Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma.

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.

Racial Disparities in Cataract Surgery Timeline and Intraocular Lens Selection: A Retrospective Study.

Purpose: There is a significant amount of literature focusing on racial inequities in utilization rates and intraoperative complications of cataract surgery. Unfortunately, little is known about racial disparities regarding the timeline of cataract surgery and intraocular lens (IOL) selection. This study investigated whether black patients have a different preoperative and postoperative cataract surgery timeline and IOL selection than white patients. Methods: A total of 10,235 patients (83.47% white) were retrospectively identified from a tertiary academic center who underwent cataract surgery between 2015 and 2022. Each patient's best corrected visual acuity (BCVA), slit lamp findings, and surgical timeline were recorded. IOL selection was categorized as standard or premium. Results: Black patients had significantly worse mean ± SD preoperative logMAR BCVA than white patients (0.47 ± 0.55 vs. 0.58 ± 0.70, respectively; P = 0.0117) and were significantly less likely to receive surgery within 120 days of referral (RR, 0.71 [95% confidence interval {CI}, 0.64-0.79]; P < 0.0001). White patients were 25%, 24%, and 29% less likely to follow-up than black patients at postoperative day 1, day 7, and day 30, respectively (P < 0.0001). White patients were 6.09 (95% CI, 3.49, 10.63) times more likely to receive a premium IOL compared to black patients (P < 0.0001). Conclusions: Black patients experienced more delays with receiving cataract surgery but are more adherent with postoperative follow-up. Black patients were far less likely to receive a premium IOL than white patients. Translational Relevance: Increased awareness of racial inequities in cataract surgery may improve the delivery of eye care to minority groups.

Non-Invasive Evaluation of Retinal Vascular Alterations in a Mouse Model of Optic Neuritis Using Laser Speckle Flowgraphy and Optical Coherence Tomography Angiography.

Optic neuritis, a characteristic feature of multiple sclerosis (MS), involves the inflammation of the optic nerve and the degeneration of retinal ganglion cells (RGCs). Although previous studies suggest that retinal blood flow alterations occur during optic neuritis, the precise location, the degree of impairment, and the underlying mechanisms remain unclear. In this study, we utilized two emerging non-invasive imaging techniques, laser speckle flowgraphy (LSFG) and optical coherence tomography angiography (OCTA), to investigate retinal vascular changes in a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE). We associated these changes with leukostasis, RGC injury, and the overall progression of EAE. LSFG imaging revealed a progressive reduction in retinal blood flow velocity and increased vascular resistance near the optic nerve head in the EAE model, indicating impaired ocular blood flow. OCTA imaging demonstrated significant decreases in vessel density, number of junctions, and total vessel length in the intermediate and deep capillary plexus of the EAE mice. Furthermore, our analysis of leukostasis revealed a significant increase in adherent leukocytes in the retinal vasculature of the EAE mice, suggesting the occurrence of vascular inflammation in the early development of EAE pathology. The abovechanges preceded or were accompanied by the characteristic hallmarks of optic neuritis, such as RGC loss and reduced visual acuity. Overall, our study sheds light on the intricate relationship between retinal vascular alterations and the progression of optic neuritis as well as MS clinical score. It also highlights the potential for the development of image-based biomarkers for the diagnosis and monitoring of optic neuritis as well as MS, particularly in response to emerging treatments.

PERK Inhibition Suppresses Neovascularization and Protects Neurons During Ischemia-Induced Retinopathy.

Purpose: Retinal ischemia is a common cause of a variety of eye diseases, such as retinopathy of prematurity, diabetic retinopathy, and vein occlusion. Protein kinase RNA-activated-like endoplasmic reticulum (ER) kinase (PERK), one of the main ER stress sensor proteins, has been involved in many diseases. In this study, we investigated the role of PERK in ischemia-induced retinopathy using a mouse model of oxygen-induced retinopathy (OIR). Methods: OIR was induced by subjecting neonatal pups to 70% oxygen at postnatal day 7 (P7) followed by returning to room air at P12. GSK2606414, a selective PERK inhibitor, was orally administrated to pups right after they were returned to room air once daily until 1 day before sample collection. Western blot, immunostaining, and quantitative PCR were used to assess PERK phosphorylation, retinal changes, and signaling pathways in relation to PERK inhibition. Results: PERK phosphorylation was prominently increased in OIR retinas, which was inhibited by GSK2606414. Concomitantly, PERK inhibition significantly reduced retinal neovascularization (NV) and retinal ganglion cell (RGC) loss, restored astrocyte network, and promoted revascularization. Furthermore, PERK inhibition downregulated the recruitment/proliferation of mononuclear phagocytes but did not affect OIR-upregulated canonical angiogenic pathways. Conclusions: Our results demonstrate that PERK is involved in ischemia-induced retinopathy and its inhibition using GSK2606414 could offer an effective therapeutic intervention aimed at alleviating retinal NV while preventing neuron loss during retinal ischemia.

Secondary Syphilis Presenting as Bilateral Simultaneous Papillitis in an Immunocompetent Individual.

Ocular syphilis is a common presentation for patients with secondary or tertiary syphilis and usually includes posterior uveitis or panuveitis, though a myriad of symptoms have been associated. We report the case of a 58-year-old Caucasian male who presented with fast-progressing vision loss and a new onset of floaters in both eyes. An initial fundus exam revealed only bilateral optic disc edema, and neurological evaluation was negative. Subsequent ophthalmology evaluation in the clinic revealed a ragged retinal pigmented epithelium on optical coherence tomography (OCT) and posterior placoid chorioretinitis, raising suspicion of syphilis. Intravenous penicillin therapy was immediately initiated based on high clinical suspicion of ocular syphilis while awaiting lab confirmation, which was later confirmed as a new syphilis infection. He was subsequently given oral prednisone 48 hours into penicillin therapy for a significant posterior inflammatory response in both his eyes. His visual recovery was drastic due to the timely use of oral steroids. Classical findings such as ragged retinal pigmented epithelium on OCT and posterior placoid chorioretinitis demonstrate strong clinical suspicion of ocular syphilis. Oral prednisone when used timely with penicillin therapy in special situations such as bilateral severe posterior uveitis, panuveitis, or optic neuritis may aid in a faster and smoother visual recovery. A high index of clinical suspicion of ocular syphilis should be maintained in patients with human immunodeficiency virus (HIV) infection presenting with uveitis, posterior placoid morphology, or optic disc edema. Oral prednisone may be an effective adjuvant treatment for immunocompetent patients who mount a strong inflammatory response to ocular syphilis infection.

Quantification of Leukocyte Trafficking in a Mouse Model of Multiple Sclerosis through In Vivo Imaging.

Purpose: Optic neuritis occurring in multiple sclerosis (MS) is a disease characterized by chronic inflammation and demyelination in the optic nerve. Although it has been well appreciated that leukocyte infiltration into the optic nerve is an early event during the course of the disease, there has been no study on visualizing and quantifying leukocyte trafficking in the retina during the progression of MS. Methods: In this study, we generated green fluorescent protein (GFP)+ bone marrow chimeric mice, in which GFP-labeled leukocytes facilitate the visualization of their trafficking in the retina. This reporter was then integrated with a well-established rodent model for MS-experimental autoimmune encephalomyelitis (EAE), allowing high resolution in vivo scanning laser ophthalmoscopy (SLO) to track leukocyte movement in the retina in real time. Quantification of leukocyte trafficking was accomplished through Imaris software. Results: Through SLO, we were able to localize the GFP signal, allowing us to clearly identify leukocytes within the vascular space. We observed more intense leukocyte migration in the retina of EAE mice, exhibiting three distinct movement behaviors: flowing, rolling/crawling and adherent. There was a marked increase in leukocyte rolling and adhesion in retinal vasculature, particularly in the veins and capillaries after induction of EAE. The velocity of rolling leukocytes ranged from 12.0 to 1065.0 µm/sec in the veins as compared to 14.1 to 942.0 in the capillaries. Furthermore, focal areas of recurrent leukocyte adhesion to endothelial surfaces were observed in EAE retinas. Conclusion: We generated a novel model that makes it possible to non-invasively track leukocyte trafficking in the retina of EAE mice. Our study demonstrates that leukocyte migration in an MS model is distinctly different from the control, suggesting that leukocytes may play a key role in the development of retinal vascular inflammation and optic neuritis during MS, warranting further investigation of the pathological roles of leukocytes in the disease onset and progression.