Japanese Age-related Macular Degeneration Research Articles

Characteristics of Retinal Pigment Epithelium Elevations Preceding Exudative Age-Related Macular Degeneration in Japanese

Introduction: Drusen and pigmentary abnormality are found as the hallmark to predict progression of age-related macular degeneration (AMD). In Asian populations, exudative AMD often appears in the absence of drusen but is rather accompanied by pigmentary abnormality. Recently, shallow irregular retinal pigment epithelium (RPE) elevations (SIRE) have been shown as a sign of subclinical nonexudative macular neovascularization. In this study, we aimed to investigate the characteristics of optical coherence tomography (OCT) findings including SIRE before the appearance of exudative AMD. Methods: We retrospectively reviewed 32 cases of exudative AMD that occurred in the fellow eye within the 5-year-observation period. Color fundus photography, OCT, and fluorescein/indocyanine-green angiography at the beginning of observation and at the time when exudative AMD appeared were examined to diagnose SIRE and the subtype of exudative AMD. Results: Exudative AMD was found in 19 eyes with large drusen and 13 eyes without large drusen. Mean sub-foveal choroidal thickness without large drusen was significantly thicker than that with large drusen (336 ± 109 and 220 ± 96 μm, respectively; mean ± SD). Six eyes with pachychoroid neovasculopathy, 4 eyes with type 1 macular neovascularization, and 3 eyes with PCV had occurred in the fellow eye without large drusen. Among those, 6 eyes had been accompanied by SIRE with a greatest transverse linear dimension of 1 mm or more at the beginning of observation period. Besides, small RPE elevations with a longest diameter of less than 1 mm had been observed in other 5 eyes. Three cases of polypoidal choroidal vasculopathy had originated from small RPE elevations. Moreover, pachyvessels, choriocapillaris thinning, or choroidal hyperpermeability were observed with SIRE or small RPE elevations. Conclusions: There is a non-drusen type of exudative AMD that originates from small RPE elevations as well as SIRE.

Baseline data from a multicenter, 5-year, prospective cohort study of Japanese age-related macular degeneration: an AMD2000 report.

To report research participants' baseline characteristics in the AMD2000 study, a prospective, multicenter, 5-year, observational cohort study of Japanese age-related macular degeneration (AMD). The characteristics were determined using multimodal imaging. Patients with AMD were recruited at 18 clinical sites in Japan between April 2006 and March 2009. Each patient underwent a complete ophthalmic examination, including measurement of best-corrected visual acuity (Landolt chart), indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens, optical coherence tomography imaging, fundus photography, and fluorescein and indocyanine green angiography. Four hundred sixty participants (326 men [70.9%]) were included in the study. At enrollment, 131 eyes (28.5%) had hard drusen and 125 eyes (27.2%) had soft drusen in the macular area. A total of 455 eyes (98.9%) were diagnosed as having wet AMD, and 5 eyes (1.1%), as having dry AMD. Of the 455 eyes with wet AMD, 209 eyes (45.4%) had typical AMD, 228 eyes (49.6%) had polypoidal choroidal vasculopathy (PCV), and 18 eyes (3.9%) had retinal angiomatous proliferation. The size of choroidal neovascularization (CNV) was significantly smaller with indocyanine green angiography than with fluorescein angiography (P < 0.001). Poor baseline visual acuity was associated with cystoid macular edema, older age, scar, extrafoveal macular edema, subfoveal CNV, large branching vascular network, and hard exudates. Japanese patients with AMD are predominantly male, lack drusen, and have a high rate of PCV.

HTRA1 (High Temperature Requirement A Serine Peptidase 1) Gene Is Transcriptionally Regulated by Insertion/Deletion Nucleotides Located at the 3′ End of the ARMS2 (Age-related Maculopathy Susceptibility 2) Gene in Patients with Age-related Macular Degeneration

Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knock-out mice in which HtrA1 exon 1 was replaced with β-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein that bound the insertion/deletion sequence, LYRIC (lysine-rich CEACAM1 co-isolated) protein. In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant up-regulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained up-regulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients.

TOPICAL BROMFENAC AS AN ADJUNCTIVE TREATMENT WITH INTRAVITREAL RANIBIZUMAB FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION

Intravitreal injection of ranibizumab is highly effective for wet age-related macular degeneration. Its limitation is that most patients require repeated intravitreal injections to achieve and maintain the visual gain. We assessed the effectiveness of adjunctive topical bromfenac, a nonsteroidal antiinflammatory drug, with ranibizumab. Patients with wet age-related macular degeneration with lesions smaller than 2 disk diameters were randomized 2:3 to adjunctive topical bromfenac (n = 16) or sham (n = 22) and a 0.5-mg ranibizumab injection in a double-masked fashion. Subjects were examined monthly, and ranibizumab was injected as needed from baseline. The primary endpoint was the comparison of the number of ranibizumab injections over 6 months. The visual and anatomic responses also were compared. The mean number of ranibizumab injections over 6 months was 2.2 in the bromfenac group and 3.2 in the sham, a difference that reached significance (P = 0.0274). The changes in visual acuity did not differ significantly (P = 0.3141) although the central retinal thickness was tended to decrease more in bromfenac group (P = 0.0604). Multivariate analysis showed that topical bromfenac is significantly associated with fewer ranibizumab injections. Topical bromfenac might reduce the frequency of ranibizumab over 6 months in eyes with relatively small age-related macular degeneration lesions.

Serum omega-3 fatty acids are not associated with age-related macular degeneration

Evaluation of: Kabasawa S, Mori K, Horie-Inoue K et al. Associations of cigarette smoking but not serum fatty acids with age-related macular degeneration in a Japanese population. Ophthalmology 118(6), 1082–1088 (2011).Age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly in developed countries. Risk factors for AMD are classified into endogenous nonmodifiable factors, including genetics and environmental factors such as smoking and dietary habits. Both epidemiological and experimental studies suggest that dietary omega-3 long-chain fatty acids would participate to prevent from the development of AMD. The mechanisms behind this association have been poorly defined until now. Kabasawa and coworkers recently published that Japanese AMD patients did not exhibit a different serum fatty acid profile compared with Japanese controls, although the circulating levels of omega-3 fatty acids were doubled in Japanese subjects when compared with subjects in the USA – a consequence of Japanese dietary habits privileging fish consumption.

Association of Elastin Gene Polymorphism to Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

To see if there is an association in Japanese between elastin gene (ELN) polymorphisms and neovascular age-related macular degeneration (AMD) or its subtypes, typical AMD (tAMD) and polypoidal choroidal vasculopathy (PCV). The authors genotyped five single nucleotide polymorphisms (SNPs), rs2301995, rs2856728, rs868005, rs884843, and rs13239907, at Kyoto University and Saitama Medical University. A case-control study was performed on 1296 patients with AMD and 478 controls. A statistically significant association was detected between the rs2301995 SNP and AMD (P = 0.018). Furthermore, subtype analysis revealed a significant association of rs2301995 with tAMD (P = 0.0018), but not with PCV. The genotype distribution of rs2301995 also differed significantly between tAMD and PCV (P = 0.00030). The trend in genotype distribution of rs2301995 was similar between the Kyoto and the Saitama studies. The A allele frequency was higher in tAMD, whereas it was similar in PCV and in controls, which is opposite to that reported in a previous study that the A allele frequency is higher in PCV, whereas it is similar in tAMD and in controls. Haplotype analysis also showed that the ELN polymorphism is significantly associated with tAMD (P = 0.0055), but not with PCV. ELN is associated with AMD in Japanese. Furthermore, the findings suggest that ELN is a susceptibility gene for tAMD but not for PCV, which is opposite to that reported in a previous study that ELN is the susceptibility gene for PCV but not for tAMD.

Characteristics of age-related macular degeneration in patients with diabetic retinopathy

The purpose of this study was to determine the clinical characteristics of age-related macular degeneration (AMD) in patients with diabetic retinopathy (DR). Retrospective, consecutive case series. Twenty-six eyes of 25 Japanese patients were studied. All patients were diagnosed as having exudative AMD with DR. Patients with no apparent DR, dry AMD, neovascular maculopathy associated with high myopia, and age <50 years were excluded. The clinical characteristics of AMD in patients with DR, e.g., gender, age, stage of DR, and type of AMD were evaluated. In the 26 eyes, 2 eyes (7.7%) were classified as mild nonproliferative DR (NPDR), 7 (27.0%) with moderate NPDR, 16 (61.5%) with severe NPDR and 1 eye (3.8%) with PDR. Of the 26 eyes with exudative AMD, 21 eyes (80.8%) were classified as neovascular AMD, 4 (15.4%) as polypoidal choroidal vasculopathy and 1 eye (3.8%) as a retinal angiomatous proliferation. Among the eyes with neovascular AMD, 9 eyes (42.9%) were classified as predominantly classic choroidal neovascularization (CNV). There is a predominance of men, neovascular AMD and predominantly classic CNV in Japanese AMD patients with DR. The exudative AMD in patients with DR may have different clinical characteristics from those without DR.

Associations of Cigarette Smoking But Not Serum Fatty Acids with Age-related Macular Degeneration in a Japanese Population

To assess modifiable environmental risk factors and protective factors for age-related macular degeneration (AMD) in a native Japanese population. A case-control study. We included 422 case-control samples composed of 279 consecutive AMD cases and 143 controls. Information regarding systemic conditions and lifestyle were documented in each subject by standardized questionnaire including age, gender, smoking history, body mass index (BMI), and history of cardiovascular disease, hypertension, and diabetes. Serum fatty acids profiles were analyzed by gas chromatography performed on blood samples taken from each study participant. Logistic regression and multiple comparison analyses were utilized in this study. Population-specific information assessing systemic conditions, lifestyle, and serum fatty acid profiles. Among environmental factors analyzed cigarette smoking showed the most significant association with development of all AMD (P<0.00001; odds ratio [OR], 4.06; 95% confidence interval [CI], 2.22-7.43), typical neovascular AMD (P<0.0001, OR, 4.59; 95% CI, 2.29-9.18), and polypoidal choroidal vasculopathy (P<0.001; OR, 4.87; 95% CI, 1.96-12.1). Hypertension and BMI showed a mild association with AMD. Although male prevalence was significantly higher in all case groups than in controls with conventional Scheffe correction, there was no association of gender with AMD development when logistic regression analysis was used to adjust for cigarette smoking. There was no difference in fatty acid profiles, except for a mild association of eicosapentaenoic acid concentration in the all AMD group. In the Japanese population studied, cigarette smoking influenced the risk of AMD but fractionated serum fatty acid levels did not. Although prior reports indicate a male predominance in Japanese patients with AMD, this study demonstrates that cigarette smoking accounts for this confounding bias. In addition, our population-specific data do not demonstrate significant differences in serum fatty acid composition, including ω-3 and ω-6 long chain polyunsaturated fatty acids, in Japanese patients with and without AMD. These results are consistent with the high proportion of smokers in aged Japanese men and the high fish oil intake in this population. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Utility values in Japanese patients with exudative age-related macular degeneration

To investigate the utility values associated with visual loss due to age-related macular degeneration (AMD) in Japanese patients. Utility values in 48 Japanese patients with bilateral exudative AMD were measured using the time trade-off and standard gamble methods. The time trade-off method utility values correlated with the best-corrected visual acuity (BCVA) in the better-seeing eye. The estimated utility values according to the BCVA in the better-seeing eye were 0.534 (BCVA, 0.01-0.15), 0.574 (0.2-0.3), 0.613 (0.4-0.6), and 0.653 (0.7-1.0). The utility values obtained by the standard gamble method were not significantly correlated with BCVA in the better-seeing eye. The present results concur with those of previous studies showing that AMD causes a substantial decrease in patient utility values. The utility values obtained in the current study provide important information for use in cost-utility analysis of interventions for Japanese AMD patients.

Phenotype and Genotype Characteristics of Age-related Macular Degeneration in a Japanese Population

To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients. A case-control study. A total of 550 case-control samples composed of 408 consecutive AMD cases and 142 controls. Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology. The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes. The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population.

Photodynamic therapy with verteporfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD): Results of the Japanese AMD Trial (JAT) extension

To evaluate the longer term safety of verteporfin therapy in Japanese patients with subfoveal classic choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). Patients completing 12 months of the Japanese AMD Trial (JAT) were eligible to enter the extension phase if the investigator judged they would potentially benefit from further verteporfin therapy. Patients had follow-up visits every 3 months, receiving verteporfin therapy in the study eye if leakage from CNV was observed on fluorescein angiography. Mean change from baseline in best-corrected visual acuity was a safety variable in the extension. Of the 51 patients entering the study extension, 46 (90%) completed 24 months. Adverse events were similar to those in the first 12 months of JAT; no cumulative toxic effect of verteporfin therapy was identified. Mean visual acuity letter score in the study eye increased from 50.8 (20/100(+1) at baseline to 54.0 (20/80(-1)) at month 24. At month 24, six patients (13%) had lost 15 or more letters of visual acuity, of whom four (9%) had lost 30 or more letters. Verteporfin therapy was shown to be safe and effective through 24 months in Japanese patients with subfoveal CNV due to AMD, supporting its long-term use in these patients.

Long-term follow-up of polypoidal choroidal vasculopathy after photodynamic therapy with verteporfin

To report on the clinical features of three cases of polypoidal choroidal vasculopathy (PCV) during long-term follow-up after photodynamic therapy (PDT). Interventional case reports. Among the participants in the Japanese Age-Related Macular Degeneration Trial (JAT) at our hospital, a PCV was seen in three eyes at baseline on retrospective analysis of indocyanine green angiography (ICGA) using fundus camera. We report the clinical features of these cases during more than 4 years follow-up. The mean number of PDT treatments was 5.7. Improved visual acuity (VA) and cessation of fluorescein leakage was achieved within 18 months in all eyes; however, subretinal hemorrhage and subfoveal fluid recurred due to new or recurrent PCV. The final VA decreased markedly in two eyes. The eyes with PCV, which had been treated successfully with PDT, may have developed new or recurrent PCV during long-term follow-up. Periodical ICGA would be needed to detect abnormal choroidal vascular changes.

A polymorphism of LOC387715 gene is associated with age-related macular degeneration in the Japanese population

Age-related macular degeneration (AMD) is one of the leading causes of blindness among older adults in developed countries and also in Japan. Previous research suggests that AMD is etiologically a complex disease, caused by multiple genes and environmental factors. Association studies have identified that a complement factor H gene (CFH) variant is a major risk factor for AMD in Caucasians. However, we and two other groups have reported no association between CFH and AMD in the Japanese population. Recent studies have suggested that LOC387715 on chromosome 10q26 may be the second major risk loci for AMD in Caucasians. In this study, we examined the association between LOC387715 and AMD in Japanese, and our results show that polymorphism of the LOC387715 gene is associated with AMD in Japanese as well as in Caucasians. Our data show a disease odds ratio of 6.20 (95% CI: 2.87–13.40) conferred by homozygosity for risk alleles at LOC387715 compared with the non-risk genotype. A polymorphism of LOC387715 gene is associated with AMD in the Japanese population.

No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese

Age-related macular degeneration (ARMD) is the leading cause of blindness in the elderly population not only Western but also Asian industrial countries. In Caucasian, a polymorphism of the complement factor H gene (CFH), the C allele of rs1061170 (Y402H), was established as the first strong genetic factor for excursively exudative type of ARMD. In this study, we performed an extensive sequencing of the 22 exons in the CFH gene by recruiting 146 exudative ARMD patients and 105 normal controls of Japanese origin and identified 61 polymorphisms. We found that the frequency of the C allele of rs1061170 (Y402H) is much lower (0.04) in Japanese controls than in Caucasians (0.45). No case disease susceptibility to exudative ARMD was noted for rs1061170 (Y402H) (chi (2) = 3.19, P (corr) = 0.423), or other 12 single nucleotide polymorphisms (SNPs) whose frequency is greater than 0.05. When haplotypes were inferred for 13 SNPs (these 12 SNPs with a frequency greater than 0.05 and rs1061170), three haplotypes whose pattern was similar to those in Caucasians were identified but with substantial difference in frequency. Again we failed to identify genetic association between Japanese exudative ARMD and any of the haplotypes including the J1 haplotype which was shown to be susceptible to ARMD in Caucasians (chi (2 )=( )3.92, P (corr) = 0.157). CFH does not appear to be a primary hereditary contributor to ARMD in Japanese. The absence of CFH contribution to ARMD in Japanese may correlate with the findings in ethnic differences of ARMD phenotypes.

Pulsatile ocular blood flow in asymmetric age-related macular degeneration

Ocular perfusion abnormalities have been proposed in the pathogenesis of age-related macular degeneration (AMD) with differences in pulsatile ocular blood flow (POBF) in eyes with asymmetric AMD in Japanese and Taiwanese patients. The purpose of our study was to observe POBF difference in the fellow eyes of Caucasians with asymmetric AMD. This was a cross-sectional study comparing POBF in three groups of patients with asymmetric AMD in the fellow eyes: Group 1 (n=21) with drusen and active choroidal neovascularisation (CNV); Group 2 (n=18) with drusen and disciform scar; Group 3 (n=8) with CNV and disciform scar. The POBF was adjusted for intraocular pressure (IOP), pulse rate (PR), and axial length using multiple regression analysis. Generalised estimation equation model was used to include both eyes in each group. The geometric mean (95% confidence interval) POBF values were as follows: Group 1 with drusen 1097.9 microl/min (957.0, 1259.7) in one eye and the fellow eye with CNV 1090.1 microl/min (932.3, 1274.7); Group 2 with drusen 946.0 microl/min (794.2, 1126.7) and disciform scar 966.2 microll/min (780.3, 1196.4); Group 3 with CNV 877.1 microl/min (628.3, 1224.6) and disciform scar 767.2 microl/min (530.5, 1109.7). Adjusting for differences in axial length, pulse rate and intraocular pressure, no statistically significant difference in POBF was found between fellow eyes in the same subject. POBF is not different between fellow eyes of Caucasian patients with asymmetric AMD.

Japanese age-related macular degeneration trial: 1-year results of photodynamic therapy with verteporfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration

Purpose To determine the effect and safety of verteporfin therapy (Visudyne) in Japanese age-related macular degeneration (AMD) patients. Design Open-label, multicenter, prospective, noncontrolled study. Methods The setting was five university hospitals in Japan. The study population was patients at least 50 years old, with best-corrected visual acuity of 20/40 to 20/200 inclusive and fluorescein angiography documenting subfoveal, classic-containing choroidal neovascularization (CNV) secondary to AMD and a lesion of greatest linear dimension ≤ 5,400 μm. For the intervention, patients received verteporfin intravenously followed by light administration 15 minutes after the infusion start. Additional treatment was given every 3 months through month 9 if leakage from CNV was observed on angiogram. The main outcome measure was percentage of lesions with progression of classic CNV beyond the area of the baseline lesion. Results Sixty-four patients were enrolled at five centers, and 61 patients completed the study. The me-dian number of treatments given during the trial was three. At the 12-month examination, 12 patients (19%; 95% confidence interval: 11%–31%) had progression of classic CNV whereas 32 (50%) and 49 (77%) patients had no leakage from classic or occult CNV, respectively. The median visual acuity score (approximate Snellen equivalent) from baseline to month 12 increased from 50.0 (20/100)–56.5 (20/80 +2) letters. Fourteen patients (22%) had visual disturbances, including two patients (3%) with acute vision decrease considered as serious adverse events and one patient (2%) with infusion-related back pain. No photosensitivity reactions were reported. Conclusions Verteporfin therapy for subfoveal CNV in these Japanese patients appeared to have a similar or better angiographic and vision effect as that observed in Caucasian patients, with the same safety profile, supporting its use in Japanese patients.