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LE Magazine December 2008

Macular Degeneration

Estrogen receptor alpha gene polymorphisms associated with incident aging macula disorder.

PURPOSE: It has been suggested that early menopause increases the risk of aging-macula disorder (AMD), the major cause of incurable blindness with a dry and wet late subtype, and that exposure to endogenous or postmenopausal exogenous estrogens reduces this risk. This study was undertaken to investigate whether genetic variations in the estrogen receptor alpha (ESR1) gene are associated with incident AMD. METHODS: In the Rotterdam Study, a prospective population-based cohort study of participants aged 55 years and older, associations between ESR1 PvuII-XbaI haplotypes and incident early or late AMD were studied in 4,571 participants after a mean follow-up time of 7.7 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), with adjustment for the most common confounders. RESULTS: ESR1 PvuII-XbaI haplotype 1 was a risk factor for late AMD. Persons with two copies of haplotype 1 were at 3.20 (95% CI, 1.47-6.99) times higher risk for late AMD than noncarriers of haplotype 1, after adjustment for age and sex. This increase was more pronounced for wet AMD (hazard ratio [HR] 4.29; 95% CI, 1.47-12.49) after adjustment for age, sex, smoking, and complement factor H genotype. Correction for additional confounders, including age at menopause, use of hormone replacement therapy, blood pressure, and body mass index did not essentially alter the findings. CONCLUSIONS: Persons with one or two copies of ESR1 PvuII-XbaI haplotype 1 have an increased risk of late AMD, especially of the wet form.

Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1012-7

Serum dehydroepiandrosterone sulphate level in age-related macular degeneration.

PURPOSE: To evaluate plasma dehydroepiandrosterone sulphate (DHEAS) levels in patients diagnosed with age-related macular degeneration (AMD) and controls. DESIGN: Case-controlled, prospective, comparative noninterventional study. METHODS: This study involved 32 men and 35 women with exudative AMD, 37 men and 38 women with nonexudative AMD, and 32 men and 32 women of an age-matched control group. The Wisconsin Age-Related Maculopathy Grading System was used to asses the severity of AMD lesions. DHEAS levels were measured and compared according to a gender based subdivision. Analysis of variance was used to assess the association between DHEAS and AMD. Linear regression model was used to examine the relation among DHEAS level and AMD severity scale. RESULTS: Mean +/- SD of DHEAS levels in exudative AMD, nonexudative AMD, and controls in men was 2.67 +/- 0.68 micromol/l, 2.89 +/- 0.95 micromol/l, and 4.43 +/- 1.44 micromol/l, respectively (P = .001), and in women was 1.64 +/- 0.72 micromol/l, 1.85 +/- 0.73 micromol/l, and 2.78 +/- 0.91 micromol/l, respectively (P = .001). Post hoc Tukey analyses revealed a significant reduction in serum DHEAS level in both AMD groups, compared with controls for men and women (P = .001), while no difference was found between AMD groups in both men and women (P = .668 and 0.49, respectively). Regression analyses revealed an inverse correlation among serum DHEAS level and AMD severity scale both in men and women (P = .006 and .007, respectively). CONCLUSIONS: This study suggests an inverse correlation between serum DHEAS level and AMD severity scale with a considerably reduced DHEAS level in AMD.

Am J Ophthalmol. 2007 Feb;143(2):212-216

Age-related macular degeneration and mortality from cardiovascular disease or stroke.

BACKGROUND/AIMS: Age-related macular degeneration (AMD) and vascular disease share similar risk factors. Recent data suggest AMD may independently predict stroke or coronary heart disease. We prospectively assessed the relationship between AMD and risk of stroke- or cardiovascular-related death in an Australian population. METHODS: Of 3,654 baseline participants (1992-4) aged 49+ years, 2335 were re-examined after 5 years and 1952 after 10 years. Retinal photographs were graded using the Wisconsin System. History and physical examination provided data on possible risk factors. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Risk ratios (RR) were estimated in Cox models. RESULTS: Among persons aged <75 years at baseline, early AMD predicted a doubling of cardiovascular mortality (RR, 2.32; 95% confidence interval (CI), 1.03 to 5.19), over the next decade, after controlling for traditional cardiovascular risk factors. Late AMD predicted fivefold higher cardiovascular mortality (RR, 5.57; 95% CI, 1.35 to 22.99) and 10-fold higher stroke mortality (RR, 10.21; 95% CI, 2.39 to 43.60) after adjusting for age and sex only. These associations were not present when persons older than 75 were included. CONCLUSION: AMD predicted stroke and cardiovascular events over the long term in persons aged 49-75 years. This may have potential implications for new intravitreal anti-VEGF AMD therapies.

Br J Ophthalmol. 2008 Apr;92(4):509-12

Neurosteroids in the retina: neurodegenerative and neuroprotective agents in retinal degeneration.

Steroids may have a powerful role in neuronal degeneration. Recent research has revealed that steroids may influence the onset and progression of some retinal disorders as well as neurodegenerative diseases and, as in brain, they accumulate in the retina via a local synthesis (neurosteroids) and metabolism of blood-circulating steroid hormones. Their crucial role as neurodegenerative and neuroprotective agents has been also upheld in a retinal excitotoxic paradigm. These findings are reviewed especially from the emerging perspective that after an insult local changes in steroidogenic responses and consequent neurosteroid availability might turn out to be offensive or defensive cellular adaptations for the potentiation or prevention of neuronal death.

Ann N Y Acad Sci. 2003 Dec;1007:117-28

Basal deposits and drusen in eyes with age-related maculopathy: evidence for solid lipid particles.

Neutral lipid, including esterified cholesterol, and apolipoproteins B and E are abundant in basal deposits and drusen of aged and age-related maculopathy (ARM) eyes. The principal component of basal linear deposit (BlinD), a specific ARM lesion, is membranous debris, which if actually derived from membranes cannot account for extracellular neutral lipid. We therefore used a lipid-preserving ultrastructural method to obtain improved images of membranous debris. Maculas from 44 human donors (71-96 yr) were preserved <7.5 hr after death. Blocks were post-fixed in 2% osmium or osmium-tannic acid-paraphenylenediamine (OTAP) to preserve neutral lipid for thin-section transmission electron microscopic (TEM) examination. Solid particles identified by OTAP were considered closest to the in vivo state of extracellular lipids. Micrographs were examined for intermediate forms, with greatest weight given to comparable images from different preparations of same or fellow eyes. Twenty eyes of older adults (12 with ARM including fellows treated with photodynamic and radiation therapies) had adequately preserved extracellular lipid. The exterior surface of membranous debris was thicker and more electron-dense than basal infoldings of retinal pigment epithelium (RPE) cells. By OTAP, individual membranous debris profiles were solid (diameters, 80-200 nm) and formed tracks across or aggregations within basal laminar deposits. Solid particles and/or pools of neutral lipid were visible in BlinD and drusen. When processed to preserve lipid, membranous debris resembles neither membranes of surrounding cells nor vesicles possessing aqueous interiors but rather solid particles. These results are consistent with recent evidence implicating lipoprotein particles of intra-ocular origin as a potential source of neutral lipids, including esterified cholesterol, in the specific lesions of ARM.

Exp Eye Res. 2005 Jun;80(6):761-75

Role of melatonin in the eye and ocular dysfunctions.

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi, and animals. Several studies have indicated that melatonin synthesis occurs in the retina of most vertebrates, including mammals. The retinal biosynthesis of melatonin and the mechanisms involved in the regulation of this process have been extensively studied. Circadian clocks located in the photoreceptors and retinal neurons regulate melatonin synthesis in the eye. Photoreceptors, dopaminergic amacrine neurons, and horizontal cells of the retina, corneal epithelium, stroma endothelium, and the sclera all have melatonin receptors, indicating a widespread ocular function for melatonin. In addition, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect that it exerts even during ischemia. Melatonin cytoprotective properties may have practical implications in the treatment of ocular diseases, like glaucoma and age-related macular degeneration.

Vis Neurosci. 2006 Nov-Dec;23(6):853-62

Current concepts in the pathogenesis of age-related macular degeneration.

OBJECTIVE: To review and synthesize information concerning the pathogenesis of age-related macular degeneration (AMD). METHODS: Review of the English-language literature. RESULTS: Five concepts relevant to the cell biology of AMD are as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and (5) the abnormal ECM results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, both the environment and multiple genes can alter a patient’s susceptibility to AMD. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or choroidal new vessels may operate simultaneously. CONCLUSIONS: Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease. Many unanswered questions regarding AMD pathogenesis remain. Multiple animal models and in vitro models of specific aspects of AMD are needed to make rapid progress in developing effective therapies for different stages of the disease.

Arch Ophthalmol. 2004 Apr;122(4):598-614

Pregnenolone sulfate, a naturally occurring excitotoxin involved in delayed retinal cell death.

The present study was designed to investigate the neurosteroid pregnenolone sulfate (PS), known for its ability to modulate NMDA receptors and interfere with acute excitotoxicity, in delayed retinal cell death. Three hours after exposure of the isolated and intact retina to a 30-min PS pulse, DNA fragmentation as assessed by genomic DNA gel electrophoresis and a modified in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method appeared concurrently with an increase in superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels. At 7 h, the increased amount of DNA laddering was accompanied by a higher number of TUNEL-positive cells in the inner nuclear and ganglion cell layers. Necrotic signs were characterized by DNA smear migration, lactate dehydrogenase (LDH) release, and damage mainly in the inner nuclear layer. PS-induced delayed cell death was markedly reduced by the NMDA receptor antagonists 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid and 3alpha-hydroxy-5beta-pregnan-20-one sulfate but completely blocked after concomitant addition of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Steroids with antioxidant properties (progesterone, dehydroepiandrosterone and its sulfate ester, and 17beta-estradiol) differently prevented PS-induced delayed cell death. Cycloheximide treatment protected against DNA fragmentation and LDH release but failed to prevent the rise in SOD activity and TBARS level. We conclude that a brief PS pulse causes delayed cell death in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset.

J Neurochem. 2000 Jun;74(6):2380-91

Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy.

Lipids accumulate in Bruch’s membrane (BrM), a specialized vascular intima of the eye, and in extracellular lesions associated with aging and age-related maculopathy (ARM). We tested the hypothesis that ARM and atherosclerotic cardiovascular disease share molecules and mechanisms pertaining to extracellular lipid accumulation by localizing cholesterol and apolipoprotein B (apo B) in BrM, basal deposits, and drusen. Human donor eyes were preserved <4 hours postmortem and cryosectioned. Sections were stained with traditional lipid stains and filipin for esterified and unesterified cholesterol or probed with antibodies to apo B, apo E, and apo C-III. Normal adult retinal pigment epithelium (RPE) was subjected to RT-PCR and Western blot analysis for apolipoprotein mRNA and protein. Esterified and unesterified cholesterol was present in all drusen and basal deposits of ARM and normal eyes. Both apo B and apo E but not apo C-III were found in BrM, drusen, and basal deposits. Fewer macular drusen were stained by traditional lipid stains and apolipoprotein antibodies than peripheral drusen. RPE contained apo B and apo E mRNA and protein. Finding cholesterol and apo B in sub-RPE deposits links ARM with important molecules and mechanisms in atherosclerosis initiation and progression. The combination of apo B mRNA and protein in RPE raises the possibility that intraocular assembly of apo B-containing lipoproteins is a pathway involved in forming cholesterol-enriched lesions in ARM.

Am J Pathol. 2003 Feb;162(2):413-25

Distribution and composition of esterified and unesterified cholesterol in extra-macular drusen.

More details about the distribution of esterified and unesterified cholesterol (EC, UC), abundant druse components, would inform models of druse biogenesis and new technologies for ocular imaging. From donors with grossly normal maculas (n=10, 66-86years), whose eyes were preserved in paraformaldehyde within 6h of death, extra-macular drusen encased with retinal pigment epithelium (RPE) were isolated manually. Cryosections of pelleted drusen, stained with filipin for UC and EC, were used to investigate filipin staining patterns within single drusen (n=193) and to quantify fluorescence (n=146). From lipid extracts of other drusen/RPE and RPE samples, total cholesterol (TC) and UC were determined by enzymatic fluorimetry. Drusen contained cores, basally located regions that were intensely bright when stained for UC or deeply dark when stained for EC; many were surrounded by concentric lamellae. Within the same cores, the EC-poor regions were significantly smaller (13.0mum) than UC-rich regions (17.1mum). Drusen with highly fluorescent EC-rich shells lacked UC-rich shells. Small spots representing lakes were visible only in drusen stained for EC. Some drusen had small, refractive spherical inclusions lacking both UC and EC. Of drusen examined, 32% had a UC-rich core, 35% had an EC-poor core, 31% had an EC-rich shell, 25% had EC-rich lakes, and 4-5% had UC-, EC-poor inclusions. Shells and cores occurred in significantly non-overlapping druse populations. The percentage of TC that was esterified ranged from 32-66% for drusen/RPE and 5-21% for RPE. The disposition of cholesterol in cores may reflect the activity of invading cellular process. The greater size of UC-rich cores relative to EC-poor cores may reflect a declining gradient of enzymatic activity with increased radial distance from the putative invaders. The relative sizes of sub-domains defined by cholesterol composition are compared to sub-domains detected in drusen by in vivo imaging methods.

Exp Eye Res. 2007 Aug;85(2):192-201

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