Modelling the genetic risk in age-related macular degeneration

Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.     

Treatment of age-related macular degeneration

Age-related macular degeneration (AMD), while rapidly becoming more prevalent due to an aging population, is still poorly understood and treatment modalities are limited. Fortunately, advances are being made in the treatment of AMD that may greatly alter the outcome of this debilitating disease. Treatments for both wet and dry AMD are reviewed.     

Mechanisms of age-related macular degeneration

Age-related macular degeneration (AMD), a progressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in the elderly worldwide. The two forms of AMD, wet and dry, are classified based on the presence or absence of blood vessels that have disruptively invaded the retina, respectively. A detailed understanding of the molecular mechanisms underlying wet AMD has led to several robust FDA-approved therapies. In contrast, there are no approved treatments for dry AMD. In this review, we provide insight into the critical effector pathways mediating each form of the disease. A recurring theme that spans most aspects of AMD pathogenesis is defective immune modulation in the classically immune-privileged ocular haven. Interestingly, the latest advances in AMD research also highlight common molecular disease pathways with other neurodegenerative disorders. Finally, the therapeutic potential of intervening at known mechanistic steps of AMD pathogenesis is discussed.     

The molecular genetic basis of age-related macular degeneration: an overview

Age-related macular degeneration (AMD) is a complex disorder of the eye and the third leading cause of blindness worldwide. With a multifactorial etiology, AMD results in progressive loss of central vision affecting the macular region of the eye in elderly. While the prevalence is relatively higher in the Caucasian populations, it has gradually become a major public health issue among the non-Caucasian populations (including Indians) as well due to senescence, rapidly changing demographics and life-style factors. Recent genome-wide association studies (GWAS) on large case-control cohorts have helped in mapping genes in the complement cascade that are involved in the regulation of innate immunity with AMD susceptibility. Genes involved with mitochondrial oxidative stress and extracellular matrix regulation also play a role in AMD pathogenesis. Majority of the associations observed in complement (CFH, CFB, C2 and C3) and other (ARMS2 and HTRA1) genes have been replicated in diverse populations worldwide. Gene-gene (CFH with ARMS2 and HTRA1) interactions and correlations with environmental traits (smoking and body mass index) have been established as significant covariates in AMD pathology. In this review, we have provided an overview on the underlying molecular genetic mechanisms in AMD worldwide and highlight the AMD-associated-candidate genes and their potential role in disease pathogenesis.     

Genomic aspects of age-related macular degeneration

Age-related macular degeneration (AMD) is a major late-onset posterior eye disease that causes central vision to deteriorate among elderly populations. The predominant lesion of AMD is the macula, at the interface between the outer retina and the inner choroid. Recent advances in genetics have revealed that inflammatory and angiogenic pathways play critical roles in the pathophysiology of AMD. Genome-wide association studies have identified ARMS2/HTRA1 and CFH as major AMD susceptibility genes. Genetic studies for AMD will contribute to the prevention of central vision loss, the development of new treatment, and the maintenance of quality of vision for productive aging.     

Nutritional modulation of age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. It affects 30-50 million individuals and clinical hallmarks of AMD are observed in at least one third of persons over the age of 75 in industrialized countries (Gehrs et al., 2006). Costs associated with AMD are in excess of $340 billion US (American-Health-Assistance-Foundation, 2012). The majority of AMD patients in the United States are not eligible for clinical treatments (Biarnes et al., 2011; Klein et al., 2011). Preventive interventions through dietary modulation are attractive strategies because many studies suggest a benefit of micro- and macronutrients with respect to AMD, as well as other age-related debilities, and with few, if any, adverse effects (Chiu, 2011). Preservation of vision would enhance quality of life for millions of elderly people, and alleviate the personal and public health financial burden of AMD (Frick et al., 2007; Wood et al., 2011). Observational studies indicate that maintaining adequate levels of omega-3 fatty acids (i.e. with 2 servings/week of fish) or a low glycemic index diet may be particularly beneficial for early AMD and that higher levels of carotenoids may be protective, most probably, against neovascular AMD. Intervention trials are needed to better understand the full effect of these nutrients and/or combinations of nutrients on retinal health. Analyses that describe effects of a nutrient on onset and/or progress of AMD are valuable because they indicate the value of a nutrient to arrest AMD at the early stages. This comprehensive summary provides essential information about the value of nutrients with regard to diminishing risk for onset or progress of AMD and can serve as a guide until data from ongoing intervention trials are available.     

Oxidative damage in age-related macular degeneration

Epidemiologic studies have suggested that elderly patients who consumed diets rich in antioxidants throughout their lives are less likely to be afflicted with age-related macular degeneration (AMD). This led to the Age-Related Eye Disease Study, which showed that supplements containing antioxidant vitamins and zinc reduce the risk of progression to severe stages of AMD. Despite these data that indirectly implicate oxidative damage in the pathogenesis of AMD, there has not been any direct demonstration of increased oxidative damage in the retinas of patients with AMD. In this study, we used biomarkers of oxidative damage in postmortem eyes from patients with AMD and comparably aged patients without AMD to directly assess for oxidative damage. Sections from 4 eyes with no pathologic features of AMD showed no immunofluorescent staining for markers of oxidative damage, while sections from 8 of 12 eyes with advanced geographic atrophy showed evidence of widespread oxidative damage in both posterior and anterior retina. Only 2 of 8 eyes with choroidal neovascularization and 2 of 16 eyes with diffuse drusen and no other signs of AMD showed evidence of oxidative damage. These data suggest that widespread oxidative damage occurs in the retina of some patients with AMD and is more likely to be seen in patients with advanced geographic atrophy. This does not rule out oxidative damage as a pathogenic mechanism in patients with CNV, but suggests that a subpopulation of patients with geographic atrophy may have a major deficiency in the oxidative defense system that puts the majority of cells in the retina at risk for oxidative damage.     

Oxidative damage-induced inflammation initiates age-related macular degeneration

Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.     

Prednisolone neuroprotective therapy in age-related macular degeneration

134 patients with Age-related Macular Degeneration (AMD) (aging 47-75 years) were treated in therapy procedure with parabulbar injections of Methylprednisolone Acetate and Prednisolone Acetate. In the first group of patients with AMD (n = 71 patients) were treated with Methylprednisolone acetate, and second group (n = 63 patients) with Prednisolone acetate. Each patient was given doses of 60 mg, through two weeks, 10 mg every second day. It's estimated in all patients ameliorate in macular threshold, so that it's in the group with Methylprednisolone treatment, ameliorate effect begins after first week, than in second group, treated with Prednisolone, initial ameliorate effect is after second week. Complete effect in both groups is after 2 months. It can be concluded that the treatment of AMD with glucocorticoids has the ameliorate effect in vision loss and it is decided that earlier effect in the group treated with Methylprednisolone, is probably of higher affinity for glucocorticoid receptors.     

Systemic complement activation in age-related macular degeneration

Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.     

Collagen VI assemblies in age-related macular degeneration

Age-related macular degeneration (AMD) is the most common cause of incurable blindness in the developed world. Little is known about the pathogenesis of this condition, but deposits in Bruch's membrane and immediately beneath the retinal pigment epithelium are frequent findings associated with this disease. Within these deposits, molecular assemblies with an approximately 100-nm axial periodicity are seen. Two types of assembly are present: one exhibiting transverse double bands of protein density that are 30nm apart and repeat axially every approximately 100nm; the other with transverse double bands of protein density, 30nm apart and repeating axially every approximately 50nm. In this second type of assembly, more prominent pairs of bands alternate with less prominent ones. By comparison with analogous aggregates found in the vitreous of a patient with a full-thickness macular hole, collagen VI was singled out as the most probable protein constituent of the AMD aggregates. Possible models for the aggregation patterns of these assemblies are discussed in terms of collagen VI dimers and tetramers. Understanding the structure and chemical composition of the assemblies within the AMD basal deposits may prove of great help in understanding the pathophysiology of AMD itself.     

New therapies for the treatment of age-related macular degeneration]

Age-related macular degeneration has a natural progression from the precursors (the drusen) towards atrophic or neovascular complications. Choroidal neovascularization is undoubtedly the aspect of the disease that benefits most from new therapeutical approaches. Destructive photocoagulation based on fluorescein angiography has demonstrated since 20 years its efficiency on choroidal neovascularization. The same approach based on indocyanine green (ICG) angiography would increase the number of patients available to therapy. Very recently photodynamic therapy has demonstrated its efficiency to stabilize visual acuity at least at two years in patients with choroidal new vessels predominantly well defined. Other treatment developments are considered, such as refinement of photocoagulation techniques or of surgery. Until now, none has demonstrated its efficiency although they raise justified hopes. The future approaches rely upon the progress of the research both in physiopathology of the disease and on the angiogenic process requiring a constant interaction with all thematics of research. Finally, palliative treatments will be required before heading up to a preventive treatment.     

Imaging and artificial intelligence for progression of age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of severe vision loss. With our aging population, it may affect 288 million people globally by the year 2040. AMD progresses from an early and intermediate dry form to an advanced one, which manifests as choroidal neovascularization and geographic atrophy. Conversion to AMD-related exudation is known as progression to neovascular AMD, and presence of geographic atrophy is known as progression to advanced dry AMD. AMD progression predictions could enable timely monitoring, earlier detection and treatment, improving vision outcomes. Machine learning approaches, a subset of artificial intelligence applications, applied on imaging data are showing promising results in predicting progression. Extracted biomarkers, specifically from optical coherence tomography scans, are informative in predicting progression events. The purpose of this mini review is to provide an overview about current machine learning applications in artificial intelligence for predicting AMD progression, and describe the various methods, data-input types, and imaging modalities used to identify high-risk patients. With advances in computational capabilities, artificial intelligence applications are likely to transform patient care and management in AMD. External validation studies that improve generalizability to populations and devices, as well as evaluating systems in real-world clinical settings are needed to improve the clinical translations of artificial intelligence AMD applications.     

Transformation of the proteasome with age-related macular degeneration

The proteasome mediates pathways associated with oxidative stress and inflammation, two pathogenic events correlated with age-related macular degeneration (AMD). In human donor eyes corresponding to four stages of AMD, we found the proteasomal chymotrypsin-like activity increased in neurosensory retina with disease progression. Increased activity correlated with a dramatic increase in the inducible subunits of the immunoproteasome, which was not due to an increase in CD45 positive immune cells in the retina. The novel observation of proteasome transformation may reflect retinal response to local inflammation or oxidative stress with AMD.