Silva RNE, Shen LQ, Chiou CA, Shanbhag SS, Paschalis EI, Pasquale LR, Colby KA, Dohlman CH, Chodosh J, Alves MR. Glaucoma Management in Patients with Aniridia and Boston Type 1 Keratoprosthesis. Am J Ophthalmol 2019;Abstract
PURPOSE: To assess outcomes and glaucoma management in eyes with aniridia following Boston type 1 Keratoprosthesis (KPro) implantation. DESIGN: Retrospective, interventional comparative case series. METHODS: POPULATION: Patients with aniridia and patients with other preoperative diagnoses (excluding Stevens-Johnson syndrome, mucous membrane pemphigoid, and congenital disorders) who underwent KPro implantation at Massachusetts Eye and Ear with at least 2 years of follow-up. One eye per patient was selected based on the longer follow-up time. MAIN OUTCOME: Intermediate and long-term outcomes related to glaucoma. RESULTS: The aniridia (n=22) and comparison (n=61) groups had similar preoperative visual acuity (VA, mean ± standard deviation, 1.86±0.52 LogMAR, p=0.33) and follow-up time (65.6±26.3 months, p=0.25). Prior to KPro implantation, eyes with aniridia had more glaucoma (76.2%) and glaucoma surgery (57.1%) than comparison eyes (51.8%, p=0.053; 23.2%, p=0.005, respectively). More Ahmed valves were co-implanted with KPro in aniridia (47.6%) versus comparison eyes (17.9%, p=0.008). At final follow-up, more aniridia eyes had glaucoma (90.5%) than comparison eyes (64.3%, p=0.02), but the two groups had similar percentages of eyes with cup-to-disc ratio (CDR) >0.8 (23.8% vs. 30.4%, p=0.57) or CDR progression of ≥0.2 (42.9% vs. 44.6%, p=0.89, respectively). None of the eyes with prophylactic tube implantation developed glaucoma. Eyes with and without aniridia did not differ in post-KPro VA improvement (72.7%, 72.1%, p=0.96), and final VA (1.28±0.79 LogMAR, 1.23±0.98 LogMAR, p=0.51). CONCLUSION: Despite a higher glaucoma prevalence, eyes with aniridia achieved similar VA as comparison eyes with more than 5 years of mean follow-up time. Boston KPro offers satisfactory visual rehabilitation in aniridia when glaucoma is managed aggressively.
Werner AC, Shen LQ. A Review of OCT Angiography in Glaucoma. Semin Ophthalmol 2019;:1-8.Abstract
There is growing evidence that vascular dysfunction plays a role in the pathogenesis of glaucoma. The details of this relationship have remained elusive partially due to limitations in our ability to assess blood flow in the optic nerve. Optical coherence tomography angiography (OCTA) has emerged as a promising new technology well positioned to become the first clinically suitable test of optic nerve perfusion. OCTA uses the motion of red blood cells as an intrinsic contrast agent to create reproducible images of microvascular networks rapidly and non-invasively. A significant body of research regarding the use of OCTA in glaucoma has emerged in recent years. This review aims to provide an overview of the basic principles underlying OCTA technology, summarize the current literature regarding the application of OCTA in the management of glaucoma, and address the role of OCTA in explicating the vascular pathogenesis of glaucoma.
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai L-H. Single-cell transcriptomic analysis of Alzheimer's disease. Nature 2019;570(7761):332-337.Abstract
Alzheimer's disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer's disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimer's disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer's disease.
Wang JC, Miller JB. For Mass Eye and Ear Special Issue: Optical Coherence Tomography Angiography: Review of Current Technical Aspects and Applications in Chorioretinal Disease. Semin Ophthalmol 2019;:1-7.Abstract
Optical coherence tomography angiography (OCT-A) has enabled fast, non-invasive, high-resolution visualization of vasculature within the eye. In the past few years, it has become increasingly utilized for a range of disorders including age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, and uveitis among others. This article reviews technical aspects of OCT-A, its applications in chorioretinal disease, and known limitations of the technology.
Rosales MAB, Shu DY, Iacovelli J, Saint-Geniez M. Loss of PGC-1α in RPE induces mesenchymal transition and promotes retinal degeneration. Life Sci Alliance 2019;2(3)Abstract
The retinal pigment epithelium (RPE) supports visual processing and photoreceptor homeostasis via energetically demanding cellular functions. Here, we describe the consequences of repressing peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α), a master regulator of mitochondrial function and biogenesis, on RPE epithelial integrity. The sustained silencing of PGC-1α in differentiating human RPE cells affected mitochondria/autophagy function, redox state, and impaired energy sensor activity ultimately inducing epithelial to mesenchymal transition (EMT). Adult conditional knockout of PGC-1 coactivators in mice resulted in rapid RPE dysfunction and transdifferentiation associated with severe photoreceptor degeneration. RPE anomalies were characteristic of autophagic defect and mesenchymal transition comparable with the ones observed in age-related macular degeneration. These findings demonstrate that PGC-1α is required to maintain the functional and phenotypic status of RPE by supporting the cells' oxidative metabolism and autophagy-mediated repression of EMT.
Mölzer C, Shankar SP, Griffith M, Islam MM, Forrester JV, Kuffová L. Activation of dendritic cells by crosslinked collagen hydrogels (artificial corneas) varies with their composition. J Tissue Eng Regen Med 2019;13(9):1528-1543.Abstract
Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen-containing matrices, Matrigel and de-cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a "tolerogenic" phenotype. The same applied to singly crosslinked CMP-PEG gels. RHCIII gels singly crosslinked using either N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide with the coinitiator N-hydroxy succinimide (EDC-NHS) or N-cyclohexyl-N-(2-morpholinoethyl)carbodiimide metho-p-toulenesulfonate with NHS (CMC-NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2-methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte-associated immunoglobulin-like receptor-1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.
Laville V, Kang JH, Cousins CC, Iglesias AI, Nagy R, Cooke Bailey JN, Igo RP, Song YE, Chasman DI, Christen WG, Kraft P, Rosner BA, Hu F, Wilson JF, Gharahkhani P, Hewitt AW, Mackey DA, Hysi PG, Hammond CJ, van Duijn CM, Haines JL, Vitart V, Fingert JH, Hauser MA, Aschard H, Wiggs JL, Khawaja AP, Macgregor S, Pasquale LR, UK Biobank, International Glaucoma Genetics Consortium NEIGHBORHOODC. Genetic correlations between diabetes and glaucoma: an analysis of continuous and dichotomous phenotypes. Am J Ophthalmol 2019;Abstract
PURPOSE: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. DESIGN: Cross-sectional study. METHODS: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure (IOP), central corneal thickness (CCT), corneal hysteresis (CH), corneal resistance factor (CRF), cup-disc ratio (CDR), and primary open-angle glaucoma (POAG)). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank and the International Glaucoma Genetics Consortium. We calculated genetic correlation (r) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT and selected diabetes-related traits based on individual level phenotype data in two Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines (SOLAR). RESULTS: Overall, there was little r between diabetes- and glaucoma-related traits. Specifically, we found a non-significant negative correlation between T2D and POAG (r=-0.14; p=0.16). Using SOLAR, the genetic correlations between measured IOP, CCT, FBS, fasting insulin and hemoglobin A1c, were null. In contrast, genetic correlations between IOP and POAG (r ≥0.45; p≤3.0E-04) and between CDR and POAG were high (r =0.57; p=2.8E-10). However, genetic correlations between corneal properties (CCT, CRF and CH) and POAG were low (r range: -0.18 - 0.11) and non-significant (p≥0.07). CONCLUSION: These analyses suggest there is limited genetic correlation between diabetes- and glaucoma-related traits.
Dohlman JC, Habib LA, Freitag SK. Punctal agenesis: Embryology, presentation, management modalities and outcomes. Ann Anat 2019;224:113-116.Abstract
Punctal agenesis is defined as the absence of the punctum occurring secondary to a failure of embryogenesis. This review synthesizes existing data on the embryology, anatomy, clinical presentation, symptomatology, management options and treatment outcomes of punctal agenesis. A foundational knowledge of the underlying embryologic and anatomical abnormalities is fundamental to understanding its clinical presentation and assists in choosing an appropriate management strategy. Existing outcomes data is generally favorable and suggests management with a step-wise approach can alleviate symptoms in patients across a spectrum of disease.
Smits DJ, Elze T, Wang H, Pasquale LR. Machine Learning in the Detection of the Glaucomatous Disc and Visual Field. Semin Ophthalmol 2019;:1-11.Abstract
Glaucoma is the leading cause of irreversible blindness worldwide. Early detection is of utmost importance as there is abundant evidence that early treatment prevents disease progression, preserves vision, and improves patients' long-term quality of life. The structure and function thresholds that alert to the diagnosis of glaucoma can be obtained entirely via digital means, and as such, screening is well suited to benefit from artificial intelligence and specifically machine learning. This paper reviews the concepts and current literature on the use of machine learning for detection of the glaucomatous disc and visual field.
Ponce CR, Xiao W, Schade PF, Hartmann TS, Kreiman G, Livingstone MS. Evolving Images for Visual Neurons Using a Deep Generative Network Reveals Coding Principles and Neuronal Preferences. Cell 2019;177(4):999-1009.e10.Abstract
What specific features should visual neurons encode, given the infinity of real-world images and the limited number of neurons available to represent them? We investigated neuronal selectivity in monkey inferotemporal cortex via the vast hypothesis space of a generative deep neural network, avoiding assumptions about features or semantic categories. A genetic algorithm searched this space for stimuli that maximized neuronal firing. This led to the evolution of rich synthetic images of objects with complex combinations of shapes, colors, and textures, sometimes resembling animals or familiar people, other times revealing novel patterns that did not map to any clear semantic category. These results expand our conception of the dictionary of features encoded in the cortex, and the approach can potentially reveal the internal representations of any system whose input can be captured by a generative model.
Gaiha GD, Rossin EJ, Urbach J, Landeros C, Collins DR, Nwonu C, Muzhingi I, Anahtar MN, Waring OM, Piechocka-Trocha A, Waring M, Worrall DP, Ghebremichael MS, Newman RM, Power KA, Allen TM, Chodosh J, Walker BD. Structural topology defines protective CD8 T cell epitopes in the HIV proteome. Science 2019;364(6439):480-484.Abstract
Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen () class I alleles. Moreover, CD8 T cell targeting of highly networked epitopes distinguished individuals who naturally control HIV, even in the absence of protective alleles. This approach thereby provides a mechanistic basis for immune control and a means to identify CD8 T cell epitopes of topological importance for rational immunogen design, including a T cell-based HIV vaccine.
Bagdonaite-Bejarano L, Hansen RM, Fulton AB. Microperimetry in Three Inherited Retinal Disorders. Semin Ophthalmol 2019;:1-6.Abstract
Microperimetry (MP) is used to assess visual sensitivity mediated by the central retina. As such, MP performance is a candidate outcome measure for gene therapy trials. Herein, we review MP results in three inherited retinal disorders for which gene therapy trials have been initiated-choroideremia, Stargardt disease, and X-linked juvenile retinoschisis. Each of these disorders typically presents in childhood and each has distinct effects on the central retina. Our review indicates that microperimetry is feasible in each of these conditions. The MP sensitivity maps vary among conditions consistent with known effects of each of the three conditions. There is, however, within each of the three disorders considerable variability in fixation stability and in the pattern of sensitivity loss. Microperimetry is a valuable tool for monitoring functional aspects of central retina in an individual patient, especially in combination with other modalities such as OCT, autofluorescence, and acuity and thus may contribute to evaluating the efficacy of gene treatments. Variability of the MP parameters raises some cautions in application of MP as an outcome measure in treatment trials that may have small sample sizes. Nonetheless, we suspect that MP will continue to have a rightful place in future gene therapy trials.