Correlation between serum biomarkers, brain volume, and retinal neuronal loss in early-onset Alzheimer's disease.

PURPOSE: To compare the peripapillary retinal nerve fiber layer (pRNFL), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) thickness measurement in early-onset Alzheimer's disease (EOAD) and controls using spectral domain optical coherence tomography (SD-OCT). We also assessed the relationship between SD-OCT measurements and cognitive measures, serum biomarkers for Alzheimer's disease (AD), and cerebral microstructural volume. METHODS: pRNFL, RNFL, and GCC thicknesses were measured in 43 EOAD and 42 controls using SD-OCT. Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) were used to assess cognitive status, magnetic resonance imaging (MRI) tool was used to quantify cerebral microstructural volume, and serum biomarkers were quantified from peripheral blood. RESULTS: EOAD patients had thinner pRNFL (P < 0.001), RNFL (P = 0.008), and GCC (P = 0.018) thicknesses compared to controls after adjusting for multiple factors. pRNFL thickness correlated (P = 0.016) with serum t-tau level. Serum Aß42 (P < 0.05) concentration correlated with RNFL thickness. Importantly, occipital lobe volume (P = 0.010) correlated with GCC thicknesses in EOAD patients. CONCLUSION: Our findings suggest that retinal thickness may be useful markers for assessing neurodegenerative process in EOAD.

Defects of full-length dystrophin trigger retinal neuron damage and synapse alterations by disrupting functional autophagy.

Dystrophin (dys) mutations predispose Duchenne muscular disease (DMD) patients to brain and retinal complications. Although different dys variants, including long dys products, are expressed in the retina, their function is largely unknown. We investigated the putative role of full-length dystrophin in the homeostasis of neuro-retina and its impact on synapsis stabilization and cell fate. Retinas of mdx mice, the most used DMD model which does not express the 427-KDa dys protein (Dp427), showed overlapped cell death and impaired autophagy. Apoptotic neurons in the outer plexiform/inner nuclear layer and the ganglion cell layer had an impaired autophagy with accumulated autophagosomes. The autophagy dysfunction localized at photoreceptor axonal terminals and bipolar, amacrine, and ganglion cells. The absence of Dp427 does not cause a severe phenotype but alters the neuronal architecture, compromising mainly the pre-synaptic photoreceptor terminals and their post-synaptic sites. The analysis of two dystrophic mutants of the fruit fly Drosophila melanogaster, the homozygous DysE17 and DysEP3397, lacking functional large-isoforms of dystrophin-like protein, revealed rhabdomere degeneration. Structural damages were evident in the internal network of retina/lamina where photoreceptors make the first synapse. Both accumulated autophagosomes and apoptotic features were detected and the visual system was functionally impaired. The reactivation of the autophagosome turnover by rapamycin prevented neuronal cell death and structural changes of mutant flies and, of interest, sustained autophagy ameliorated their response to light. Overall, these findings indicate that functional full-length dystrophin is required for synapsis stabilization and neuronal survival of the retina, allowing also proper autophagy as a prerequisite for physiological cell fate and visual properties.

Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction.

AIMS/HYPOTHESIS: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health. We have previously demonstrated that IF prevents the development of diabetic retinopathy in a mouse model of type 2 diabetes (db/db); however the mechanisms of fasting-induced health benefits and fasting-induced risks for individuals with diabetes remain largely unknown. Sirtuin 1 (SIRT1), a nutrient-sensing deacetylase, is downregulated in diabetes. In this study, the effect of SIRT1 stimulation by IF, fasting-mimicking cell culture conditions (FMC) or pharmacological treatment using SRT1720 was evaluated on systemic and retinal metabolism, systemic and retinal inflammation and vascular and bone marrow damage. METHODS: The effects of IF were modelled in vivo using db/db mice and in vitro using bovine retinal endothelial cells or rat retinal neuroglial/precursor R28 cell line serum starved for 24 h. mRNA expression was analysed by quantitative PCR (qPCR). SIRT1 activity was measured via histone deacetylase activity assay. NR1H3 (also known as liver X receptor alpha [LXRα]) acetylation was measured via western blot analysis. RESULTS: IF increased Sirt1 mRNA expression in mouse liver and retina when compared with non-fasted animals. IF also increased SIRT1 activity eightfold in mouse retina while FMC increased SIRT1 activity and expression in retinal endothelial cells when compared with control. Sirt1 expression was also increased twofold in neuronal retina progenitor cells (R28) after FMC treatment. Moreover, FMC led to SIRT1-mediated LXRα deacetylation and subsequent 2.4-fold increase in activity, as measured by increased mRNA expression of the genes encoding ATP-binding cassette transporter (Abca1 and Abcg1). These changes were reduced when retinal endothelial cells expressing a constitutively acetylated LXRα mutant were tested. Increased SIRT1/LXR/ABC-mediated cholesterol export resulted in decreased retinal endothelial cell cholesterol levels. Direct activation of SIRT1 by SRT1720 in db/db mice led to a twofold reduction of diabetes-induced inflammation in the retina and improved diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response. In the bone marrow, there was prevention of diabetes-induced myeloidosis and decreased inflammatory cytokine expression. CONCLUSIONS/INTERPRETATION: Taken together, activation of SIRT1 signalling by IF or through pharmacological activation represents an effective therapeutic strategy that provides a mechanistic link between the advantageous effects associated with fasting regimens and prevention of microvascular and bone marrow dysfunction in diabetes.

Association of Antihypertensive Medication with Retinal Nerve Fiber Layer and Ganglion Cell-Inner Plexiform Layer Thickness.

PURPOSE: To evaluate the association between different classes of antihypertensive medication with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness in a nonglaucomatous multiethnic Asian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 9144 eyes for RNFL analysis (2668 Malays, 3554 Indians, and 2922 Chinese) and 8549 eyes for GC-IPL analysis (2460 Malays, 3230 Indians, and 2859 Chinese) aged 44 to 86 years. METHODS: Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for collection of data on medication and other variables. Intraocular pressure (IOP) readings were obtained by Goldmann applanation tonometry before pupil dilation for fundoscopy and OCT imaging. Blood pressure (BP) was measured with an automatic BP monitor. Mean arterial pressure (MAP) was defined as diastolic BP plus 1/3 (systolic BP - diastolic BP). Regression models were used to investigate the association of antihypertensive medication with OCT measurements of RNFL and GC-IPL. MAIN OUTCOME MEASURES: Average and sectoral RNFL and GC-IPL thickness. RESULTS: After adjusting for age, gender, ethnicity, MAP, IOP, body mass index (BMI), and presence of diabetes, we found that participants taking any type of antihypertensive medication (ß = -0.83; 95% confidence interval [CI], -1.46 to -0.02; P = 0.01), specifically angiotensin-converting enzyme inhibitors (ACEIs) (ß = -1.66; 95% CI, -2.57 to -0.75; P < 0.001) or diuretics (ß = -1.38; 95% CI, -2.59 to -0.17; P < 0.05), had thinner average RNFL in comparison with participants who were not receiving antihypertensive treatment. Use of a greater number of antihypertensive medications was significantly associated with thinner average RNFL (P for trend = 0.001). This association was most evident in the inferior RNFL quadrant in participants using ACEIs (ß = -2.44; 95% CI, -3.99 to -0.89; P = 0.002) or diuretics (ß = -2.76; 95% CI, -4.76 to -0.76; P = 0.007). A similar trend was noted in our analysis of macular GC-IPL thickness. CONCLUSIONS: Use of 2 or more antihypertensive medications, ACEI, and diuretics were associated with a loss of structural markers of retinal ganglion cell health in a multiethnic Asian population.

Development and characterization of a chronic photoreceptor degeneration model in adult zebrafish that does not trigger a regenerative response.

Zebrafish (Danio rerio) have become a highly-utilized model system in the field of regenerative biology because of their endogenous ability to regenerate many tissues and organs, including the retina. The vast majority of previous research on retinal regeneration in adult zebrafish utilizes acute methodologies for retinal damage. Acute retinal cell death triggers a reactive gliosis response of Müller glia (MG), the resident macroglia of the retina. In addition, each activated MG undergoes asymmetric cell division to produce a neuronal progenitor, which continues to divide and ultimately gives rise to new retinal neurons. Studies using these approaches have uncovered many crucial mechanisms by which MG respond to acute damage. However, they may not adequately mimic the chronic neuronal degeneration observed in many human retinal degenerative diseases. The current study aimed to develop a new long-term, chronic photoreceptor damage and degeneration model in adult zebrafish. Comparing the subsequent cellular responses to that of the commonly-used acute high-intensity model, we found that low, continuous light exposure damaged the outer segments of both rod and cone photoreceptors, but did not result in significant apoptotic cell death, MG gliosis, or MG cell-cycle re-entry. Instead, chronic light nearly completely truncated photoreceptor outer segments and resulted in a recruitment of microglia to the area. Together, these studies present a chronic photoreceptor model that can be performed in a relatively short time frame (21 days), that may lend insight into the cellular events underlying non-regenerative photoreceptor degeneration observed in other model systems.

Damaging effects of BMAA on retina neurons and Müller glial cells.

B-N-methylamino-L-alanine (BMAA), a cyanotoxin produced by most cyanobacteria, has been proposed to cause long term damages leading to neurodegenerative diseases, including Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) and retinal pathologies. Previous work has shown diverse mechanisms leading to BMAA-induced degeneration; however, the underlying mechanisms of toxicity affecting retina cells are not fully elucidated. We here show that BMAA treatment of rat retina neurons in vitro induced nuclear fragmentation and cell death in both photoreceptors (PHRs) and amacrine neurons, provoking mitochondrial membrane depolarization. Pretreatment with the N-Methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevented BMAA-induced death of amacrine neurons, but not that of PHRs, implying activation of NMDA receptors participated only in amacrine cell death. Noteworthy, BMAA stimulated a selective axonal outgrowth in amacrine neurons, simultaneously promoting growth cone destabilization. BMAA partially decreased the viability of Müller glial cells (MGC), the main glial cell type in the retina, induced marked alterations in their actin cytoskeleton and impaired their capacity to protect retinal neurons. BMAA also induced cell death and promoted axonal outgrowth in differentiated rat pheochromocytoma (PC12) cells, implying these effects were not limited to amacrine neurons. These results suggest that BMAA is toxic for retina neurons and MGC and point to the involvement of NMDA receptors in amacrine cell death, providing new insight into the mechanisms involved in BMAA neurotoxic effects in the retina.

Melatonin protects inner retinal neurons of newborn mice after hypoxia-ischemia.

Retinopathy of prematurity is a vision-threatening disease associated with retinal hypoxia-ischemia, leading to the death of retinal neurons and chronic neuronal degeneration. During this study, we used the oxygen-induced retinopathy mice model to mimic retinal hypoxia-ischemia phenotypes to investigate further the neuroprotective effect of melatonin on neonatal retinal neurons. Melatonin helped maintain relatively normal inner retinal architecture and thickness and preserve inner retinal neuron populations in avascular areas by rescuing retinal ganglion and bipolar cells, and horizontal and amacrine neurons, from apoptosis. Meanwhile, melatonin recovered visual dysfunction, as reflected by the improved amplitudes and implicit times of a-wave, b-wave, and oscillatory potentials. Additionally, elevated cleaved caspase-3 and Bax protein levels and reduced Bcl-2 protein levels in response to hypoxia-ischemia were diminished after melatonin treatment. Moreover, melatonin increased BDNF and downstream phospho-TrkB/Akt/ERK/CREB levels. ANA-12, a TrkB receptor antagonist, antagonized these melatonin actions and reduced melatonin-induced neuroprotection. Furthermore, melatonin rescued the reduction in melatonin receptor expression. This study suggests that melatonin exerted anti-apoptotic and neuroprotective effects in inner retinal neurons after hypoxia-ischemia, at least partly due to modulation of the BDNF-TrkB pathway.

Optical Coherence Tomography findings in patients with Multiple Substance Use Disorder.

OBJECTIVE: Optical Coherence Tomography (OCT) is a relatively new diagnosis method displaying biological tissue layers by with high-resolution sections. In the present study, the purpose was to examine the OCT findings of patients with Multiple Substance Use Disorder (MSUD) by comparing these findings with healthy controls. METHODS: The study included 30 MSUD and 30 controls. Detailed biomicroscopic examinations were carried out for all participants, and intraocular pressure, followed by OCT. The central macular thickness (CMT), mean macular thickness (MMT), mean macular volume (MMV), and retinal nerve fibre layer thickness (RNFL) were measured by using OCT. RESULTS: It was determined that the MMT and CMT were thinned in both eyes compared to the healthy controls. The MMV was decreased in both eyes in patients with substance use disorders compared to healthy controls. The RNFL and total thickness were thickened in temporal and inferior parts in patients with MSUD in both eyes compared to healthy. In the superior quadrant, thickening was detected only in the left eye. CONCLUSIONS: Based on our results obtained here, it was concluded that vision-related findings should be carefully questioned and evaluated when treatment is planned for patients with substance use.

Optimal intereye difference thresholds by optical coherence tomography in multiple sclerosis: An international study.

OBJECTIVE: To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions. METHODS: In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis. RESULTS: Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5µm and ganglion cell + inner plexiform layer threshold of 4µm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001). INTERPRETATION: Intereye differences of 5µm for retinal nerve fiber layer and 4µm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629.

Smelling multiple sclerosis: Different qualities of olfactory function reflect either inflammatory activity or neurodegeneration.

BACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) thickness and olfactory function are both emerging biomarkers in multiple sclerosis (MS). Impairment of odor identification and discrimination is an irreversible feature of more advanced MS suggested to be associated with neurodegeneration, while olfactory threshold is a transient feature of early, active MS possibly associated with short-term inflammatory disease activity. OBJECTIVE: The aim of this study was to validate the association of olfactory (dys)function and parameters of MS disease course in a large cohort of MS patients and to correlate olfactory function with pRNFL thickness as a surrogate biomarker of neurodegeneration. METHODS: In a cross-sectional design, olfactory function was assessed using the Sniffin' Sticks test, which quantifies three different qualities of olfactory function (threshold, discrimination, and identification). pRNFL thickness was measured by spectral-domain optical coherence tomography (OCT). Results were correlated with age, sex, disease duration, relapses, Expanded Disability Status Scale (EDSS), cognitive function, depression, smoking, and pRNFL thickness by multivariable linear regression models. RESULTS: We included 260 MS patients (mean age of 35.9 years, 68.7% female). Olfactory threshold correlated significantly with number of relapses in the year prior to assessment and shorter disease duration. Odor discrimination, identification, and their sum score were significantly correlated with longer disease duration, higher EDSS, and reduced cognitive function. pRNFL thickness was associated with identification and discrimination, but not with threshold. CONCLUSION: Olfactory threshold is a marker of short-term inflammatory relapse activity unrelated to parameters of neurodegeneration, while odor identification and discrimination are markers of neurodegeneration mostly independent of relapse activity. Assessment of olfactory function provides an opportunity to stratify MS patients with regard to inflammation and neurodegeneration.

Restoring Vision to the Blind with Chemical Photoswitches.

Degenerative retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) affect millions of people around the world and lead to irreversible vision loss if left untreated. A number of therapeutic strategies have been developed over the years to treat these diseases or restore vision to already blind patients. In this Review, we describe the development and translational application of light-sensitive chemical photoswitches to restore visual function to the blind retina and compare the translational potential of photoswitches with other vision-restoring therapies. This therapeutic strategy is enabled by an efficient fusion of chemical synthesis, chemical biology, and molecular biology and is broadly applicable to other biological systems. We hope this Review will be of interest to chemists as well as neuroscientists and clinicians.

Long-Term Stability of Neuroaxonal Structure in Alemtuzumab-Treated Relapsing-Remitting Multiple Sclerosis Patients.

BACKGROUND: Patients with multiple sclerosis (MS) experience progressive thinning in optical coherence tomography (OCT) measures of neuroaxonal structure regardless of optic neuritis history. Few prospective studies have investigated the effects of disease-modifying therapies on neuroaxonal degeneration in the retina. Alemtuzumab is a monoclonal antibody shown to be superior to interferon ß-1a in treating relapsing-remitting MS (RRMS). The purpose of this study was to assess the effects of alemtuzumab and first-line injectable treatments on OCT measures of neuroaxonal structure including peripapillary retinal nerve fiber layer (RNFL) thickness and combined ganglion cell-inner plexiform (GCIP) layer volume in RRMS patients followed up over 5 years. METHODS: In this retrospective pilot study with prospectively collected double cohort data, spectral domain OCT measures of RNFL thickness and GCIP volume were compared between alemtuzumab-treated RRMS patients (N = 24) and RRMS patients treated with either interferon-ß or glatiramer acetate (N = 21). RESULTS: Over a median of 60 months (range 42-60 months), the alemtuzumab cohort demonstrated a change in the mean RNFL thickness (thinning from baseline) of -0.88 µm (95% confidence interval [CI] -2.63 to 0.86; P = 0.32) and mean GCIP volume of +0.013 mm (95% CI -0.006 to 0.032; P = 0.18). Over the same time period, the first-line therapy-treated cohort demonstrated greater degrees of RNFL thinning (mean change in RNFL thickness was -3.65 µm [95% CI -5.40 to -1.89; P = 0.0001]). There was also more prominent GCIP volume loss relative to baseline in the first-line therapy group (-0.052 mm [95% CI -0.070 to -0.034; P < 0.0001]). CONCLUSIONS: Alemtuzumab-treated patients with RRMS demonstrated relative stability of OCT-measured neuroaxonal structure compared with RRMS patients treated with either interferon-ß or glatiramer acetate over a 5-year period. These findings, along with previous demonstration of improved brain atrophy rates, suggest that alemtuzumab may offer long-term preservation of neuroaxonal structure in patients with RRMS.

Optical coherence tomography of the retina, nerve fiber layer, and optic nerve head in dogs with glaucoma.

OBJECTIVE: To evaluate the retina and optic nerve head (ONH) in canine eyes predisposed to glaucoma using optical coherence tomography (OCT). ANIMALS: Twenty-five eyes (24 dogs). METHODS: Measures of peripapillary retinal, retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) thickness and ONH parameters were obtained in vivo by OCT of the unaffected eye in dogs diagnosed with unilateral primary glaucoma (predisposed; n = 12) and compared with measures of healthy control eyes (normal; n = 13). Repeatability and intrarater reliability were explored using intraclass correlation coefficients (ICC). RESULTS: Compared to normal eyes, predisposed eyes had a thinner retina in the temporal (P = 0.005), inferior quadrants (P = 0.003), and decreased inner retinal thickness (superior: P = 0.003, temporal: P = 0.001, inferior: P < 0.001, nasal: P = 0.001). Predisposed eyes had a thinner RNFL compared to normal eyes (P = 0.005), and when analyzed in quadrants, it was thinner in the superior (P < 0.001), temporal (P = 0.034), and nasal quadrants (P = 0.001). Repeatability (ICC 0.763-0.835) and intrarater reliability (ICC 0.824-0.942) were good to excellent for measures of retinal thickness and adequate for RNFL measurements (ICC 0.701-0.798). Reliable measurements of optic disk area were obtained and were similar between groups (P = 0.597). Measurements of parameters relying on automated software detection (GCC, optic cup, optic rim) had inadequate repeatability and reliability. CONCLUSION: Statistically significant differences in retinal and RNFL thicknesses were identified in normal and predisposed eyes. Reliable and consistent measurements of variables with manual adjustment of software detected parameters were obtained. Validation of OCT as a diagnostic tool for clinical assessment in canine glaucoma is warranted.

Potential retinal biomarkers for dementia: what is new?

PURPOSE OF REVIEW: To summarize the current findings on clinical retinal diseases and retinal imaging changes with dementia, focusing on Alzheimer's disease. RECENT FINDINGS: Studies observed that clinical retinal diseases such as age-related macular degeneration, open-angle glaucoma and diabetic retinopathy are related to dementia, but the associations are not entirely consistent. In terms of the retinal neuronal structure, multiple retinal neuronal layers are significantly thinner in Alzheimer's disease dementia, such as the parapapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GC-IPL). Recent studies further demonstrated that macular GC-IPL and macular RNFL are also significantly thinner in the preclinical stage of Alzheimer's disease. A thinner RNFL is also associated with a significantly increased risk of developing both cognitive decline and Alzheimer's disease dementia. In addition, studies consistently showed that retinal vascular changes are associated with poorer cognitive performance, as well as prevalent and incident Alzheimer's disease dementia. SUMMARY: The current findings support the concept that changes in the retina, particular in retinal neuronal structure and vasculature, can reflect the status of cerebral neuronal structure and vasculature, highlighting the potential role of retinal changes as biomarkers of dementia.

The agonistic TSPO ligand XBD173 attenuates the glial response thereby protecting inner retinal neurons in a murine model of retinal ischemia.

BACKGROUND: Ligand-driven modulation of the mitochondrial translocator protein 18 kDa (TSPO) was recently described to dampen the neuroinflammatory response of microglia in a retinal light damage model resulting in protective effects on photoreceptors. We characterized the effects of the TSPO ligand XBD173 in the postischemic retina focusing on changes in the response pattern of the major glial cell types of the retina-microglia and Müller cells. METHODS: Retinal ischemia was induced by increasing the intraocular pressure for 60 min followed by reperfusion of the tissue in mice. On retinal cell types enriched via immunomagnetic separation expression analysis of TSPO, its ligand diazepam-binding inhibitor (DBI) and markers of glial activation were performed at transcript and protein level using RNA sequencing, qRT-PCR, lipid chromatography-mass spectrometry, and immunofluorescent labeling. Data on cell morphology and numbers were assessed in retinal slice and flatmount preparations. The retinal functional integrity was determined by electroretinogram recordings. RESULTS: We demonstrate that TSPO is expressed by Müller cells, microglia, vascular cells, retinal pigment epithelium (RPE) of the healthy and postischemic retina, but only at low levels in retinal neurons. While an alleviated neurodegeneration upon XBD173 treatment was found in postischemic retinae as compared to vehicle controls, this neuroprotective effect of XBD173 is mediated putatively by its action on retinal glia. After transient ischemia, TSPO as a marker of activation was upregulated to similar levels in microglia as compared to their counterparts in healthy retinae irrespective of the treatment regimen. However, less microglia were found in XBD173-treated postischemic retinae at 3 days post-surgery (dps) which displayed a more ramified morphology than in retinae of vehicle-treated mice indicating a dampened microglia activation. Müller cells, the major retinal macroglia, show upregulation of the typical gliosis marker GFAP. Importantly, glutamine synthetase was more stably expressed in Müller glia of XBD173-treated postischemic retinae and homeostatic functions such as cellular volume regulation typically diminished in gliotic Müller cells remained functional. CONCLUSIONS: In sum, our data imply that beneficial effects of XBD173 treatment on the postischemic survival of inner retinal neurons were primarily mediated by stabilizing neurosupportive functions of glial cells.

Eyes are mirror of the brain: comparison of multiple sclerosis patients and healthy controls using OCT.

Objective: To evaluate the thickness of choroid and retinal nerve fiber layer (RNFL) in multiple sclerosis (MS) patients with and without optic neuritis using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods: In this cross-sectional study, both eyes of 52 MS patients [n = 104 eyes; 62 eyes of MS patients without optic neuritis (MS-NON) and 42 eyes of MS patients with optic neuritis (MS-ON)] and only one eye of 36 healthy control subjects (n = 36 eyes) were evaluated. Complete ophthalmologic examination and EDI-OCT scanning were completed for all participants. Choroidal thickness measurements were executed at three different points. Results: Choroidal thickness measurements were similar between MS patients and healthy control subjects. However, the mean subfoveal choroidal thickness was increased significantly in MS-ON group (399.13 ± 82.91 µm) compared to MS-NON group (342.71 ± 82.46 µm; p = 0.004). Mean RNFL thickness was significantly reduced in MS patients (90.42 ± 13.31 µm) compared to healthy controls (101.18 ± 10.75 µm; p < 0.001). Moreover, temporal RNFL thickness was significantly thinner in MS-ON group (54 ± 14.50 µm) than MS-NON group (62.15 ± 15.88 µm; p = 0.01). In MS patients, temporal RNFL thickness was correlated with both Expanded Disability Status Score (r = 0.383; p < 0.001) and longer disease duration (r=-0.202; p = 0.04). Conclusion: The results of the present study suggest that RNFL thickness can be used as an important parameter while following up with MS patients. However, more studies using EDI-OCT are required with larger MS patient groups and automated method.

Cellular Mechanisms of Angiogenesis in Neonatal Rat Models of Retinal Neurodegeneration.

Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, N-methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, 20 nmol) was injected into the vitreous chamber of the eye on postnatal day (P)7. Morphological changes in retinal neurons and vasculature were assessed on P14, P21, and P35. Prevention of vascular growth and regression of some capillaries were observed on P14 in retinas of NMDA- and KA-treated eyes. However, vascular growth and re-vascularization started on P21, and the retinal vascular network was established by P35 in retinas with neurodegenerative injuries. The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22. Astrocytes and Müller cells expressed vascular endothelial growth factor (VEGF), and the distribution pattern of VEGF was almost the same between the control and the NMDA-induced retinal neurodegenerative injury model, except for the difference in the thickness of the inner retinal layer. During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration.

Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7.

Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes.

Evaluation of intraocular pressure and retinal nerve fiber layer, retinal ganglion cell, central macular thickness, and choroidal thickness using optical coherence tomography in obese children and healthy controls.

OBJECTIVE: Obesity affects many organ systems. There have been few studies on the ophthalmological effects of obesity. The aim of the present study was to evaluate the changes in the ophthalmological parameters in obese children. SUBJECTS AND METHODS: The study included 61 obese and 35 age-and gender-matched control subjects. Obesity was defined as body mass index-standard deviation score (BMI-SDS) >2 SD. Children with a BMI-SDS between >-1 SD and <+1 SD whilst otherwise healthy were recruited as the control group. All clinical and ophthalmological investigations were performed by a pediatric endocrinologist and an experienced ophthalmologist. The ophthalmological examination and intraocular pressure (IOP) measurement was performed. The average retinal fiber layer (RNFL), retinal ganglion cell (RGC), central macular thickness (CMT), cup-to-disk ratio (C/D), and central choroidal thickness (CT) were measured using spectral domain optical coherence tomography. The anthropometric, biochemical, and ophthalmological parameters of the obese and control subjects were compared. RESULTS: IOP was higher in the obese group compared to the control group (P = 0.008), whereas the average RNFL was lower in the obese group (P = 0.035). There was a negative correlation between the average RNFL and BMI-SDS (P = -0.044) and waist-hip ratio (P = 0.015). There was no statistically significant difference between the RGC, C/D, CMT, and CT of the obese and control groups. IOP was negatively correlated with HOMA-IR, body fat mass, body fat percentage, and diastolic blood pressure. CONCLUSION: In the present study, which evaluated obesity and its effects on ophthalmological parameters, the elevated IOP and decreased RNFL thickness detected in the obese group may suggest an increased risk for these patients of developing glaucoma at a younger age. Therefore, regular ophthalmological examinations of obese children are essential for prompt diagnosis and appropriate management.

Retinal neuronal cell loss prevents abnormal retinal vascular growth in a rat model of retinopathy of prematurity.

A short-term blockade of the vascular endothelial growth factor (VEGF)-mediated pathway in neonatal rats results in formation of severe retinopathy of prematurity (ROP)-like retinal blood vessels. The present study aimed to examine the role of retinal neurons in the formation of abnormal retinal blood vessels. Newborn rats were treated subcutaneously with the VEGF receptor tyrosine kinase inhibitor, KRN633 (10 mg/kg), or its vehicle (0.5% methylcellulose in water) on postnatal day (P) 7 and P8. To induce excitotoxic loss of retinal neurons, N-methyl-D-aspartic acid (NMDA) was injected into the vitreous chamber of the eye on P9. Changes in retinal morphology, blood vessels, and proliferative status of vascular cells were evaluated on P11 and P14. The number of cells in the ganglion cell layer and the thickness of the inner plexiform layer and inner nuclear layer were significantly decreased 2 days (P11) after NMDA treatment. The pattern and degree of NMDA-induced changes in retinal morphology were similar between vehicle-treated (control) and KRN633-treated (ROP) rats. In ROP rats, increases in the density of capillaries, the tortuosity index of arteries, and the proliferating vascular cells were observed on P14. The expansion of the endothelial cell network was prevented, and the capillary density and the number of proliferating cells were reduced in NMDA-treated retinas of both control and ROP rats. Following NMDA-induced neuronal cell loss, no ROP-like blood vessels were observed in the retinas. These results suggest that retinal neurons play an important role in the formation of normal and ROP-like retinal blood vessels.