Visual field and structural correlates of progression in age-related macular degeneration

Presentation Purpose:To examine the correlation of central visual field loss and progression of structural changes in the macular area in age-related macular degeneration (AMD). Methods:Central 10° standard and short-wavelength automated perimetry (SWAP) visual fields were acquired in 39 eyes of 24 patients with AMD using a Humphrey Field Analyzer. Stereoscopic fundus photographs were graded1 by two independent observers and the stage of disease determined2. Custom software mapped perimetric data onto fundus images in order to relate structural changes to functional loss. Results:Mean deviation (MD) in standard perimetry changed from 0.04 dB at stage 1 to -12.39 dB at stage 4 (r2=0.48, p<0.001). The group mean SWAP MD was -5.26 dB at stage 1 and increased to -17.08 dB at stage 4 (r2=0.53, p<0.001). Pattern standard deviation (PSD) also increased with advancing stage in standard perimetry; 1.32 dB to 8.67 dB at stage 1 and 4, respectively (r2=0.54, p<0.001). In SWAP, PSD increased from 2.86 dB to 5.63 dB at stage 1 and stage 4 (r2=0.43, p<0.001). Defect frequency was greater in SWAP than standard perimetry. Early stage defects occurred with the greatest frequency at eccentricities of 3.2° and 5.1° in standard perimetry and at 4.2° in SWAP. Late stage defects were most frequent at 1° eccentricity in standard perimetry and at 1° and 9° in SWAP. MD declined with increasing affected retinal area over the central 3000µm; by 0.20 dB (r2=0.67, p<0.001) and 0.18 dB (r2=0.49, p<0.001) per % increase in defect area for standard perimetry and SWAP respectively. 41% of defects were associated with structural changes on the retina in standard perimetry and 43% in SWAP. Conclusions:Sensitivity decreased with advancing stage of AMD, with a greater effect demonstrated in SWAP compared to standard perimetry. The central field became less uniform as stage increased. SWAP defects occurred at similar locations but were deeper and wider than corresponding defects in standard perimetry. Central loss in SWAP is a sensitive marker of functional progression in AMD.1. Bird et al. (1995) Surv Ophthalmol 39:367-3742. van Leeuwen et al. (2003) Arch Ophthalmol 121:519-526

The effects of a lutein-based supplement on objective and subjective measures of retinal and visual function in eyes with age-related maculopathy - a randomised controlled trial

Lutein and zeaxanthin are lipid-soluble antioxidants found within the macula region of the retina. Links have been suggested between increased levels of these carotenoids and reduced risk for age-related macular disease (ARMD). Therefore, the effect of lutein-based supplementation on retinal and visual function in people with early stages of ARMD (age-related maculopathy, ARM) was assessed using multi-focal electroretinography (mfERG), contrast sensitivity and distance visual acuity. A total of fourteen participants were randomly allocated to either receive a lutein-based oral supplement (treated group) or no supplement (non-treated group). There were eight participants aged between 56 and 81 years (65·50 (sd 9·27) years) in the treated group and six participants aged between 61 and 83 years (69·67 (sd 7·52) years) in the non-treated group. Sample sizes provided 80 % power at the 5 % significance level. Participants attended for three visits (0, 20 and 40 weeks). At 60 weeks, the treated group attended a fourth visit following 20 weeks of supplement withdrawal. No changes were seen between the treated and non-treated groups during supplementation. Although not clinically significant, mfERG ring 3 N2 latency (P= 0·041) and ring 4 P1 latency (P= 0·016) increased, and a trend for reduction of mfERG amplitudes was observed in rings 1, 3 and 4 on supplement withdrawal. The statistically significant increase in mfERG latencies and the trend for reduced mfERG amplitudes on withdrawal are encouraging and may suggest a potentially beneficial effect of lutein-based supplementation in ARM-affected eyes. Copyright © 2012 The Authors.

Does metabolic reprogramming underpin age-associated changes in T cell phenotype and function?

T cells are required for an effective adaptive immune response. The principal function of T cells is to promote efficient removal of foreign material by identifying and mounting a specific response to nonself. A decline in T cell function in aging is thought to contribute to reduced response to infection and vaccination and an increase in autoimmunity. This may in part be due to the age-related decrease in naïve CD4+ T cells and increase in antigen-experienced CD4+ T cells, loss of redox homeostasis, and impaired metabolic switching. Switching between subsets is triggered by the integration of extracellular signals sensed through surface receptors and the activation of discrete intracellular metabolic pathways. This article explores how metabolic programming and loss of redox homeostasis during aging may contribute to age-associated changes in T cell phenotype and function. © 2014 Elsevier Inc.

Benefit of coloured lenses for age-related macular degeneration

Purpose: To evaluate and compare the functional and perceived benefits of wearing coloured lenses by patients with age-related macular degeneration (ARMD). Method: Ten subjects with early ARMD and five elderly controls wore a selection of NoIR wrap-around coloured lenses (yellow 29.7% light transmission, orange 22.9%, red 16.8% and grey 10.3%), each for a duration of 7 days. Contrast sensitivity, colour vision, visual acuity, the effect of glare and peripheral sensitivity were measured for each lens and compared with a control (no lens) condition. Subjective ratings of visual performance were also scored. Results: Compared with the no filter condition, red and grey lenses reduced contrast sensitivity whereas yellow and orange lenses increased contrast sensitivity. These objective changes were supported by subjective ratings in subjects with ARMD. Grey lenses reduced the loss of contrast sensitivity usually suffered in the presence of glare, whereas visual acuity and peripheral sensitivity decreased with red lenses. Colour vision became distorted with red lenses in control subjects, but was relatively unaffected by the use of coloured lenses in subjects with ARMD. Conclusions: The subjective benefit of coloured lenses appears to be due to a minor enhancement of contrast sensitivity. © 2002 The College of Optometrists.

The role of DNA methylation in aging, rejuvenation, and age-related disease

DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation. © Copyright 2012, Mary Ann Liebert, Inc. 2012.

Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.

Overview of risk factors for age-related macular degeneration

Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make life style choices that may reduce the risk of disease. This review discusses the role of genetics, sunlight, diet, cardiovascular factors, smoking, and alcohol as possible risk factors for AMD. Genetics plays a more significant role in AMD than previously thought, especially in younger patients, histocompatibility locus antigen (HLA) and complement system genes being the most significant. Whether the risk of AMD is increased by exposure to sunlight, cardiovascular risk factors, and diet is more controversial. Smoking is the risk factor most consistently associated with AMD. Current smokers are exposed to a two to three times higher risk of AMD than non-smokers and the risk increases with intensity of smoking. Moderate alcohol consumption is unlikely to increase the risk of AMD. Optometrists as front-line informers and educators of ocular health play a significant role in increasing public awareness of the risks of AMD. Cessation of smoking, the use of eye protection in high light conditions, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD.

Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.

Multispectral retinal image analysis (MRIA) for the assessment of subretinal fibrosis in neovascular age-related macular degeneration (nAMD)

Purpose: To investigate the use of MRIA for quantitative characterisation of subretinal fibrosis secondary to nAMD. Methods: MRIA images of the posterior pole were acquired over 4 months from 20 eyes including those with inactive subretinal fibrosis and those being treated with ranibizumab for nAMD. Changes in morphology of the macula affected by nAMD were modelled and reflectance spectra at the MRIA acquisition wavelengths (507, 525, 552, 585, 596, 611 and 650nm) were computed using Monte Carlo simulation. Quantitative indicators of fibrosis were derived by matching image spectra to the model spectra of known morphological properties. Results: The model spectra were comparable to the image spectra, both normal and pathological. The key morphological changes that the model associated with nAMD were gliosis of the IS-OS junction, decrease in retinal blood and decrease in RPE melanin. However, these changes were not specific to fibrosis and none of the quantitative indicators showed a unique association with the degree of fibrosis. Moderate correlations were found with the clinical assessment, but not with the treatment program. Conclusion: MRIA can distinguish subretinal fibrosis from healthy tissue. The methods used show high sensitivity but low specificity, being unable to distinguish scarring from other abnormalities like atrophy. Quantification of scarring was not achieved with the wavelengths used due to the complex structural changes to retinal tissues in the process of nAMD. Further studies, incorporating other wavelengths, will establish whether MRIA has a role in the assessment of subretinal fibrosis in the context of retinal and choroidal pathology

Overview of risk factors for age-related macular degeneration (AMD)

Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make life style choices that may reduce the risk of disease. This review discusses the role of genetics, sunlight, diet, cardiovascular factors, smoking, and alcohol as possible risk factors for AMD. Genetics plays a more significant role in AMD than previously thought, especially in younger patients, histocompatibility locus antigen (HLA) and complement system genes being the most significant. Whether the risk of AMD is increased by exposure to sunlight, cardiovascular risk factors, and diet is more controversial. Smoking is the risk factor most consistently associated with AMD. Current smokers are exposed to a two to three times higher risk of AMD than non-smokers and the risk increases with intensity of smoking. Moderate alcohol consumption is unlikely to increase the risk of AMD. Optometrists as front-line informers and educators of ocular health play a significant role in increasing public awareness of the risks of AMD. Cessation of smoking, the use of eye protection in high light conditions, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD.

Overview of risk factors for age-related macular degeneration (AMD)

Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make life style choices that may reduce the risk of disease. This review discusses the role of genetics, sunlight, diet, cardiovascular factors, smoking, and alcohol as possible risk factors for AMD. Genetics plays a more significant role in AMD than previously thought, especially in younger patients, histocompatibility locus antigen (HLA) and complement system genes being the most significant. Whether the risk of AMD is increased by exposure to sunlight, cardiovascular risk factors, and diet is more controversial. Smoking is the risk factor most consistently associated with AMD. Current smokers are exposed to a two to three times higher risk of AMD than non-smokers and the risk increases with intensity of smoking. Moderate alcohol consumption is unlikely to increase the risk of AMD. Optometrists as front-line informers and educators of ocular health play a significant role in increasing public awareness of the risks of AMD. Cessation of smoking, the use of eye protection in high light conditions, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD.

Mobility changes in older age: neuropsychological, neurophysiological and cognitive predictors of successful adaptation in a real world scenario

The aims of this thesis were to investigate the neuropsychological, neurophysiological, and cognitive contributors to mobility changes with increasing age. In a series of studies with adults aged 45-88 years, unsafe pedestrian behaviour and falls were investigated in relation to i) cognitive functions (including response time variability, executive function, and visual attention tests), ii) mobility assessments (including gait and balance and using motion capture cameras), iii) motor initiation and pedestrian road crossing behavior (using a simulated pedestrian road scene), iv) neuronal and functional brain changes (using a computer based crossing task with magnetoencephalography), and v) quality of life questionnaires (including fear of falling and restricted range of travel). Older adults are more likely to be fatally injured at the far-side of the road compared to the near-side of the road, however, the underlying mobility and cognitive processes related to lane-specific (i.e. near-side or far-side) pedestrian crossing errors in older adults is currently unknown. The first study explored cognitive, motor initiation, and mobility predictors of unsafe pedestrian crossing behaviours. The purpose of the first study (Chapter 2) was to determine whether collisions at the near-side and far-side would be differentially predicted by mobility indices (such as walking speed and postural sway), motor initiation, and cognitive function (including spatial planning, visual attention, and within participant variability) with increasing age. The results suggest that near-side unsafe pedestrian crossing errors are related to processing speed, whereas far-side errors are related to spatial planning difficulties. Both near-side and far-side crossing errors were related to walking speed and motor initiation measures (specifically motor initiation variability). The salient mobility predictors of unsafe pedestrian crossings determined in the above study were examined in Chapter 3 in conjunction with the presence of a history of falls. The purpose of this study was to determine the extent to which walking speed (indicated as a salient predictor of unsafe crossings and start-up delay in Chapter 2), and previous falls can be predicted and explained by age-related changes in mobility and cognitive function changes (specifically within participant variability and spatial ability). 53.2% of walking speed variance was found to be predicted by self-rated mobility score, sit-to-stand time, motor initiation, and within participant variability. Although a significant model was not found to predict fall history variance, postural sway and attentional set shifting ability was found to be strongly related to the occurrence of falls within the last year. Next in Chapter 4, unsafe pedestrian crossing behaviour and pedestrian predictors (both mobility and cognitive measures) from Chapter 2 were explored in terms of increasing hemispheric laterality of attentional functions and inter-hemispheric oscillatory beta power changes associated with increasing age. Elevated beta (15-35 Hz) power in the motor cortex prior to movement, and reduced beta power post-movement has been linked to age-related changes in mobility. In addition, increasing recruitment of both hemispheres has been shown to occur and be beneficial to perform similarly to younger adults in cognitive tasks (Cabeza, Anderson, Locantore, & McIntosh, 2002). It has been hypothesised that changes in hemispheric neural beta power may explain the presence of more pedestrian errors at the farside of the road in older adults. The purpose of the study was to determine whether changes in age-related cortical oscillatory beta power and hemispheric laterality are linked to unsafe pedestrian behaviour in older adults. Results indicated that pedestrian errors at the near-side are linked to hemispheric bilateralisation, and neural overcompensation post-movement, 4 whereas far-side unsafe errors are linked to not employing neural compensation methods (hemispheric bilateralisation). Finally, in Chapter 5, fear of falling, life space mobility, and quality of life in old age were examined to determine their relationships with cognition, mobility (including fall history and pedestrian behaviour), and motor initiation. In addition to death and injury, mobility decline (such as pedestrian errors in Chapter 2, and falls in Chapter 3) and cognition can negatively affect quality of life and result in activity avoidance. Further, number of falls in Chapter 3 was not significantly linked to mobility and cognition alone, and may be further explained by a fear of falling. The objective of the above study (Study 2, Chapter 3) was to determine the role of mobility and cognition on fear of falling and life space mobility, and the impact on quality of life measures. Results indicated that missing safe pedestrian crossing gaps (potentially indicating crossing anxiety) and mobility decline were consistent predictors of fear of falling, reduced life space mobility, and quality of life variance. Social community (total number of close family and friends) was also linked to life space mobility and quality of life. Lower cognitive functions (particularly processing speed and reaction time) were found to predict variance in fear of falling and quality of life in old age. Overall, the findings indicated that mobility decline (particularly walking speed or walking difficulty), processing speed, and intra-individual variability in attention (including motor initiation variability) are salient predictors of participant safety (mainly pedestrian crossing errors) and wellbeing with increasing age. More research is required to produce a significant model to explain the number of falls.

Effects of advanced glycation end-products (AGEs) on retinal pigment epithelial (RPE) cells lysosomal function:implications for age-related macular degeneration (AMD)

Purpose: RPE lysosomal dysfunction is a major contributor to AMD pathogenesis. Controlled activity of a major class of RPE proteinases, the cathepsins, is crucial in maintaining correct lysosomal function. Advanced glycation end-products (AGEs) accumulate in the Bruch’s membrane (BM) with age, impacting critical RPE functions and in turn, contributing to the development of AMD. The aim of this study was to assess the effect of AGEs on lysosomal function by analysing the expression, processing and activity of the cysteine proteinases cathepsins B, L and S, and the aspartic proteinase cathepsin D. Methods: ARPE-19 cells were cultured on AGE-containing BM mimics (matrigel) for 14 days and compared to untreated substrate. Expression levels and intracellular processing of cathepsins B, D, L and S, were assessed by qPCR and immunoblotting of cell lysates. Lysosomal activity was investigated using multiple activity assays specific to each of the analysed cathepsins. Statistical analysis was performed using the Student’s independent T-test. Results: AGE exposure produced a 36% decrease in cathepsin L activity when compared to non-treated controls (p=0.02, n= 3) although no significant changes were observed in protein expression/processing under these conditions. Both the pro and active forms of cathepsin S decreased by 40% (p=0.04) and 74% (p=0.004), respectively (n=3). In contrast, the active form of the cathepsin D increased by 125% (p=0.005, n= 4). However, no changes were observed in the activity levels of both cathepsins S and D. In addition, cathepsin B expression, processing and activity also remained unaltered following AGE exposure. Conclusions: AGEs accumulation in the extracellular matrix, a phenomenon associated with the natural aging process of the BM, attenuates the expression, intracellular processing and activity of specific lysosomal effectors. Altered enzymatic function may impair important lysosomal processes such as endocytosis, autophagy and phagocytosis of photoreceptor outer segments, each of which may influence the age-related dysfunction of the RPE and subsequently, AMD pathogenesis.

Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice

Rapamycin consistently increases longevity in mice although the mechanism of action of this drug is unknown. In the present investigation we studied the effect of rapamycin on mitochondrial oxidative stress at the same dose that is known to increase longevity in mice (14 mg of rapamycin/kg of diet). Middle aged mice (16 months old) showed significant age-related increases in mitochondrial ROS production at complex I, accumulation of mtDNA fragments inside nuclear DNA, mitochondrial protein lipoxidation, and lipofuscin accumulation compared to young animals (4 months old) in the liver. After 7 weeks of dietary treatment all those increases were totally or partially (lipofuscin) abolished by rapamycin, middle aged rapamycin-treated animals showing similar levels in those parameters to young animals. The decrease in mitochondrial ROS production was due to qualitative instead of quantitative changes in complex I. The decrease in mitochondrial protein lipoxidation was not due to decreases in the amount of highly oxidizable unsaturated fatty acids. Rapamycin also decreased the amount of RAPTOR (of mTOR complex) and increased the amounts of the PGC1-α and ATG13 proteins. The results are consistent with the possibility that rapamycin increases longevity in mice at least in part by lowering mitochondrial ROS production and increasing autophagy, decreasing the derived final forms of damage accumulated with age which are responsible for increased longevity. The decrease in lipofuscin accumulation induced by rapamycin adds to previous information suggesting that the increase in longevity induced by this drug can be due to a decrease in the rate of aging. © 2016 Elsevier Inc.