macular cube scan, including all 128 B-scans, is available for review. The macular cube scan provides considerable information about nonglaucomatous ocular pathology that may be missed if clinicians review only the GCA printout.ObjectiveTo determine the frequency and type of nonglaucomatous macular findings that are observable in the full macular cube scan but not the GCA printout.Design, Setting, and ParticipantsA retrospective cross-sectional analysis of GCA printouts and full macular cube scans to detect nonglaucomatous macular pathology at a tertiary care academic center. Consecutive patients undergoing ganglion cell complex imaging during routine glaucoma evaluations over a 1-week period in a multi-clinician glaucoma clinic.Main Outcomes and MeasuresThe prevalence and type of nonglaucomatous macular pathology visible on the GCA printout or macular cube scan.ResultsAmong 105 patients (mean (SD) age, 67 (15.46) years; 63 [60%] female and 42 [40%] male) 201 eyes were imaged (64 [31.7%] with suspected glaucoma, 126 [62.4%] with open-angle glaucoma, 6 [3.0%] with closed-angle glaucoma, and 6 [3.0%] with other glaucoma). GCA printouts and macular cube scans revealed nonglaucomatous macular pathology in 65 eyes (32.2%). Of these, 25 eyes (38.5%) included findings that were not visible on the GCA printout. Of the cases not visible on the printout, 16 eyes (64.0% ) included macular pathology that required further evaluation.Conclusions and RelevanceThe findings indicate that nonglaucomatous macular pathology may be missed based on GCA printouts alone. While it may be beneficial to review the full macular cube to detect potentially vision-threatening disease and ensure proper patient care, this study cannot determine if this missed pathology affects clinical outcomes.

The intrinsically photosensitive retinal ganglion cells (ipRGCs) regulate pupil size and circadian rhythms. Stimulation of the ipRGCs using short-wavelength blue light causes a sustained pupil constriction known as the post-illumination pupil response (PIPR). Here we examined the effects of ipRGC stimulation on axial length changes to imposed optical defocus in young adults.Nearly emmetropic young participants were given either myopic (+3 D, n = 16) or hyperopic (-3 D, n = 17) defocus in their right eye for 2 h. Before and after defocus, a series of axial length measurements for up to 180 s were performed in the right eye using the IOL Master following exposure to 5 s red (625 nm, 3.74 × 10The PIPR with blue light was significantly stronger after 2 h of hyperopic defocus as indicated by a lower 6 and 30 s PIPR and a larger early and late AUC (all p0.05). Short-wavelength ipRGC stimulation also significantly exaggerated the ocular response to hyperopic defocus, causing a significantly greater increase in axial length than that resulting from the hyperopic defocus alone (p = 0.017). Neither wavelength had any effect on axial length with myopic defocus.These findings suggest an interaction between myopiagenic hyperopic defocus and ipRGC signaling.

To estimate the number of OCT scans necessary to detect moderate and rapid rates of retinal nerve fiber layer (RNFL) thickness worsening at different levels of accuracy using a large sample of glaucoma and glaucoma-suspect eyes.Descriptive and simulation study.Twelve thousand one hundred fifty eyes from 7392 adult patients with glaucoma or glaucoma-suspect status followed up at the Wilmer Eye Institute from 2013 through 2021. All eyes had at least 5 measurements of RNFL thickness on the Cirrus OCT (Carl Zeiss Meditec) with signal strength of 6 or more.Rates of RNFL worsening for average RNFL thickness and for the 4 quadrants were measured using linear regression. Simulations were used to estimate the accuracy of detecting worsening-defined as the percentage of patients in whom the true rate of RNFL worsening was at or less than different criterion rates of worsening when the OCT-measured rate was also at or less than these criterion rates-for two different measurement strategies: evenly spaced (equal time intervals between measurements) and clustered (approximately half the measurements at each end point of the period).The 75th percentile (moderate) and 90th percentile (rapid) rates of RNFL worsening for average RNFL thickness and the accuracy of diagnosing worsening at these moderate and rapid rates.The 75th and 90th percentile rates of worsening for average RNFL thickness were -1.09 μm/year and -2.35 μm/year, respectively. Simulations showed that, for the average measurement frequency in our sample of approximately 3 OCT scans over a 2-year period, moderate and rapid RNFL worsening were diagnosed accurately only 47% and 40% of the time, respectively. Estimates for the number of OCT scans needed to achieve a range of accuracy levels are provided. For example, 60% accuracy requires 7 measurements to detect both moderate and rapid worsening within a 2-year period if the more efficient clustered measurement strategy is used.To diagnose RNFL worsening more accurately, the number of OCT scans must be increased compared with current clinical practice. A clustered measurement strategy reduces the number of scans required compared with evenly spacing measurements.

To investigate longitudinal changes in peripapillary choroidal thickness (pCT) and retinal nerve fiber thickness (pRNFLT) in patients with Type 2 diabetes mellitus.This was a prospective observational cohort study. Patients with Type 2 diabetes mellitus without diabetic retinopathy (DR) at baseline were recruited, followed up for three years, and further divided into an incident DR group and a non-DR group according to the outcome. The pCT and pRNFLT were measured through swept-source optical coherence tomography at 1-year interval, and the mean rates of pCT and pRNFLT thinning were compared between the DR groups.A total of 682 patients (682 eyes) were included in the final analysis. After 3-years follow-up, 122 (17.89%) developed DR. Both pCT and pRNFLT progressively thinned (-2.37 [-2.80 to -1.95] µm/year; -0.40 [-0.55 to -0.25] µm/year, respectively, P0.05) and accelerated thinning was observed in the incident DR group. The rates of pCT thinning (-3.92 [-4.96 to -2.88] µm/year, -2.03 [-2.49 to -1.57] µm/year, respectively) and pRNFLT loss (-1.03 [-1.31 to -0.76] µm/year, -0.26 [-0.43 to -0.09] µm/year, respectively) in the incident DR group were 1.93 and 3.96 times faster than those in the non-DR group, respectively. In addition, pCT and pRNFLT thinning were negatively related in Type 2 diabetes mellitus population, and faster pCT thinning indicated slower pRNFLT loss.Patients with Type 2 diabetes mellitus were at a higher risk of developing DR when accelerated pCT and pRNFLT thinning were present, indicating that heavier choroidal damage and retinal neurodegeneration precede clinical DR. The pCT and pRNFLT have the potential to serve as novel sensitive biomarkers of preclinical and early DR.

To investigate a potential association between retinal layer thinning and pregnancy-related adverse outcomes.A prospective observational study included 32 pregnant women between the ages of 18 and 45. Seventeen had uneventful pregnancies, and 15 experienced an adverse obstetrical outcome. Macular swept-source ocular coherence tomography was performed, and selective layers of the retina were evaluated. Adverse obstetrical outcome was defined as any of the following: preterm delivery, preeclampsia, pregnancy-induced hypertension, elevated liver function tests, thrombocytopenia and need for magnesium.The inner superior ganglion cell layer (GCL) was found to be thinner in the cohort with composite adverse obstetrical outcomes than in the cohort without complications (84.5±6.9 vs. 89.5±6.1μm respectively; P=0.04). Total inner superior (295.5±39.1 vs. 302.5±12.7μm; P=0.03) and inferior retinal thickness (289.0±13.9 vs. 301.0±17.1μm; P=0.03) as well as total macular volume (7.5±0.3 vs. 7.7±0.3 mmThinning of the macular ganglion cell layer was associated with adverse outcomes in pregnancy. Larger studies are necessary to assess the potential role of macular GCL analysis in pregnancy.

Objective Pituitary tumours that compress the optic chiasm are associated with long-term alterations in sleep–wake rhythm. This may result from damage to intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting from the retina to the hypothalamic suprachiasmatic nucleus via the optic chiasm to ensure photoentrainment (i.e. synchronisation to the 24-h solar cycle through light). To test this hypothesis, we compared the post-illumination pupil response (PIPR), a direct indicator of ipRGC function, between hypopituitarism patients with and without a history of optic chiasm compression. Design Observational study, comparing two predefined groups. Methods We studied 49 patients with adequately substituted hypopituitarism: 25 patients with previous optic chiasm compression causing visual disturbances (CC+ group) and 24 patients without (CC– group). The PIPR was assessed by chromatic pupillometry and expressed as the relative change between baseline and post-blue-light stimulus pupil diameter. Objective and subjective sleep parameters were obtained using polysomnography, actigraphy, and questionnaires. Results Post-blue-light stimulus pupillary constriction was less sustained in CC+ patients compared with CC– patients, resulting in a significantly smaller extended PIPR (mean difference: 8.1%, 95% CI: 2.2–13.9%, P = 0.008, Cohen's d = 0.78). Sleep–wake timing was consistently later in CC+ patients, without differences in sleep duration, efficiency, or other rest–activity rhythm features. Subjective sleep did not differ between groups. Conclusion Previous optic chiasm compression due to a pituitary tumour in patients with hypopituitarism is associated with an attenuated PIPR and delayed sleep timing. Together, these data suggest that ipRGC function and consequently photoentrainment of the central biological clock is impaired in patients with a history of optic chiasm compression.

Glaucoma is the most prevalent form of optic neuropathy where a progressive degeneration of retinal ganglion cells (RGCs) leads to irreversible loss of vision. The mechanism underlying glaucomatous degeneration remains poorly understood. However, evidence suggests that microglia, which regulate RGC numbers and synaptic integrity during development and provide homeostatic support in adults, may contribute to the disease process. Hence, microglia represent a valid cellular target for therapeutic approaches in glaucoma. Here, we provide an overview of the role of microglia in RGC development and degeneration in the backdrop of neurogenesis and neurodegeneration in the central nervous system and discuss how pathological recapitulation of microglia-mediated developmental mechanisms may help initiate or exacerbate glaucomatous degeneration.

Purposeof Review To outline the current landscape of treatments for Leber hereditary optic neuropathy (LHON) along the therapeutic delivery pipeline, exploring the mechanisms of action and evidence for these therapeutic approaches. Recent Findings Treatments for LHON can be broadly classified as either mutation-specific or mutation-independent. Mutation-specific therapies aim to correct the underlying mutation through the use of a gene-editing platform or replace the faulty mitochondrial DNA-encoded protein by delivering the wild-type gene using a suitable vector. Recent gene therapy clinical trials assessing the efficacy of allotopically expressed MT-ND4 for the treatment of LHON due to the m.11778G > A mutation in MT-ND4 have shown positive results when treated within 12 months of symptom onset. Mutation-independent therapies can have various downstream targets that aim to improve mitochondrial respiration, reduce mitochondrial stress, inhibit or delay retinal ganglion cell apoptosis, and/or promote retinal ganglion cell survival. Idebenone, a synthetic hydrosoluble analogue of co-enzyme Q10 (ubiquinone), is the only approved treatment for LHON. Mutation-independent approaches to gene therapy under pre-clinical investigation for other neurodegenerative disorders may have the potential to benefit patients with LHON. Summary Although approved treatments are presently limited, innovations in gene therapy and editing are driving the expansion of the therapeutic delivery pipeline for LHON.

To investigate the relationship of longitudinal changes in macular vessel density (VD) from OCT angiography and in ganglion cell complex (GCC) from OCT with central visual field (VF) in eyes with early glaucoma.Observational cohort.A total of 95 eyes, 37 preperimetric and 58 with early glaucoma (24-2 VF mean deviation [MD] ≥ -6 decibels), with an average follow-up of 3.8 years and 5.3 visits, were included.Whole-image VD (wiVD) and whole-image GCC (wiGCC) and parafoveal scans, as well as localized regions of interest (LROIs), hemiretinae of whole images, and superior, inferior, temporal, and nasal sectors of parafoveal maps, were matched with central VF locations. Age-adjusted rates of change of VD, GCC, mean sensitivity of VF locations, and 10-2 VF MD were calculated using linear mixed-effect models. Normalized rates of change were calculated for comparison of change rates in wiVD and wiGCC.Structure-function (SF) correlations of VD and GCC with central VF measurement change rates and comparison of different correlations of SF relationships after bootstrapping the difference of the correlation coefficients.Vessel density loss and GCC thinning demonstrated significant correlations with central VF damage, globally and with most LROIs. The SF correlation (r, 95% confidence interval [CI]) between wiVD and 10-2 VF MD change rates was 0.42 [0.24, 0.58], whereas it was 0.27 [0.08, 0.45] between wiGCC and 10-2 VF MD changes rates (all P0.05). In contrast to GCC thinning, VD loss in the parafoveal sectors demonstrated significant correlations with central VF damage in inferior and temporal sectors. Differences in the relationship of SF with central VF damage were not significant between VD loss and GCC thinning. The mean (95% CI) normalized change rates of wiVD (-7.40 [-7.71 to 7.09] %/year) was faster than that of wiGCC (-2.39 [-2.94 to 1.84] %/year) (P0.05).Rates of VD loss and GCC thinning are associated with central VF loss over time. Assessment of both macular VD and GCC thickness should be considered for evaluation of glaucoma progression.

Glaucoma, a common cause of blindness, is characterized by the progressive loss of retinal ganglion cells (RGCs). Growing evidence suggests that nobiletin (NOB) is a promising neuroprotective drug; however, its effects on glaucomatous neurodegeneration remain unknown. Using rat models of microbead occlusion in vivo and primary RGCs model of hypoxia in vitro, we first demonstrate that NOB reduces RGC apoptosis by a TUNEL assay, Hoechst 33342 staining and FluoroGold (FG) retrograde labeling. This effect does not depend on intraocular pressure (IOP) lowering. Additionally, NOB partially restored the functional and structural damage of inner retinas, attenuated Müller glial activation and oxidative stress caused by ocular hypertension. At 2 weeks after IOP elevation, NOB further enhanced Nrf2/HO-1 pathway in RGCs to withstand the cumulative damage of ocular hypertension. With the administration of HO-1 inhibitor tin-protoporphyrin IX (SnPP), the protective effect of NOB was attenuated. Overall, these results indicate that NOB exerts an outstanding neuroprotective effect on RGCs of glaucomatous neurodegeneration. Besides, interventions to enhance activation of Nrf2/HO-1 pathway can slow the loss of RGCs and are viable therapies for glaucoma.

Glaucoma is a neurodegenerative disease that causes irreversible blindness due to loss of retinal ganglion cells (RGCs) and their axons. We previously identified a G661R mutation of ADAMTS10 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif 10) as the disease-causing mutation in a beagle model of glaucoma. ADAMTS10 is a secreted matrix metalloproteinase that belongs to the ADAMTS family which is involved in extracellular matrix (ECM) turnover. Previous studies have shown that ADAMTS10 binds fibrillin microfibrils, promotes their formation, and influences their fibrillin isoform composition. Here, we established a mouse model carrying the G661R mutation of ADAMTS10 (ADAMTS10

To report long-term ophthalmic findings in Wolfram syndrome, including rates of visual decline, macular thinning, retinal nerve fiber layer (RNFL) thinning, and outer plexiform layer (OPL) lamination.Single-center, cohort study.A total of 38 participants were studied, who underwent a complete ophthalmic examination as well as optical coherence tomography imaging of the macula and nerve on an annual basis. Linear mixed-effects models for longitudinal data were used to examine both fixed and random effects related to visual acuity and optic nerve quadrants of RNFL and macula thickness.Participants completed a mean of 6.44 years of follow-up (range 2-10 years). Visual acuity declined over time in all participants, with a mean slope of 0.059 logMAR/y (95% CI = 0.07-0.05 logMAR/y), although nearly 25% of participants experienced more rapid visual decline. RNFL thickness decreased in superior, inferior, and nasal quadrants (β = -0.5 µm/y, -0.98 µm/y, -0.28 µm/y, respectively). OPL lamination was noted in 3 study participants, 2 of whom had autosomal dominant mutations.Our study describes the longest and largest natural history study of visual acuity decline and retinal morphometry in Wolfram syndrome to date. Results suggest that there are slower and faster progressing subgroups and that OPL lamination is present in some individuals with this disease.

To evaluate the effects of pressure changes induced by a multipressure dial (MPD) on circumpapillary retinal nerve fiber layer (RNFL) and capillary density (CD) measurements in patients with glaucoma using OCT angiography (OCTA).Prospective interventional study.Twenty-four patients with primary open-angle glaucoma.One eye of each patient underwent negative pressure application with the MPD. The MPD alters intraocular pressure (IOP) relative to atmospheric pressure by generating a negative pressure vacuum within a goggle chamber that is placed over the eye. Each participant underwent serial high density OCTA imaging (AngioVue) of the optic nerve head at different negative pressure increments of -5 mmHg, starting from 0 mmHg, ending at -20 mmHg, and then returning to baseline. Images were acquired after 2 minutes of sustained negative pressure at each target pressure to allow for stabilization of the retinal structures and microvasculature. The RNFL thickness and CD measurements were automatically calculated using the native AngioVue software, and then exported for analysis.The influence of different levels of negative pressure on circumpapillary RNFL thickness and CD measurements, assessed by a linear mixed-effects model with repeated measures.The mean (± SD) age was 71.0 years (± 7.8 years), the baseline IOP was 17.5 mmHg (± 3.6 mmHg), and there was a mean 24-2 mean deviation of -2.80 dB (± 2.55 dB). Serial circumpapillary CD measurements showed a statistically significant dose-dependent increase from baseline, without negative pressure application, to the maximum negative pressure application of -20 mmHg (difference, 2.27%; P = 0.010). Capillary density measurements then decreased symmetrically when lowering the negative pressure to baseline. Circumpapillary CD measurements at target negative pressures of -10 mmHg, -15 mmHg, and -20 mmHg were significantly higher than the baseline measurements (all P values0.05). Circumpapillary RNFL thickness remained the same throughout different levels of negative pressure.Circumpapillary CD measurements showed a dose-dependent increase with the induction of negative pressure, while RNFL thickness measurements remained unchanged.

Brain-derived neurotrophic factor (BDNF) is an important regulator of circuit development, neuronal survival, and plasticity throughout the nervous system. In the visual system, BDNF is produced by retinal ganglion cells (RGCs) and transported along their axons to central targets. Within the dorsolateral geniculate nucleus (dLGN), a key RGC projection target for conscious vision, the BDNF receptor tropomyosin receptor kinase B (TrkB) is present on RGC axon terminals and postsynaptic thalamocortical (TC) relay neuron dendrites. Based on this, the goal of this study was to determine how BDNF modulates the conveyance of signals through the retinogeniculate (RG) pathway of adult mice. Application of BDNF to dLGN brain slices increased TC neuron spiking evoked by optogenetic stimulation of RGC axons. There was a modest contribution to this effect from a BDNF-dependent enhancement of TC neuron intrinsic excitability including increased input resistance and membrane depolarization. BDNF also increased evoked vesicle release from RGC axon terminals, as evidenced by increased amplitude of evoked excitatory postsynaptic currents (EPSCs), which was blocked by inhibition of TrkB or phospholipase C. High-frequency stimulation revealed that BDNF increased synaptic vesicle pool size, release probability, and replenishment rate. There was no effect of BDNF on EPSC amplitude or short-term plasticity of corticothalamic feedback synapses. Thus, BDNF regulates RG synapses by both presynaptic and postsynaptic mechanisms. These findings suggest that BNDF influences the flow of visual information through the retinogeniculate pathway.

The electroretinogram (ERG) allows the investigation of retinal signaling pathways and has increasingly been applied in individuals with mental disorders in search for potential biomarkers of neurodevelopmental disorders. Preceding ERG examinations in individuals with autism spectrum disorders (ASD) showed inconsistent results, which might be due to the small number of participants, heterogeneity of the ASD population, differences in age ranges, and stimulation methods. The aim of this study was to investigate functional retinal responses in adults with ASD by means of the light-adapted (photopic) ERG. Light-adapted ERG measurements were obtained with the RETeval® system applying three different stimulation protocols. In the final analysis, the ERG parameters a-wave, b-wave, the photopic negative response (PhNR), the photopic hill parameters as well as additional amplitude ratios were compared between 32 adults with high-functioning ASD and 31 non-autistic controls. Both groups were matched with regard to sex and age. No significant functional retinal differences in amplitude or peak time of the a- or b-wave, PhNR, the photopic hill parameters or the ERG-amplitude ratios could be detected in individuals with ASD compared to non-autistic participants. The absence of electrophysiological functional retinal alterations in ASD, suggests that changes in visual perception, such as increased attention to detail or visual hypersensitivity in ASD, are not due to impairments at early levels of retinal signal processing.

Background. Traumatic optic neuropathy (TON) refers to damage to the optic nerve resulting from direct and indirect trauma to the head and face. One of the important pathological processes in TON is the death of retinal ganglion cells (RGCs), but the cause of RGCs death remains unclear. We aimed to explore the mechanisms of RGCs death in an experimental TON model. Methods. Optic nerve crush injury was induced in ten New Zealand white rabbits. On the 1st, 3rd, 7th, 14th, and 28th days after the operation, the retinal tissues of the rabbits were observed pathologically by hematoxylin-eosin staining. The expression of POU-homeodomain transcription factor Brn3a and glial fibrillary acidic protein (GFAP) was measured by immunofluorescence to evaluate the number of RGCs and astrocytes, respectively. miRNA expression and protein levels were assessed by RT-qPCR and western blot methods, respectively. Finally, the malondialdehyde content, superoxide dismutase activity, and proinflammatory factor levels were measured by ELISA. Western blot and dual-luciferase reporter assays were used to elucidate the relationship between miR-181d-5p and nuclear factor I-A (NFIA). Results. Blunt ocular trauma increased oxidative stress and apoptosis and reduced ganglion cell layer (GCL) density. The expression of miR-181d-5p was decreased in retinal tissues, and its overexpression relieved RGCs death, astrocyte development, oxidative stress, and inflammation of the retina, which were reversed by NFIA overexpression. Conclusion. miR-181d-5p can protect against the deterioration of TON by inhibiting RGCs death, astrocyte development, oxidative stress, and inflammation by targeting NFIA. This study provides new insight into early medical intervention in patients with TON.

Irreversible damage to the structure of axons and death of the retinal ganglion cell (RGC) soma in primary open-angle glaucoma (POAG) and Alzheimer’s disease (AD) develop against the background of the already existing clinical manifestation, which is preceded by a slow period of progressive loss of synapses and dendrites of the RGCs. Recent studies have shown that the integrity of the RGC’s dendritic branching can serve as both a target of neuroprotective therapy and a sensitive marker of retinal degeneration in AD and glaucoma. To develop methods of complex neuroprotective therapy, it is necessary to substantiate the targets and tactics of affecting the dendritic tree of the RGCs, the remodeling of which, according to modern concepts, can be closely and antagonistically related to the regeneration of the axon after its damage in trauma and neurodegenerative diseases. RGCs are highly capable of functional modification. Currently, it has been proven that the use of neuroprotective drugs and neurotrophins is promising for maintaining the adaptive plasticity of RGCs and restoring their synaptic contacts at the level of the retina and brain. Understanding the features of the adaptive plasticity of RGCs in AD and glaucoma will make it possible to use technologies to activate the internal potential of neuronal remodeling, including the modification of dendritic branching of RGCs and regeneration of their axons, in the preclinical stages of these diseases. Increasing knowledge about the sequence and mechanisms of early events in the retina’s inner plexiform layer will contribute to the development of targeted neuroprotective therapy and new technologies to detect early POAG, AD, and, possibly, other systemic and local neurodegenerative conditions.

To assess macular and optic nerve head characteristics in patients after kidney transplantation using noninvasive optical coherence tomography (OCT) imaging.The study had a prospective character and was performed during period from November 2019 to November 2020 at the University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina, and included 59 patients with renal graft who underwent OCT. The obtained OCT images, pathologic changes on the fundus, including macula and optic nerve, were analyzed by reviewing nonparametric measures such as scanning laser ophthalmoscope, B-scan, 3D display, as well as parametric measurements such as central macular thickness, optic nerve head excavation, and retinal nerve thickness fiber (RNFL).There is a statistically significant difference in RNFL values (P = 0.031) and cup to disc (P = 0.002) ratio in relation to duration of graft. The highest average values of RNFL was in patients with creatinine clearance30 mL/min, while average cup to disc ratio was lowest in patients with creatinine clearance60 mL/min. Optic nerve head edema was bilateral in 9 and unilateral in 5 patients. Fundus examination also revealed changes on posterior segment, including retinal detachment (1 patient), bilateral macular edema (9 patients), unilateral macular edema (3 patients), central serous chorioretinopathy (2 patients), and macular pseudo hole (3 patients).Different retinal pathology is present in high incidence in patients secondary to renal transplant. Immunosuppressive therapy, older age, and comorbidities are the usual causes of these changes.

To evaluate the diagnostic accuracy of a novel optical coherence tomography texture-based en face image analysis (SALSA-Texture) that requires segmentation of only 1 retinal layer for glaucoma detection in eyes with axial high myopia, and to compare SALSA-Texture with standard macular ganglion cell-inner plexiform layer (GCIPL) thickness, macular retinal nerve fiber layer (mRNFL) thickness, and ganglion cell complex (GCC) thickness maps.Comparison of diagnostic approaches.Cross-sectional data were collected from 92 eyes with primary open-angle glaucoma (POAG) and 44 healthy control eyes with axial high myopia (axial length26 mm). Optical coherence tomography texture en face images, developed using SALSA-Texture to model the spatial arrangement patterns of the pixel intensities in a region, were generated from 70-μm slabs just below the vitreal border of the inner limiting membrane. Areas under the receiver operating characteristic curves (AUROCs) and areas under the precision recall curves (AUPRCs) adjusted for both eyes, axial length, age, disc area, and image quality were used to compare different approaches.The best parameter-adjusted AUROCs (95% confidence intervals) for differentiating between healthy and glaucoma high myopic eyes were 0.92 (0.88-0.94) for texture en face images, 0.88 (0.86-0.91) for macular RNFL thickness, 0.87 (0.83-0.89) for macula GCIPL thickness, and 0.87 (0.84-0.89) for GCC thickness. A subset analysis of highly advanced myopic eyes (axial length ≥27 mm; 38 glaucomatous eyes and 22 healthy eyes) showed the best AUROC was 0.92 (0.89-0.94) for texture en face images compared with 0.86 (0.84-0.88) for macular GCIPL, 0.86 (0.84-0.88) for GCC, and 0.84 (0.81-0.87) for RNFL thickness (P ≤ .02 compared with texture for all comparisons).The current results suggest that our novel en face texture-based analysis method can improve on most investigated macular tissue thickness measurements for discriminating between highly myopic glaucomatous and highly myopic healthy eyes. While further investigation is needed, texture en face images show promise for improving the detection of glaucoma in eyes with high myopia where traditional retinal layer segmentation often is challenging.

Purpose To derive and validate structure–function models for estimating retinal ganglion cell (RGC) count using optical coherence tomography (OCT) and steady-state pattern electroretinography (ssPERG) parameters in glaucoma suspects (GS) and preperimetric glaucoma (PPG). Methods In this prospective cross-sectional study, 25 subjects (50 eyes) were recruited at the Manhattan Eye, Ear, and Throat Hospital. Subjects underwent comprehensive eye examinations, OCT, standard automated perimetry (SAP), and ssPERG testing. Eyes were divided into three groups based on the Global Glaucoma Staging System: healthy (N = 30), GS (N = 10), and PPG (N = 10) eyes. The combined structure–function index (CSFI), which estimates retinal ganglion cell count (eRGCCSFI) from SAP and OCT parameters, was calculated in each study subject. Two prediction formulas were derived using a generalized linear mixed model (GLMM) to predict eRGCCSFI from ssPERG parameters, age, and average retinal nerve fiber layer thickness (ARNFLT) in 30 eyes selected at random (training group). GLMM predicted values were cross-validated with the remaining 20 eyes (validation group). Results The ARNFLT, ssPERG parameters magnitude (Mag) and magnitudeD (MagD), and eRGCCSFI were significantly different among study groups (ANOVA p ≤ 0.001). Pearson correlations demonstrated significant associations among ARNFLT, ssPERG parameters, and eRGCCSFI (r2 ≥ 0.31, p CSFI from Mag (eRGCMag) and MagD (eRGCMagD), respectively, with significant equations (F(3,18), F(3,19) ≥ 58.37, R2 = 0.90, p Mag and eRGCMagD in the validation group (R2 = 0.89) correlated with eRGCCSFI similarly to the training group. Multivariate pairwise comparisons revealed that eRGCMag and eRGCMagD distinguished between healthy, GS, and PPG eyes (p ≤ 0.035), whereas independent Mag, MagD, and ARNFLT measures did not distinguish between GS and PPG eyes. Conclusion This pilot study offers the first combined structure–function models for estimating RGC count using ssPERG parameters. RGC counts estimated with these models were generalizable, strongly associated with CSFI estimates, and performed better than individual ssPERG and OCT measures in distinguishing healthy, GS, and PPG eyes.

Glaucoma is a common disorder in which the death of retinal ganglion cells (RGCs) results in a progressive loss of sight, even blindness. This study was performed to reveal the key molecular mechanism of RGC damage in glaucoma based on the Gene Expression Omnibus database. Glaucoma-related microarray datasets were identified, followed by collection of differentially expressed genes (DEGs) with the key genes discovered by weighted gene co-expression network analysis. Through LASSO regression analysis, candidate genes involved in the pathogenesis of glaucoma were identified with their accuracy evaluated by receiver operating characteristic curve analysis. The glaucoma-specific transcriptional regulatory network was constructed to determine the key transcription factor regulatory axis. Then, in vitro cell models were established using H

Retinal circuits transform the pixel representation of photoreceptors into the feature representations of ganglion cells, whose axons transmit these representations to the brain. Functional, morphological, and transcriptomic surveys have identified more than 40 retinal ganglion cell (RGC) types in mice. RGCs extract features of varying complexity; some simply signal local differences in brightness (i.e., luminance contrast), whereas others detect specific motion trajectories. To understand the retina, we need to know how retinal circuits give rise to the diverse RGC feature representations. A catalog of the RGC feature set, in turn, is fundamental to understanding visual processing in the brain. Anterograde tracing indicates that RGCs innervate more than 50 areas in the mouse brain. Current maps connecting RGC types to brain areas are rudimentary, as is our understanding of how retinal signals are transformed downstream to guide behavior. In this article, I review the feature selectivities of mouse RGCs, how they arise, and how they are utilized downstream. Not only is knowledge of the behavioral purpose of RGC signals critical for understanding the retinal contributions to vision; it can also guide us to the most relevant areas of visual feature space.

There are several indirect methods used to estimate retinal ganglion cell (RGC) count in an individual eye, but there is limited information as to the agreement between these methods. In this work, RGC receptive field (RGC-RF) count underlying a spot stimulus (0.43°, Goldmann III) was calculated and compared using three different methods.RGC-RF count was calculated at a retinal eccentricity of 2.32 mm for 44 healthy adult participants (aged 18-58 years, refractive error -9.75 DS to +1.75 DS) using: (i) functional measures of achromatic peripheral grating resolution acuity (PGRA), (ii) structural measures of RGC-layer thickness (OCT-model, based on the method outlined by Raza and Hood) and (iii) scaling published histology density data to simulate a global expansion in myopia (Histology-Balloon).Whilst average RGC-RF counts from the OCT-model (median 105.3, IQR 99.6-111.0) and the Histology-Balloon model (median 107.5, IQR 97.7-114.6) were similar, PGRA estimates were approximately 65% lower (median 37.7, IQR 33.8-46.0). However, there was poor agreement between all three methods (Bland-Altman 95% limits of agreement; PGRA/OCT: 55.4; PGRA/Histology-Balloon 59.3; OCT/Histology-Balloon: 52.4). High intersubject variability in RGC-RF count was evident using all three methods.The lower PGRA RGC-RF counts may be the result of targeting only a specific subset of functional RGCs, as opposed to the coarser approach of the OCT-model and Histology-Balloon, which include all RGCs, and also likely displaced amacrine cells. In the absence of a 'ground truth', direct measure of RGC-RF count, it is not possible to determine which method is most accurate, and each has limitations. However, what is clear is the poor agreement found between the methods prevents direct comparison of RGC-RF counts between studies utilising different methodologies and highlights the need to utilise the same method in longitudinal work.

In the dorsal lateral geniculate nucleus (LGN) of mice that lack retinal input, a population of large terminals supplants the synaptic arrangements normally made by the missing retinogeniculate terminals. To identify potential sources of these "retinogeniculate replacement terminals," we used mutant mice (math5

PURPOSE: To describe the clinical phenotype of a cohort of patients with Wolfram syndrome (WS), focusing on the pattern of optic atrophy correlated with brain magnetic resonance imaging (MRI) measurements, as compared with patients with OPA1-related dominant optic atrophy (DOA).center dot DESIGN: Retrospective, comparative cohort study.center dot METHODS: We reviewed 25 patients with WS and 33 age-matched patients affected by OPA1-related DOA. Ophthalmologic, neurologic, endocrinologic, and MRI data from patients with WS were retrospectively retrieved. Ophthalmologic data were compared with data from patients with OPA1-related DOA and further analyzed for age dependency dividing patients in age quartiles. In a subgroup of patients with WS, we correlated the structural damage assessed by optical coherence tomography (OCT) with brain MRI morphologic measurements. Visual acuity (VA), visual field mean defect (MD), retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness were assessed by OCT and MRI morphologic measurements of anterior and posterior visual pathways.center dot RESULTS: Optic atrophy was present in 100% of patients with WS. VA, MD, and RNFL thickness loss were worse in patients with WS with a faster decline since early age as compared with patients with DOA, who displayed a more stable visual function over the years. Conversely, GCL sectors were overall thinner in patients with DOA since early age compared to patients with WS, in which GCL thickness started to decline later in life. The neuroradiologic subanalysis on 11 patients with WS exhibited bilateral thinning of the anterior optic pathway, especially the prechiasmatic optic nerves and optic tracts. Optic tract thinning was significantly correlated with GCL thickness but not with RNFL parameters.center dot CONCLUSIONS: Our results showed a generally more severe and diffuse degeneration of both anterior and posterior visual pathways in patients with WS, with fast deterioration of visual function and structural OCT parameters since early age. The pattern observed with OCT suggests that retinal ganglion cell axonal degeneration (ie, RNFL) precedes cellular body atrophy (ie, GCL) by about a decade. This differs substantially from DOA, in which a more stable visual function is evident with predominant early loss of GCL, indirectly supporting the lack of a primary mitochondrial dysfunction in patients with WS. (Am J Ophthalmol 2022;241: 206-216. (c) 2022 Elsevier Inc. All rights reserved.)

A quantitative analysis was performed to evaluate the morphologic changes of the retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) in patients with Parkinson's disease (PD).Thirty PD patients were enrolled, and they were allocated to the mild-to-moderate PD group (n = 15) or severe PD group (n = 15) according to the severity of PD. Twenty healthy volunteers (20 eyes) were included as controls. Optical coherence tomography (OCT) was used to measure the thickness of mean RNFL and each of the sectors: temporal-upper (TU), superior-temporal (ST), superior-nasal (SN), nasal-upper (NU), nasal-lower (NL), inferior-nasal (IN), inferior-temporal (IT), temporal-lower (TL). The thickness of macular GCC, superior GCC, and inferior GCC was also measured.No difference was found between the three groups with respect to age, sex and disease course (p 0.05). The mean RNFL thickness was 118.15 ± 10.25 µm in the control group, 96.12 ± 9.45 µm in the mild-to-moderate PD group, and 80.48 ± 10.35 µm in the severe PD group. Significant differences were found in the mean RNFL thickness and thickness of TU, IN, IT and TL sectors among the three groups (p 0.05). These values, mean RNFL, TU, IN, IT, and TL, were lower in both the PD groups than those in the control, among them the severe PD group had the lowest values. A quantitative analysis of the macula GCC was also performed. Overall, there were significant differences in mean macula, superior, and inferior GCC thickness among the three groups (p 0.05). The two PD groups had lower values of mean macula, superior, and inferior GCC thickness than that in the controls (p 0.05); and the severe PD group had lowest values of these parameters.In this study, significant thinning of RNFL and macular GCC was found in PD patients. The more serious the illness, the more the thickness becomes thinner. The OCT measurement was found useful in detecting the structural alterations in the retina of PD. The technique may be useful in follow-up of the disease progression after further validation.

Superior segmental optic nerve hypoplasia (SSONH) is a congenital condition characterized by developmental abnormalities of the superior optic disc and an underappreciated differential diagnosis for glaucoma. The reported prevalence is less than 1%, although likely underestimated due to the difficulties with diagnosis. The exact pathophysiology of SSONH remains elusive, but a mechanism involving developmental attrition of retinal ganglion cells has been proposed, and maternal diabetes is recognized as a major risk factor. SSONH often is observed incidentally, and the patients typically are then evaluated for an acquired optic atrophy, often glaucoma because of the presence of inferior visual field defects. There are 4 characteristic signs of SSONH: superior entrance of the central retinal artery, superior disc pallor, superior peripapillary halo, and thinning of the superior peripapillary nerve fiber layer; however, the presence of these signs is variable. Optical coherence tomography can be helpful in distinguishing SSONH by demonstrating superonasal retinal nerve fiber layer thinning, as compared to the inferotemporal thinning seen in glaucoma, and an aberrant extension of retinal pigment epithelium over Bruch membrane. Overall, the prognosis of SSONH is favorable, with a non-progressive course. It is essential that ophthalmologists recognize and differentiate SSONH from glaucoma to avoid misdiagnosis and unnecessary treatment.

To assess safety of gene therapy in G11778A Leber hereditary optic neuropathy (LHON).Phase 1 clinical trial.Setting: single institution.Patients with G11778A LHON and chronic bilateral visual loss12 months (group 1, n = 11), acute bilateral visual loss12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8).unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3.Best-corrected visual acuity (BCVA), adverse events, and vector antibody responses. Mean follow-up was 24 months (range, 12-36 months); BCVAs were compared with a published prospective natural history cohort with designated surrogate study and fellow eyes.Incident uveitis (8 of 28, 29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose: 5 of 7 (71%) higher-dose eyes vs 3 of 21 (14%) low-, medium-, or high-dose eyes (P.001). Incident uveitis requiring treatment was associated with increased serum AAV2 neutralizing antibody titers (p=0.007) but not serum AAV2 polymerase chain reaction. Improvements of ≥15-letter BCVA occurred in some treated and fellow eyes of groups 1 and 2 and some surrogate study and fellow eyes of natural history subjects. All study eyes (BCVA ≥20/40) in group 3 lost ≥15 letters within the first year despite treatment.G11778A LHON gene therapy has a favorable safety profile. Our results suggest that if there is an efficacy effect, it is likely small and not dose related. Demonstration of efficacy requires randomization of patients to a group not receiving vector in either eye.

To determine if obstructive sleep apnea syndrome (OSAS) predisposes patients to glaucoma and macular disease due to vascular compromise by evaluating retinal and optic nerve vasculature and function using optical coherence tomography angiography and Humphrey visual field testing, respectively.In this prospective, observational, cross-sectional study 45 patients undergoing polysomnography ordered per standard of care were selected and stratified based on apnea-hypopnea index (AHI). Medical history, visual acuity testing, 24-2 Humphrey visual field, intraocular pressure measurement, and optical coherence tomography angiography studies of the macular and peripapillary retina were obtained. Correlations between polysomnography parameters and imaging data were analyzed.The radial peripapillary capillary vascular density demonstrated no relationship to AHI (95% confidence interval [CI] [-0.026,0.038]) or severity of OSAS (95% CI: [-0.772, 3.648]) for moderate OSAS compared to mild/normal and (-1.295, 3.1421) for severe compared to mild/normal. Optical coherence tomography angiography superficial parafoveal vascular density (95% CI: [-0.068,0.011], deep parafoveal vascular density (95% CI: [-0.080,0.009]), and foveal avascular zone (95% CI: [-0.001, 0.001]) showed no statistically significant relationship to AHI or OSAS severity after controlling for confounders. Optical coherence tomography retinal nerve fiber layer thickness increased with AHI (The severity of OSAS did not show a statistically significant effect on parameters associated with glaucoma or macular vascular disease. Larger cohorts may be required to determine the physiologic consequences of OSAS on the macular and optic nerve vasculature, structure, and function.Davanian A, Williamson L, Taylor C, et al. Optical coherence tomography angiography and Humphrey visual field in patients with obstructive sleep apnea.

To investigate longitudinal changes in the retinal and choroidal microstructure of the macula in patients with retinitis pigmentosa (RP).Retrospective, observational cohort study.A total of 69 patients with RP and 69 age- and sex-matched controls who underwent optical coherence tomography (OCT) over a 4-year follow-up period were included. The severity of RP was classified into 3 stages according to the integrity of the inner segment ellipsoid zone. The retinal and choroidal layers were segmented manually from OCT images. The areas of retinal pigment epithelium (RPE) atrophy and choroidal vascular index (CVI) were also analyzed. Longitudinal changes in the OCT parameters were compared among the groups.Significant decreases (median [interquartile range]) in the thickness of the ganglion cell inner plexiform layer (GCIPL; -1.04 [-2.41 to -0.17]), outer nuclear layer (ONL; -1.44 [-1.86 to -0.28]), and inner segment ellipsoid (ISE; -0.74 [-1.33 to -0.49]) at the moderate stage and retinal nerve fiber layer (RNFL; -1.49 [-2.08 to -0.66]) and GCIPL (0.58 [-1.79 to 0.06]) at the advanced stage were observed. Choroidal thickness decreased significantly from -7.62 to -9.40 μm per year at all stages. RPE atrophy and CVI reduction were observed at the advanced stage. There was no change in the control group.ONL and GCIPL thicknesses decreased at the moderate and advanced stages of RP; RNFL thickness decreased only at the advanced stage; and choroidal thickness decreased continuously. In addition, RPE atrophy and CVI reduction were prominent at the advanced stage. These results indicate that there is a temporal variation in the damage of each retinal layer and the choroid in RP patients.

Mice detect decreases in illumination in dim light near the visual threshold with OFF retinal ganglion cells.

Background Several studies have suggested that the retina structure is affected in schizophrenia spectrum disorders (SSD). We aimed to investigate the location and size of the potential differences between patients and healthy controls (HC) in several thickness and volume measures across the retina Study Design We included cross-sectional studies comparing peripapillary retinal nerve fiber layer (pRNFL) thickness, macular volume, macular thickness (MT), foveal thickness, ganglion cell and inner plexiform layer thickness (GCL+IPL), cup volume, and cup/disc ratio (C/D) in the right and/or left eyes and/or the pRNFL and MT quadrants between patients with SSD and HC. Search databases were MEDLINE, Web of Science, PsycINFO, Cochrane Central, and medrxiv.org. Risk of bias was assessed with the Newcastle-Ottawa Scale. Standardized mean differences (SMD), subgroup analysis, and meta-regression with several variables were computed using the dmetar package in R. PROSPERO: CRD42021287873. Study Results Data from 22 reports (942 patients, 742 HC) were included. We found a retinal thinning in pRNFL (−0.30; 95% CI: −0.46, −0.14), macula (−0.37; 95% CI: −0.61, −0.13), and GCL+IPL (−0.33; 95% CI: −0.57, −0.10). The retinal thinning was especially pronounced in the superior and inferior quadrants of the inner ring of the macula. We also observed a decrease of macular volume (−0.44; 95% CI: −0.68, −0.20) and an increase in C/D ratio (0.35; 95% CI: 0.03, 0.67). Conclusions Current evidence demonstrates retinal thinning in SSD, affecting both axonal and cellular structures, specially focused in the inner ring of the macula.

The role of the RNA-binding protein FUS in axonal organisation and disease In this thesis, I discuss the role of the RNA-binding protein Fused in sarcoma (FUS) in axonal organisation and disease. FUS aggregates in forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and ALS-associated mutations change its phase transitions and subcellular localisation. This is known to compromise axonal local protein synthesis (LPS), but it is not well-understood which critical LPS-dependent processes are affected. This is important, as these processes represent potential therapeutic targets. In my work, I built on insights from the field of developmental neurobiology to formulate hypotheses on the physiological consequences of altered FUS phase behaviour. Specifically, I focussed on axonal survival signalling and cytoskeletal remodelling. I tested these hypotheses using the Xenopus laevis retinal ganglion cell (RGC) model system, which is an established model system for combining in vitro and in vivo studies into LPS-dependent axonal properties. First, I studied the effect of FUS mutation on LPS of axonal survival-associated proteins, as changes in the local activity of these could be linked directly to axonal degeneration. I focussed on the essential axonal survival factor nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), as its mRNA is a potential FUS binding target. I hypothesised that axonal NMNAT2 levels are sustained by LPS, as this protein is known to have a very short half-life. However, by combining in situ hybridisation and quantitative PCR approaches, I found that nmnat2 mRNA does not localise to RGC axons, falsifying this hypothesis. Therefore, I shifted the focus of my research to axonal cytoskeletal reorganisation, as this is known to be regulated by LPS, and ALS is associated with mutations in cytoskeleton-linked genes. I next hypothesised that reorganisation of the axonal cytoskeleton is compromised by mutant FUS, as this process is strongly LPS-dependent, and so studied the dynamic axon terminal. I used two previously reported ALS/FTD X. laevis models: the juvenile ALS-associated nuclear localisation signal mutant FUS(P525L) and an artificial FTD-mimic of hypomethylated FUS, FUS(16R). Mutant FUS compromised the actin cytoskeleton of the growth cone in vitro, resulting in considerable changes in growth cone mechanoproperties. This occurred without detectable reductions in axonal microtubule density or RNA transport function, indicating this defect may be specific to the dynamic actin cytoskeleton. However, axonal cytoskeletal organisation is dependent on local cues in vivo, and ALS is considered a non-cell-autonomous disease. Therefore, I subsequently studied whether this actin change correlates with in vivo phenotypes, hypothesising that mutant FUS would compromise actin-dependent axon branching in vivo. Mutant FUS indeed reduced axon complexity in vivo, and FUS(P525L) additionally induced axon looping, pointing to the occurrence of signalling defects. This loss of branching complexity has implications for synaptic connectivity, changes in which are a key feature of neurological disorders. Therefore, altered actin remodelling could be a central phenotype on which multiple pathomechanisms associated with ALS/FTD converge. These results have wider conceptual implications for our understanding of the nature of ALS/FTD. In particular, the present work demonstrates that mutant FUS-associated changes to axonal organisation can occur early in development already, which supports the emerging concept that neurodevelopmental and neurodegenerative diseases may have overlapping molecular players and may therefore share aspects of pathomechanisms. I conclude this thesis by discussing how mutant FUS-induced developmental phenotypes may be connected to onset of symptoms in adolescence or adulthood, and which future research directions emerge from this perspective. Francesca Wilhelmina van Tartwijk December 2022

Retinal ischemia–reperfusion (IR)—which ultimately results in retinal ganglion cell (RGC) death—is a common cause of visual impairment and blindness worldwide. IR results in various types of programmed cell death (PCD), which are of particular importance since they can be prevented by inhibiting the activity of their corresponding signaling cascades. To study the PCD pathways in ischemic RGCs, we used a mouse model of retinal IR and a variety of approaches including RNA-seq analysis, knockout animals, and animals treated with an iron chelator. In our RNA-seq analysis, we utilized RGCs isolated from retinas 24 h after IR. In ischemic RGCs, we found increased expression of many genes that regulate apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos. Our data indicate that genetic ablation of death receptors protects RGCs from IR. We showed that the signaling cascades regulating ferrous iron (Fe2+) metabolism undergo significant changes in ischemic RGCs, leading to retinal damage after IR. This data suggests that the activation of death receptors and increased Fe2+ production in ischemic RGCs promote the simultaneous activation of apoptosis, necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos pathways. Thus, a therapy is needed that concurrently regulates the activity of the multiple PCD pathways to reduce RGC death after IR.

p58IPK is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58IPK leads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58IPK in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58IPK using conditional knockout (cKO) mouse lines where p58IPK is deleted in retinal neurons (Chx10-p58IPK cKO) or in myeloid cells (Lyz2-p58IPK cKO). In addition, we overexpressed p58IPK by adeno-associated virus (AAV) in the retina to examine the effect of p58IPK on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58IPK by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58IPK on reducing RGC injury. Conditional knockout of p58IPK in retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58IPK cKO mice. Deletion of p58IPK in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58IPK in myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58IPK in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58IPK is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58IPK specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.

A-Kinase anchoring protein 1 (AKAP1) is a multifunctional mitochondrial scaffold protein that regulates mitochondrial dynamics, bioenergetics, and calcium homeostasis by anchoring several proteins, including protein kinase A, to the outer mitochondrial membrane. Glaucoma is a complex, multifactorial disease characterized by a slow and progressive degeneration of the optic nerve and retinal ganglion cells (RGCs), ultimately resulting in vision loss. Impairment of the mitochondrial network and function is linked to glaucomatous neurodegeneration. Loss of AKAP1 induces dynamin-related protein 1 dephosphorylation-mediated mitochondrial fragmentation and loss of RGCs. Elevated intraocular pressure triggers a significant reduction in AKAP1 protein expression in the glaucomatous retina. Amplification of AKAP1 expression protects RGCs from oxidative stress. Hence, modulation of AKAP1 could be considered a potential therapeutic target for neuroprotective intervention in glaucoma and other mitochondria-associated optic neuropathies. This review covers the current research on the role of AKAP1 in the maintenance of mitochondrial dynamics, bioenergetics, and mitophagy in RGCs and provides a scientific basis to identify and develop new therapeutic strategies that could protect RGCs and their axons in glaucoma.

With high specificity and less variability than perimetry, more frequent testing resulted in shorter time to detect progression, though a 6-month testing interval provides a reasonable trade-off for following glaucoma patients using optical coherence tomography (OCT).To investigate the time to detect progression in glaucomatous eyes using different OCT test intervals.Participants with manifest glaucoma from the African Descent and Glaucoma Evaluation Study (ADAGES), a multicenter, prospective, observational cohort study, were included. A total of 2699 OCT tests from 171 glaucomatous and 149 normal eyes of 182 participants, with at least 5 tests and 2 years of follow-up, were analyzed. Computer simulations (n=10,000 eyes) were performed to estimate time to detect progression of global circumpapillary retinal nerve fiber layer thickness (cpRNFL) measured with OCT tests. Simulations were based on different testing paradigms (every 4, 6, 12, and 24 mo) and different rates of change (µm/year). Time to detect significant progression ( P0.05) at 80% and 90% power were calculated for each paradigm and rate of cpRNFL change.As expected, more frequent testing resulted in shorter time to detect progression. Although there was clear disadvantage for testing at intervals of 24 versus 12 months (~22.4% time [25 mo] increase in time to progression detection) and when testing 12 versus 6 months (~22.1% time [20 mo] increase), the improved time to detect progression was less pronounced when comparing 6 versus 4 months (~11.5% time [10 mo] reduction).With high specificity and less variability than perimetry, a 6-month testing interval provides a reasonable trade-off for following glaucoma patients using OCT.

An appropriate sensory experience during the early developmental period is important for brain maturation. Dark rearing during the visual critical period delays the maturation of neuronal circuits in the visual cortex. Although the formation and structural plasticity of the myelin sheaths on retinal ganglion cell axons modulate the visual function, the effects of dark rearing during the visual critical period on the structure of the retinal ganglion cell axons and their myelin sheaths are still unclear. To address this question, mice were reared in a dark box during the visual critical period and then normally reared to adulthood. We found that myelin sheaths on the retinal ganglion cell axons of dark-reared mice were thicker than those of normally reared mice in both the optic chiasm and optic nerve. Furthermore, whole-mount immunostaining with fluorescent axonal labeling and tissue clearing revealed that the myelin internodal length in dark-reared mice was shorter than that in normally reared mice in both the optic chiasm and optic nerve. These findings demonstrate that dark rearing during the visual critical period affects the morphology of myelin sheaths, shortens and thickens myelin sheaths in the visual pathway, despite the mice being reared in normal light/dark conditions after the dark rearing.

The pathological basis of optic nerve crush (ONC) is the apoptosis of retinal ganglion cells (RGCs), which leads to an irreversible impairment of visual function. When stimulated by external stimuli, microglia polarize into different types and play different roles in repairing retinal injury. In this study, gadolinium chloride (GdCl

Major depressive disorder (MDD) is linked to degenerative and inflammatory processes in the brain. The retina, as well as the brain, originates from the ectoderm. The changes in the retina that occur in concert with MDD and sleep quality are not very clear. This study aimed to detect changes in the retinal nerve fibre layer (RNFL) and macular thickness in Chinese patients in correlation with MDD and sleep quality.Thirty-six MDD patients and 187 age- and sex-matched healthy controls were enrolled in this study. All subjects were scanned by spectral-domain optical coherence tomography (OCT) and completed the Stroop Colour-Word Test (SCWT), Pittsburgh Sleep Quality Index, and Patient Health Questionnaire-9.The RNFL and macular thickness were significantly thinner and disc-area enlargement of the right eye and cup-volume enlargement of both eyes were present in MDD patients. Linear regression analysis revealed that the RNFL and macular thickness in patients with MDD were correlated with sleep quality and the severity of depression. SCWT scores were higher following expansion of the cup volume of the right eye (all p 0.01) and in correlation with larger disc areas.Serious degrees of depression and insomnia in MDD patients may reflect obvious atrophy of the inner and outer rings of the right macula and enlargement of the optic disc in both eyes. These retinal structural changes might influence the visual cognition of patients with MDD.

To study orthograde axonal transport with amyloid precursor protein (APP-A4) immunohistochemistry (IHC) in the retina and lamina cribrosa (LC) portion of the optic nerve in abusive head trauma (AHT) suspects.Retrospective, case-control study.Seventy-two eyes from suspected AHT victims referred by the Los Angeles Coroner and control eyes from nontraumatized infants were included. IHC was conducted using University of California, Irvine (UCI), Lab Medicine Department's standard protocol and results analyzed by light microcopy after paraffin processing. Quantitation of LC APP-A4 block was estimated in 21 cases with known survival using MetaMorph, a proprietary biomicroscopy imaging software.The presence or absence of APP-A4 label accumulations in retinal ganglion cells, nerve fiber layer at the disc margin, and in LC axonal bundles were compared to matching tissues from nontraumatized control eyes with only background staining. Among the globes from AHT suspects with nerve heads available for study, 94% were positive for LC accumulation of marker. Among suspect AHT cases with known survival after injury of 1 to 1588 days, most demonstrated LC APP-A4 accumulations.Our findings reinforce a recent publication based on APP-A4 IHC that demonstrated similar orthograde axonal transport block in the LC in children with AHT and recommend that intraocular pressures be recorded and addressed in these patients.

PURPOSE: Reflectance of retinal nerve fibre layer (RNFL) can contribute to detecting the presence of glaucomatous damage and defining its extent. As a step towards developing a normative database for RNFL reflectance, we assessed within-eye and between-subject variability for RNFL reflectance in healthy eyes. METHODS: Vertical 30° x 15° volume scans at the optic disc were gathered using SD-OCT (Spectralis OCT) from people free of eye disease. Scans were gathered for both eyes of 30 younger adults (mean ± SD = 27 ± 3 years) and for one eye of 30 older adults (68 ± 8 years). Reflectance was quantified for each voxel as the depth-resolved attenuation coefficient (AC). Values for AC were extracted for four slabs (0-52 μm, 24-52 μm, 24-36 μm and 36-60 μm) and at depths from 24-60 μm below the inner limiting membrane (ILM) in 4 μm steps. RESULTS: Between-subject and within-eye standard deviations (SD) for the logarithm of AC were similar; median differences were 0.02-0.03 log unit across all four slabs and depths from 24-48 μm. Means for the logarithm of AC were higher for younger than older eyes by ~0.1 log unit; this age effect was not due to differences in the raw reflectance of the RNFL, but rather to age-related changes in reflectance of deeper retina affecting the calculation of AC. CONCLUSIONS: In both groups, within-eye variability in RNFL reflectance near the optic disc was similar to between-subject variability. A better understanding of within-eye variability would be useful for developing normative databases.

The purpose of this study was to determine changes in optical coherence tomography (OCT) color codes after applying a myopic normative database. The diagnostic performance of the retinal nerve fiber layer analysis improved with the use of this database.To evaluate the peripapillary retinal nerve fiber layer (pRNFL) OCT color codes based on a newly generated myopic normative database in comparison to the built-in normative database.A total of 371 subjects were included in this validation study in an attempt to generate a myopic normative database. Eighty myopic glaucomatous and 80 myopic healthy eyes were evaluated to determine the diagnostic performance of this database. The distribution of the color codes was investigated among the groups with reference to the built-in and myopic normative databases, and the 2 databases were compared in terms of abnormal color code frequency. The diagnostic performance of the myopic database was presented with sensitivity, specificity and area under the receiver operating characteristic curve values.The agreement between the databases decreased with increasing myopia degree. The distribution of the color codes of the built-in software significantly differed among the study groups in all sectors ( P =0.009 for the temporal sector and P0.001 for the remaining sectors). When the myopic database was used, there were no longer significant differences among the groups for the temporosuperior, temporoinferior, temporal, and nasal sectors ( P =0.561, 0.299, 0.201, and 0.089, respectively). After applying the myopic normative database, the specificity of the pRNFL color codes increased from 70.1% to 90.2%, and the area under the receiver operating characteristic curve value from 0.851 to 0.945.The use of a myopic normative database for pRNFL using SD-OCT significantly decreased differences among myopia severity groups, and may help to more reliably assess glaucoma in myopic eyes.

Relay neurons of the dorsal lateral geniculate nucleus (dLGN) receive inputs from retinal ganglion cells via retinogeniculate synapses. These connections undergo pruning in the first 2 weeks after eye opening. The remaining connections are strengthened several-fold by the insertion of AMPA receptors (AMPARs) into weak or silent synapses. In this study, we found that the AMPAR auxiliary subunit CKAMP44 is required for receptor insertion and function of retinogeniculate synapses during development. Genetic deletion of CKAMP44 resulted in decreased synaptic strength and a higher number of silent synapses in young (P9-11) mice. Recovery from desensitisation of AMPARs was faster in CKAMP44 knockout (CKAMP44

To compare outer macular and retinal thickness in the circumpapillary area in unilateral advanced glaucomatous eyes to the normal or mild glaucomatous fellow eyes.Seventy-eight eyes of 39 patients with unilateral advanced glaucoma (mean deviation (MD) worse than -12.00 dB based on visual field 24-2) were included in this cross-sectional study as the cases. The healthy or mild glaucomatous fellow eyes were enrolled as the control group. All eyes underwent optical coherence tomography of the macula and circumpapillary retina by Topcon DRI Triton (Topcon, Tokyo, Japan). Ganglion cell layer 2+ was considered as the inner retina. Total retinal thickness minus the thickness of the inner retina was considered as the outer retina. Comparison between groups was done by paired-sample sign test. The correlation between structural and functional parameters was evaluated by a partial correlation coefficient.Seventeen (43.6%), 15 (38.5%), and 7 (17.9%) patients had pseudoexfoliation, primary angle-closure, and primary open-angle glaucoma, respectively. The mean age was 62.69 ± 12.00 years. Thirty-three (84.6%) patients were male. The outer retinal thickness in the circumpapillary area was higher in temporal, superior, and inferior quadrants (p0.05). The outer macula in different parafoveal and perifoveal quadrants was also thicker (p0.05). Average outer parafoveal thickness in the case group had a significant negative correlation with MD (r = -0.339; p = 0.035).Advanced glaucomatous eyes had a thicker outer retina in the macula and circumpapillary area. There was a significant negative correlation between outer perifoveal thickness and MD.

Senile glaucoma is a common ophthalmological disease in the elderly. It is a disease of visual papillary perfusion caused by elevated intraocular pressure, complicated by visual dysfunction. Glaucoma can cause serious damage to the normal vision of the elderly. Therefore, exploring the related molecular mechanisms of glaucoma is of great significance to the diagnosis and treatment of glaucoma. This is an exploratory study. Establish a mouse model and conduct experimental groupings. After one week of adaptive feeding, the mice were intraperitoneally injected with an anesthetic mixture: ketamine + xylazine. Then the mice were sacrificed by neck dissection, and the eyeball tissues were immediately dissected. HE staining was used to analyze the histopathological characteristics of the retina of each group of mice. MitoSOX fluorescent probe was used to analyze the content of ROS in retinal tissue. The ELISA analysis was used to detect the activation of β-galactosidase for the aging characteristics of retinal ganglion cells in retinal tissues. Immunohistochemistry experiments were used to analyze the expression of telomerase TERT in retinal tissues. Western blot analysis was used to determine the expression of proteins POT1, TERF1, TERF2, and TINF2 in retinal tissues. The HE staining experiment showed that the damage of retinal tissue decreased from group Glaucoma to group Old, group Old to group Young. The experimental results of MitoSOX fluorescent probe show that ROS content is positively correlated with the degree of tissue damage. ELISA analysis results showed that the expression trend of β-galactosidase was the same as the ROS content. The protein expression levels related to telomere protection (TRET, POT1, TREF1, TREF2 and TINF2) all increased from group Glaucoma to group Old, group Old to group Young. The increase in ROS content, the decrease in telomere protection-related protein expression (telomere shortening) induced by ROS, and the increase of the expression of β-galactosidase, are all potential molecular mechanisms for the occurrence of angle-closure glaucoma in elderly patients.

Glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell degeneration and visual field loss, is the leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is presently the only modifiable risk factor demonstrated to slow or halt disease progression; however, glaucomatous damage persists in almost 50% of patients despite significant IOP reduction. Many studies have investigated the non-IOP-related risk factors that contribute to glaucoma progression as well as interventions that can prevent or delay glaucomatous neurodegeneration and preserve vision throughout life, independently of IOP. A vast number of experimental studies have reported effective neuroprotection in glaucoma, and clinical studies are ongoing attempting to provide strong evidence of effectiveness of these interventions. We look into the current understanding of the pathophysiology of glaucoma and explore the recent advances in non-IOP related strategies for neuroprotection and neuroregeneration in glaucoma.

Although the degeneration of retinal ganglion cells (RGCs) is a primary characteristic of glaucoma, astrocytes also contribute to their neurodegeneration in disease states. Although studies often explore cell-autonomous aspects of RGC neurodegeneration, a more comprehensive model of glaucoma should take into consideration interactions between astrocytes and RGCs. To explore this concept, RGCs and astrocytes were differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated OPTN(E50K) mutation along with corresponding isogenic controls. Initial results indicated significant changes in OPTN(E50K) astrocytes, including evidence of autophagy dysfunction. Subsequently, co-culture experiments demonstrated that OPTN(E50K) astrocytes led to neurodegenerative properties in otherwise healthy RGCs, while healthy astrocytes rescued some neurodegenerative features in OPTN(E50K) RGCs. These results are the first to identify disease phenotypes in OPTN(E50K) astrocytes, including how their modulation of RGCs is affected. Moreover, these results support the concept that astrocytes could offer a promising target for therapeutic intervention in glaucoma.

Detecting the direction of motion underlies many visually guided behaviors, from reflexive eye movements to identifying and catching moving objects. A subset of motion sensitive cells are direction selective - responding strongly to motion in one direction and weakly to motion in other directions. In mammals, direction-selective cells are found throughout the visual system, including the retina, superior colliculus, and primary visual cortex. Direction selectivity maps are well characterized in the mouse retina, where the preferred directions of retinal direction-selective cells follow the projections of optic flow, generated by the movements animals make as they navigate their environment. Here, we synthesize recent findings implicating activity-dependent mechanisms in the development of retinal direction selectivity maps, with primary focus on studies in mice, and discuss the implications for the development of direction-selective responses in downstream visual areas.