The genetics of age‐related macular degeneration

Aim: To review the genetics of age‐related macular degeneration (AMD). The pathogenesis of AMD, the leading cause of severe visual disability and blindness in our community, remains unknown. However, AMD is regarded as a genetic disease where family history of AMD is a significant risk factor for the disease. Understanding the genetic factors associated with AMD offers the greatest chance for understanding the underlying disease processes. Methods: Through a review of the literature and the use of original research findings, the current knowledge of the genetics of AMD is explored. Conclusion: AMD is increasing in prevalence and remains a major challenge for eye heath providers. Finding the genes that are associated with AMD offers the greatest chance for the development of preventative strategies and treatments.     

Illumination and reading performance in age‐related macular degeneration

Background: Previous studies have compared low vision reading performance at optimal task illuminance and consulting room illuminance (500 to 600 lux). However, it is uncertain the extent to which low vision reading performance can be improved when task illumination is increased from levels more representative of those found in the typical living room (50 lux) to levels likely to maximise performance. Methods: Reading performance of 20 subjects with age‐related macular degeneration (AMD) was assessed for a range of print sizes using sentence reading charts at six levels of task illuminance (50 to 5,000 lux). Subjects read without low vision devices. Results: Sentence reading acuity and critical print size improved by a factor of two over the 50 to 5,000 lux range, while maximum reading rate improved by a factor of 1.4. For the majority of subjects (70 per cent), the optimal task illuminance (determined objectively) was higher (median 3,500 lux) than the subjectively preferred task illuminance (median 2,450 lux). Reading performance was significantly better at the optimal illuminance than at illuminances equivalent to those found in the domestic environment (50 lux) or consulting room (600 lux). Conclusions: The majority of AMD patients will require task illumination of at least 2,000 lux to maximise reading performance. Optimal illumination should be determined individually for each patient using both objective measures of performance, such as reading acuity, and subjective assessments of visual comfort.     

Leucocyte telomere length in age‐related macular degeneration

Purpose: To evaluate the association between telomere length and age‐related macular degeneration (AMD). Methods: Circulating leucocyte telomere length and the proportion of telomeres <5 kb were analysed in blood DNA samples taken from 121 patients with exudative AMD (83%), large drusen (14%) or central geographic atrophy (3%). Controls consisted of 77 age‐matched subjects without AMD. The AMD status was assessed by a masked analysis of fundus photographs or angiographs. Telomere length was measured by Southern blotting. Results: Mean (SD) telomere length was 7.76 kb (0.68) in AMD patients and 7.83 (0.69) in controls (p = 0.485). The corresponding proportions of telomeres <5 kb were 10.60 (2.76) and 10.05 (2.64) (p = 0.197). In this material, there was no correlation between telomere length and age, gender or smoking status. There were no differences between the major AMD risk single‐nucleotide polymorphisms (SNPs) of the CFH, HTRA1 or C3 genes, expect for somewhat longer telomeres in controls with the C3 risk SNP. There were no differences in telomere length between patients with drusen or exudative AMD. Conclusions: Telomere length is not associated with exudative AMD or high‐risk drusen.     

Outer retinal cysts in age‐related macular degeneration

Purpose: To describe novel cystic structures (‘outer retinal cysts’ or ORC) found in the outer retina in age‐related macular degeneration (AMD). Methods: One hundred and seventy‐three consecutive eyes of 88 AMD patients were prospectively examined with spectral domain optical coherence tomography (SD‐OCT). The prevalence of ORCs was searched, and their sizes and shapes were determined. Results: SD‐OCT revealed round or ovoid, intraretinal, hyporeflective cystic structures with a hyperreflective border in 60 eyes (56%) with neovascular AMD and in six eyes (21%) with atrophic AMD. These cystic structures were of different sizes and shapes. They remained stable in all the patients after a follow‐up period of 6 months. Conclusions: Outer retinal cyst is a new type of cystic structure recently identified in AMD patients. ORCs should not be confused with intraretinal exudates or cystoid cavities and therefore do not require any treatment. The histopathological nature of ORC remains to be determined. Further studies are necessary to determine their true origin.     

Multimodal imaging of dry age‐related macular degeneration

Purpose: The purpose of this study was to understand clinical significance of near‐infrared reflectance (NIR), blue fundus autofluorescence (FAF) and near‐infrared autofluorescence (NIA) in dry age‐related macular degeneration (AMD), by correlation with fluorescein angiography (FA) and cross‐sectional spectral domain optical coherence tomography (SD OCT). Methods: We evaluated 110 eyes (62 patients, mean age: 64 ± 8 years) diagnosed with dry AMD between January 2010 and December 2010, which underwent NIR (λ = 830 nm), FAF and FA (excitation λ = 488 nm; emission λ > 500 nm), NIA (excitation λ = 787 nm; emission λ > 800 nm), and simultaneous SD OCT scanning using a combined confocal scanning laser ophthalmoscope/SD OCT device (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany). Results: Drusen showed variable increased/decreased NIR, FAF, NIA and FA, which corresponded to variable increased/decreased thickness of the retinal pigment epithelium (RPE) and possible presence of subretinal deposits on SD OCT. Geographic atrophy (GA) was present in 43/110 eyes (39.0%) and showed increased NIR and fluorescence (FA), absent FAF and NIA, and loss of RPE on SD OCT. The hyperautofluorescence of the GA margin was never larger in FAF than that in NIA, while in 16.2% of cases, it was larger in NIA than that in FAF and corresponded to mild choroidal hyperreflectivity on SD OCT. Conclusions: Simultaneous recording of SD OCT scans provided ultrastructural data for the evaluation of NIR, FAF, NIA and FA in dry AMD. Near‐infrared autofluorescence might detect earlier than FAF areas of RPE cell loss at the GA margin.     

Genetic cardiovascular risk factors and age‐related macular degeneration

Purpose: To investigate the association between genetic cardiovascular risk factors and exudative age‐related macular degeneration (AMD) in a White Austrian population. Methods: Seventy‐five unrelated AMD patients and 75 unrelated healthy, sex‐ and age‐matched control patients were genotyped for the following 19 single nucleotide polymorphisms (SNPs) in 14 different genes: blood coagulation factor V (FV) R506Q, factor II (prothrombin) G20210A and factor XIII (FXIII) V34L; 5,10‐methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C; plasminogen activator inhibitor 1 (PAI‐1) 4G/5G; endothelial protein C receptor (EPCR) 4600 A>G (A3 haplotype), 4678 G>C (A1 haplotype); apolipoprotein B (ApoB) R3500Q; apolipoprotein E (ApoE) E2/E3/E4; β‐fibrinogen ?455 G>A; human platelet antigen 1 (HPA1) a/b; angiotensin‐converting enzyme (ACE) I/D; endothelial nitric oxide synthase (eNOS) 786 T>C, 894 G>T; lymphotoxin alpha (LTA) 804 C>A and 9p21 rs10757278. Genotyping was carried out by polymerase chain reaction (PCR) followed by reverse hybridization (CVD StripAssays; ViennaLab Diagnostics, Vienna, Austria). Results: No statistically significant association could be observed between AMD and the investigated genetic risk factors for cardiovascular disease (CVD). All factors seem to be uniformly distributed in the two groups of AMD patients and healthy controls. Two variables –β‐fibrinogen: ?455 G>A (p = 0.0786) and apolipoprotein E4 (p = 0.0636) – were not as far from association as the others. Conclusion: Our data show that the 19 tested CVD risk markers do not play a significant role in AMD. β‐Fibrinogen and apolipoprotein E4 should be examined in a larger cohort.     

Relationship between macular pigment and visual acuity in eyes with early age‐related macular degeneration

Purpose: Today the extent to which MP impacts visual function in early AMD remains unclear. This study examines the relationship between macular pigment optical density (MPOD) and high‐contrast visual acuity (HC‐VA) and low‐contrast visual acuity (LC‐VA) in eyes with early age‐related macular degeneration (AMD). Methods: Measurements were made in 22 subjects with early AMD and 27 healthy control subjects. Distance best‐corrected VA was measured using HC (96%) and LC (10%) Bailey‐Lovie logMAR letter charts under photopic luminance conditions. MPOD was determined at the fovea through apparent motion photometry using the cathode ray tube‐based Metropsis psychophysical vision test (Cambridge Research Systems). Results: No significant differences in foveal MPOD were detected between the control eyes (0.30 ± 0.24 log units) and eyes with early AMD (0.27 ± 0.15 log units). Neither were differences detected between the two groups in mean HC‐ and LC‐VA. Foveal MPOD showed significant correlation with both photopic HC‐VA (r = ?0.47, p = 0.0008) and LC‐VA (r = ?0.46, p = 0.0008) such that as MPOD increased, photopic HC‐VA and LC‐VA improved (lower logMAR values). Conclusions: Low MP levels were related to worse visual function in both healthy eyes and eyes with early AMD. Our findings provide direction for future studies designed to improve retinal function through the use of oral supplements known to increase MP levels, especially in eyes with AMD and a low MPOD.     

Peripheral autofluorescence findings in age‐related macular degeneration

Purpose: To describe the peripheral autofluorescent findings in patients with age‐related macular degeneration (AMD) using ultrawide‐field imaging. Methods: We retrospectively reviewed the ultra‐wide‐field autofluorescent images of all patients diagnosed with AMD or macular drusen at the Department of Ophthalmology of Weill Cornell Medical College from July 2010 to September 2011. Peripheral autofluorescent phenotypes included normal autofluorescence, focal pinpoint hyperfluorescence, granular fluorescent changes, patchy hypofluorescence, and reticular hypofluorescence. Results: One hundred and ten consecutive patients (220 eyes) with a diagnosis of AMD or macular drusen were imaged using ultra‐wide‐field autofluorescent technology during the study period. Eighty‐three patients (157 eyes) were included in the final analysis. Peripheral autofluorescent abnormalities were present in 63.6% of eyes with AMD versus 35.7% of control eyes (p = 0.049). Granular fluorescent changes (p = 0.0001) and patchy hypofluorescence (p = 0.0015) were more common in eyes with advanced AMD than in eyes with early AMD or control eyes. Granular fluorescent changes were also more common in eyes with choroidal neovascularization (p = 0.026) or geographic atrophy (p = 0.0001). Patchy hypofluorescence (0.0001) was more common in eyes with geographic atrophy. Conclusions: Peripheral autofluorescent abnormalities are common in eyes with AMD. The peripheral findings in eyes with AMD may represent different phenotypes, which may indicate different environmental or genetic factors in the development of AMD. Characterizing the different peripheral phenotypes may have implications for diagnosis and treatment of AMD subtypes.     

Projected prevalence of age‐related macular degeneration in Scandinavia 2012–2040

Purpose: To project the number of persons with late age‐related macular degeneration (AMD) in Scandinavia through 2040. Methods: Age‐ and sex‐specific prevalence rates of late AMD (choroidal neovascularization and geographic atrophy) from the European Eye Study and the Eye Diseases Prevalence Research Group were applied to the projected Danish, Norwegian and Swedish population from 2012 to 2040. Results: A total of 187 000 persons aged ≥65 years in Scandinavia are currently affected by late AMD: 47 000 in Denmark, 43 000 in Norway and 97 000 in Sweden. Owing to an ageing population, the number of persons affected by late AMD will increase 75% to 328 000 in 2040. Conclusion: The number of patients with late AMD in Scandinavia is expected to increase substantially over the next three decades, resulting in increased demand for ophthalmic health services.     

Daytime levels of melatonin in patients with age‐related macular degeneration

Purpose: Melatonin (N‐acetyl‐5‐methoxytryptamine) (MT) is a hormone that acts as an antioxidant. It is produced by the pineal gland and within the retina; its release is blocked by light entering the eye. We examined whether MT daytime levels differ between pseudophakic patients with age‐related macular degeneration (ARMD) and pseudophakic subjects without any ocular pathology of the same age. Methods: A prospective, cross‐sectional, observational study was performed. Pseudophakic patients of the same age group were included. Patients underwent complete ophthalmic examinations and blood sampling between 08:00 and 10:00 hr. MT daytime value in the serum was the main outcome measure. Results: Sixty‐nine pseudophakic patients were included. Fifty patients with exudative and non‐exudative ARMD were in the study group while 19 patients were controls. Patients with ARMD had significantly higher daytime levels of MT (P = 0.003). There were significant differences in MT daytime levels between the exudative and non‐exudative forms (P = 0.009). MT values also correlated with the best‐corrected visual acuity (r = ?0.285, P = 0.019). Conclusion: These data indicate that pseudophakic patients with ARMD produce more MT during the day compared to pseudophakic subjects without ARMD. This may be caused by the reduced visual acuity in patients with ARMD, whereby less light reaches the photoreceptors, allowing MT secretion to continue during the day. Because MT also acts as an antioxidant and daytime levels are higher in patients with ARMD, these results might be interpreted as a rescue factor.     

Vitreomacular traction and exudative age‐related macular degeneration

Vitreomacular traction resulting from lacking, incomplete or anomalous posterior vitreous detachment is suspected to play a crucial role in the pathogenesis of different forms of age‐related macular degeneration (AMD) along with the known mechanisms. It is probable that the fundamental pathomechanisms of AMD formation have already begun by the time tractional forces lead to a change for the worse. Vitreomacular traction alone is perhaps not able to induce AMD. It would seem sensible to consider vitreous changes when diagnosing and treating AMD patients because of the high coincidence of vitreomacular traction and choroidal neovascularization (CNV) and the often successful treatment of other diseases of the vitreoretinal interface by vitrectomy. The concept of the pathogenesis of AMD should therefore be extended to include the influence of the vitreous, especially where therapeutic concepts such as pharmacological vitreolysis and vitreous separation have been established as causative treatment of late forms of AMD.