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Special Issue "Age-Related Macular Disease"

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (31 August 2014)

Special Issue Editors

Guest Editor
Prof. Dr. Lindsay Farrer

Division of Biomedical Genetics E200, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
Website | E-Mail
Fax: +1 617 638 4275
Interests: age-related macular degeneration; Alzheimer disease; substance dependence; genetic epidemiology; gene mapping; genotype-phenotype correlations; genomics; personalized medicine
Guest Editor
Dr. Margaret DeAngelis

Department of Ophthalmology and Visual Sciences, School of Medicine, University of Utah, Moran Eye Center, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA
Website | E-Mail
Phone: +801 213 4052
Fax: +801 581 5335
Interests: age-related macular degeneration; retinopathy of prematurity; diabetic retinopathy; myopia; genomics; epigenetics; gene expression; systems biology; precision medicine

Special Issue Information

Dear Colleagues,

Major advances have been made in our understanding of mechanisms leading to age-related macular degeneration (AMD) using genetic and genomic approaches. For example, genome wide significant associations of AMD with variants at 19 loci have been discovered. Most notably, CFH and ARMS2/HTRA1 have the largest influence on AMD risk. However, these variants, individually or together, are insufficient for accurately predicting disease onset, progression or response to treatment. Moreover, there is a gap in our knowledge concerning the functional significance of these genes and their variants in AMD pathophysiology.

Next generation sequencing technologies, including RNA-Seq, ChIP-Seq, BiSulfate Sequencing, Whole Genome Methylation, Whole Genome Sequencing, Whole Exome Sequencing, and other approaches, are expected to generate data to help bridge this gap in our knowledge. An improved understanding of mechanisms leading to AMD will provide crucial insights for devising new in vivo and in vitro models so that the most efficacious and least harmful therapeutics can be developed to treat this leading cause of blindness in the aging population.

Prof. Dr. Lindsay Farrer
Dr. Margaret DeAngelis
Guest Editors

Submission

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • age-related macular degeneration
  • genomics
  • epigenetics
  • gene Expression
  • pathway analysis
  • biomarkers
  • proteomics

Published Papers (16 papers)

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Research

Jump to: Review

Open AccessArticle Quality of Life with Macular Degeneration Is Not as Dark as It May Seem: Patients’ Perceptions of the MacDQoL Questionnaire
J. Clin. Med. 2015, 4(9), 1841-1852; doi:10.3390/jcm4091841
Received: 19 June 2015 / Revised: 14 September 2015 / Accepted: 16 September 2015 / Published: 22 September 2015
Cited by 1 | PDF Full-text (110 KB) | HTML Full-text | XML Full-text
Abstract
To determine the perceived relevance and value of an individualized measure of the impact of macular degeneration on quality of life (QoL) for elderly people with Age-Related Macular Degeneration (AMD) in the USA, through the assessment of the suitability of the measure’s domains
[...] Read more.
To determine the perceived relevance and value of an individualized measure of the impact of macular degeneration on quality of life (QoL) for elderly people with Age-Related Macular Degeneration (AMD) in the USA, through the assessment of the suitability of the measure’s domains and by gaining a deeper insight into the impact of AMD on patients’ QoL vis-á-vis these domains, community-dwelling older adults in the metropolitan Salt Lake City, Utah area were interviewed using the macular degeneration on quality of life (MacDQoL) instrument. Participants felt that the MacDQoL was a relevant instrument for use in this US study population, though it could be improved by adding items pertaining to transportation, and independent driving, in particular, as an important QoL indicator. The emerging theme from analysis of the respondent’s commentary was that, in spite of AMD, these respondents were committed to engage in, and enjoy life. This is an important concept for clinicians and those who offer support programs to integrate into their care planning and reinforce in messaging to patients with the condition. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessArticle Long-Term Visual Outcomes for a Treat and Extend Anti-Vascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration
J. Clin. Med. 2015, 4(7), 1380-1402; doi:10.3390/jcm4071380
Received: 5 April 2015 / Revised: 22 June 2015 / Accepted: 26 June 2015 / Published: 8 July 2015
Cited by 4 | PDF Full-text (714 KB) | HTML Full-text | XML Full-text
Abstract
With the advent of anti-vascular endothelial growth factor (VEGF) therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD), a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified
[...] Read more.
With the advent of anti-vascular endothelial growth factor (VEGF) therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD), a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified based on fluorescein angiography (FA) alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT) and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER) with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes) were followed over an average of 3.5 years (range 1–6.6) with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (±1.6) (± standard deviation) intravitreal anti-VEGF injections/year (range 4–13). The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessArticle Small Drusen and Age-Related Macular Degeneration: The Beaver Dam Eye Study
J. Clin. Med. 2015, 4(3), 425-440; doi:10.3390/jcm4030425
Received: 15 January 2015 / Accepted: 24 February 2015 / Published: 9 March 2015
PDF Full-text (477 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We tested the hypothesis that large areas of small hard drusen (diameter <63 µm) and intermediate drusen (diameter 63–124 µm) are associated with the incidence of age-related macular degeneration (AMD). Eyes of 3344 older adults with at least two consecutive visits spaced five
[...] Read more.
We tested the hypothesis that large areas of small hard drusen (diameter <63 µm) and intermediate drusen (diameter 63–124 µm) are associated with the incidence of age-related macular degeneration (AMD). Eyes of 3344 older adults with at least two consecutive visits spaced five years apart over a 20-year period were included. A 6-level severity scale, including no drusen, four levels of increasing area (from minimal (<2596 µm²) to large (>9086 µm²)) of only small hard drusen, and intermediate drusen, was used. The five-year incidence of AMD was 3% in eyes at the start of the interval with no, minimal, small, and moderate areas of only small drusen and 5% and 25% for eyes with large area of only small drusen and intermediate drusen, respectively. Compared to eyes with a moderate area of small drusen, the odds ratio (OR) of developing AMD in eyes with a large area of only small drusen was 1.8 (p < 0.001). Compared to eyes with large area of only small drusen, eyes with intermediate drusen had an OR of 5.5 (p < 0.001) of developing AMD. Our results are consistent with our hypothesis that large areas of only small drusen are associated with the incidence of AMD. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessArticle Association of OCT-Derived Drusen Measurements with AMD-Associated Genotypic SNPs in the Amish Population
J. Clin. Med. 2015, 4(2), 304-317; doi:10.3390/jcm4020304
Received: 23 December 2014 / Revised: 23 December 2014 / Accepted: 13 January 2015 / Published: 12 February 2015
PDF Full-text (129 KB) | HTML Full-text | XML Full-text
Abstract
Purpose: To investigate the association of optical coherence tomography (OCT)-derived drusen measures in Amish age-related macular degeneration (AMD) patients with known loci for macular degeneration. Methods: Members of the Old Order Amish community in Pennsylvania ages 50 and older were assessed for drusen
[...] Read more.
Purpose: To investigate the association of optical coherence tomography (OCT)-derived drusen measures in Amish age-related macular degeneration (AMD) patients with known loci for macular degeneration. Methods: Members of the Old Order Amish community in Pennsylvania ages 50 and older were assessed for drusen area, volume and regions of retinal pigment epithelium (RPE) atrophy using a Cirrus High-Definition OCT. Measurements were obtained in the macula region within a central circle (CC) of 3 mm in diameter and a surrounding perifoveal ring (PR) of 3 to 5 mm in diameter using the Cirrus OCT RPE analysis software. Other demographic information, including age, gender and smoking status, were collected. Study subjects were further genotyped to determine their risk for the AMD-associated SNPs in the SYN3, LIPC, ARMS2, C3, CFB, CETP, CFI and CFH genes using TaqMan genotyping assays. The association of genotypes with OCT measures were assessed using linear trend p-values calculated from univariate and multivariate generalized linear models. Results: 432 eyes were included in the analysis. Multivariate analysis (adjusted by age, gender and smoking status) confirmed the known significant association between AMD and macular drusen with the number of CFH risk alleles for the drusen area (the area increased 0.12 mm2 for a risk allele increase, p < 0.01), drusen volume (the volume increased 0.01 mm3 for a risk allele increase, p ≤ 0.05) and the area of RPE atrophy (the area increased 0.43 mm2 for a risk allele increase, p = 0.003). SYN3 risk allele G is significantly associated with larger area PR (the area increased 0.09 mm2 for a risk allele increase, p = 0.03) and larger drusen volume in the central circle (the volume increased 0.01 mm3 for a risk allele increase, p = 0.04). Conclusion: Among the genotyped SNPs tested, the CFH risk genotype appears to play a major role in determining the drusen phenotype in the Amish AMD population. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessArticle Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease
J. Clin. Med. 2014, 3(4), 1335-1356; doi:10.3390/jcm3041335
Received: 4 September 2014 / Revised: 7 November 2014 / Accepted: 12 November 2014 / Published: 28 November 2014
PDF Full-text (468 KB) | HTML Full-text | XML Full-text
Abstract
The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and
[...] Read more.
The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and cost. There is a critical need to find clinical markers that, when combined with the specificity of genetic testing, will identify individuals at the earliest stages of AMD who would benefit from preventive therapies. These clinical markers are endophenotypes for AMD, present in those who are likely to develop AMD, as well as in those who have clinical evidence of AMD. Clinical characteristics associated with AMD may also be possible endophenotypes if they can be detected before or at the earliest stages of the condition, but we and others have shown that this may not always be valid. Several studies have suggested that dynamic changes in rhodopsin regeneration (dark adaptation kinetics and/or critical flicker fusion frequencies) may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)

Review

Jump to: Research

Open AccessReview The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review
J. Clin. Med. 2016, 5(3), 31; doi:10.3390/jcm5030031
Received: 1 December 2015 / Revised: 19 February 2016 / Accepted: 29 February 2016 / Published: 4 March 2016
Cited by 1 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review
[...] Read more.
Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review the ability and utility of these numerous models for prediction of AMD and suggest additional risk factors to be incorporated into clinically useful predictive models of AMD. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessReview Individualized Treatment of Neovascular Age-Related Macular Degeneration: What are Patients Gaining? Or Losing?
J. Clin. Med. 2015, 4(5), 1079-1101; doi:10.3390/jcm4051079
Received: 6 January 2015 / Revised: 30 April 2015 / Accepted: 12 May 2015 / Published: 21 May 2015
Cited by 4 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
The widespread use of drugs that bind diffusible vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (AMD). The pivotal ranibizumab and aflibercept registration trials featured monthly intravitreal injections for 12 months, during which visual acuities and macular
[...] Read more.
The widespread use of drugs that bind diffusible vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (AMD). The pivotal ranibizumab and aflibercept registration trials featured monthly intravitreal injections for 12 months, during which visual acuities and macular edema rapidly improved for the first 3 months and modest gains or stabilization continued until the primary endpoint. In many subsequent trials, patients were evaluated monthly and treated as-needed (PRN) according to the results of visual acuity (VA) testing, fundus examinations and optical coherence tomography scans. Compared to monthly-treated control groups, PRN treated patients require fewer injections during the first year but they also experience smaller VA gains (1–3 letters). A small number of prospective trials that directly compared monthly with PRN therapy showed that VA gains with discontinuous therapy lag slightly behind those achieved with monthly injections. Physicians recognize that monthly office visits with frequent intraocular injections challenge patients’ compliance, accrue high drug and professional service costs, and clog office schedules with frequently returning patients. To decrease the numbers of both office visits and anti-VEGF injections without sacrificing VA gains, physicians have embraced the treat-and-extend strategy. Treat-and-extend has not been studied as rigorously as PRN but it has become popular among both vitreoretinal specialists and patients. Despite the possible risks associated with discontinuous therapy (decreased VA and increased macular fluid), most physicians individualize treatment (PRN or treat-and-extend) for the majority of their patients. This review chapter explores the many advantages of individualized therapy, while balancing these against suboptimal responses due to the decreased frequency of anti-VEGF injections. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessReview Can Novel Treatment of Age-Related Macular Degeneration Be Developed by Better Understanding of Sorsby’s Fundus Dystrophy
J. Clin. Med. 2015, 4(5), 874-883; doi:10.3390/jcm4050874
Received: 25 September 2014 / Accepted: 17 April 2015 / Published: 4 May 2015
PDF Full-text (629 KB) | HTML Full-text | XML Full-text
Abstract
Sorsby’s Fundus Dystrophy (SFD) is a rare autosomal dominant maculopathy that shares many clinical features with Age-Related Macular Degeneration (AMD). It is caused by a mutation in a single gene, TIMP-3, which accumulates in Bruch’s membrane (BM). BM thickening and TIMP-3 accumulation can
[...] Read more.
Sorsby’s Fundus Dystrophy (SFD) is a rare autosomal dominant maculopathy that shares many clinical features with Age-Related Macular Degeneration (AMD). It is caused by a mutation in a single gene, TIMP-3, which accumulates in Bruch’s membrane (BM). BM thickening and TIMP-3 accumulation can also be found in AMD. From our understanding of the pathophysiology of SFD we hypothesize that BM thickening could be responsible for making the elastic layer vulnerable to invasion by choriocapillaris, thereby leading to choroidal neovascularization in some cases of AMD, whilst in others it could deprive the retinal pigment epithelium of its blood supply, thereby causing geographic atrophy. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessReview Polypoidal Choroidal Vasculopathy in Asians
J. Clin. Med. 2015, 4(5), 782-821; doi:10.3390/jcm4050782
Received: 15 March 2015 / Accepted: 13 April 2015 / Published: 24 April 2015
Cited by 4 | PDF Full-text (1217 KB) | HTML Full-text | XML Full-text
Abstract
Age related macular degeneration (AMD) in Asians has been suggested to differ from their Western counterparts in terms of epidemiology, pathogenesis, clinical presentation and treatment. In particular, polypoidal choroidal vasculopathy (PCV) appears to be the predominant subtype of exudative AMD in Asian populations,
[...] Read more.
Age related macular degeneration (AMD) in Asians has been suggested to differ from their Western counterparts in terms of epidemiology, pathogenesis, clinical presentation and treatment. In particular, polypoidal choroidal vasculopathy (PCV) appears to be the predominant subtype of exudative AMD in Asian populations, in contrast to choroidal neovascularization secondary to AMD (CNV-AMD) in Western populations. Epidemiological data on PCV has been largely limited to hospital-based studies and there are currently no data on the incidence of PCV. Similarities and differences in risk factor profile between PCV and CNV-AMD point to some shared pathogenic mechanisms but also differential underlying mechanisms leading to the development of each phenotype. Serum biomarkers such as CRP, homocysteine and matrix metalloproteinases suggest underlying inflammation, atherosclerosis and deranged extracellular matrix metabolism as possible pathogenic mechanisms. In addition, recent advances in genome sequencing have revealed differences in genetic determinants of each subtype. While the standard of care for CNV-AMD is anti-vascular endothelial growth factor (VEGF) therapy, photodynamic therapy (PDT) has been the mainstay of treatment for PCV, although long-term visual prognosis remains unsatisfactory. The optimal treatment for PCV requires further clarification, particularly with different types of anti-VEGF agents and possible benefits of reduced fluence PDT. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Figures

Open AccessReview Age-Related Macular Degeneration: Advances in Management and Diagnosis
J. Clin. Med. 2015, 4(2), 343-359; doi:10.3390/jcm4020343
Received: 24 December 2014 / Revised: 24 December 2014 / Accepted: 20 January 2015 / Published: 12 February 2015
Cited by 10 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in older populations in industrialized nations. AMD is a late-onset deterioration of photoreceptors and retinal pigment epithelium in the central retina caused by various environmental and genetic factors. Great strides
[...] Read more.
Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in older populations in industrialized nations. AMD is a late-onset deterioration of photoreceptors and retinal pigment epithelium in the central retina caused by various environmental and genetic factors. Great strides in our understanding of AMD pathogenesis have been made in the past several decades, which have translated into revolutionary therapeutic agents in recent years. In this review, we describe the clinical and pathologic features of AMD and present an overview of current diagnosis and treatment strategies. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessReview Tapping Stem Cells to Target AMD: Challenges and Prospects
J. Clin. Med. 2015, 4(2), 282-303; doi:10.3390/jcm4020282
Received: 1 September 2014 / Accepted: 13 January 2015 / Published: 29 January 2015
Cited by 4 | PDF Full-text (437 KB) | HTML Full-text | XML Full-text
Abstract
Human pluripotent stem cells (hPSCs) are increasingly gaining attention in biomedicine as valuable resources to establish patient-derived cell culture models of the cell type known to express the primary pathology. The idea of “a patient in a dish” aims at basic, but also
[...] Read more.
Human pluripotent stem cells (hPSCs) are increasingly gaining attention in biomedicine as valuable resources to establish patient-derived cell culture models of the cell type known to express the primary pathology. The idea of “a patient in a dish” aims at basic, but also clinical, applications with the promise to mimic individual genetic and metabolic complexities barely reflected in current invertebrate or vertebrate animal model systems. This may particularly be true for the inherited and complex diseases of the retina, as this tissue has anatomical and physiological aspects unique to the human eye. For example, the complex age-related macular degeneration (AMD), the leading cause of blindness in Western societies, can be attributed to a large number of genetic and individual factors with so far unclear modes of mutual interaction. Here, we review the current status and future prospects of utilizing hPSCs, specifically induced pluripotent stem cells (iPSCs), in basic and clinical AMD research, but also in assessing potential treatment options. We provide an outline of concepts for disease modelling and summarize ongoing and projected clinical trials for stem cell-based therapy in late-stage AMD. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Figures

Open AccessReview NLRP3 Inflammasome and Pathobiology in AMD
J. Clin. Med. 2015, 4(1), 172-192; doi:10.3390/jcm4010172
Received: 1 October 2014 / Accepted: 19 December 2014 / Published: 14 January 2015
Cited by 5 | PDF Full-text (326 KB) | HTML Full-text | XML Full-text
Abstract
Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by
[...] Read more.
Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by drusen deposition between the RPE and underlying choroid and accumulation of lipofuscin in the RPE. End-stage disease is characterized by geographic atrophy (dry AMD) or choroidal neovascularization (wet AMD). The NLRP3 inflammasome has recently been implicated in the disease pathology. Here we review the current knowledge on the involvement of this multiprotein complex and its effector cytokines interleukin-1β (IL-1β) and IL-18 in AMD progression. We also describe cell death mechanisms that have been proposed to underlie RPE degeneration in AMD and discuss the role of autophagy in the regulation of disease progression. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Figures

Open AccessReview Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration
J. Clin. Med. 2015, 4(1), 18-31; doi:10.3390/jcm4010018
Received: 19 September 2014 / Accepted: 24 November 2014 / Published: 26 December 2014
Cited by 4 | PDF Full-text (1576 KB) | HTML Full-text | XML Full-text
Abstract
The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains
[...] Read more.
The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains genes encoding complement factor H (FH) and the factor H related proteins (FHR proteins). In macular tissue, especially Bruch’s membrane, relatively high levels of a truncated splice variant of FH called factor H-like protein 1 (FHL-1) are present. Here we discuss how genetic variations may alter the amounts, or by altering their protein sequences, the functions of these proteins. In particular, the common Y402H polymorphism affects the ability of FHL-1 and FH to localize to Bruch’s membrane and the inner choroid because it alters the ability of these complement regulators to bind heparan sulphate (HS) in these structures. In addition, there is an age-related loss of HS from Bruch’s membrane. We hypothesize that a combination of poor binding of the 402H variants of FHL-1 and FH to Bruch’s membrane, combined with a decrease in binding due to age-related HS loss, eventually results in insufficient FHL-1 and FH binding to Bruch’s membrane. This could result in complement activation, inflammation and thereby predispose to AMD. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessReview Inflammation and Cell Death in Age-Related Macular Degeneration: An Immunopathological and Ultrastructural Model
J. Clin. Med. 2014, 3(4), 1542-1560; doi:10.3390/jcm3041542
Received: 5 September 2014 / Revised: 26 November 2014 / Accepted: 1 December 2014 / Published: 22 December 2014
Cited by 7 | PDF Full-text (758 KB) | HTML Full-text | XML Full-text
Abstract
The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and
[...] Read more.
The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and complement, microglial accumulation with age, etc. These point to an allostatic overload, possibly due to a breakdown in self vs. non-self when endogenous compounds and structures acquire the appearance of non-self over time. The result is inflammation and inflammation-mediated cell death. While it is clear that these processes ultimately result in degeneration of retinal pigment epithelium and photoreceptor, the prevalent type of cell death contributing to the various phenotypes is unknown. Both molecular studies as well as ultrastructural pathology suggest pyroptosis, and perhaps necroptosis, are the predominant mechanisms of cell death at play, with only minimal evidence for apoptosis. Herein, we attempt to reconcile those factors identified by experimental AMD models and integrate these data with pathology observed under the electron microscope—particularly observations of mitochondrial dysfunction, DNA leakage, autophagy, and cell death. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Open AccessReview Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration
J. Clin. Med. 2014, 3(4), 1302-1321; doi:10.3390/jcm3041302
Received: 28 August 2014 / Revised: 4 November 2014 / Accepted: 6 November 2014 / Published: 17 November 2014
Cited by 5 | PDF Full-text (1342 KB) | HTML Full-text | XML Full-text
Abstract
Genes that increase susceptibility to age-related macular degeneration (AMD) have been identified; however, since many individuals carrying these risk alleles do not develop disease, other contributors are involved. One additional factor, long implicated in the pathogenesis of AMD, is the lipofuscin of retinal
[...] Read more.
Genes that increase susceptibility to age-related macular degeneration (AMD) have been identified; however, since many individuals carrying these risk alleles do not develop disease, other contributors are involved. One additional factor, long implicated in the pathogenesis of AMD, is the lipofuscin of retinal pigment epithelium (RPE). The fluorophores that constitute RPE lipofuscin also serve as a source of autofluorescence (AF) that can be imaged by confocal laser ophthalmoscopy. The AF originating from lipofuscin is excited by the delivery of short wavelength (SW) light. A second autofluorescence is emitted from the melanin of RPE (and choroid) upon near-infrared (NIR-AF) excitation. SW-AF imaging is currently used in the clinical management of retinal disorders and the advantages of NIR-AF are increasingly recognized. Here we visit the damaging properties of RPE lipofuscin that could be significant when expressed on a background of genetic susceptibility. To advance interpretations of disease-related patterns of fundus AF in AMD, we also consider the photochemical and spectrophotometric features of the lipofuscin compounds responsible for generating the fluorescence emission. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)
Figures

Open AccessReview Age-Related Macular Degeneration: A Disease of Systemic or Local Complement Dysregulation?
J. Clin. Med. 2014, 3(4), 1234-1257; doi:10.3390/jcm3041234
Received: 4 August 2014 / Revised: 20 October 2014 / Accepted: 22 October 2014 / Published: 3 November 2014
Cited by 3 | PDF Full-text (753 KB) | HTML Full-text | XML Full-text
Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement
[...] Read more.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement activation in association with AMD. It is unclear which one is the primary driver of disease. This has important implications for designing novel complement-based AMD therapies. We present a summary of the current literature and suggest that intraocular rather than systemic modulation of complement may prove more effective. Full article
(This article belongs to the Special Issue Age-Related Macular Disease)

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