Macular Degeneration: Chew EY

Chew EY, Clemons T. · No affiliation provided · Arch Ophthalmol. · Pubmed #15767485 No free full text.

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Chew EY. · No affiliation provided · Ophthalmology. · Pubmed #13129860 No free full text.

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Chew EY. · No affiliation provided · Arch Ophthalmol. · Pubmed #11296024 No free full text.

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SanGiovanni JP, Chew EY. · Division of Epidemiology and Clinical Research, National Eye Insitute, National Institutes of Health, 31 Center Drive, Building 31, Room 6A52, MSC 2510, Bethesda, MD 20892-2510, USA. · Prog Retin Eye Res. · Pubmed #15555528 No free full text.

Abstract: In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.

SanGiovanni JP, Chew EY, Agrón E, Clemons TE, Ferris FL, Gensler G, Lindblad AS, Milton RC, Seddon JM, Klein R, Sperduto RD, Anonymous00450. · National Eye Institute, Bethesda, Maryland, USA. · Arch Ophthalmol. · Pubmed #18779490 No free full text.

Abstract: OBJECTIVE: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). METHODS: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. RESULTS: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. CONCLUSIONS: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.

Chew EY, Ferris FL, Csaky KG, Murphy RP, Agrón E, Thompson DJ, Reed GF, Schachat AP. · National Eye Institute/National Institutes of Health, Division of Epidemiology and Clinical Research, Bethesda, Maryland 20892-2510, USA. · Ophthalmology. · Pubmed #13129862 No free full text.

Abstract: OBJECTIVES: To evaluate the long-term natural history and effects of laser photocoagulation treatment in patients with diabetic retinopathy. DESIGN: Follow-up study of the 214 surviving patients enrolled originally at the Johns Hopkins Clinical Center for the Early Treatment Diabetic Retinopathy Study (ETDRS), which was a clinical trial designed to evaluate the role of laser photocoagulation and aspirin treatment in patients with diabetic retinopathy. METHODS: Early Treatment Diabetic Retinopathy Study patients enrolled in the Johns Hopkins Clinical Center had complete eye examinations, including best-corrected visual acuity measurements, fundus photographs, and medical questionnaires throughout the 7-year study. They had the same examinations at the final long-term follow-up visit at the National Eye Institute, National Institutes of Health, 13 to 19.5 years after the initial laser photocoagulation (median, 16.7 years). MAIN OUTCOME MEASURES: The major outcomes were mortality and the rates of moderate and severe vision loss. The secondary outcomes were progression of diabetic retinopathy and need for other eye surgery. RESULTS: Of the 214 patients who were alive at the end of the original ETDRS in 1989, 130 (61%) were deceased at the time of the re-examination. Of the 84 who were alive, 71 (85%) were examined at their long-term follow-up visit at the National Institutes of Health. At the long-term follow-up examination, 42% had visual acuity of 20/20 or better, and 84% had visual acuity of 20/40 or better in the better eye. Compared with baseline, 20% of patients had moderate vision loss (loss of 3 lines or more vision) in the better eye at follow-up. Only one patient had visual acuity of 20/200 bilaterally. He had visual acuity loss secondary to age-related macular degeneration. No patient had severe vision loss (worse than 5/200). All the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse by the time of the ETDRS closeout visit of the original study received scatter photocoagulation treatment. Focal photocoagulation was performed in 43% bilaterally and 22% unilaterally. Cataract surgery was performed in 31% of the patients, vitrectomy in 17%, and glaucoma surgery in one patient. CONCLUSIONS: As previously reported, the mortality rate of patients with diabetic retinopathy is much higher than that of the general population. For those who survived, aggressive follow-up, with treatment when indicated, seems to be associated with maintenance of good long-term visual acuity for most patients. The need for laser scatter photocoagulation with long-term follow-up seems to be high.

Clemons TE, Chew EY, Bressler SB, McBee W, Anonymous00036. · AREDS Coordinating Center, The EMMES Corporation, 401 N Washington Street, Suite 700, Rockville, MD 20850-1707, USA. · Arch Ophthalmol. · Pubmed #12583787 links to  free full text

Abstract: OBJECTIVES: To describe the vision-targeted, health-related quality of life, measured with the National Eye Institute Visual Function Questionnaire (NEI-VFQ), in patients with age-related macular degeneration, cataract, or reduced visual acuity; to determine the relationship between the NEI-VFQ subscale scores and clinical measures of visual function; and to assess the internal consistency and reliability of the NEI-VFQ subscales. DESIGN: The 39-item NEI-VFQ was administered at the 5-year clinic visit to 4077 Age-Related Eye Disease Study participants. RESULTS: The subscales of the NEI-VFQ had moderate to high internal consistency (Cronbach's alpha = 0.58-0.91). The NEI-VFQ scores for participants with advanced age-related macular degeneration in 1 or both eyes, severe nuclear opacity, reduced visual acuity, or cataract surgery generally were lower than scores for disease-free participants (P<.001). CONCLUSION: These findings support the use of the NEI-VFQ as a measure of vision-targeted, health-related quality of life among patients with age-related macular degeneration, cataract, or reduced visual acuity.

Christen WG, Glynn RJ, Ajani UA, Schaumberg DA, Chew EY, Buring JE, Manson JE, Hennekens CH. · Division of Preventive Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02215-1204, USA. · Arch Ophthalmol. · Pubmed #11483080 No free full text.

Abstract: OBJECTIVE: To examine the development of age-related maculopathy (ARM) in a large-scale trial of low-dose aspirin treatment. METHODS: The Physicians' Health Study I was a randomized, double-masked, placebo-controlled trial of low-dose aspirin (325 mg every other day) and beta carotene (50 mg every other day) in the prevention of cardiovascular disease and cancer conducted among 22 071 US male physicians aged 40 to 84 years in 1982. A total of 21 216 participants did not report ARM at baseline, were followed up for at least 7 years, and are included in this analysis. MAIN OUTCOME MEASURES: Total ARM, defined as a self-report confirmed by medical record evidence of an initial diagnosis subsequent to randomization, and ARM with vision loss, defined as total ARM but with vision loss to 20/30 or worse attributable to ARM. RESULTS: Early termination of the randomized aspirin component of the Physicians' Health Study I, after an average of 60.2 months of treatment and follow-up due to a statistically extreme 44% reduced risk of first myocardial infarction, resulted in a far lower number of incident cases of ARM during the aspirin treatment period than would have accrued without early termination. Thus, during an average of 60.2 months of follow-up, a total of 117 cases of ARM were confirmed, including 57 cases responsible for vision loss to 20/30 or worse. There were 51 cases of ARM in the aspirin group and 66 in the placebo group (relative risk, 0.77; 95% confidence interval, 0.54-1.11). For ARM with vision loss, there were 25 cases in the aspirin group and 32 in the placebo group (relative risk, 0.78; 95% confidence interval, 0.46-1.32). CONCLUSIONS: These randomized trial data tend to exclude any large beneficial effect of 5 years of low-dose aspirin treatment on ARM. However, a smaller, but potentially important, beneficial effect cannot be ruled out and would require testing in randomized trials of adequate size and duration.

Chew EY, Benson WE, Remaley NA, Lindley AA, Burton TC, Csaky K, Williams GA, Ferris FL. · Division of Biometry and Epidemiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-2510, USA. · Arch Ophthalmol. · Pubmed #10604663 No free full text.

Abstract: OBJECTIVE: To assess the visual results after surgical lens removal in patients with diabetic retinopathy. DESIGN: A multicenter randomized clinical trial designed to assess the effect of photocoagulation and aspirin in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy and/or macular edema. PARTICIPANTS: Of the 3711 patients enrolled in the Early Treatment Diabetic Retinopathy Study, lens surgery was performed on 205 patients (270 eyes) during follow-up that ranged from 4 to 9 years. OUTCOME MEASUREMENTS: Visual acuity, macular edema status, and degree of diabetic retinopathy. In addition, risk factors associated with lens extraction and with poor postoperative visual acuity (worse than 20/100) were assessed. RESULTS: The risk of lens extraction increased with increasing age, female sex, and baseline proteinuria. Ocular variables associated with increased risk of lens surgery included poor baseline visual acuity and vitrectomy performed during the course of the study. At 1 year after lens surgery, visual acuity improvement of 2 or more lines from preoperative levels occurred in 64.3% of the operated-on eyes assigned to early photocoagulation and 59.3% of eyes assigned to deferral of photocoagulation. In eyes assigned to early photocoagulation, 46% of eyes achieved visual acuity better than 20/40; 73%, better than 20/100; and 8%, 5/200 or worse at 1 year after surgery. Visual acuity results for eyes assigned to deferral of laser photocoagulation at 1 year were not as favorable; 36% achieved visual acuity better than 20/40; 55%, better than 20/100; and 17%, 5/200 or worse at 1 year after surgery. Evaluation of 1-year postoperative visual acuities for all eyes with mild to moderate nonproliferative diabetic retinopathy at the annual visit before lens surgery showed that 53% were better than 20/40; 90%, better than 20/100; and 1%, 5/200 or worse. However, for eyes with severe nonproliferative or worse retinopathy at the annual visit before lens surgery, only 25% were better than 20/40; 42%, better than 20/100; and 22%, 5/200 or worse at 1 year after lens surgery. There was little change in visual acuity between 1 and 2 years postoperatively. Increased severity of retinopathy and poor visual acuity before surgery were associated with visual acuity of worse than 20/100 at 1 year after surgery. Lens surgery was associated with a borderline statistically significant increased risk of progression of diabetic retinopathy in the adjusted analyses (P = .03). No statistically significant long-term increased risk of macular edema was documented after lens surgery. CONCLUSIONS: Visual acuity results after lens surgery in patients in the Early Treatment Diabetic Retinopathy Study were better than published results for similar patients. This may be because of more intensive photocoagulation for lesions of diabetic retinopathy in the Early Treatment Diabetic Retinopathy Study than in previously reported studies. Although patients with severe nonproliferative retinopathy or worse before lens surgery had poorer visual results, visual improvement was seen in 55% of these patients at 1-year follow-up. The main causes of poor visual results in eyes after lens surgery were complications of proliferative retinopathy and/or macular edema.

Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. · Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. · Retina. · Pubmed #19516114 No free full text.

Abstract: PURPOSE: To describe tachyphylaxis to intravitreal bevacizumab (IVB) in patients with exudative age-related macular degeneration (AMD). METHODS: We retrospectively reviewed the records of 59 consecutive patients treated with IVB at the National Eye Institute over a 14-month period and identified cases demonstrating loss of treatment efficacy as revealed by spectral domain optical coherence tomography. We defined tachyphylaxis as a loss of therapeutic response to IVB 28 +/- 7 days after administration in an eye that had previously demonstrated a therapeutic response in the same time interval. RESULTS: Five patients (six eyes) were identified as developing tachyphylaxis after repeated treatment with IVB. High-dose IVB (2.50 mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to IVB was seen after an episode of unilateral postinjection anterior uveitis. After the first treatment of IVB, the median time taken to develop tachyphylaxis was 100 weeks (range: 31-128 weeks), and the median number of IVB treatments to the development of tachyphylaxis was 8 treatments (range: 5-10 treatments). CONCLUSION: Tachyphylaxis can occur after long-term intravitreal use of bevacizumab in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved.

SanGiovanni JP, Arking DE, Iyengar SK, Elashoff M, Clemons TE, Reed GF, Henning AK, Sivakumaran TA, Xu X, DeWan A, Agrón E, Rochtchina E, Sue CM, Wang JJ, Mitchell P, Hoh J, Francis PJ, Klein ML, Chew EY, Chakravarti A. · National Eye Institute (NEI)/National Institutes of Health (NIH), Bethesda, Maryland, United States of America. · PLoS One. · Pubmed #19434233 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. METHODOLOGY/PRINICIPAL FINDINGS: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P<or=0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19-22.69, P<or=0.029). CONCLUSION: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.

Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue E, Boston, MA 02215-1204, USA. · Arch Intern Med. · Pubmed #19237716 No free full text.

Abstract: BACKGROUND: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 5442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition. RESULTS: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]). CONCLUSIONS: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.

SanGiovanni JP, Agrón E, Clemons TE, Chew EY. · No affiliation provided · Arch Ophthalmol. · Pubmed #19139352 No free full text.

This publication has no abstract.

Chew EY, Sperduto RD, Milton RC, Clemons TE, Gensler GR, Bressler SB, Klein R, Klein BE, Ferris FL. · National Eye Institute, Bethesda, Maryland, USA. · Ophthalmology. · Pubmed #19091420 No free full text.

Abstract: PURPOSE: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). METHODS: Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. MAIN OUTCOME MEASURES: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). RESULTS: The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82-1.75) for NV AMD, 0.80 (95% CI, 0.61-1.06) for GA, and 0.87 (95% CI, 0.64-1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72-1.58) for NV AMD, 0.94 (95% CI, 0.71-1.25) for GA, and 0.86 (95% CI, 0.63-1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65-1.72) for NV AMD and 0.98 (95% CI, 0.64-1.49) for CGA. CONCLUSIONS: The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Coleman HR, Chan CC, Ferris FL, Chew EY. · Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. · Lancet. · Pubmed #19027484 links to  free full text

Abstract: Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent. The most consistent risk factors associated with this ocular condition are increasing age and cigarette smoking. Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration. Although the pathogenesis of this disease is unknown, oxidative stress might have an important role. Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk. Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration. These findings, combined with assessments of possible environmental and genetic interactions and new approaches to modulate inflammatory pathways, will hopefully further expand our ability to understand and treat age-related macular degeneration.

Shen D, Tuo J, Patel M, Herzlich AA, Ding X, Chew EY, Chan CC. · 10 Center Drive, 10/10N103, National Institutes of Health/National Eye Institute, Bethesda, MD 20892-1857, USA. · Br J Ophthalmol. · Pubmed #18996904 No free full text.

Abstract: BACKGROUND/AIMS: Impaired inhibition of the alternative complement pathway by complement factor H (CFH) is linked to age-related macular degeneration (AMD) based on the strong association between CFH variant and AMD. Chlamydia pneumoniae (C pneumoniae) infection can trigger the alternative pathway, but the evidence for an association between C pneumoniae and AMD is contradictory. This study investigated whether C pneumoniae infection is associated with AMD and whether the presence of C pneumonia modulates AMD risk conferred by CFH variants. METHODS: Genomic DNA extracted from peripheral blood of 148 advanced AMD patients and 162 controls was subjected to Taqman and PCR-RFLP for the CFH polymorphism and PCR for the C pneumoniae gene. Genomic DNA was also examined from microdissected macular cells from 59 AMD and 16 age-matched non-AMD archived slides. chi(2) testing was performed for case-control analysis. RESULTS: C pneumoniae infection was associated with increased risk of AMD (OR = 2.17, p<0.017). A CFH variant was also linked to increased risk of AMD (OR = 1.98, p<0.0001). However, no relationship was found between risk-conferring CFH variant and C pneumoniae (OR = 1.81, p = 0.08). CONCLUSION: There is a possible association between AMD and C pneumoniae infection, although CFH may not be directly involved in the pathogenesis of C pneumoniae infection-mediated AMD.

Tuo J, Ross RJ, Reed GF, Yan Q, Wang JJ, Bojanowski CM, Chew EY, Feng X, Olsen TW, Ferris FL, Mitchell P, Chan CC. · Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Ophthalmology. · Pubmed #18718667 No free full text.

Abstract: OBJECTIVE: To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking, and serum cholesterol. DESIGN: Clinic-based and population-based case control study. PARTICIPANTS: A total of 805 AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study, Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank. METHODS: DNA samples were genotyped for polymorphisms of rs11200638 in HtrA1 promoter and rs380390 in CFH. HtrA1 protein in ocular tissue was measured. Interactions of the HtrA1 risk allele with the CFH risk variant, smoking status, and cholesterol were assessed. MAIN OUTCOME MEASURES: AMD was evaluated by retinal specialists, and AMD subtypes (geographic atrophy and neovascularization) were determined. RESULTS: Strong associations of the HtrA1 risk allele (A) with AMD were present in all sample sets. A similar magnitude of association was observed for central geographic atrophy and neovascular AMD. The combination of the HtrA1 and CFH risk alleles increased AMD susceptibility, as did the combination of the HtrA1 risk allele with smoking. No combined effect of HtrA1 risk allele and cholesterol level was found. Enhanced expression of HtrA1 protein was detected in retina with AMD. CONCLUSIONS: Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA1 was combined with either CFH risk alleles or history of smoking.

Gangnon RE, Davis MD, Hubbard LD, Aiello LM, Chew EY, Ferris FL, Fisher MR, Anonymous00112. · Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin 53711-1068, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18539929 No free full text.

Abstract: PURPOSE: To develop a severity scale for diabetic macular edema (DME) and to assess relationships between severity and duration of DME and visual acuity (VA). METHODS: From the Early Treatment Diabetic Retinopathy Study (ETDRS), mean baseline VA scores were tabulated for 7422 eyes cross-classified by (1) location of retinal thickening (RT) and its area within 1 disc diameter of the macular center, and (2) degree of RT at the center. Adjacent (row, column, and off-diagonal) cells with the greatest similarity in baseline VA (mean and SD) based on a Gaussian (normal) likelihood were merged. An initial eight-step scale was chosen using the Schwarz criterion (Bayesian information criterion; BIC) and was revised based on clinical judgment to nine steps. Relationships between baseline VA and other photographic and fluorescein angiographic characteristics were examined singly and in combination with the scale. RESULTS: Modeling baseline VA as a function of the nine-step scale yielded an R(2) of 38.0%, compared with 38.4% using the full cross-classification of these variables. Addition of each of the other baseline characteristics changed the adjusted R(2) for the combination very little. Between scale levels 1A and 5B mean (SD) VA decreased from 86.8 (5.8) letters to 59.8 (13.6) letters. In a model of change in VA as a function of time spent at each DME severity level, VA loss increased progressively from 1 letter per year at level 2 to 17 letters per year at level 5B. CONCLUSIONS: The scale facilitates documentation of the relationship of severity and duration of DME with VA.

Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. · Division of Epidemiology and Clinical Research, National Eye Institute, National Institutesof Health, Bethesda, Maryland 20892, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18515567 No free full text.

Abstract: PURPOSE: To evaluate macular thickness and volume measurements and their intrasession repeatability in two optical coherence tomography (OCT) systems: the Stratus OCT, a time domain system, and the Cirrus HD-OCT, a spectral domain system (both by Carl Zeiss Meditec, Inc., Dublin, CA), in the context of diabetic macular edema (DME). METHODS: Thirty-three eyes of 33 diabetic patients with clinically significant macular edema (CSME) were scanned in a single session by a single operator on both OCT systems. Macular thickness measurements of nine standard macular subfields and total macular volume were obtained and analyzed. Bland-Altman plots were constructed to assess agreement in macular measurements. Intraclass correlation coefficients (ICCs), coefficients of repeatability (CR(W)), and coefficients of variation (CV(W)) were used to assess intrasession repeatability. RESULTS: Macular thickness in nine retinal subfields and macular volume were significantly higher in the Cirrus HD-OCT system compared with the Stratus OCT system. Subfield thickness and total volume measurements, respectively, were 30 to 55 microm and 3.2 mm(3) greater for the Cirrus HD-OCT system compared with the Stratus OCT system. Both Stratus OCT and Cirrus HD-OCT systems demonstrated high intrasession repeatability, with overlapping ranges for CR(W), CV(W), and ICC. Repeatability measures (CR(W) and CV(W)) differed significantly between systems in only one of nine subfields (outer temporal subfield). CONCLUSIONS: Absolute measures of macular thickness and volume in patients with DME differed significantly in magnitude between the Stratus OCT and Cirrus HD-OCT systems. However, both OCT systems demonstrated high intrasessional repeatability. Although the two systems may not be used interchangeably, they appear equally reliable in generating macular measurements for clinical practice and research.

Huang LL, Coleman HR, Kim J, de Monasterio F, Wong WT, Schleicher RL, Ferris FL, Chew EY. · Clinical Trials Branch, Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18450596 No free full text.

Abstract: PURPOSE: Increased dietary intake of lutein/zeaxanthin and omega-long-chain polyunsaturated fatty acids (omega-3 LCPUFA) was found to be associated with reduced risk of advanced age-related macular degeneration (AMD). The purpose of the study was to examine the effect of oral supplementation of omega-3 LCPUFA on changes in serum levels of lutein/zeaxanthin during supplementation in persons 60 years of age and older, with or without AMD. METHODS: Forty participants with AMD of various degrees of severity received lutein (10 mg) and zeaxanthin (2 mg) daily and were equally randomized to receive omega-3 LCPUFA (350 mg docosahexaenoic acid [DHA] and 650 mg eicosapentaenoic acid [EPA]) or placebo for 6 months. Serum levels of lutein, zeaxanthin, and omega-3 LCPUFAs and macular pigment optical densities were measured at baseline, 1 week, and 1, 3, 6, and 9 months. RESULTS: By month 6, the median serum levels of lutein/zeaxanthin increased by two- to threefold compared with baseline. Increases in serum levels of lutein/zeaxanthin did not differ by omega-3 LCPUFA treatment (P > 0.5). After 1 month, in the omega-3 LCPUFA-treated group, the median levels of DHA and EPA increased and the placebo group had no changes. At month 6, participants with AMD had a lower increase in serum lutein concentration than did those without AMD (P < 0.05). CONCLUSIONS: The addition of omega-3 LCPUFA to oral supplementation of lutein/zeaxanthin did not change the serum levels of lutein and zeaxanthin. A long-term large clinical trial is necessary to investigate the benefits and adverse effects of these factors for the treatment of AMD.

Klein ML, Ferris FL, Armstrong J, Hwang TS, Chew EY, Bressler SB, Chandra SR, Anonymous00008. · Devers Eye Institute, Legacy Good Samaritan Hospital and Medical Center, Portland, Oregon, USA. · Ophthalmology. · Pubmed #17981333 No free full text.

Abstract: PURPOSE: To determine specific retinal precursor lesions and sequence of events preceding the onset of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). DESIGN: Retrospective review. PARTICIPANTS: All participants in the Age-Related Eye Disease Study (AREDS) at 2 clinical centers (Devers Eye Institute, Portland, Oregon, and University of Wisconsin, Madison, Wisconsin) in whom GA initially appeared in at least one eye a minimum of 4 years after the baseline study visit. METHODS: All stereoscopic fundus photographs taken before the appearance of GA in the involved (study) eye were reviewed. Fundus features at the site of future GA were graded and recorded. Three graders reviewed photographs, with independent grading and adjudication by mutual agreement. Features graded included drusen (classified by size and confluence), focal hyperpigmentation, hypopigmentation, and refractile deposits. The time between first appearance of these features and initial appearance of GA was recorded. MAIN OUTCOME MEASURE: Appearance of GA. RESULTS: Of all AREDS participants at the 2 sites, 95 eyes of 77 developed GA at least 4 years after entrance into the study. Average time from baseline to initial appearance of GA was 6.6 years (range, 4-11). Drusen were found in 100% of eyes at the site of later developing GA, drusen >125 mum in diameter in 96% of eyes, confluent drusen in 94%, hyperpigmentation in 96%, drusen > 250 mum in 83%, hypopigmentation in 82%, and refractile deposits in 23%. Time from lesion appearance to onset of GA varied by lesion type, ranging from 5.9 years for drusen confluence to 2.5 years for hypopigmentation or refractile deposits. Lesions generally followed a uniform sequence of appearance. CONCLUSIONS: By focusing on the location of initial GA appearance and then retrospectively analyzing prior photographs, we were able to identify specific precursor lesions and the most common sequence of events leading to GA formation in eyes with AMD. The progression was usually characterized by large drusen formation and development of hyperpigmentation, followed by regression of drusen, appearance of hypopigmentation, and ultimately development of GA, sometimes preceded by the appearance of refractile deposits.

Chucair AJ, Rotstein NP, Sangiovanni JP, During A, Chew EY, Politi LE. · Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) and Universidad Nacional del Sur (UNS), Bahía Blanca, Buenos Aires, Argentina. · Invest Ophthalmol Vis Sci. · Pubmed #17962470 links to  free full text

Abstract: PURPOSE: Oxidative stress has been proposed as a major pathogenic factor in age-related macular degeneration (AMD), the leading cause of vision loss among elderly people of western European ancestry. Lutein (LUT) and zeaxanthin (ZEA), major components in macular pigment, are among the retinal antioxidants. Though xanthophyll intake may reduce the likelihood of having advanced AMD, direct evidence of neuroprotection is lacking. Prior work has shown that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, delays apoptosis and promotes differentiation of photoreceptors. This study was conducted to investigate whether LUT, ZEA, and beta-carotene (BC), major dietary carotenoids protect photoreceptors from oxidative stress and whether this protection is synergistic with that of DHA. METHODS: Pure rat retinal neurons in culture, supplemented with LUT, ZEA, or BC, with or without DHA, were subjected to oxidative stress induced with paraquat and hydrogen peroxide. Apoptosis, preservation of mitochondrial membrane potential, cytochrome c translocation, and opsin expression were evaluated. RESULTS: Pretreatment with DHA, LUT, ZEA, and BC reduced oxidative stress-induced apoptosis in photoreceptors, preserved mitochondrial potential, and prevented cytochrome c release from mitochondria. ZEA and LUT also enhanced photoreceptor differentiation. In control cultures, photoreceptors failed to grow their characteristic outer segments; addition of DHA, ZEA, or LUT increased opsin expression and promoted the development of outer-segment-like processes. CONCLUSIONS: These results show for the first time the direct neuroprotection of photoreceptors by xanthophylls and suggest that ZEA and LUT, along with DHA, are important environmental influences that together promote photoreceptor survival and differentiation.

Anonymous00220, SanGiovanni JP, Chew EY, Clemons TE, Ferris FL, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD. · The EMMES Corporation, 401 N Washington St, Ste 700, Rockville, MD 20850-1707, USA. · Arch Ophthalmol. · Pubmed #17846363 links to  free full text

Abstract: OBJECTIVE: To evaluate the relationship of dietary carotenoids, vitamin A, alpha-tocopherol, and vitamin C with prevalent age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Demographic, lifestyle, and medical characteristics were ascertained on 4519 AREDS participants aged 60 to 80 years at enrollment. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with < 15 small drusen). Nutrient intake was estimated from a self-administered semiquantitative food frequency questionnaire at enrollment. Intake values were energy adjusted and classified by quintiles. The relationship between diet and AMD status was assessed using logistic regression analyses. RESULTS: Dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.45-0.93), geographic atrophy (OR, 0.45; 95% CI, 0.24-0.86), and large or extensive intermediate drusen (OR, 0.73; 95% CI, 0.56-0.96), comparing the highest vs lowest quintiles of intake, after adjustment for total energy intake and nonnutrient-based covariates. Other nutrients were not independently related to AMD. CONCLUSION: Higher dietary intake of lutein/zeaxanthin was independently associated with decreased likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen.

SanGiovanni JP, Chew EY, Clemons TE, Davis MD, Ferris FL, Gensler GR, Kurinij N, Lindblad AS, Milton RC, Seddon JM, Sperduto RD, Anonymous00204. · AREDS Coordinating Center, The EMMES Corporation, 401 N. Washington Street, Rockville, MD 20850, USA. · Arch Ophthalmol. · Pubmed #17502507 links to  free full text

Abstract: OBJECTIVE: To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). RESULTS: Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. CONCLUSION: Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

Christen WG, Manson JE, Glynn RJ, Gaziano JM, Chew EY, Buring JE, Hennekens CH. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02215-1204, USA. · Arch Ophthalmol. · Pubmed #17353403 links to  free full text

Abstract: OBJECTIVE: To test whether beta carotene supplementation affects the incidence of age-related maculopathy (ARM) in a large-scale randomized trial. DESIGN: Randomized, double-masked, placebo-controlled trial among 22 071 apparently healthy US male physicians aged 40 to 84 years. Participants were randomly assigned to receive beta carotene (50 mg every other day) or placebo. Main Outcome Measure Incident ARM responsible for a reduction in best-corrected visual acuity to 20/30 or worse. RESULTS: After 12 years of treatment and follow-up, there were 162 cases of ARM in the beta carotene group vs 170 cases in the placebo group (relative risk [RR], 0.96; 95% confidence interval [CI], 0.78-1.20). The results were similar for the secondary end points of ARM with or without vision loss (275 vs 274 cases; RR, 1.01; 95% CI, 0.86-1.20) and advanced ARM (63 vs 66 cases; RR, 0.97; 95% CI, 0.69-1.37). CONCLUSIONS: These randomized data relative to 12 years of treatment among a large population of apparently healthy men indicate that beta carotene supplementation has no beneficial or harmful effect on the incidence of ARM. Long-term supplemental use of beta carotene neither decreases nor increases the risk of ARM.