Search

IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33-/- and WT mice after ON injury, but not in ST2-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic retinopathy (DR) is a common complication of diabetes. Retinal neuronal degeneration is an early event in DR, indicated by the declined electroretinogram (ERG). Dipeptide alanine-glutamine (Ala-Gln) is widely used as a nutritional supplement in the clinic and has anti-inflammatory effects on the gastrointestinal system. Studies also reported that glutamine has beneficial effects on diabetes. This study aimed to investigate the possible therapeutic effects of Ala-Gln in diabetic retinal neurodegeneration and to delineate its mechanism of action. Methods: The Streptozotocin (STZ)-induced rat model was used as a DR model. ERG was used to measure the neuronal function of the retina. Western blot analysis was performed to test the expression of proteins. Immunofluorescence staining was used for the detection and localization of proteins. Results: In diabetic rats, the amplitudes of ERG were declined, while Ala-Gln restored the declined ERG. Retinal levels of inflammatory factors were significantly decreased in Ala-Gln-treated diabetic rats. Ala-Gln mitigated the declined levels of glutamine synthetase and ameliorated the upregulated levels of glial fibrillary acidic protein (GFAP) in diabetic retinas. Moreover, Ala-Gln upregulated the glycolytic enzymes pyruvate kinase isozymes 2 (PKM2), lactate dehydrogenase A (LDHA) and LDHB and stimulated the mTOR signaling pathway in diabetic retinas. The mitochondrial function was improved after the treatment of Ala-Gln in diabetic retinas. Discussion: Ala-Gln ameliorates retinal neurodegeneration by reducing inflammation and enhancing glucose metabolism and mitochondrial function in DR. Therefore, manipulation of metabolism by Ala-Gln may be a novel therapeutic avenue for retinal neurodegeneration in DR. [ABSTRACT FROM AUTHOR]

Purpose: Neurovascular coupling impairment and inner retinal layer thinning are early detectable retinal changes in diabetes, and both worsen during progression of diabetic retinopathy (DR). However, direct interactions between these features have not been investigated so far. Therefore, we aimed to analyze associations between the retinal functional hyperemic response to light stimulation and the thickness of individual neuroretinal layers in eyes with early non-proliferative DR. Methods: Thirty patients with type 1 diabetes featuring mild (n = 15) or moderate (n = 15) non-proliferative DR and 14 healthy subjects were included in this cross-sectional study. Retinal vessel diameters were measured before and during illumination with flickering light using a dynamic vessel analyzer. Individual layer thickness in the macula was analyzed from spectral domain optical coherence tomography. Results: Flicker light-induced vessel dilation was significantly reduced in patients compared to healthy controls (veins: 3.0% vs. 6.1%, p < 0.001; arteries: 1.3% vs. 5.1%, p = 0.005). Univariately, the response in retinal veins of diabetes patients correlated significantly with ganglion cell layer (GCL) thickness (r = 0.46, p = 0.010), and negatively with hemoglobin A1c (HbA1c) levels (r=-0.41, p = 0.023) and age (r=-0.38, p = 0.037), but not with baseline diameters, glucose levels, or diabetes duration. In a multiple regression model only GCL thickness (p = 0.017, β = 0.42) and HbA1c (p = 0.045, β=-0.35) remained significantly associated with the vascular flicker light response. Conclusion: The results indicate that thinner GCL and worse glycemic control both contribute to reduced retinal neurovascular coupling in patients with clinical signs of DR. Progression of neurovascular dysfunction in DR might be related to structural degeneration of the neurovascular complex in the inner retina. Key message: What is known: • Neurovascular coupling dysfunction and neurodegeneration in the inner retina are early features in eyes of diabetes patients, and both worsen during progression of diabetic retinopathy. However, direct interactions between these changes have not been investigated so far. What is new: • Our study shows that in patients with early diabetic retinopathy the reduced functional hyperemic response to flicker light stimulation correlates significantly with inner retinal layer thickness, and concurrently with worse glycemic control. • This demonstrates for the first time that retinal neurodegeneration may be an important contributor to the advancing disturbance of neurovascular coupling in eyes with clinically established diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Retinal neurodegeneration (RN), an early marker of diabetic retinopathy (DR), is closely associated with Müller glia cells (MGs) in diabetic subjects. MGs play a pivotal role in maintaining retinal homeostasis, integrity, and metabolic support and respond to diabetic stress. In lower vertebrates, MGs have a strong regenerative response and can completely repair the retina after injuries. However, this ability diminishes as organisms become more complex. The aim of this study was to investigate the gliotic response and reprogramming potential of the human Müller cell line MIO-M1 cultured in normoglycemic (5 mM glucose, NG) and hyperglycemic (25 mM glucose, HG) conditions and then exposed to sustained high-glucose and glucose fluctuation (GF) treatments to mimic the human diabetic conditions. The results showed that NG MIO-M1 cells exhibited a dynamic activation to sustained high-glucose and GF treatments by increasing GFAP and Vimentin expression together, indicative of gliotic response. Increased expression of SHH and SOX2 were also observed, foreshadowing reprogramming potential. Conversely, HG MIO-M1 cells showed increased levels of the indexes reported above and adaptation/desensitization to sustained high-glucose and GF treatments. These findings indicate that MIO-M1 cells exhibit a differential response under various glucose treatments, which is dependent on the metabolic environment. The in vitro model used in this study, based on a well-established cell line, enables the exploration of how these responses occur in a controlled, reproducible system and the identification of strategies to promote neurogenesis over neurodegeneration. These findings contribute to the understanding of MGs responses under diabetic conditions, which may have implications for future therapeutic approaches to diabetes-associated retinal neurodegeneration. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the retinal neurodegeneration findings caused by diabetes and diabetic neuropathy in patients without retinopathy, anatomically with spectral domain optical coherence tomography (SD-OCT) and functionally with contrast sensitivity (CS). Methods: The presence of diabetic neuropathy was objectively revealed together with neurologists by electromyography (EMG). SD-OCT and CS were evaluated in patients with peripheral neuropathy (diabetic peripheral neuropathy [DPN] + group), without neuropathy (DPN-group), and healthy controls. Average and sectoral retinal nerve fiber layer (RNFL) thickness, average, and 6 sectoral quadrants ganglion cell complex (GCC) were compared between groups. Furthermore, CS measurement values were calculated between groups. Results: Although there were significant differences between the three groups in the average RNFL, in pairwise comparisons there were no statistical differences in the average RNFL between the DPN (-) and healthy control groups (p=0.679). Average GCC thickness also showed significant differences between the three groups (p<0.001). The post hoc test was performed to determine the group that made the difference, it was seen that the average ganglion cell values of the DPN+ group were lower than the other groups. Furthermore noteworthy, when the diabetic group with "no neuropathy" compared to the healthy control group, GCC values were significantly lower in the diabetic group. When the DPN group was compared with the healthy group, CS values were significantly lower in the diabetic group (p<0.001). Analysis of mesopic CS values and each of the average RNFL and GCC thickness indicated significant positive correlations (r=0.238, 0.326, respectively). Conclusion: Our results suggest that there is evidence of early retinal neuronal damage, particularly on SD-OCT, before DPN occurs in patients with type 2 diabetes mellitus. Although visual acuity is unaffected in diabetic patients, decreased CS and GCC may be an early warning for DPN. [ABSTRACT FROM AUTHOR]

Glaucoma is a major global health concern and the leading cause of irreversible blindness worldwide, characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons. This review focuses on the need for neuroprotective strategies in glaucoma management, addressing the limitations of current treatments that primarily target intraocular pressure (IOP) reduction. Despite effective IOP management, many patients continue to experience RGC degeneration, leading to irreversible blindness. This review provides an overview of both pharmacological interventions and emerging technologies aimed at directly protecting RGCs and the optic nerve, independent of IOP reduction. Pharmacological agents such as brimonidine, neurotrophic factors, memantine, Ginkgo biloba extract, citicoline, nicotinamide, insulin, and resveratrol show promise in preclinical and early clinical studies for their neuroprotective properties. Emerging technologies, including stem cell therapy, gene therapy, mitochondrial-targeted therapies, and nanotechnologies, offer innovative approaches for neuroprotection and regeneration of damaged RGCs. While these interventions hold significant potential, further research and clinical trials are necessary to confirm their efficacy and establish their role in clinical practice. This review highlights the multifaceted nature of neuroprotection in glaucoma, aiming to guide future research and clinical practice toward more effective management of glaucoma-induced neurodegeneration. [ABSTRACT FROM AUTHOR]

This review examines circadian dysregulation and the role of Müller glial cells (MGCs) in retinal degeneration associated with Alzheimer's disease (AD). Evidence supporting the interdependence of circadian rhythm (CR) disruption and AD progression is presented. Also reviweed are reports substantiating the role of MGCs in maintaining CR. Studies documenting MGC dysfunction in AD retinas suggest that gliosis, altered diurnal patterns in water homeostasis, blood-retina barrier breakdown, and impaired ocular glymphatic clearance are relevant to disease progression. Similarities between AD and various retinopathies are explored with respect to MGC physiology and CR dysfunction. We propose that MGC circadian dysregulation is diagnostically and therapeutically relevant to AD retinopathy. [ABSTRACT FROM AUTHOR]

Background and purpose: The eye is a well‐established model of brain structure and function, yet region‐specific structural correlations between the retina and the brain remain underexplored. Therefore, we aim to explore and describe the relationships between the retinal layer thicknesses and brain magnetic resonance image (MRI)‐derived phenotypes in UK Biobank. Methods: Participants with both quality‐controlled optical coherence tomography (OCT) and brain MRI were included in this study. Retinal sublayer thicknesses and total macular thickness were derived from OCT scans. Brain image‐derived phenotypes (IDPs) of 153 cortical and subcortical regions were processed from MRI scans. We utilized multivariable linear regression models to examine the association between retinal thickness and brain regional volumes. All analyses were corrected for multiple testing and adjusted for confounders. Results: Data from 6446 participants were included in this study. We identified significant associations between volumetric brain MRI measures of subregions in the occipital lobe (intracalcarine cortex), parietal lobe (postcentral gyrus), cerebellum (lobules VI, VIIb, VIIIa, VIIIb, and IX), and deep brain structures (thalamus, hippocampus, caudate, putamen, pallidum, and accumbens) and the thickness of the innermost retinal sublayers and total macular thickness (all p < 3.3 × 10−5). We did not observe statistically significant associations between brain IDPs and the thickness of the outer retinal sublayers. Conclusions: Thinner inner and total retinal thicknesses are associated with smaller volumes of specific brain regions. Notably, these relationships extend beyond anatomically established retina–brain connections. [ABSTRACT FROM AUTHOR]

IntroductionDiabetic retinopathy (DR) is a common complication of diabetes. Retinal neuronal degeneration is an early event in DR, indicated by the declined electroretinogram (ERG). Dipeptide alanine-glutamine (Ala-Gln) is widely used as a nutritional supplement in the clinic and has anti-inflammatory effects on the gastrointestinal system. Studies also reported that glutamine has beneficial effects on diabetes. This study aimed to investigate the possible therapeutic effects of Ala-Gln in diabetic retinal neurodegeneration and to delineate its mechanism of action.MethodsThe Streptozotocin (STZ)-induced rat model was used as a DR model. ERG was used to measure the neuronal function of the retina. Western blot analysis was performed to test the expression of proteins. Immunofluorescence staining was used for the detection and localization of proteins.ResultsIn diabetic rats, the amplitudes of ERG were declined, while Ala-Gln restored the declined ERG. Retinal levels of inflammatory factors were significantly decreased in Ala-Gln-treated diabetic rats. Ala-Gln mitigated the declined levels of glutamine synthetase and ameliorated the upregulated levels of glial fibrillary acidic protein (GFAP) in diabetic retinas. Moreover, Ala-Gln upregulated the glycolytic enzymes pyruvate kinase isozymes 2 (PKM2), lactate dehydrogenase A (LDHA) and LDHB and stimulated the mTOR signaling pathway in diabetic retinas. The mitochondrial function was improved after the treatment of Ala-Gln in diabetic retinas.DiscussionAla-Gln ameliorates retinal neurodegeneration by reducing inflammation and enhancing glucose metabolism and mitochondrial function in DR. Therefore, manipulation of metabolism by Ala-Gln may be a novel therapeutic avenue for retinal neurodegeneration in DR.

Reactive oxygen species, inflammation, angiogenesis, and retinal neurodegeneration lead to diabetic retinopathy (DR) progression. The inhibition of VEGF and prevention from retinal neurodegeneration pave the way to developing DR treatment. Melatonin is a potent anti-inflammatory agent and a promising therapeutic candidate for DR therapy. However, melatonin has a lower absorption kinetic that limits its therapeutic efficiency. Recently, nanotechnology-based nanodrug delivery systems have gained attention to overcome limitations of existing potent drugs. Therefore, we have prepared melatonin-loaded polydopamine nanoparticles to improve the melatonin release profile that result in endowed therapeutic potential of melatonin. The evaluation of in vitro and in vivo DR studies have shown the protection efficiency of our nanoformulation. The mechanism of protection is attributed to downregulated vascular endothelial growth factor (VEGF), inhibited CASPASE3, and upregulated nerve/glial antigen 2 (NG2) and choline acetyltransferase (CHAT) that reflect the antiangiogenesis, antiapoptosis, and neuroprotective potential of our nanoformulation in the preclinical DR model. Thus, the antiangiogenesis and retinal neuroprotection efficiency of melatonin-loaded polydopamine nanoparticles suggests our nanoformulation as a promising nanotherapeutic agent for DR treatment. [ABSTRACT FROM AUTHOR]

This review examines circadian dysregulation and the role of Müller glial cells (MGCs) in retinal degeneration associated with Alzheimer’s disease (AD). Evidence supporting the interdependence of circadian rhythm (CR) disruption and AD progression is presented. Also reviweed are reports substantiating the role of MGCs in maintaining CR. Studies documenting MGC dysfunction in AD retinas suggest that gliosis, altered diurnal patterns in water homeostasis, blood-retina barrier breakdown, and impaired ocular glymphatic clearance are relevant to disease progression. Similarities between AD and various retinopathies are explored with respect to MGC physiology and CR dysfunction. We propose that MGC circadian dysregulation is diagnostically and therapeutically relevant to AD retinopathy.

Adverse childhood experiences (ACEs) are associated with developing systemic diseases and mental illnesses, affecting multiple body systems, including those that affect allostasis, such as the immune, endocrine, and nervous systems. Numerous different biomarkers reflect the biological manifestations of ACEs across these systems and point to possible mechanisms of pathology following early adversity. Retinal layer thickness values and retinal microvasculature parameters, which may reflect central nervous system structure and function, have scarcely been explored in relation to early life stress in humans but could potentially be valuable indicators of early life adversity sequelae. Animal models of early life stress using rodents demonstrate that early adversity is associated with structural and functional alterations of the retina. Thus, given the widespread impact of ACEs across several different allostatic systems in the body, including the central nervous system of which the retina is a part, and evidence in animal models suggesting a relationship between early life stress and retinal alterations, the retina is likely to be affected by ACEs in humans. Retinal biomarkers may also represent especially feasible methods for exploring the effects of early adversity on the body, as they can be examined in vivo using optical coherence tomography (OCT), OCT angiography (OCTA), and electroretinography (ERG), which are quick and noninvasive retinal imaging and electrophysiological techniques. Therefore, future research should focus on the impact of ACEs on the retina in humans and what retinal changes predict in terms of symptoms, course, and functional impairment associated with negative physical and mental health outcomes. This can further our understanding of the pathological mechanisms of diseases and disorders that individuals with ACEs are at risk of developing.

Based on the neurovascular unit(NVU), neurovascular coupling functions as a barrier to maintain the homeostasis of the microenvironment by regulating the signaling and metabolic activity of nerve cells and capillaries. Widely dispersed across the retina, the NVU is essential to preserving its normal physiological function. A disturbance in retinal neurovascular homeostasis produced by a range of factors can result in a variety of retinal disorders, such as diabetic retinopathy(DR), glaucoma, retinitis pigmentosa(RP)and age-related macular degeneration(ARMD). The retina also has a widespread distribution of brain-derived neurotrophic factor(BDNF), which functions to promote neuron growth and repair damage by binding to its receptor TrkB. In recent years, BDNF was found to play a protective role against damage in the early stage of retinal neurovascular homeostasis imbalance, often known as the neurodegenerative stage. It also helps to reduce the production of pro-angiogenic substances of neurological origin and offers a fresh approach for the early detection and treatment of associated eye disorders.

This study aimed to examine the impact of diabetes and hypertension on retinal nerve fiber layer (RNFL) thickness components. Optical coherence tomography (OCT) measurements do not consider blood vessel contribution, which this study addressed. We hypothesized that diabetes and/or hypertension would lead to thinner RNFL versus controls due to the vascular component. OCT angiography was used to measure the RNFL in 121 controls, 50 diabetes patients, 371 hypertension patients, and 177 diabetes patients with hypertension. A novel technique separated the RNFL thickness into original (vascular component) and corrected (no vascular component) measurements. Diabetes‐only (98 ± 1.7 µm; p = 0.002) and diabetes with hypertension (99 ± 0.8 µm; p = 0.001) patients had thinner original RNFL versus controls (102 ± 0.8 µm). No difference was seen between hypertension‐only patients (101 ± 0.5 µm; p = 0.083) and controls. After removing the blood vessel component, diabetes/hypertension groups had thinner corrected RNFL versus controls (p = 0.024). Discrepancies in diabetes/hypertension patients were due to thicker retinal blood vessels within the RNFL thickness (p = 0.002). Our findings suggest that diabetes and/or hypertension independently contribute to neurodegenerative thinning of the RNFL, even in the absence of retinopathy. The differentiation of neuronal and vascular components in RNFL thickness measurements provided by the novel technique highlights the importance of considering vascular changes in individuals with these conditions. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The retina may provide non‐invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross‐sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all‐cause dementia and Alzheimer's disease (AD). METHODS: We performed an individual participant data meta‐analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all‐cause dementia; n = 520 cases incident AD; follow‐up time median [interquartile range] 11.3 [8.8–11.5] years). RESULTS: General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all‐cause dementia and AD, respectively. Lower baseline macular ganglion cell‐inner plexiform layer thickness was not significantly associated with these outcomes. DISCUSSION: These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia. [ABSTRACT FROM AUTHOR]

The neurovascular unit (NVU) refers to the functional building unit of the brain and the retina, where neurons, glia, and microvasculature orchestrate to meet the demand of the retina's and brain's function. Neurotrophins (NTs) are structural families of secreted proteins and are known for exerting neurotrophic effects on neuronal differentiation, survival, neurite outgrowth, synaptic formation, and plasticity. NTs include several molecules, such as nerve growth factor, brain-derived neurotrophic factor, NT-3, NT-4, and their precursors. Furthermore, NTs are involved in signaling pathways such as inflammation, apoptosis, and angiogenesis in a nonneuronal cell type. Interestingly, NTs and the precursors can bind and activate the p75 neurotrophin receptor (p75NTR) at low and high affinity. Mature NTs bind their cognate tropomyosin/tyrosine-regulated kinase receptors, crucial for maintenance and neuronal development in the brain and retina axis. Activation of p75NTR results in neuronal apoptosis and cell death, while tropomysin receptor kinase upregulation contributes to differentiation and cell growth. Recent findings indicate that modulation of NTs and their receptors contribute to neurovascular dysfunction in the NVU. Several chronic metabolic and acute ischemic diseases affect the NVU, including diabetic and ischemic retinopathy for the retina, as well as stroke, acute encephalitis, and traumatic brain injury for the brain. This work aims to review the current evidence through published literature studying the impact of NTs and their receptors, including the p75NTR receptor, on the injured and healthy brain-retina axis. [ABSTRACT FROM AUTHOR]

This study quantified age-related changes to retinal autophagy using the CAG-RFP-EGFP-LC3 autophagy reporter mice and considered how aging impacts autophagic responses to acute intraocular pressure (IOP) stress. IOP was elevated to 50 mm Hg for 30 minutes in 3-month-old and 12-month-old CAG-RFP-EGFP-LC3 (n = 7 per age group) and Thy1-YFPh transgenic mice (n = 3 per age group). Compared with younger eyes, older eyes showed diminished basal autophagy in the outer retina, while the inner retina was unaffected. Autophagic flux (red:yellow puncta ratio) was elevated in the inner plexiform layer. Three days following IOP elevation, older eyes showed poorer functional recovery, most notably in ganglion cell responses compared to younger eyes (12 months old: −33.4 ± 5.3% vs. 3 months mice: −13.4 ± 4.5%). This paralleled a reduced capacity to upregulate autophagic puncta volume in the inner retina in older eyes, a response that was seen in younger eyes. Age-related decline in basal and stress-induced autophagy in the retina is associated with greater retinal ganglion cells' susceptibility to IOP elevation. [ABSTRACT FROM AUTHOR]

Purpose: To compare the central macular thickness (CMT), retinal nerve fiber layer thickness (RNFLT), ganglion cell layer thickness (GCLT), and choroidal thickness (CT) measurements in patients with diabetic retinopathy (DRP) and age-related macular degeneration (AMD) before and after intravenous sodium fluorescein application. Methods: The study was conducted cross-sectionally on patients with non-prolipherative DRP and non-neovascular AMD who received intravenous sodium fluorescein for fluorescein angiography (FA). The CMT, RNFLT (in four quadrants), GCLT (in six sectors of two different boundaries), and CT (in five locations) measurements were obtained by swept-source optical coherence tomography (SSOCT) at baseline, two days after, and one month after FA imaging. Results: The mean age of the patients with DRP (20 women, 18 men) was 64.42 ± 8.98 years (49-87), and that of patients with AMD (20 women, 18 men) was 71.95 ± 10.38 years (48-97). Regarding SS-OCT measurements, all mean CMT, RNFLT (in four quadrants), CT (in five locations), and GCLT values (except temporal-superior quadrant of GCLT+ (p=0.007) and superior quadrant of GCLT++ (p=0.06) in patients with DRP) were similar in baseline, two days, and one month after imaging (p>0.05 for all). Conclusion: The current study has shown that sodium fluorescein may be affect the measurements of ganglion cell layer thicknesses. This effect may be reversible, however due to the better understood of this issue, large-participated study groups are needed. [ABSTRACT FROM AUTHOR]

Abstract Background The main clinical symptoms characteristic of Parkinson’s disease (PD) are bradykinesia, tremor, and other motor deficits. However, non-motor symptoms, such as visual disturbances, can be identified at early stages of the disease. One of these symptoms is the impairment of visual motion perception. Hence, we sought to determine if the starburst amacrine cells, which are the main cellular type involved in motion direction selectivity, are degenerated in PD and if the dopaminergic system is related to this degeneration. Methods Human eyes from control (n = 10) and PD (n = 9) donors were available for this study. Using immunohistochemistry and confocal microscopy, we quantified starburst amacrine cell density (choline acetyltransferase [ChAT]-positive cells) and the relationship between these cells and dopaminergic amacrine cells (tyrosine hydroxylase-positive cells and vesicular monoamine transporter-2-positive presynapses) in cross-sections and wholemount retinas. Results First, we found two different ChAT amacrine populations in the human retina that presented different ChAT immunoreactivity intensity and different expression of calcium-binding proteins. Both populations are affected in PD and their density is reduced compared to controls. Also, we report, for the first time, synaptic contacts between dopaminergic amacrine cells and ChAT-positive cells in the human retina. We found that, in PD retinas, there is a reduction of the dopaminergic synaptic contacts into ChAT cells. Conclusions Taken together, this work indicates degeneration of starburst amacrine cells in PD related to dopaminergic degeneration and that dopaminergic amacrine cells could modulate the function of starburst amacrine cells. Since motion perception circuitries are affected in PD, their assessment using visual tests could provide new insights into the diagnosis of PD.

AIM: To evaluate the effects of metabolic syndrome (MetS) on retinal neurodegeneration by optical coherence tomography (OCT). METHODS: Patients diagnosed as MetS were compared with the age and sex-matched healthy control group (CG). Waist circumference measurements, fasting serological biochemical tests, and systemic blood pressures of all participants were evaluated. The MetS group was divided into 3 subgroups according to the number of MetS components: hypertension, diabetes mellitus, dyslipidemia (low-, high-density lipoprotein, hypertriglyceridemia), and visceral obesity findings; 3-component MetS3, 4-component MetS4, and all-component MetS5. All patients underwent complete eye examination and spectral OCT retinal imaging. RESULTS: Totally 58 eyes of 58 patients were included in the MetS group and 63 eyes of 63 age and sex-matched healthy subjects were included in CG. MetS group was composed of 22 subjects in MetS3, 21 subjects in MetS4, and 15 subjects in the MetS5 subgroup. Mean foveal thickness (MetS, 218.7±23.1 µm vs CG, 228.8±21.9 µm, P=0.015), mean inferior (MetS, 283.4±17.0 µm vs CG, 288.7±38.4 µm, P=0.002), superior (MetS, 287.0±18.5 µm vs CG 297.3±17.1 µm, P=0.001), nasal (MetS 287.3±16.7 µm vs CG 297.9±13.9 µm, P=0.000) and temporal (274.5±17.6 µm vs CG 285.6±13.6 µm, P=0.000) thickness in the 3 mm Early Treatment of Diabetic Retinopathy Study (ETDRS) circle was significantly lower in the MetS group. There was no statistically significant difference in the mean inferior, superior, nasal, and temporal thickness of 6 mm ETDRS circle, total macular volume, peripapillary and macular retinal nerve fiber layer, macular ganglion cell layer with inner plexiform layer, and ganglion cell complex. No statistically significant difference was found in these values ??between the MetS3, MetS4, and the MetS5 groups. CONCLUSION: A significant reduction in central macular region thickness in MetS is detected and macular thickness is more susceptible to MetS induced neurodegeneration than peripapillary retinal nerve fiber layer.

Retinal neurodegeneration is a major cause of vision loss. Retinoic acid signaling is critical for the maintenance of retinal function, and its dysfunction can cause retinal neurodegeneration. However, the therapeutic effects of retinoic acid drugs on retinal neurodegeneration remain unclear. In this study, we designed a novel retinoic acid drug called EYE-503 and investigated its therapeutic effects of EYE-503 on retinal neurodegeneration. The optic nerve crush (ONC) model was selected for the retinal neurodegeneration study. H&E staining, TUNEL staining, immunofluorescence staining, and visual electrophysiology assays were performed to determine the role of EYE-503 in retinal neurodegeneration in vivo. The CCK-8 assay, EdU incorporation assay, PI staining, and flow cytometry assays were performed to investigate the effects of EYE-503 administration on retinal neurodegeneration in vitro. The potential mechanism of EYE-503 in retinal neurodegeneration was investigated by network pharmacology and Western blots. The results showed that EYE-503 administration had no detectable cytotoxicity and tissue toxicity. EYE-503 administration alleviated ONC-induced retinal injury and optic nerve injury in vivo. EYE-503 administration attenuated retinal ganglion cell apoptosis, inhibited reactive gliosis, and retarded the progression of retinal neurodegeneration. Mechanistically, EYE-503 regulated retinal neurodegeneration by targeting the JNK/p38 signaling pathway. This study suggests that EYE-503 is a promising therapeutic agent for retinal neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. Objective: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. Methods: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). Results: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. Conclusion: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to quantitatively assess retinal neurodegenerative changes with optical coherence tomography (Cirrus HD-OCT) in type 2 diabetes mellitus (T2DM) patients without diabetic retinopathy (DR) and evaluate their relationships with insulin resistance (IR) and associated systemic indicators. Methods: 102 T2DM patients without DR and 48 healthy controls were included in this observational cross-sectional study. The OCT parameters of macular retinal thickness (MRT) and ganglion cell-inner plexiform layer (GCIPL) thicknesses were evaluated between diabetic and normal eyes. The receiver operating characteristics (ROC) curve was generated to evaluate the discrimination power of early diabetes. Correlation and multiple regression analysis were performed between ophthalmological parameters and T2DM-related demographic and anthropometric variables, and serum biomarkers and homeostasis model assessment of insulin resistance (HOMA-IR) scores. Results: MRT and GCIPL thicknesses showed significant thinning in patients, especially in inferotemporal area. High body mass index (BMI) correlated with decreased GCIPL thicknesses and elevated intraocular pressure (IOP). A negative correlation between waist-to-hip circumference ratio (WHR) and GCIPL thicknesses was also found. High-density lipoprotein (HDL) and fasting C-peptide (CP0) were associated with GCIPL thickness but only in inferotemporal region (r = 0.20, p = 0.04; r = −0.20, p = 0.05, respectively). Multiple regression analysis showed that increased HOMA-IR scores independently predicted both average (β = −0.30, p = 0.05) and inferotemporal (β = −0.34, p = 0.03) GCIPL thinning. Conclusion: Retinal thinning in early T2DM was associated with obesity-related metabolic disorders. IR as an independent risk factor for retinal neurodegeneration may increase the risk of developing glaucoma. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to evaluate associations of different risk factors with odds of diabetic retinopathy (DR) diagnosis and retinal neurodegeneration represented by macular ganglion cell-inner plexiform layer (mGCIPL). Methods: This cross-sectional study analyzed data from individuals aged over 50 years examined between June 2020 and February 2022 in the community-based Beichen Eye Study on ocular diseases. Baseline characteristics included demographic data, cardiometabolic risk factors, laboratory findings, and medications at enrollment. Retinal thickness in both eyes of all participants was measured automatically via optical coherence tomography. Risk factors associated with DR status were investigated using multivariable logistic regression. Multivariable linear regression analysis was performed to explore associations of potential risk factors with mGCIPL thickness. Results: Among the 5037 included participants with a mean (standard deviation, SD) age of 62.6 (6.7) years (3258 women [64.6%]), 4018 (79.8%) were control individuals, 835 (16.6%) were diabetic individuals with no DR, and 184 (3.7%) were diabetic individuals with DR. The risk factors significantly associated with DR status were family history of diabetes (odds ratio [OR], 4.09 [95% CI, 2.44-6.85]), fasting plasma glucose (OR, 5.88 [95% CI, 4.66-7.43]), and statins (OR, 2.13 [95% CI, 1.03-4.43]) relative to the control individuals. Compared with the no DR, diabetes duration (OR, 1.17 [95% CI, 1.13-1.22]), hypertension (OR, 1.60 [95% CI, 1.26-2.45]), and glycated hemoglobin A1C (HbA1c) (OR, 1.27 [95% CI, 1.00-1.59]) were significantly correlated with DR status. Furthermore, age (adjusted b = -0.19 [95% CI, -0.25 to -0.13] mm; P < 0.001), cardiovascular events (adjusted b = -0.95 [95% CI, -1.78 to -0.12] mm; P = 0.03), and axial length (adjusted b = -0.82 [95% CI, -1.29 to -0.35] mm; P = 0.001) were associated with mGCIPL thinning in diabetic individuals with no DR. Conclusion: Multiple risk factors were associated with higher odds of DR development and lower mGCIPL thickness in our study. Risk factors affecting DR status varied among the different study populations. Age, cardiovascular events, and axial length were identified as potential risk factors for consideration in relation to retinal neurodegeneration in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: The main clinical symptoms characteristic of Parkinson's disease (PD) are bradykinesia, tremor, and other motor deficits. However, non-motor symptoms, such as visual disturbances, can be identified at early stages of the disease. One of these symptoms is the impairment of visual motion perception. Hence, we sought to determine if the starburst amacrine cells, which are the main cellular type involved in motion direction selectivity, are degenerated in PD and if the dopaminergic system is related to this degeneration. Methods: Human eyes from control (n = 10) and PD (n = 9) donors were available for this study. Using immunohistochemistry and confocal microscopy, we quantified starburst amacrine cell density (choline acetyltransferase [ChAT]-positive cells) and the relationship between these cells and dopaminergic amacrine cells (tyrosine hydroxylase-positive cells and vesicular monoamine transporter-2-positive presynapses) in cross-sections and wholemount retinas. Results: First, we found two different ChAT amacrine populations in the human retina that presented different ChAT immunoreactivity intensity and different expression of calcium-binding proteins. Both populations are affected in PD and their density is reduced compared to controls. Also, we report, for the first time, synaptic contacts between dopaminergic amacrine cells and ChAT-positive cells in the human retina. We found that, in PD retinas, there is a reduction of the dopaminergic synaptic contacts into ChAT cells. Conclusions: Taken together, this work indicates degeneration of starburst amacrine cells in PD related to dopaminergic degeneration and that dopaminergic amacrine cells could modulate the function of starburst amacrine cells. Since motion perception circuitries are affected in PD, their assessment using visual tests could provide new insights into the diagnosis of PD. [ABSTRACT FROM AUTHOR]

Background: Hypertension might be a modifiable risk factor for neurodegeneration diseases. However, the associations between blood pressure (BP), arterial stiffness index and retinal neurodegeneration remain unclear. Methods: This study used cross-sectional data from the United Kingdom BioBank (UKB) and longitudinal data from the Chinese Ocular Imaging Project (COIP). The macular ganglion cell-inner plexiform layer thickness (mGCIPLT) and macular retinal nerve fiber layer thickness were measured using spectral domain optical coherence tomography imaging. Swept-source optical coherence tomography was performed to obtain the longitudinal trajectory of the mGCIPLT and peripapillary retinal nerve fiber layer thickness in the COIP cohort. Multivariable linear models were used to analyze the associations between BP and retinal measurements. Results: In a cross-sectional analysis of 22 801 participants from UKB, thinner mGCIPLT was related to higher systolic BP (β: −0.103 [−0.146 to −0.061]; P <0.001), and higher diastolic BP (β: −0.191 [−0.265 to −0.117]; P <0.001), and was significantly associated with higher mean arterial pressure (β: −0.174 [−0.238 to −0.109]; P <0.001) and higher mean pulse pressure (β: −0.080 [−0.139 to −0.020]; P =009). In a longitudinal analysis of 2012 eligible COIP participants, higher levels of baseline systolic BP, diastolic BP, mean arterial pressure, and mean pulse pressure were associated with faster thinning in mGCIPLT and peripapillary retinal nerve fiber layer thickness (all P <0.001). The strongest association was the effect of mean arterial pressure on mGCIPLT (β: −0.118 [−0.175 to −0.061]; P <0.001). The results of the analysis of macular retinal nerve fiber layer thickness and peripapillary retinal nerve fiber layer thickness were consistent with those of mGCIPLT. Conclusions: BP levels were independently and consistently associated with various retinal neurodegenerative exacerbations. [ABSTRACT FROM AUTHOR]

Abstract Purpose To evaluate retinal thickness and capillary density in patients with type 2 diabetes (T2D) and their association with diabetic kidney disease (DKD) using swept-source optical coherence tomography (SS-OCT). Methods A cross-sectional study was conducted with T2D patients with mild or no diabetic retinopathy (DR) and nondiabetic controls. Inner retinal layer thickness was measured with SS-OCT. Retinal capillary density and the foveal avascular zone (FAZ) were measured with SS-OCT angiography (OCTA). SS-OCT parameters were compared in patients with and without diabetic kidney disease (DKD) and nondiabetic controls. Results 131 DKD eyes showed decreased ganglion cell layer plus (GCL+) (p = 0.005 TI; p = 0.022 I), retinal nerve fiber layer (RNFL) (p = 0.003), and central retinal thickness (CRT) (p = 0.032), as well as foveal avascular zone (FAZ) enlargement (p = 0.003) and lower capillary density in the superficial vascular plexus (p = 0.016, central quadrant), compared to controls. No statistically significant changes were found between diabetic patients without significant DKD and controls. Conclusion Our findings suggest early neurovascular damage in patients with T2D; these changes were more significant in patients with DKD. Larger longitudinal studies are warranted to determine the role of early neurovascular damage in the pathophysiology of severe DR.

Ling Yu,1,&ast; Yang Chen,2,&ast; Xiang Xu,2 Qiwei Dong,2,3 Wenbo Xiu,2 Qinyuan Chen,2 Jinxia Wang,2 Chong He,2,3 Jian Ye,1 Fang Lu2,3 1Department of Ophthalmology, Daping Hospital, Army Medical Center, Army Medical University, Chongqing, People’s Republic of China; 2Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang LuClinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, 32 The First Ring Road West 2, Chengdu, Sichuan, 610072, People’s Republic of ChinaTel/Fax +86-028-87394201Email lufangfang@126.comJian YeDepartment of Ophthalmology, Daping Hospital, Army Medical Center, Army Medical University, No. 10, Changjiang Branch, Daping, Yuzhong District, Chongqing, 400042, People’s Republic of ChinaTel/Fax +86-023-68811229Email yejian1979@163.comBackground: Glaucoma is a group of retinal neurodegenerative diseases causing irreversible visual impairment. The pathogenesis of this disease is complicated. Studies have shown that the immune system is involved in the neurodegenerative process of glaucoma. There are continuous evidences that autoantibodies play a crucial role in the pathogenesis of glaucoma. However, focuses on B cells, the antibody-producing cells in glaucoma are surprisingly limited.Methods: Fresh peripheral blood samples were collected from 44 glaucoma patients (38 with primary angle-closure glaucoma (PACG) and 6 with (primary open-angle glaucoma POAG)) and 36 age-matched healthy donors (HD). Density gradient centrifugation was performed to obtain peripheral blood mononuclear cells (PBMC). Flow cytometry was performed to determine B cell phenotypes. The severity of glaucoma was determined based on the mean deviation (MD) of visual field.Results: In this study, we demonstrated that total B cells was significantly increased in glaucoma patients compared to HD. Next, we checked changes of different B cell subsets in glaucoma. Glaucoma patients were found to have a significant increase in the frequencies of antibody-secreting cells (ASC)/plasmablasts, naïve, and CD19+ CD27− IgD− double negative (DN) subpopulations, but a decrease in the CD27+ IgD+ unswitched memory compartment. Notably, we found that the increment of CD27− IgD− DN B cells was significantly magnified according to the clinical severity.Conclusion: We demonstrate, for the first time, that peripheral B cell subsets are altered and unveil the correlation of a newly identified pro-inflammatory CD27− IgD− DN subset with clinical features of glaucoma, suggesting that these B cell subsets could serve as potential biomarkers to monitor the disease progression of glaucoma patients.Keywords: glaucoma, B cells, CD27− IgD− double negative B cells, retinal neurodegeneration

Ischemia/reperfusion (I/R) injury is a common pathological mechanism involved in many ocular diseases. I/R is characterized by microvascular dysfunction and neurodegeneration. However, the mechanisms of neurodegeneration induced by I/R remain largely unknown. This study showed that the expression of long non-coding RNA-CRNDE was significantly upregulated after retinal ischemia-reperfusion (RIR). LncRNA-CRNDE knockdown alleviated retinal neurodegeneration induced by RIR injury, as shown by decreased reactive gliosis and reduced retinal cells loss. Furthermore, lncRNA-CRNDE knockdown directly regulated Müller cell function and indirectly affected RGC function in vitro. In addition, lncRNA-CRNDE knockdown led to a significant reduction in the release of several cytokines after RIR. This study suggests that lncRNA-CRNDE is a promising therapeutic target for RIR.

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma. Design: Retrospective analysis of prospective cohort data. Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion cell–inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (β = –0.13 μm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; β = –0.20 μm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 μm vs. 71.9 μm; P = 0.011) and pRNFL (77.6 μm vs. 79.2 μm; P = 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.

To explore the role of microRNA-26a-5p (miR-26a) in early diabetic retinal neuronal cell death and reveal the underlying mechanism(s). A streptozotocin (STZ)-induced diabetic mouse model was established using C57BL/6 J mice. Control or miR-26a mimic was intravitreally injected. Hematoxylin-eosin (H&E) and transmission electron microscopy (TEM) were used to observe the morphologic alterations in the retinal structure and ultrastructure, respectively. The expression of miR-26a and phosphatase and tensin homolog (PTEN) was assayed using qRT-PCR and western blotting, respectively. An immunofluorescence assay was used to investigate the distribution of PTEN expression in the retina. The expression of glial fibrillary acidic protein (GFAP) was measured to identify glial cell activation. The mRNA levels of IL-1β, NF-κB, and VEGF were examined to assess diabetic retinal inflammation. miR-26a expression was decreased in retinal tissues of diabetic mice, and injection of miR-26a mimic restored the miR-26a level. Diabetic mice had significantly reduced neuroretinal thickness and ganglion cell number; miR-26a mimic delayed the thinning of neuroretinal layers and the loss of ganglion numbers. TEM showed damaged ultrastructure of retinal ganglions in diabetic mice, while miR-26a mitigated the damages. PTEN expression was increased mainly in the inner and outer nuclear layer of the retina in diabetic mice; miR-26a mimics lowered PTEN expression. GFAP, IL-1β, NF-κB, and VEGF expression were significantly increased in the diabetic mice, and intravitreal delivery of miR-26a resulted in a down-regulated expression of these factors. miR-26a can protect against retinal neuronal impairment in diabetic mice by down-regulating PTEN, highlighting the potential of miR-26a as a target for DR treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate retinal thickness and capillary density in patients with type 2 diabetes (T2D) and their association with diabetic kidney disease (DKD) using swept-source optical coherence tomography (SS-OCT). Methods: A cross-sectional study was conducted with T2D patients with mild or no diabetic retinopathy (DR) and nondiabetic controls. Inner retinal layer thickness was measured with SS-OCT. Retinal capillary density and the foveal avascular zone (FAZ) were measured with SS-OCT angiography (OCTA). SS-OCT parameters were compared in patients with and without diabetic kidney disease (DKD) and nondiabetic controls. Results: 131 DKD eyes showed decreased ganglion cell layer plus (GCL+) (p = 0.005 TI; p = 0.022 I), retinal nerve fiber layer (RNFL) (p = 0.003), and central retinal thickness (CRT) (p = 0.032), as well as foveal avascular zone (FAZ) enlargement (p = 0.003) and lower capillary density in the superficial vascular plexus (p = 0.016, central quadrant), compared to controls. No statistically significant changes were found between diabetic patients without significant DKD and controls. Conclusion: Our findings suggest early neurovascular damage in patients with T2D; these changes were more significant in patients with DKD. Larger longitudinal studies are warranted to determine the role of early neurovascular damage in the pathophysiology of severe DR. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether abnormal retinal microcirculation correlates with retinal neuronal changes in untreated diabetic eyes without macular edema. Methods: This study enrolled 29 diabetic patients without diabetic retinopathy (DR), 18 patients with mild non-proliferative diabetic retinopathy (NPDR), 15 patients with moderate NPDR, 14 patients with severe NPDR, 27 patients with proliferative diabetic retinopathy (PDR), and 25 healthy control subjects. Pattern electroretinography (PERG) and optical coherence tomography angiography (OCT-A) tests were performed. Results: Differences in the mean values for the area, acircularity index, and perimeter of foveal avascular zone were statistically significant between the healthy control group and the diabetic patients (P < 0.05 for all). P50 and N95 amplitudes were statistically significantly lower in the PDR group compared to diabetic patients without DR, control, and moderate NPDR groups (P < 0.05 for all). The whole retina vessel densities in superficial and deep capillary plexus were lower in the PDR group compared to the diabetic patients without DR and control group (P < 0.05 for all). There were statistically significant positive correlations between the amplitudes of the P50 and N95 waves with the vessel densities. Conclusion: The existence of significant correlations between PERG and OCT-A parameters in diabetic patients has shown that vascular and neuronal changes in the macula affect each other in diabetic patients. [ABSTRACT FROM AUTHOR]

Background and purpose: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image‐derived phenotypes (IDPs) in a large cohort of healthy older people. Methods: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell‐inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. Results: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. Conclusions: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Diabetic retinopathy is characterised by retinal neurodegeneration and retinal vascular abnormalities, affecting one third of diabetic patients with disease duration of more than 10 years. Accumulated evidence suggests that serine racemase (SR) and D-serine are correlated with the pathogenesis of diabetic retinopathy and the deletion of the Srr gene reverses neurovascular pathologies in diabetic mice. Since D-serine content is balanced by SR synthesis and D-amino acid oxidase (DAAO) degradation, we examined the roles of DAAO in diabetic retinopathy and further explored relevant therapy. Methods: Rats were used as a model of diabetes by i.p. injection of streptozotocin at the age of 2 months and blood glucose was monitored with a glucometer. Quantitative real-time PCR was used to examine Dao mRNA and western blotting to examine targeted proteins in the retinas. Bisulphite sequencing was used to examine the methylation of Dao mRNA promoter in the retinas. Intravitreal injection of DAAO-expressing adenovirus (AAV8-DAAO) was conducted one week before streptozotocin administration. Brain specific homeobox/POU domain protein 3a (Brn3a) immunofluorescence was conducted to indicate retinal ganglion cells at 3 months after virus injection. The permeability of the blood–retinal barrier was examined by Evans blue leakage from retinal capillaries. Periodic acid–Schiff staining and haematoxylin counterstaining were used to indicate retinal vasculature, which was further examined with double immunostaining at 7 months after virus injection. Results: At the age of 12 months, DAAO mRNA and protein levels in retinas from diabetic animals were reduced to 66.2% and 70.4% of those from normal (control) animals, respectively. The Dao proximal promoter contained higher levels of methylation in diabetic than in normal retinas. Consistent with the observation, DNA methyltransferase 1 was increased in diabetic retinas. Injection of DAAO-expressing virus completely prevented the loss of retinal ganglion cells and the disruption of blood–retinal barrier in diabetic rats. Diabetic retinas contained retinal ganglion cells at a density of 54 ± 4/mm2, which was restored to 68 ± 9/mm2 by DAAO overexpression, similar to the levels in normal retinas. The ratio between the number of endothelial cells and pericytes in diabetic retinas was 6.06 ± 1.93/mm2, which was reduced to 3.42 ± 0.55/mm2 by DAAO overexpression; the number of acellular capillaries in diabetic retinas was 10 ± 5/mm2, which was restored to 6 ± 2/mm2 by DAAO overexpression, similar to the levels in normal retinas. Injection of the DAAO-expressing virus increased the expression of occludin and reduced gliosis, which were examined to probe the mechanism by which the disrupted blood–retinal barrier in diabetic rats was rescued and retinal neurodegeneration was prevented. Conclusions/interpretation: Altogether, overexpression of DAAO before the onset of diabetes protects against neurovascular abnormalities in retinas from diabetic rats, which suggests a novel strategy for preventing diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Abstract Background Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. Methods To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. Results We demonstrate for the first time that tau hyperphosphorylation via GSK3β activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3β reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3β-dependent manner. Conclusions Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities.

AIM: To explore the more suitable concentration of glutamate or N-methyl-D-aspartic acid (NMDA) for intravitreal injection to establish a rat model of retinal neurodegeneration. METHODS: We injected different doses of glutamate (20 or 50 nmol) or NMDA (40 nmol) into the vitreous chambers of rats, then measured the concentration of glutamate and retinal thickness, quantified apoptotic cells and determined the degree of tau hyperphosphorylation at different time points. T-test was used for comparison of two groups. One-way ANOVA and Turkey's multiple comparisons test were used for comparisons of different groups, and P values below 0.05 were considered statistically significant. RESULTS: The glutamate level in the rats treated with 50 nmol of glutamate was twice that of the control group and persisted two weeks. Seven days after intravitreal injection of 50 nmol of glutamate, three parameters [inner retinal thickness (IRT), retinal thickness (RT) and ganglion cell layer (GCL) cell number] were reduced significantly. Furthermore, numerous TUNEL-positive cells were observed in the GCL one day after intravitreal injection of 50 nmol of glutamate, the expression of the apoptosis-related factor cleaved casepase-3 was markedly increased compared with the expression levels in the other treatment groups, and the expression levels of tau s396 and tau s404 were significantly increased compared with those in the control group. CONCLUSION: This study demonstrates that the intravitreal injection of 50 nmol of glutamate can establish the more effective retinal neurodegeneration animal model relative to other treatment groups.

The neurovascular unit (NVU) plays an essential role in the development of diabetic retinopathy (DR). We previously reported that the topical administration (eye drops) of sitagliptin and saxagliptin, two dipeptidyl peptidase-4 inhibitors (DPP-4i), prevents retinal neurodegeneration and vascular leakage in db/db mice. The aim of the present study is to evaluate the minimum effective dose of the topical administration of these DPP-4i. For this purpose, sitagliptin and saxagliptin were tested at different concentrations (sitagliptin: 1 mg/mL, 5 and 10 mg/mL, twice per day; saxagliptin: 1 and 10 mg/mL, once or twice per day) in db/db mice. As end points of efficacy, the hallmarks of NVU impairment were evaluated: reactive gliosis, neural apoptosis, and vascular leakage. These parameters were assessed by immunohistochemistry, cell counting, and the Evans blue method, respectively. Our results demonstrated that the minimum effective dose is 5 mg/mL twice per day for sitagliptin, and 10 mg/mL twice per day for saxagliptin. In conclusion, this study provides useful results for the design of future preclinical regulatory studies and for planning clinical trials.

Retinal neurodegeneration affects an increasing number of people worldwide causing vision impairments and blindness, reducing quality of life, and generating a great economic challenge. Due to the complexity of the tissue, and the diversity of retinal neurodegenerative diseases in terms of etiology and clinical presentation, so far, there are no cures and only a few early pathological markers have been identified. Increasing efforts have been made to identify and potentiate endogenous protective mechanisms or to abolish detrimental stress responses to preserve retinal structure and function. The discovering of the intracellular monomeric globin neuroglobin (NGB), found at high concentration in the retina, has opened new possibilities for the treatment of retinal disease. Indeed, the NGB capability to reversibly bind oxygen and its neuroprotective function against several types of insults including oxidative stress, ischemia, and neurodegenerative conditions have raised the interest in the possible role of the globin as oxygen supplier in the retina and as a target for retinal neurodegeneration. Here, we provide the undercurrent knowledge on NGB distribution in retinal layers and the evidence about the connection between NGB level modulation and the functional outcome in terms of retinal neuroprotection to provide a novel therapeutic/preventive target for visual pathway degenerative disease.

Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role.

The possible interconnection between the eye and central nervous system (CNS) has been a topic of discussion for several years just based on fact that the eye is properly considered an extension of the brain. Both organs consist of neurons and derived from a neural tube. The visual process involves photoreceptors that receive light stimulus from the external environment and send it to retinal ganglionic cells (RGC), one of the cell types of which the retina is composed. The retina, the internal visual membrane of the eye, processes the visual stimuli in electric stimuli to transfer it to the brain, through the optic nerve. Retinal chronic progressive neurodegeneration, which may occur among the elderly, can lead to different disorders of the eye such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Mainly in the elderly population, but also among younger people, such ocular pathologies are the cause of irreversible blindness or impaired, reduced vision. Typical neurodegenerative diseases of the CSN are a group of pathologies with common characteristics and etiology not fully understood; some risk factors have been identified, but they are not enough to justify all the cases observed. Furthermore, several studies have shown that also ocular disorders present characteristics of neurodegenerative diseases and, on the other hand, CNS pathologies, i.e., Alzheimer disease (AD) and Parkinson disease (PD), which are causes of morbidity and mortality worldwide, show peculiar alterations at the ocular level. The knowledge of possible correlations could help to understand the mechanisms of onset. Moreover, the underlying mechanisms of these heterogeneous disorders are still debated. This review discusses the characteristics of the ocular illnesses, focusing on the relationship between the eye and the brain. A better comprehension could help in future new therapies, thus reducing or avoiding loss of vision and improve quality of life.