The complexities underlying age-related macular degeneration： could amyloid beta play an important role？

e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.

Risk Factors for Age-Related Macular Degeneration in Elderly Chinese Population in Shenyang of China

Objective The paper aims to evaluate the risk factors for age‐related macular degeneration （AMD） in elderly Chinese population in Shenyang,a northeast city of China.Methods A case‐control study was conducted to investigate the risk factors for the prevalence of AMD.Ninety three AMD patients diagnosed by a complete ophthalmic examination were recruited as cases from the outpatient departments of two eye hospitals in Shenyang,while 108 normal subjects of similar age and sex were recruited as controls.A questionnaire was administered among both cases and controls.Results AMD patients aged 60 years and older accounted for 75.3%.There were significantly higher educational levels,shorter smoking history,less sunlight exposure and cataract,and higher proportion of antioxidants intake in controls than in AMD patients.The frequency of intake of fruits,legumes,fish and shrimps was significantly higher in controls than in AMD patients.In a binary logistic regression analysis,smoking and cataract were the risk factors for AMD （OR：4.44,95% CI：2.27‐8.69;OR：4.47,95% CI：2.26‐8.85 respectively）.The high educational background was a protective factor for AMD （OR：0.761,95% CI：0.51‐0.98）.Conclusion A low educational background,smoking and cataract are associated with a higher prevalence of AMD.

Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C（IL-17RC）,a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration（AMD）,was associated with altered activation of phosphatidylinositide 3-kinase（PI3K）,Akt,and glycogen synthase kinase 3（GSK3）.We wondered whether or not altered PI3 K,Akt,and GSK3 activities could be detected in peripheral blood mononuclear cells（PBMC） obtained from AMD patients.In the patients＇ PBMC,absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed,which was accompanied with increased phosphorylation of GSK3 substrates（e.g.CCAAT enhancer binding protein a,insulin receptor substrate 1,and TAU）,indicative of enhanced GSK3 activation.In addition,decreased protein mass of PI3K85α and tyrosinephosphorylation of PI3K50α was present in PBMC of the AMD patients,suggesting impaired PI3 K activation.Moreover,abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients.These data demonstrate that despite the presence of high levels of IL-17 RC,Wnt-3a and vascular endothelial growth factor,the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients.Thus,measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

Research progress of age-related macular degeneration related gene polymorphism at high altitude

Age-related macular degeneration(AMD)is a kind of progressive eye disease that seriously damages vision,and it is one of the important causes of blindness.In recent years,a large number of studies have found that there is a significant correlation between genetic factors and the occurrence and development of AMD.The study of gene polymorphism provides new ideas and directions for clinical diagnosis and treatment.In this paper,we will make a brief review of the research progress related to complement factor H(CFH),serine protease(HtrA1),age-related macular degeneration susceptibility factor 2(ARMS2)and vascular endothelial growth factor(VEGF)gene single nucleotide polymorphisms(SNP).

Vitreomacular Traction Post Intravitreal Bevacizumab for Age Related Macular Degeneration

Purpose: To report the significant worsening of Vitreomacular Traction (VMT), following the intravitreal injection of Bevacizumab (Avastin) in an Age Related Macular Degeneration (AMD) eye;thereby raising the awareness of this possibility. Method: Retrospective observational case report. Results: After 3 monthly doses of intravitreal injection of 1.25 mg/0.05 cc bevacizumab for treatment of AMD, a post injection OCT revealed the presence of VMT and an increased central macular thickness (CMT) by additional 268 microns compared to pre injection levels. Conclusion: Worsening of VMT and increase in CMT following injection of intravitreal drugs can occur. This VMT worsening effect of intravitreal injections is under recognized. It demands greater attention since it is seen with a new common route of ocular drug delivery and may be responsible for cases of pharmacological failure.

Treatment options for the wet form of age-related macular degeneration--a perspective

Treatment of the wet form of age-related macular degeneration(wet AMD) has been revolutionized a decade ago with the introduction of vascular endothelial growth factor(VEGF) blockers that reduce neovascularization and macular edema. Two approved drugs are marketed for the treatment of wet AMD—ranibizumab and aflibercept, but there is a third drug, bevacizumab, which is widely used offlabel; a cancer drug that also blocks VEGF but was never tested in pivotal trials and never approved for ophthalmic indications including wet AMD. Similarity of bevacizumab to ranibizumab led to off-label use and even to government-sponsored studies comparison the approved ranibizumab head-to-head to the offlabel cancer drug bevacizumab in wet AMD, like the Comparison of Age-related Macular Degeneration Treatments Trials(CATT) study, discussed in this perspective paper. Recent publication of 5-year follow-up from the initial 2-year CATT study provided the occasion to discuss the similarities and differences between these two drugs and the lessons learned from the last decade of anti-VEGF therapy for wet AMD. Clinical efficacy is comparable, with an advantage for ranibizumab. Likewise, safety finding favor ranibizumab over bevacizumab in some aspects. The latest addition of approved anti-VEGF drugs for wet AMD, aflibercept, may provide even more benefit to patients. In this perspective we discuss results of CATT and other longterm follow-up and comparative studies. While all demonstrate clinical benefit of anti-VEGF, all reveal that most patients' loose visual acuity(VA) in real-life situations over 5–7 years. This loss is based on—what we believe—significant under-treatment of wet AMD patients, due to economic or practical limitations and overestimation of perceived risks as geographic atrophy. We compare own data that showed more intensive treatment(more than twice the CATT-follow-up injections) with ranibizumab or aflibercept can maintain a sustained gain in VA in wet AMD patients after 6 years. We encourage retina specialists to treat wet AMD patients more aggressively and frequently in order to provide the maximum benefit for their patients.

Amyloid beta deposition related retinal pigment epithelium cell impairment and subretinal microglia activation in aged APPswePS1 transgenic mice

AIM：To identify the pathological role of amyloid beta（Aβ） deposition in retinal degeneration,and explore Aβ deposition on the retinal pigment epithelium cells（RPE） layer and the associated structural and functional changes in Alzheimer＇s disease transgenic mice.METHODS：RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic（NTG） mice over 20 months old were examined.Histological changes were investigated via hematoxylin and eosin（H＆E） staining and transmission electron microscopy（TEM） examination,whereas the expression of amyloid precursor protein（APP）,Aβ,Zonula occludens-1（ZO-1） and Ionized calcium binding adaptor molecule-1（IBA-1） were investigated using immunohistochemistry and immunofluorescence techniques.All of the obtained results were quantitatively and statistically analyzed.RESULTS：In aged transgenic mice,an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice.The RPE demonstrated some vacuole changes,shortened basal infoldings and basal deposition in histopathological examination and TEM tests,wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence.Furthermore,IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch＇s membrane（Br M） complex,which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice.The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts.CONCLUSION：The observed Aβ deposition in the RPE layer may cause RPE dysfunction,which is associated with microglia cells infiltration into the retina of aged transgenic mice,suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.

Blue light induced retinal oxidative stress:Implications for macular degeneration

A number of studies have shown that oxidative stress can be harmful for the retina. The real causal circumstances that lead to degenerative diseases like age related macular degeneration remain obscure. Whether light induced radical stress is a direct interaction of light with photoreceptors or a secondary mechanism within the pigment epithelium or choroid is in discussion. Among the molecular mechanisms involved are production of reactive oxygen species(ROS), secondary lipid peroxidation, protein oxidation and DNA-damage. The initial trigger to write this review was first a recent finding of our group that the photoreceptor outer segments produce great amounts of ROS and second the detection of ectopic enzymes of the respiratory chainlocalized there- in addition to the hitherto known ROS sources like the visual pigments with their intermediates and the photoreceptor mitochondria harbouring the respiratory chain.

Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype

Age-related Macular Degeneration(AMD)is a leading cause of blindness in the developed world,especially in aging populations,and is therefore an important target for new therapeutic development.Recently,there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci,including a highly significant association at 10q26.The 10q26 risk region contains two genes,HTRA1 and ARMS2,both of which have been separately implicated as causative for the disease,as well as dozens of sites of non-coding variation.To date,no studies have successfully pinpointed which of these variant sites are functional in AMD,nor definitively identified which genes in the region are targets of such regulatory variation.In order to efficiently decipher which sites are functional in AMD phenotypes,we describe a general framework for combinatorial assembly of large‘synthetic haplotypes’along with delivery to relevant disease cell types for downstream functional analysis.We demonstrate the successful and highly efficient assembly of a first-draft 119kb wild-type‘assemblon’covering the HTRA1/ARMS2 risk region.We further propose the parallelized assembly of a library of combinatorial variant synthetic haplotypes covering the region,delivery and analysis of which will identify functional sites and their effects,leading to an improved understanding of AMD development.We anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variants from those discovered via GWAS or other genetic association studies.

视网膜色素上皮细胞间紧密连接及其在AMD发病过程中的作用研究进展

年龄相关性黄斑变性(AMD)是引起老年人群不可逆性视力损害的常见眼病。视网膜色素上皮细胞(RPECs)间紧密连接(TJ)是血-视网膜外屏障(oBRB)的重要结构单元。紧密连接在AMD的发病过程中有所缺陷,进而促进oBRB的破坏,加速AMD的发生和进展。本文将对紧密连接与紧密连接蛋白在维持oBRB功能、紧密连接蛋白异常与oBRB破坏在AMD发病过程中的作用研究进行综述,以期为AMD治疗的研究提供新的思路。

AB041.The implication of miRNA let-7f in retinal pigment epithelium degeneration under oxidative stress

Background:Age-related macular degeneration(AMD)is the most suspected cause of vision loss in the elderly.Given the considerable evidence,oxidative stress is thought to be a primary contributing factor to AMD.Retinal pigment epithelium(RPE)could be detrimentally compromised by oxidative stress along which blebs called retinal microparticles(RMPs)start to shed.In continue these particles would be taken by retina,causing RPE senescence,dysfunction and ultimately cell death.Along with the intracellular damages,accumulative deposit of microparticles in subretinal region can cause most known histological hallmark of dry AMD namely drusen.Based on our preliminary study,of 20 present miRNAs,Let-7f is the most abundant microRNAs in RMPs.As the accused substrate of RMPs through which retina function is compromised has yet to be well understood,we aimed to investigate pathophysiological role of let-7f and specific signaling triggered in RPE dysfunction.In brief,the principal objective is to further understand how RMPs implicate in RPE dysfunction.Methods:By oxidative stress inducing,RMPs were isolated from cultured ARPE-19 cells.We considered the effect of RMPs on ARPE-19 cells viability using MTT assay.In addition,to see whether RMPs effect could be ascribed to let-7f,ARPE-19 cells were transfected by carrier containing miRNA Let-7f.These transfected cells were then subjected senescence(β-galactosidase)and cell cycle assay to explore the molecular events responsible for Let-7f induced RPE cell dysfunction.Results:Regarding result we found that RMPs adversely affected RPE cell growth and resulted in significant decrease(≥30%)in cell viability.Let-7f-treated cells also revealed considerable increases of the senescence-associatedβ-galactosidase activity.Alongside RMPs impact,let-7f treatment group also showed similar result in cell growth.Conclusions:To the best of our knowledge,RPE cells uptake microparticles derived from oxidative-injured retinal cells,deteriorating integrity of vision compartments.Not only these finding would suggest that RMP’s impression likely corresponds to the miRNA let-7f,but introduce Let-7f as a mediator exacerbating the oxidative damages to RPE cells.This undesirable interplay is followed probably by dry AMD.Taken together,it seems by finding involved downstream pathways under RMPs pathogenesis,we can inhibit AMD disease in the early stage as well.In this line,we plan to investigate consecutive effect of RMP-associated miRNA inhibition in oxidative damage of retinal pigment epithelium.

年龄相关性黄斑变性的研究进展

年龄相关性黄斑变性(AMD)严重威胁老年人视力健康,视网膜色素上皮细胞(RPE)功能障碍是其关键环节。年龄增长导致RPE复制性衰老,光暴露、香烟暴露等导致RPE压力性早衰,衰老的RPE细胞溶酶体消化能力下降导致脂褐素积累,触发早期AMD的发生。老化的视网膜内细胞衰老-更新失衡、氧化压力-抗氧化失衡、慢性炎性反应-抗炎失衡、肠道屏障和肠道微生态失衡、促血管生成-抗血管生成失衡一系列内稳态失衡进一步促进AMD的发展。

Macular atrophy after combined intravitreal triamcinolone and photodynamic therapy to treat choroidal neovascularization

AIMTo report the appearance of choriocapillaris atrophy after combined high dose intravitreal triamcinolone acetonide (TA) and photodynamic therapy (PDT) to treat choroidal neovascularization (CNV) associated with age related macular degeneration (AMD).

Management of subretinal hemorrhage

Subretinal hemorrhage is a vision threatening complication of exudative age related macular degeneration(AMD) and polypoidal choroidal vasculopathy(PCV). Timely removal or displacement of subretinal hemorrhage from the central macula, ideally within 7 to 10 days after onset, is critical to allowing potential recovery of vision. Surgical techniques with the use of a bubble to displace the subretinal hemorrhage can now be performed with tissue plasminogen activator to lyze the blood and with or without vitrectomy.

杞黄颗粒对肝肾阴虚型年龄相关性黄斑变性临床证候的影响

[目的]观察杞黄颗粒治疗肝肾阴虚型年龄相关性黄斑变性的临床疗效。[方法]肝肾阴虚型年龄相关性黄斑变性干性、湿性患者共120例,随机分为杞黄颗粒治疗组62例、维生素C对照组58例,观察治疗前后视力及中医证候评分变化。[结果]视力方面:对年龄相关性黄斑变性(AMD)患者治疗组与对照组治疗前后的总体视力进行组间比较,差异无统计学意义(P>0.05);对AMD患者治疗组与对照组治疗前后的总体视力进行组内比较,差异有统计学意义(P<0.05);杞黄颗粒治疗组显效24例,有效36例,无效2例,总有效率为96.77%。维生素C对照组显效4例,有效31例,无效23例,总有效率为60.35%。治疗组中医证候的改善明显优于对照组,经秩和检验,两组治疗前后对比差异有统计学意义(P<0.05)。杞黄颗粒治疗组内干性共45例,显效19例,有效24例,无效2例,总有效率为95.56%;湿性共17例,显效5例,有效12例,无效0例,总有效率为100%。经秩和检验,干性与湿性对比结果差异无统计学意义(P>0.05)。[结论]杞黄颗粒和维生素C对肝肾阴虚型AMD患者的视力均有一定的改善作用;杞黄颗粒对AMD患者的中医证候改善作用明显,具有良好的临床疗效。

叶黄素治疗年龄相关性黄斑变性的临床研究

目的:观察叶黄素治疗年龄相关性黄斑变性的临床疗效。方法:采用随机、对照、双盲方法,观察83例患者服食叶黄素咀嚼片前后137只眼睛视力、眼底黄斑变化。结果:治疗组显效11眼,有效31眼,无效32眼,总有效率56.76%;对照组显效0眼,有效19眼,无效44眼,总有效率30.16%。2组比较有统计学意义(P<0.001)。结论:叶黄素对年龄相关性黄斑变性患者眼底表现及视力有一定改善作用。

年龄相关性黄斑变性中医证型与CFH基因Y402H、CFB基因R32Q多态性的相关性研究

目的探讨补体因子H(CFH)及补体因子B(CFB)基因变异与年龄相关性黄斑变性(AMD)中医证型的相关性。方法门诊确诊AMD患者125例,按脾虚湿困、痰瘀互结及肝肾亏虚3个证型分成3组。采集患者的外周血,提取DNA,PCR扩增后测序,检测CFH与CBF单核昔酸多态性,分析所得到的基因变异结果与AMD中医证型的相关性。结果①AMD 3个证型组中,干性与湿性病例数分布有显著性差异(χ2=33.524,P<0.01),脾虚湿困证以干性为主,肝肾亏虚证以湿性为主,痰瘀互结证则干性、湿性比大致相当。②3组CFH基因Y402H的基因型频率比较差异有显著性(χ2=10.036,P<0.05);等位基因T/C频率分布比较差异有显著性(χ2=9.501,P<0.01),其中肝肾亏虚证等位基因C型比例最高(23.44%)。③3组CFB基因R32Q的基因型频率比较差异有显著性(χ2=6.171,P<0.05),等位基因G/A频率分布比较差异有显著性(χ2=10.455,P<0.01),其中脾虚湿困证等位基因A型比例最高(16.67%)。结论 AMD脾虚湿困证多数是AMD早期病例,肝肾亏虚证多数是AMD晚期病例;肝肾亏虚证与CFH基因Y402H中TC/CC基因型及等位基因C相关,脾虚湿困证与CFB基因R32Q的GA基因型及等位基因A相关。

老年黄斑变性发病机理的研究

目的:探讨老年黄斑变性(AMD)的发病机理,以利对其早期预防及治疗。方法:对AMD患者及对照组作血红细胞酶及血清无机元素、抗视网膜抗体测定和患者视网膜下新生血管膜的电镜和免疫组织化学观察,并作动物光照射实验。结果:AMD患者的血红细胞超氧化物歧化酶和过氧化氧酶均降低,血清锌也降低,铜锌比增高,其视网膜抗体反应均较正常人高,新生血管膜呈炎症性肉芽肿表现。结论:AMD除与年龄有关外,并可能与光损伤,个体防卫系统改变及慢性炎症过程有关。眼科学报 1996;12:58—63。

中药治疗湿性老年性黄斑变性临床观察

目的观察凉血化瘀法对湿性老年性黄斑变性(age-relatedmaculardegeneration,AMD)的临床疗效。方法确诊为湿性AMD患者46例78只眼,观察治疗前后对患者的视力、眼底照相、荧光素眼底血管造影、OCT检查情况。结果62只眼治疗后视力有不同程度提高,黄斑区出血吸收并停止反复出血,随访4个月～2年,病情均无反复,视力015～03,其中31例患者51只眼行荧光素眼底血管造影和OCT检查,发现有39只眼脉络膜新生血管缩小,总有效率532%。结论中医药对AMD有较好的治疗作用,但尚需科学设计、长期随访。

虚劳干血理论指导脉络膜新生血管治疗的思路

根据中医学"虚劳干血"理论,结合现代医学知识,认为脉络膜新生血管所致的眼底出血表现类似张仲景描述的"内有干血"和"两目黯黑"。在这一理论指导下,运用大黄虫丸加减治疗湿性年龄相关性黄斑变性患者,可明显抑制脉络膜新生血管,消除瘀血,临床取得了较好的疗效。