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While Alzheimers disease and other neurodegenerative diseases have traditionally been viewed as brain disorders, there is growing evidence indicating their manifestation in the eyes as well. The retina, being a developmental extension of the brain, represents the only part of the central nervous system that can be noninvasively imaged at a high spatial resolution. The discovery of the specific pathological hallmarks of Alzheimers disease in the retina of patients holds great promise for disease diagnosis and monitoring, particularly in the early stages where disease progression can potentially be slowed. Among various retinal imaging methods, hyperspectral imaging has garnered significant attention in this field. It offers a label-free approach to detect disease biomarkers, making it especially valuable for large-scale population screening efforts. In this review, we discuss recent advances in the field and outline the current bottlenecks and enabling technologies that could propel this field toward clinical translation.

To investigate the variability in subthreshold laser treatment plans for patients with diabetic macular edema or central serous chorioretinopathy. Diagnostic images from 20 patients were utilized, and 25 retina specialists generated subthreshold treatment plans along with a self-rated experience level. Evaluation comprised of i) Area Variability (AV): quantifies the consensus regarding the covered area and is the difference between the areas planned by 75% and 25% of the participants ii) mean Centroid Distance (CD): level of agreement on the localization of a treatment. Subgroup analysis investigated the impact of participants experience levels, utilizing the Mann-Whitney-Wilcoxon test. The predominant plan style is a targeted treatment approach (92%) and avoidance of subfoveal region (89%). Mean CD is 71.0 ± 37.5 pixels (≈half disc diameter) and mean AV is 9.8%±8.9%. A slight difference is observed between the 50-75% areas, but a notable distinction exists between the 25-50% areas. Subgroup analysis revealed CD and AV value of 75.9 pixels and 24% in the lower experience level group as opposed to 55.9 pixels and 8.6% in the higher experience level group. There is significant variability in treatment planning which reduces with increased experience of retina specialists. While consensus is observed around focal points, differences in the surrounding extents persist.

The preferred retinal locus (PRL) is the position on the retina to which humans direct stimuli during fixation. In healthy normal eyes, it has been shown to be very stable across time and between different tasks. Previous measurements of the PRL have been made under monocular viewing conditions. The current study examines where the PRLs in the two eyes retinas are when subjects fixate binocularly and whether they shift when the demand for the eyes to converge is changed. Our apparatus allows us to see exactly where binocular stimuli fell on the two retinas during binocular fixation. Thus, our technique bypasses some of the issues involved in measuring binocular alignment with subjective techniques and previous objective techniques that use conventional eye trackers. These results show that PRLs shift slightly but systematically as the demand for convergence increases. The shifts cause under-convergence (also called exo fixation disparity) for near targets. They are not large enough to cause a break in binocular fusion. The fixation disparity we observed with increasing vergence demand is similar to fixation disparity observed in previous reports.

The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

Photoreceptor degeneration is a major cause of untreatable blindness worldwide and has recently been targeted by emerging technologies, including cell- and gene-based therapies. Cell types of neural lineage have shown promise for replacing either photoreceptors or retinal pigment epithelial cells following delivery to the subretinal space, while cells of bone marrow lineage have been tested for retinal trophic effects following delivery to the vitreous cavity. Here we explore an alternate approach in which cells from the immature neural retinal are delivered to the vitreous cavity with the goal of providing trophic support for degenerating photoreceptors. Rat and human retinal progenitor cells were transplanted to the vitreous of rats with a well-studied photoreceptor dystrophy, resulting in substantial anatomical preservation and functional rescue of vision. This work provides scientific proof-of-principle for a novel therapeutic approach to photoreceptor degeneration that is currently being evaluated in clinical trials.

Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson's disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases.

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimers disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ42 and arterial Aβ40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

Adaptation is a universal aspect of neural systems that changes circuit computations to match prevailing inputs. These changes facilitate efficient encoding of sensory inputs while avoiding saturation. Conventional artificial neural networks (ANNs) have limited adaptive capabilities, hindering their ability to reliably predict neural output under dynamic input conditions. Can embedding neural adaptive mechanisms in ANNs improve their performance? To answer this question, we develop a new deep learning model of the retina that incorporates the biophysics of photoreceptor adaptation at the front-end of conventional convolutional neural networks (CNNs). These conventional CNNs build on 'Deep Retina,' a previously developed model of retinal ganglion cell (RGC) activity. CNNs that include this new photoreceptor layer outperform conventional CNN models at predicting male and female primate and rat RGC responses to naturalistic stimuli that include dynamic local intensity changes and large changes in the ambient illumination. These improved predictions result directly from adaptation within the phototransduction cascade. This research underscores the potential of embedding models of neural adaptation in ANNs and using them to determine how neural circuits manage the complexities of encoding natural inputs that are dynamic and span a large range of light levels.

Detailed binding experiments reveal new insights into the Norrin/Wnt signaling pathway that helps to control vascularization in the retina.

Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration. This study explores the effects of AdipoR1 gene deficiency in mice, revealing a striking decline in ω3 polyunsaturated fatty acids (PUFA), an increase in ω6 fatty acids, and elevated ceramides in the retina. The AdipoR1 deficiency impairs peroxisome proliferator-activated receptor α signaling, which is crucial for FA metabolism, particularly affecting proteins associated with FA transport and oxidation in the retina and retinal pigmented epithelium. Our lipidomic and proteomic analyses indicate changes that could affect membrane composition and viscosity through altered ω3 PUFA transport and synthesis, suggesting a potential influence of AdipoR1 on these properties. Furthermore, we noted a reduction in the Bardet-Biedl syndrome proteins, which are crucial for forming and maintaining photoreceptor outer segments that are PUFA-enriched ciliary structures. Diminution in Bardet-Biedl syndrome-proteins content combined with our electron microscopic observations raises the possibility that AdipoR1 deficiency might impair ciliary function. Treatment with inhibitors of ceramide synthesis led to substantial elevation of ω3 LC-PUFAs, alleviating photoreceptor degeneration and improving retinal function. These results serve as the proof of concept for a ceramide-targeted strategy to treat retinopathies linked to PUFA deficiency, including age-related macular degeneration.

An organizational feature of neural circuits is the specificity of synaptic connections. A striking example is the direction-selective (DS) circuit of the retina. There are multiple subtypes of DS retinal ganglion cells (DSGCs) that prefer motion along one of four preferred directions. This computation is mediated by selective wiring of a single inhibitory interneuron, the starburst amacrine cell (SAC), with each DSGC subtype preferentially receiving input from a subset of SAC processes. We hypothesize that the molecular basis of this wiring is mediated in part by unique expression profiles of DSGC subtypes. To test this, we first performed paired recordings from isolated mouse retinas of both sexes to determine that postnatal day 10 (P10) represents the age at which asymmetric synapses form. Second, we performed RNA sequencing and differential expression analysis on isolated P10 ON-OFF DSGCs tuned for either nasal or ventral motion and identified candidates which may promote direction-specific wiring. We then used a conditional knock-out strategy to test the role of one candidate, the secreted synaptic organizer cerebellin-4 (Cbln4), in the development of DS tuning. Using two-photon calcium imaging, we observed a small deficit in directional tuning among ventral-preferring DSGCs lacking Cbln4, though whole-cell voltage-clamp recordings did not identify a significant change in inhibitory inputs. This suggests that Cbln4 does not function primarily via a cell-autonomous mechanism to instruct wiring of DS circuits. Nevertheless, our transcriptomic analysis identified unique candidate factors for gaining insights into the molecular mechanisms that instruct wiring specificity in the DS circuit.

Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns of spiking in retinal ganglion cells (RGCs) in response to electrical stimulation, but less work has examined the underlying retinal circuitry that is activated by electrical stimulation to drive these responses. Surprisingly, little is known about the role of inhibition in generating electrical responses or how inhibition might be altered during degeneration. Using whole-cell voltage-clamp recordings during subretinal electrical stimulation in the rd10 and wild-type (wt) retina, we found electrically evoked synaptic inputs differed between ON and OFF RGC populations, with ON cells receiving mostly excitation and OFF cells receiving mostly inhibition and very little excitation. We found that the inhibition of OFF bipolar cells limits excitation in OFF RGCs, and a majority of both pre- and postsynaptic inhibition in the OFF pathway arises from glycinergic amacrine cells, and the stimulation of the ON pathway contributes to inhibitory inputs to the RGC. We also show that this presynaptic inhibition in the OFF pathway is greater in the rd10 retina, compared with that in the wt retina.

Because derivation of retinal organoids (ROs) and transplantation are frequently split between geographically distant locations, we developed a special shipping device and protocol capable of the organoids' delivery to any location. Human embryonic stem cell (hESC)-derived ROs were differentiated from the hESC line H1 (WA01), shipped overnight to another location, and then transplanted into the subretinal space of blind immunodeficient retinal degeneration (RD) rats. Development of transplants was monitored by spectral-domain optical coherence tomography. Visual function was accessed by optokinetic tests and superior colliculus (SC) electrophysiology. Cryostat sections through transplants were stained with hematoxylin and eosin; or processed for immunohistochemistry to label human donor cells, retinal cell types, and synaptic markers. After transplantation, ROs integrated into the host RD retina, formed functional photoreceptors, and improved vision in rats with advanced RD. The survival and vision improvement are comparable with our previous results of hESC-ROs without a long-distance delivery. Furthermore, for the first time in the stem cell transplantation field, we demonstrated that the response heatmap on the SC showed a similar shape to the location of the transplant in the host retina, which suggested the point-to-point projection of the transplant from the retina to SC. In conclusion, our results showed that using our special device and protocol, the hESC-derived ROs can be shipped over long distance and are capable of survival and visual improvement after transplantation into the RD rats. Our data provide a proof-of-concept for stem cell replacement as a therapy for RD patients.

The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mutant analyses revealed that Pten and Down syndrome cell adhesion molecule Dscam) are co-expressed and function additively to pattern starburst amacrine cell mosaics. Mechanistically, Pten loss accelerates the endocytic trafficking of DSCAM, FAT3, and MEGF10 off the cell membrane and into endocytic vesicles in amacrine cells. Accordingly, the vesicular proteome, a molecular signature of the cell of origin, is enriched in exocytosis, vesicle-mediated transport, and receptor internalization proteins in Pten conditional knockout (PtencKO) retinas. Wnt signaling molecules are also enriched in PtencKO retinal vesicles, and the genetic or pharmacological disruption of Wnt signaling phenocopies amacrine cell patterning defects. Pten thus controls vesicular trafficking of cell adhesion and signaling molecules to establish retinal amacrine cell mosaics.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Glaucoma leads to vision loss due to retinal ganglion cell death. Astrocyte reactivity contributes to neurodegeneration. Our recent study found that lipoxin B4 (LXB4), produced by retinal astrocytes, has direct neuroprotective actions on retinal ganglion cells. In this study, we aimed to investigate how the autacoid LXB4 influences astrocyte reactivity in the retina under inflammatory cytokine-induced activation and during ocular hypertension. The protective activity of LXB4 was investigated in vivo using the mouse silicone-oil model of chronic ocular hypertension. By employing a range of analytical techniques, including bulk RNA-seq, RNAscope in-situ hybridization, qPCR, and lipidomic analyses, we discovered the formation of lipoxins and expression of the lipoxin pathway in rodents (including the retina and optic nerve), primates (optic nerve), and human brain astrocytes, indicating the presence of this neuroprotective pathway across various species. Findings in the mouse retina identified significant dysregulation of the lipoxin pathway in response to chronic ocular hypertension, leading to an increase in 5-lipoxygenase (5-LOX) activity and a decrease in 15-LOX activity. This dysregulation was coincident with a marked upregulation of astrocyte reactivity. Reactive human brain astrocytes also showed a significant increase in 5-LOX. Treatment with LXB4 amplified the lipoxin biosynthetic pathway by restoring and amplifying the generation of another member of the lipoxin family, LXA4, and mitigated astrocyte reactivity in mouse retinas and human brain astrocytes. In conclusion, the lipoxin pathway is functionally expressed in rodents, primates, and human astrocytes, and is a resident neuroprotective pathway that is downregulated in reactive astrocytes. Novel cellular targets for LXB4s neuroprotective action are inhibition of astrocyte reactivity and restoration of lipoxin generation. Amplifying the lipoxin pathway is a potential target to disrupt or prevent astrocyte reactivity in neurodegenerative diseases, including retinal ganglion cell death in glaucoma.

PURPOSE: To describe and evaluate a novel method to determine the validity of measurements made using cycle-by-cycle (CxC) recording techniques in patients with advanced retinal degenerations (RD) having low-amplitude flicker electroretinogram (ERG) responses. METHODS: The method extends the original CxC recording algorithm introduced by Sieving et al., retaining the original recording setup and the preliminary analysis of raw data. Novel features include extended use of spectrum analysis, reduction of errors due to known sources, and a comprehensive statistical assessment using three different tests. The method was applied to ERG recordings from seven patients with RD and two patients with CNGB3 achromatopsia. RESULTS: The method was implemented as a Windows application to processes raw data obtained from a commercial ERG system, and it features a computational toolkit for statistical assessment of ERG recordings with amplitudes as low as 1 µV, commonly found in advanced RD patients. When recorded using conditions specific for eliciting cone responses, none of the CNGB3 patients had a CxC validated response, indicating that no signal artifacts were present with our recording conditions. A comparison of the presented method with conventional 30 Hz ERG was performed. Bland-Altman plots indicated good agreement (mean difference, -0.045 µV; limits of agreement, 0.193 to -0.282 µV) between the resulting amplitudes. Within-session test-retest variability was 15%, comparing favorably to the variability of standard ERG amplitudes. CONCLUSIONS: This novel method extracts highly reliable clinical recordings of low-amplitude flicker ERGs and effectively detects artifactual responses. It has potential value both as a cone outcome variable and planning tool in clinical trials on natural history and treatment of advanced RDs.

PurposeThis study aimed to compare a new Artificial Intelligence (AI) method to conventional mathematical warping in accurately overlaying peripheral retinal vessels from two different imaging devices: confocal scanning laser ophthalmoscope (cSLO) wide-field images and SLO ultra-wide field images.MethodsImages were captured using the Heidelberg Spectralis 55-degree field-of-view and Optos ultra-wide field. The conventional mathematical warping was performed using Random Sample Consensus-Sample and Consensus sets (RANSAC-SC). This was compared to an AI alignment algorithm based on a one-way forward registration procedure consisting of full Convolutional Neural Networks (CNNs) with Outlier Rejection (OR CNN), as well as an iterative 3D camera pose optimization process (OR CNN + Distortion Correction [DC]). Images were provided in a checkerboard pattern, and peripheral vessels were graded in four quadrants based on alignment to the adjacent box.ResultsA total of 660 boxes were analysed from 55 eyes. Dice scores were compared between the three methods (RANSAC-SC/OR CNN/OR CNN + DC): 0.3341/0.4665/4784 for fold 1-2 and 0.3315/0.4494/4596 for fold 2-1 in composite images. The images composed using the OR CNN + DC have a median rating of 4 (out of 5) versus 2 using RANSAC-SC. The odds of getting a higher grading level are 4.8 times higher using our OR CNN + DC than RANSAC-SC (p

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Information about motion is encoded by direction-selective retinal ganglion cells (DSGCs). These cells reliably transmit this information across a broad range of light levels, spanning moonlight to sunlight. Previous work indicates that adaptation to low light levels causes heterogeneous changes to the direction tuning of ON-OFF (oo)DSGCs and suggests that superior-preferring ON-OFF DSGCs (s-DSGCs) are biased toward detecting stimuli rather than precisely signaling direction. Using a large-scale multielectrode array, we measured the absolute sensitivity of ooDSGCs and found that s-DSGCs are 10-fold more sensitive to dim flashes of light than other ooDSGCs. We measured their receptive field (RF) sizes and found that s-DSGCs also have larger receptive fields than other ooDSGCs; however, the size difference does not fully explain the sensitivity difference. Using a conditional knock-out of gap junctions and pharmacological manipulations, we demonstrate that GABA-mediated inhibition contributes to the difference in absolute sensitivity and receptive field size at low light levels, while the connexin36-mediated gap junction coupling plays a minor role. We further show that under scotopic conditions, ooDSGCs exhibit only an ON response, but pharmacologically removing GABA-mediated inhibition unmasks an OFF response. These results reveal that GABAergic inhibition controls and differentially modulates the responses of ooDSGCs under scotopic conditions.

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.

DNA methylation provides a crucial epigenetic mark linking genetic variations to environmental influence. We have analyzed array-based DNA methylation profiles of 160 human retinas with co-measured RNA-seq and >8 million genetic variants, uncovering sites of genetic regulation in cis (37,453 methylation quantitative trait loci and 12,505 expression quantitative trait loci) and 13,747 DNA methylation loci affecting gene expression, with over one-third specific to the retina. Methylation and expression quantitative trait loci show non-random distribution and enrichment of biological processes related to synapse, mitochondria, and catabolism. Summary data-based Mendelian randomization and colocalization analyses identify 87 target genes where methylation and gene-expression changes likely mediate the genotype effect on age-related macular degeneration. Integrated pathway analysis reveals epigenetic regulation of immune response and metabolism including the glutathione pathway and glycolysis. Our study thus defines key roles of genetic variations driving methylation changes, prioritizes epigenetic control of gene expression, and suggests frameworks for regulation of macular degeneration pathology by genotype-environment interaction in retina.

The retina and primary visual cortex (V1) both exhibit diverse neural populations sensitive to diverse visual features. Yet it remains unclear how neural populations in each area partition stimulus space to span these features. One possibility is that neural populations are organized into discrete groups of neurons, with each group signaling a particular constellation of features. Alternatively, neurons could be continuously distributed across feature-encoding space. To distinguish these possibilities, we presented a battery of visual stimuli to the mouse retina and V1 while measuring neural responses with multi-electrode arrays. Using machine learning approaches, we developed a manifold embedding technique that captures how neural populations partition feature space and how visual responses correlate with physiological and anatomical properties of individual neurons. We show that retinal populations discretely encode features, while V1 populations provide a more continuous representation. Applying the same analysis approach to convolutional neural networks that model visual processing, we demonstrate that they partition features much more similarly to the retina, indicating they are more like big retinas than little brains.

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

PURPOSE: To compare optical coherence tomography angiography (OCTA) retina metrics between cognitively healthy subjects with pathological versus normal cerebrospinal fluid (CSF) Aβ42/tau ratios. METHODS: Swept-source OCTA scans were collected using the Zeiss PLEX Elite 9000 and analyzed on 23 cognitively healthy (CH) subjects who had previously undergone CSF analysis. Thirteen subjects had a pathological Aβ42/tau (PAT) ratio of

Though rod and cone photoreceptors use similar phototransduction mechanisms, previous model calculations have indicated that the most important differences in their light responses are likely to be differences in amplification of the G-protein cascade, different decay rates of phosphodiesterase (PDE) and pigment phosphorylation, and different rates of turnover of cGMP in darkness. To test this hypothesis, we constructed TrUx;GapOx rods by crossing mice with decreased transduction gain from decreased transducin expression, with mice displaying an increased rate of PDE decay from increased expression of GTPase-activating proteins (GAPs). These two manipulations brought the sensitivity of TrUx;GapOx rods to within a factor of 2 of WT cone sensitivity, after correcting for outer-segment dimensions. These alterations did not, however, change photoreceptor adaptation: rods continued to show increment saturation though at a higher background intensity. These experiments confirm model calculations that rod responses can mimic some (though not all) of the features of cone responses after only a few changes in the properties of transduction proteins.

The fovea centralis (fovea) is a specialized region of the primate retina that plays crucial roles in high-resolution visual acuity and color perception. The fovea is characterized by a high density of cone photoreceptors and no rods, and unique anatomical properties that contribute to its remarkable visual capabilities. Early histological analyses identified some of the key events that contribute to foveal development, but the mechanisms that direct the specification of this area are not understood. Recently, the expression of the retinoic acid-metabolizing enzyme CYP26A1 has become a hallmark of some of the retinal specializations found in vertebrates, including the primate fovea and the high-acuity area in avian species. In chickens, the retinoic acid pathway regulates the expression of FGF8 to then direct the development of a rod-free area. Similarly, high levels of CYP26A1, CDKN1A, and NPVF expression have been observed in the primate macula using transcriptomic approaches. However, which retinal cells express these genes and their expression dynamics in the developing primate eye remain unknown. Here, we systematically characterize the expression patterns of CYP26A1, FGF8, CDKN1A, and NPVF during the development of the rhesus monkey retina, from early stages of development in the first trimester until the third trimester (near term). Our data suggest that some of the markers previously proposed to be fovea-specific are not enriched in the progenitors of the rhesus monkey fovea. In contrast, CYP26A1 is expressed at high levels in the progenitors of the fovea, while it localizes in a subpopulation of macular Müller glia cells later in development. Together these data provide invaluable insights into the expression dynamics of several molecules in the nonhuman primate retina and highlight the developmental advancement of the foveal region.

Purpose: Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas. Methods: We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD). Results: Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments. Conclusion: We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate ECG-gated retinal vessel calibre as a novel measure of aberrant pulsatile retinal flow in diabetes mellitus. Methods: A novel mydriatic ECG-gated fundoscope was used to acquire retinal vessel calibre measurements at four cardiac cycle time points from end diastole to early diastole. An inhouse software recorded the exact time when an image was captured to corroborate ECG-synchronisation. Arterial applanation tonometry, an alternative method of assessing aberrant blood flow, was used to measure carotid-femoral pulse wave velocity (cPWV) and augmentation index (AIx). The intraclass correlation (ICC) was used to perform intra- and inter-observer reliability analyses. Two reviewers measured the retinal vessel calibre in single retinal arterioles and venules. A receiver operating characteristic curve determined associations with diabetes mellitus. Results: In this study 119 controls and 120 participants with diabetes mellitus were recruited. Mean peak change in retinal arteriolar calibre from baseline was higher in diabetes mellitus compared with controls (controls: 0.92%, IQR 0.63 vs diabetes mellitus: 2.05%, IQR 1.25, p<0.0001). In a subset of 9 controls and 11 participants, the intra-and inter-observer reliability was high (ICC 0.87-0.97) in mean peak changes in retinal vascular responses from baseline. In a subset of 36 controls and 95 participants with diabetes mellitus, diabetes mellitus was more strongly associated with retinal arteriolar pulsatility (AUC 0.85, 95%CI 0.76-0.93) than applanation tonometry (cfPWV AUC 0.72, 95%CI 0.62-0.82 vs AIx AUC 0.56, 95%CI 0.45-0.68). Conclusion: Higher retinal arteriolar pulsatility appears to be more strongly correlated with diabetes mellitus than arterial applanation tonometry. [ABSTRACT FROM AUTHOR]

The much larger appearance of the moon near horizon than the perceived size of the moon at zenith has motivated many scientists to develop theories that aim at explaining this puzzling phenomenon. Considering that the size of retinal images of the moon in these positions are very similar, the explanation of difference in their apparent sizes has relied on perceptual cues of distance embedded in the retinal image of their respective contexts. Although this account of the moon illusion is quite popular, it does not explain all aspects of this phenomenon. The theoretical formulation of the moon illusion based on other factors such as size contrast later may have had some advantages but has also created some new problems. Although the moon is perceived in a three-dimensional (3D) environment, the present analysis proposes that an explanation of the moon illusion based on two-dimensional (2D) cues can remove some of the unnecessary problems. The empty space and size contrast that have already been considered in explaining classic geometric-optical illusions play a parallel role in explaining the moon illusion. In other words, the role of open space in interaction with the image of the moon and different objects near horizon, all reflected on the retina, are considered as the main explaining factors. The advantages of this approach will be discussed and some of the facts pertaining to the moon illusion will be explained within this theoretical framework. [ABSTRACT FROM AUTHOR]

Background and Purpose: The human visual system relies on neural networks throughout the brain that are easily accessible for tests exploring eye structures and movements. Over the past two decades, investigations have been carried out on both afferent and efferent components of the visual system in people with amyotrophic lateral sclerosis (ALS). This approach might represent an innovative biomarker research strategy to better characterise the phenotypic variability of ALS. The purpose of this review was to determine whether exploring the visual system of patients with ALS (pwALS) is an effective strategy. Methods: The Medline and Web of science databases were searched for studies with terms relating to ALS and vision. Of 1146 references identified, 43 articles were included. Results: In this review article, both afferent and efferent components of the visual system were found to be impaired in pwALS in the absence of visual complaint, thereby contributing to the hypothesis that ALS is a multisystem disease with sensory involvement. Of note, some areas of the eye remain unexplored (i.e., tears, and retinal function using electroretinography). Conclusions: According to the findings available in the literature, investigating the oculomotor system and exploring the ocular surface could represent two key promising strategies to identify new diagnostic biomarkers in pwALS. Further longitudinal studies are needed to identify relevant indicators of disease progression and response to therapeutic intervention. [ABSTRACT FROM AUTHOR]

The evolutionary origin of the inverted retina in the vertebrate eye is unknown. This paper explores a hypothetical evolutionary scenario that explains the unique orientation of the photoreceptors in the vertebrate retina. The proposed scenario follows the scientific accepted scenario for eye evolution and gradually builds up towards an eye prototype by considering light direction detection and increase in achievable spatial resolution as the driving forces. It suggests that eye retinas developed along two different morphological processes, an evagination process that results in the inverted retina in vertebrate eyes and an invagination process that results in a verted retina in cephalopod eyes. The development of the inverted vertebrate retina and eye prototype morphology is strongly substantiated by physics of vision. The proposed evolutionary sequence for vertebrate eye development is simple and has the full potential to explain the origin of the inverted retina and leads to an eye prototype enabling visual detection and orientation. It allows the emergence of eye structures like, extraocular muscles, tapetum lucidum, biconvex lens, cornea, and pupil. This study supports the suggestion that a primitive inverted retina in the predecessor of vertebrates is of ectodermal origin and available before neurulation occurred. [ABSTRACT FROM AUTHOR]

Introduction: An important goal of biomedical physics and engineering is to study possible confounding factors in diagnosis or treatment to minimize erogenous interpretations due to overestimation or covering pathology-related changes. We aimed to examine the effect of refractive error on corneal thickness, retinal thickness (including its layers), and optic disc parameters in low myopia and moderate myopia, as compared to the emmetropic group. Material and methods: Sixty eyes from 30 (18 women) young, healthy, physically active, non-smokers, with normal color perception, and no ophthalmological or neurological medical history Caucasians at the age of 24.6 ± 1.5 years were examined. The studied groups were defined based on the SE (spherical equivalent): emmetropia (−0.5 D ≤ SE ≤ 0.75 D, 20 eyes), low myopia (−3 D < SE < -0.5 D, 20 eyes), and moderate myopia (−6 ≤ SE ≤ −3 D, 20 eyes). Spectral optical coherence tomography imaging (SOCT) through SOCT Copernicus HR device (OPTOPOL Technology Sp. z o.o., Poland) was used. Results: Corneal thickness, peripapillary RNFL thickness, and optic disc parameters didn't change between emmetropic, low myopia, and moderate myopia groups. However, macular retinal thickness decreased with increasing refractive error. Interestingly, particular retinal layers' thicknesses changed differently with increasing spherical equivalent (SE). A thickening of external macular retina layers was observed in the central and inner sectors, while a thinning of internal retinal layers was seen mainly in the outer ring when SE increased from emmetropia to moderate myopia. Conclusions: Our findings suggest that changes in retinal thickness due to refractive error may appear even in earlier stages than high myopia. Moreover, different retina layers change differently with SE and not every sector behaves in the same manner. These results are especially worth noting, as they point out the necessity of taking into account different behaviors of retinal layers in low and moderately myopic eyes in interpreting the measurement results when diagnosing ocular pathologies or preparing ophthalmologic surgeries. [ABSTRACT FROM AUTHOR]

The protective effects of time spent outdoors emphasize the major role of daylight in myopia. Based on the pathophysiology of myopia, the impact of blue light stimulation on the signaling cascade, from melanopsin at the blind spot to clinically relevant biomarkers for myopia, was investigated. Parameters and site of light stimulation are mainly defined by the photopigment melanopsin, that is sensitive to blue light with a peak wavelength of 480 nm and localized on the intrinsically photosensitive retinal ganglion cells (ipRGC) whose axons converge to the optic disc, corresponding to the physiological blind spot. Blue light at the blind spot (BluSpot) stimulation provides the opportunity to activate the vast majority of ipRGC and avoids additional involvement of rods and cones which may exert incalculable effects on the signaling cascade. Experimental studies have applied anatomical, histochemical, electrophysiological, imaging, and psychophysical methods to unravel the mode of action of BluSpot stimulation. Results indicate activation of melanopsin, improvement of contrast sensitivity, gain in electrical retinal activity, and increase of choroidal thickness following BluSpot stimulation. Short-term changes of clinically relevant biomarkers lead to the hypothesis that BluSpot stimulation may exert antimyopic effects with long-term application. [ABSTRACT FROM AUTHOR]

Introduction: Light profoundly influences human physiology, behaviour and cognition by affecting various functions through light-sensitive cells in the retina. Light therapy has proven effective in treating seasonal depression and other disorders. However, designing appropriate control conditions for light-based interventions remains a challenge. Materials and methods: This article presents a novel framework for selecting, implementing and evaluating control conditions in light studies, offering theoretical foundations and practical guidance. It reviews the fundamentals of photoreception and discusses control strategies such as dim light, darkness, different wavelengths, spectral composition and metameric conditions. Special cases like dynamic lighting, simulated dawn and dusk, complex interventions and studies involving blind or visually impaired patients are also considered. Results: The practical guide outlines steps for selection, implementation, evaluation and reporting, emphasizing the importance of α-opic calculations and physiological validation. Conclusion: In conclusion, constructing effective control conditions is crucial for demonstrating the efficacy of light interventions in various research scenarios. [ABSTRACT FROM AUTHOR]

Ion channels in retinal pigment epithelial (RPE) cells are crucial for retinal health and vision functions. Defects in such channels are intricately associated with the development of various retinopathies that cause blindness. Human pluripotent stem cells (hPSC)-derived RPE cells, including those from human-induced pluripotent stem cells (hiPSC) and human embryonic stem cells (hESC), have been used as in vitro models for investigating pathogenic mechanisms and screening potential therapeutic strategies for retinopathies. Therefore, the cellular status of hPSC-RPE cells, including maturity and physiologic functions, have been widely explored. Particularly, research on ion channels in hPSC-RPE cells can lead to the development of more stable models upon which robust investigations and clinical safety assessments can be performed. Moreover, the use of patient-specific hiPSC-RPE cells has significantly accelerated the clinical translation of gene therapy for retinal channelopathies, such as bestrophinopathies. This review consolidates current research on ion channels in hPSC-RPE cells, specifically Kir7.1, Bestrophin-1, CLC-2, and CaV1.3, providing a foundation for future research. [ABSTRACT FROM AUTHOR]

Background: Neovascular age-related macular degeneration (nAMD) is one of the largest single-disease contributors to hospital outpatient appointments. Challenges in finding the clinical capacity to meet this demand can lead to sight-threatening delays in the macular services that provide treatment. Clinical artificial intelligence (AI) technologies pose one opportunity to rebalance demand and capacity in macular services. However, there is a lack of evidence to guide early-adopters seeking to use AI as a solution to demand-capacity imbalance. This study aims to provide guidance for these early adopters on how AI-enabled macular services may best be implemented by exploring what will influence the outcome of AI implementation and why. Methods: Thirty-six semi-structured interviews were conducted with participants. Data were analysed with the Nonadoption, Abandonment, Scale-up, Spread and Sustainability (NASSS) framework to identify factors likely to influence implementation outcomes. These factors and the primary data then underwent a secondary analysis using the Fit between Individuals, Technology and Task (FITT) framework to propose an actionable intervention. Results: nAMD treatment should be initiated at face-to-face appointments with clinicians who recommend year-long periods of AI-enabled scheduling of treatments. This aims to maintain or enhance the quality of patient communication, whilst reducing consultation frequency. Appropriately trained photographers should take on the additional roles of inputting retinal imaging into the AI device and overseeing its communication to clinical colleagues, while ophthalmologists assume clinical oversight and consultation roles. Interoperability to facilitate this intervention would best be served by imaging equipment that can send images to the cloud securely for analysis by AI tools. Picture Archiving and Communication Software (PACS) should have the capability to output directly into electronic medical records (EMR) familiar to clinical and administrative staff. Conclusion: There are many enablers to implementation and few of the remaining barriers relate directly to the AI technology itself. The proposed intervention requires local tailoring and prospective evaluation but can support early adopters in optimising the chances of success from initial efforts to implement AI-enabled macular services. Protocol registration: Hogg HDJ, Brittain K, Teare D, Talks J, Balaskas K, Keane P, Maniatopoulos G. Safety and efficacy of an artificial intelligence-enabled decision tool for treatment decisions in neovascular age-related macular degeneration and an exploration of clinical pathway integration and implementation: protocol for a multi-methods validation study. BMJ Open. 2023 Feb 1;13(2):e069443. https://doi.org/10.1136/bmjopen-2022-069443. PMID: 36725098; PMCID: PMC9896175. [ABSTRACT FROM AUTHOR]

Schizophrenia and Autism spectrum disorders (SSD and ASD) are neurodevelopmental disorders involving cognitive impairment. Timely diagnosis is important for early intervention; currently, no tools are available to help with early diagnosis. Molecular biomarkers of cognitive impairment have been extensively studied, but clinical correlation is crucial in screening for cognitive impairment in SSD and ASD. There has been growing interest in examining the retina to scan for neurological disorders since the retina is the only part of the central nervous system that can be directly imaged non-invasively and in a timely manner. This review discusses biomarkers of cognitive impairment and their correlation to the retina in SSD and ASD. It also discusses the possible involvement of the retina and molecular biomarkers, specifically Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and ciliary neurotrophic factor (CNTF) in the pathophysiology of SSD and ASD. A protocol for early diagnosing cognitive impairment and its severity in SSD and ASD is also suggested. This review also mentions insights into the potential use of molecular biomarkers of cognitive impairment to enhance cognitive performance in ASD and SSD and areas where more research is needed to solve the mystery of the relationship between the retina and cognitive impairment in neurodevelopmental psychiatric disorders. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a significant contributor to the pathology of glaucoma. Targeting key-mediators in this process is a realistic option to slow disease progression. Galectin-3 is a β-galactoside binding lectin that has been associated with inflammation in both systemic and central nervous system diseases. Elevated Galectin-3 has recently been detected in multiple animal models of glaucoma and inhibiting Galectin-3 using an intravitreal injection of TD139 (a Galectin-3 small molecule inhibitor) is neuroprotective. We queried whether this neuroprotective effect was translatable to another animal model and species. TD139 was intravitreally injected, in a rat ocular hypertensive model of glaucoma, 3 days after the induction of ocular hypertension (at peak intraocular pressure). Retinal ganglion cell survival and glial morphological markers were quantified. The degeneration of retinal ganglion cells was prevented by TD139 injection, but gross glial markers remained unaffected. These data confirm that the intravitreal injection of TD139 is neuroprotective in a rat ocular hypertensive model of glaucoma, while suggesting that the inhibition of Galectin-3 is not sufficient to alter the gross inflammatory outcome. [ABSTRACT FROM AUTHOR]

Background: The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap. Methods: Cellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student's t-test and one-way ANOVA. Results: Single-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment. Conclusion: We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions To evaluate the myopic and hyperopic defocus delivered to the retina by a dual focus (DF) myopia control contact lens when myopia exceeds 6.00 D.Individuals with high myopia were fitted bilaterally with high‐powered DF lenses containing power profiles matching a Coopervision MiSight 1 day contact lens (omafilcon A) and a Coopervision Proclear 1 day single vision (SV) lens. Wavefront measurements along the primary line of sight and across the central ±20° of the horizontal retina were acquired using a pyramidal aberrometer, while subjects accommodated to high‐contrast letter stimuli (6/12 equivalent) at six target vergences (−0.25 and −1.00 to −5.00 D). Linear mixed‐effects regression models explored the relationship between the spherical equivalent refractive error (SERE) and induced defocus.Thirteen teenagers and young adults (ages 13–32 years, mean [standard deviation, SD] age = 22.8 [4.9] years) with high myopia (SERE −6.50 to −9.25 D) were tested. The treatment optic zone of the DF lens shifted retinal defocus by the expected −2.00 D, with a mean (SD) difference (DF–SV) of −2.21 (0.18) D for the inner treatment ring. Inclusion of the treatment optic had no significant impact on accommodative accuracy (p = 0.51). Accommodative lags were larger at the nearer viewing distances, with lag increasing by approximately 0.30 D for every additional dioptre of SERE. Measured retinal defocus within the annular treatment zone was approximately −2.00 D at the foveal centre, 10° nasal and temporal and 20° nasal and reduced to −1.90 (0.57) D at 20° temporal.Relative to eyes with lower levels of myopia, the increased accommodative lags and more prolate retinas of highly myopic eyes reduced the myopic retinal defocus from the DF myopia control lens, while the treatment optical zones generated the combined effect of reducing hyperopic and introducing myopic retinal defocus relative to an SV correction. [ABSTRACT FROM AUTHOR]

Feedback at the photoreceptor synapse is the first neuronal circuit computation in vision, which influences downstream activity patterns within the visual system. Yet, the identity of the feedback signal and the mechanism of synaptic transmission are still not well understood. Here, we combined perturbations of cell-type-specific genes of mouse horizontal cells with two-photon imaging of the result of light-induced feedback in cones and showed that the electrogenic bicarbonate transporter Slc4a5, but not the electroneutral bicarbonate transporter Slc4a3, both expressed specifically in horizontal cells, is necessary for horizontal cell-to-cone feedback. Pharmacological blockage of bicarbonate transporters and buffering pH also abolished the feedback but blocking sodium-proton exchangers and GABA receptors did not. Our work suggests an unconventional mechanism of feedback at the first visual synapse: changes in horizontal cell voltage modulate bicarbonate transport to the cell, via Slc4a5, which leads to the modulation of feedback to cones. [Display omitted] • Feedback from horizontal cells to cones was measured by imaging calcium in cones • Slc4a5 is an electrogenic Na+-HCO 3 − cotransporter specific to horizontal cells • Knocking out or down Slc4a5 abolished horizontal cell-to-cone feedback • Blocking HCO 3 − transporters and buffering pH also abolished feedback Molecular mechanisms of horizontal cell-to-cone feedback in the retina have been under debate. Morikawa et al. show that Slc4a5, an electrogenic sodium-bicarbonate cotransporter specific to horizontal cells, is crucial for feedback. They suggest that Slc4a5, through its voltage-dependent transport of bicarbonate, regulates pH in the synaptic cleft that mediates feedback. [ABSTRACT FROM AUTHOR]

Extra‐cerebral manifestations of Alzheimer's disease (AD) develop in the retina, which is, therefore, considered a “window to the brain”. Recent studies demonstrated the dysregulation of the endocannabinoid (eCB) system (ECS) in AD brain. Here, we explored the possible alterations of ECS and the onset of gliosis in the retina of AD‐like mice. Tg2576 (TG) mice overexpressing the amyloid precursor protein (APP) were used at the age of 12 months, when hippocampal β‐amyloid plaques had not been developed yet. Analysis of retinal gliosis showed a significant increase in the number of IBA1 (+) microglia cells in TG versus wild type (WT). Gliosis was not associated with retinal β‐amyloid plaques, evident retinal degenerative signatures, or excitotoxicity; instead, oxidative stress burden was observed as increased acrolein levels. Analysis of the ECS (receptors/metabolic enzymes) through western blotting (WB) revealed the up‐regulation of cannabinoid receptor 2 (CB2) and monoacylglycerol lipase (MAGL), the enzyme responsible for the degradation of 2‐arachidonoylglycerol (2‐AG), in TG retinas. Fluorescence intensity analysis of anti‐CB2 and anti‐MAGL immuno‐stained cryosections was consistent with WB, showing their up‐regulation throughout the retinal layers. No statistically significant differences were found for the other enzymes/receptors of the ECS under study. However, linear regression analysis for individual animals showed a significant correlation between CB2 and fatty acid amide hydrolase (FAAH), diacylglycerol lipase α/β (DAGLα/β), and APP; instead, a significant negative correlation was found between MAGL and APP. Finally, ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) demonstrated a significant reduction of 2‐AG in TG retinas (~0.34 ng/mg) compared to WT (~1.70 ng/mg), while a trend toward increase was found for the other eCB anandamide (AEA). Overall, our data indicate that gliosis and ECS dysregulation—in particular of CB2, MAGL and 2‐AG—occur in the retina of AD‐like mice before retinal degeneration and development of hippocampal β‐amyloid plaques. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a prevalent complication of type 2 diabetes mellitus, characterized by progressive damage to the retinal structure and function. Photobiomodulation therapy, using red or near-infrared light, has been proposed as a non-invasive intervention to mitigate retinal damage, but has been tested generally with short-term stimuli. This study aimed to evaluate the effects of prolonged photobiomodulation with deep red light on retinal structure and function in a type 2 diabetes mouse model. Transgenic LepRdb/J (db/db) mice were exposed to photobiomodulation therapy via LED devices emitting 654 nm light for 12 h daily over ten weeks and compared to untreated mice. Retinal function was evaluated by flash electroretinography, while structural changes were assessed through histology and immunohistochemistry to detect astro- and microgliosis. At 33 weeks of age, db/db mice were obese and severely diabetic, but exhibited only incipient indicators of retinal deterioration. Electroretinogram b-wave peak latencies were prolonged at intermediate flash intensities, while the outer plexiform layer displayed significantly elevated IBA1 expression. Photobiomodulation therapy prevented these two markers of early retinal deterioration but had no effect on other morphological and functional parameters. Photobiomodulation is well-tolerated and maintains potential as a complementary treatment option for diabetic retinopathy but requires further optimization of therapeutic settings and combinatory treatment approaches. [ABSTRACT FROM AUTHOR]

The development of eye pathology is a serious concern for astronauts who spend time in deep space. Microgravity is a major component of the spaceflight environment which could have adverse effects on ocular health. The use of centrifugation to exert forces that partially or fully mimic Earth-level gravity in space is a possible countermeasure to mitigate the effects of microgravity on the eye. Therefore, we subjected mice on the International Space Station (ISS) to microgravity (0 G) or artificial gravity by centrifugation at 0.33 G, 0.67 G, and 1 G, and then performed RNA sequencing (RNA-seq) on optic nerve and retinal tissue after returning them to Earth alive. We find that the microgravity environment induces transcriptomic changes in the optic nerve and retina consistent with an increased oxidative stress load, inflammation, apoptosis, and lipid metabolic stress. We also find that adding artificial gravity on board the ISS attenuates the transcriptomic response to microgravity in a dose-dependent manner. Such attenuation may effectively protect from and mitigate spaceflight-induced detrimental effects on ocular tissue. [ABSTRACT FROM AUTHOR]

Retinal artery occlusion (RAO) is an emergency condition causing acute retinal ischemia and is considered an equivalent of ischemic stroke. The occurrence of an episode of RAO is associated with significant impairment of visual functions and correlates with an increased risk of future vascular events. Although RAO requires immediate diagnosis and treatment, there are currently no clear guidelines specifying optimal management. This review discusses current and future therapeutic strategies following an episode of RAO, including secondary prevention. [ABSTRACT FROM AUTHOR]

Purpose: Diving is an intense physical activity under hyperbaric and hyperoxic conditions. The aim of this study is to evaluate the long‐term effects of diving on the thicknesses of retinal layers and retinal anatomy in professional deep and scuba divers. Methods: The study included 52 eyes of deep divers who dive to depths of more than 130 feet (ft), 49 eyes of scuba divers who dive up to 130 ft, and 66 eyes of the control group, consisting of nondiving but regularly exercising males. Measurements of macular retinal layer thicknesses, peripapillary nerve fiber layer thickness, subfoveal choroidal thickness, and peripheral retinal examinations with scleral indentation were performed and statistically compared between the groups. Results: The mean diving duration was 455.00 ± 318.88 h in deep divers and 451.67 ± 281.10 h in scuba divers. The retinal pigment epithelium (RPE) was statistically significantly thicker in deep divers than in scuba divers and the control group on the 3 mm ring of the Early Treatment Diabetic Retinopathy Study grid. Subfoveal choroidal thickness was significantly thicker in deep divers than in scuba divers (p < 0.05). RPE abnormalities showed a significant increase in both the deep and scuba diver groups (p = 0.01). Conclusion: An increased thickening of the subfoveal choroid and RPE, resembling pachychoroid pigment epitheliopathy, was detected in deep divers over a long‐term duration. [ABSTRACT FROM AUTHOR]

To investigate the characteristics of acute visual dysfunction and fundus lesions in patients with COVID-19 pneumonia. A retrospective case series study was conducted. Data from 48 patients (96 eyes) with COVID-19 infection who presented to our ophthalmology department with acute onset visual disturbance between December 5, 2022, and February 28, 2023 were collected. Asymptomatic patients and those who had already recovered were excluded. Data collected included patient demographics, ophthalmic examinations, multicolor imaging (MCI), infrared autofluorescence (IR), spectral-domain optical coherence tomography (OCT), fundus fluorescein angiography (FFA). Of the 48 patients, 15 were male and 33 were female, with a mean age of 32 years. All patients had bilateral involvement. OCT showed hyperreflective signals in the outer plexiform layer and outer nuclear layer of the macular region in all 96 eyes of 48 patients (100%). Additionally, 66 eyes of 33 patients (68.8%) of eyes demonstrated abnormal reflectivity in the ellipsoid and interdigitation zones. MCI revealed petaloid or wedge-shaped hyperreflective areas in the macula in 46 (47.9%) of eyes, corresponding to hyporeflective areas on IR. Cotton-wool spots were observed in the peripapillary or posterior pole area in 54 (56.3%) of eyes. COVID-19 infection can lead to acute, bilateral, symmetric, and widespread retinal damage. Characteristic findings can be observed in ophthalmological examinations such as OCT, MCI, and IR. [ABSTRACT FROM AUTHOR]

Previous pattern electroretinogram studies indicate reduced retinal contrast gain in patients with a major depressive disorder (MDD) which may contribute to alterations in visual perception. In line, psychophysical investigations reported elevated contrast thresholds in MDD. This study aims to gain insights into higher-level processing of visual information in MDD by evaluating contrast suppression. We examined contrast suppression of 21 MDD patients and 23 healthy controls (HC) using four different stimulus conditions (spatial frequencies 6.3 and 12.6 cpd at 30% and 60% background contrast) in a psychophysical test. Participants were instructed to adjust perceived contrasts between two vertical target patches, embedded in a horizontally or vertically oriented grid background. With finer stimulus gratings, MDD patients exhibited less contrast suppression compared to HC, particularly when the stimulus contrast was high (p = 0.006; MDD vs. HC = − 45%). Contrast suppression in the HC group was significantly reduced for the coarse compared to the fine grating, while contrast suppression scores in MDD did not change with the spatial properties of the stimulus. The reduced contrast suppression in patients with MDD supports the hypothesis of altered dopaminergic neurotransmission and could be attributed to alterations in the retinal receptive fields or in dysfunctional adaptation mechanisms in depression. [ABSTRACT FROM AUTHOR]