Author: jfg@linkoph.com

Aging Is Not a Disease: Distinguishing Age-Related Macular Degeneration from Aging

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Publication date: Available online 9 August 2013
Source:Progress in Retinal and Eye Research
Author(s): Daniel Ardeljan , Chi-Chao Chan
Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch’s membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD.

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Retinal ganglion cells: Energetics, compartmentation, axonal transport, cytoskeletons and vulnerability

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Publication date: Available online 23 July 2013
Source:Progress in Retinal and Eye Research
Author(s): Dao-Yi Yu , Stephen J. Cringle , Chandrakumar Balaratnasingam , William H. Morgan , Paula K. Yu , Er-Ning Su
Retinal ganglion cells (RGCs) are specialized projection neurons that relay an immense amount of visual information from the retina to the brain. RGC signal inputs are collected by dendrites and output is distributed from the cell body via very thin (0.5 to 1 μm) and long (∼50 mm) axons. The RGC cell body is larger than other retinal neurons, but is still only a very small fraction (one ten thousandths) of the length and total surface area of the axon.The total distance traversed by RGCs extends from the retina, starting from synapses with bipolar and amacrine cells, to the brain, to synapses with neurons in the lateral geniculate nucleus.This review will focus on the energy demands of RGCs and the relevant tissues that surround them. RGC survival and function unexceptionally depends upon free energy, predominantly adenosine triphosphate (ATP). RGC energy metabolism is vastly different when compared to that of the photoreceptors.Each subcellular component of the RGC is remarkably different in terms of structure, function and extracellular environment. The energy demands and distribution of each component are also distinct as evidenced by the uneven distribution of mitochondria and ATP within the RGC – signifying the presence of intracellular energy gradients. In this review we will describe RGCs as having four subcellular components, (1) Dendrites, (2) Cell body, (3) Non-myelinated axon, including intraocular and optic nerve head portions, and (4) Myelinated axon, including the intra-orbital and intracranial portions.We will also describe how RGCs integrate information from each subcellular component in order achieve intracellular homeostatic stability as well as respond to perturbations in the extracellular environment. The possible cellular mechanisms such as axonal transport and axonal cytoskeleton proteins that are involved in maintaining RGC energy homeostasis during normal and disease conditions will also be discussed in depth. The emphasis of this review will be on energetic mechanisms within RGC components that have the most relevance to clinical ophthalmology.

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Arginase in Retinopathy

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Publication date: Available online 3 July 2013 Source:Progress in Retinal and Eye Research Author(s): S. Priya Narayanan , Modesto Rojas , Jutamas Suwanpradid , Haroldo A. Toque , R. William Caldwell , Ruth B. Caldwell Ischemic r…

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The complex interactions of retinal, optical and environmental factors in myopia aetiology

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Publication date: November 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 6
Author(s): D.I. Flitcroft
Myopia is the commonest ocular abnormality but as a research topic remains at the margins of mainstream ophthalmology. The concept that most myopes fall into the category of ‘physiological myopia’ undoubtedly contributes to this position. Yet detailed analysis of epidemiological data linking myopia with a range of ocular pathologies from glaucoma to retinal detachment demonstrates statistically significant disease association in the 0 to −6 D range of ‘physiological myopia’. The calculated risks from myopia are comparable to those between hypertension, smoking and cardiovascular disease. In the case of myopic maculopathy and retinal detachment the risks are an order of magnitude greater. This finding highlights the potential benefits of interventions that can limit or prevent myopia progression.Our understanding of the regulatory processes that guide an eye to emmetropia and, conversely how the failure of such mechanisms can lead to refractive errors, is certainly incomplete but has grown enormously in the last few decades. Animal studies, observational clinical studies and more recently randomized clinical trials have demonstrated that the retinal image can influence the eye’s growth. To date human intervention trials in myopia progression using optical means have had limited success but have been designed on the basis of simple hypotheses regarding the amount of defocus at the fovea.Recent animal studies, backed by observational clinical studies, have revealed that the mechanisms of optically guided eye growth are influenced by the retinal image across a wide area of the retina and not solely the fovea. Such results necessitate a fundamental shift in how refractive errors are defined. In the context of understanding eye growth a single sphero-cylindrical definition of foveal refraction is insufficient. Instead refractive error must be considered across the curved surface of the retina. This carries the consequence that local retinal image defocus can only be determined once the 3D structure of the viewed scene, off axis performance of the eye and eye shape has been accurately defined. This, in turn, introduces an under-appreciated level of complexity and interaction between the environment, ocular optics and eye shape that needs to be considered when planning and interpreting the results of clinical trials on myopia prevention.

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Novel roles for α-crystallins in retinal function and disease

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Publication date: November 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 6
Author(s): Ram Kannan , Parameswaran G. Sreekumar , David R. Hinton
α-Crystallins are key members of the superfamily of small heat shock proteins that have been studied in detail in the ocular lens. Recently, novel functions for α-crystallins have been identified in the retina and in the retinal pigmented epithelium (RPE). αB-Crystallin has been localized to multiple compartments and organelles including mitochondria, golgi apparatus, endoplasmic reticulum and nucleus. α-Crystallins are regulated by oxidative and endoplasmic reticulum stress, and inhibit apoptosis-induced cell death. α-Crystallins interact with a large number of proteins that include other crystallins, and apoptotic, cytoskeletal, inflammatory, signaling, angiogenic, and growth factor molecules. Studies with RPE from αB-crystallin deficient mice have shown that αB-crystallin supports retinal and choroidal angiogenesis through its interaction with vascular endothelial growth factor. αB-Crystallin has also been shown to have novel functions in the extracellular space. In RPE, αB-crystallin is released from the apical surface in exosomes where it accumulates in the interphotoreceptor matrix and may function to protect neighboring cells. In other systems administration of exogenous recombinant αB-crystallin has been shown to be anti-inflammatory. Another newly described function of αB-crystallin is its ability to inhibit β-amyloid fibril formation. α-Crystallin minichaperone peptides have been identified that elicit anti-apoptotic function in addition to being efficient chaperones. Generation of liposomal particles and other modes of nanoencapsulation of these minipeptides could offer great therapeutic advantage in ocular delivery for a wide variety of retinal degenerative, inflammatory and vascular diseases including age-related macular degeneration and diabetic retinopathy.

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A contemporary concept of the blood–aqueous barrier

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Publication date: January 2013
Source:Progress in Retinal and Eye Research, Volume 32
Author(s): Thomas F. Freddo
This review traces the evolution of the concept of the blood–aqueous barrier (BAB) during the past 20 years. The Classical model simply stipulated that the tight junctions of the iris vasculature and ciliary epithelium excluded plasma proteins from the aqueous humor (AH). It failed to reconcile the presence of AH protein levels equal to 1% of that found in plasma. Moreover, models of barrier kinetics assumed that the processes of AH secretion and plasma protein entry were directly linked. Thus, elevations of AH protein levels could only be explained by a pathological breakdown of the BAB. Over the last 20 years it has been shown that the plasma proteins in normal AH by-pass the posterior chamber entirely. Instead, these proteins diffuse from the capillaries of ciliary body stroma, into the iris stroma and then into the anterior chamber. This creates a reservoir of plasma-proteins in the iris stroma that is not derived from the iris vessels. This reservoir is prevented from diffusing posteriorly by tight junctions in the posterior iris epithelium. The one-way valve created by the pupil resting on the anterior lens capsule, combined with the continuous, forward flow of AH through the pupil, prevents protein reflux into the posterior chamber. Importantly, in the new paradigm, secretion of AH and the entry of plasma proteins into AH, are semi-independent events. This opens the possibility that AH protein levels could increase in the absence of breakdown of the BAB. Clinical consequences of this new paradigm of the BAB are discussed.

Graphical abstract

image

Highlights

A: Classical model -the tight junctions of the non-pigmented ciliary epithelium (•••••) and the iris vascular endothelium are the key elements. Plasma proteins are assumed to be part of aqueous as it is secreted. Elevation of protein concentrations can only be explained by an increase in blood-aqueous barrier permeability. B: New Model – Plasma proteins in aqueous humor diffuse from the ciliary body stroma, to the anterior chamber and outflow pathways (arrows). Protein entry is semi-independent of aqueous production and thus concentration can change within limits, without altering barrier permeability. The anterior and posterior chambers are different environments, with unidirectional aqueous flow and tight junctions of the iris epithelium (•••••) separating them.

► The source and route of plasma protein entry into aqueous humor is described. ► The blood–aqueous barrier is not primarily a barrier between blood and aqueous. ► The blood–aqueous barrier separates different environments in front of and behind the iris. ► Not all clinically observable anterior chamber flare is pathological.

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Herpes keratitis

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Publication date: January 2013Source:Progress in Retinal and Eye Research, Volume 32 Author(s): A.M. Rowe , A.J. St. Leger , S. Jeon , D.K. Dhaliwal , J.E. Knickelbein , R.L. Hendricks Herpes simplex virus-1 (HSV-1) infects the m…

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Optical plasticity in fish lenses

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Publication date: May 2013
Source:Progress in Retinal and Eye Research, Volume 34
Author(s): Ronald H.H. Kröger
In a typical fish eye, the crystalline lens is the only refractive element. It is spherical in shape and has high refractive power. Most fish species have elaborate color vision and spectral sensitivity may range from the near-infrared to the near-ultraviolet. Longitudinal chromatic aberration exceeds depth of focus and chromatic blur is compensated for by species-specific multifocality of the lens. The complex optical properties of fish lenses are subject to accurate regulation, including circadian reversible adjustments and irreversible developmental tuning. The mechanisms optimize the transfer of visual information to the retina in diverse and variable environments, and allow for rapid evolutionary changes in color vision. Active optical tuning of the lens is achieved by changes in the refractive index gradient and involves layers of mature, denucleated lens fiber cells. First steps have been taken toward unraveling the signaling systems controlling lens optical plasticity. Multifocal lenses compensating for chromatic blur are common in all major groups of vertebrates, including birds and mammals. Furthermore, the optical quality of a monofocal lens, such as in the human eye, is equally sensitive to the exact shape of the refractive index profile. Optical plasticity in the crystalline lens may thus be present in vertebrates in general.

Highlights

► Multifocal crystalline lenses compensate for chromatic defocus. ► Different types of optical plasticity optimize information transfer to the retina. ► Denucleated lens fiber cells participate in the regulation. ► Active optical tuning of the lens explains rapid evolution of color vision. ► Similar mechanisms may be present in vertebrates in general.

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Macular telangiectasia type 2

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Publication date: May 2013
Source:Progress in Retinal and Eye Research, Volume 34
Author(s): Peter Charbel Issa , Mark C. Gillies , Emily Y. Chew , Alan C. Bird , Tjebo F.C. Heeren , Tunde Peto , Frank G. Holz , Hendrik P.N. Scholl
Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment–outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure–function correlation may help to develop surrogate outcome measures for future clinical trials.In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

Highlights

► Macular telangiectasia (MacTel) type 2 is a neurodegenerative disease affecting the central retina. ► Its prevalence has long been underestimated and may be as high as 0.1%. ► There is central depletion of macular pigment and hyporeflective retinal cavities on OCT imaging. ► Vascular endothelial growth factor (VEGF) appears to play a significant role in the pathophysiology. ► Anti-VEGF therapy may show efficacy in neovascular disease only.

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