Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology and endothelial dysfunction

OBJECTIVE: To investigate laboratory evidence of abnormal angiogenesis, hemorheologic factors, endothelial damage/dysfunction, and age-related macular degeneration (ARMD). DESIGN: Comparative cross-sectional study. PARTICIPANTS: We studied 78 subjects (26 men and 52 women; mean age 74 years; standard deviation [SD] 9.0) with ARMD attending a specialist referral clinic. Subjects were compared with 25 healthy controls (mean age, 71 years; SD, 11). INTERVENTION AND OUTCOME MEASURES: Levels of vascular endothelial growth factor (VEGF, an index of angiogenesis), hemorheologic factors (plasma viscosity, hematocrit, white cell count, hemoglobin, platelets), fibrinogen (an index of rheology and hemostasis), and von Willebrand factor (a marker of endothelial dysfunction) were measured. RESULTS: Median plasma VEGF (225 vs. 195 pg/ml, P = 0.019) and mean von Willebrand factor (124 vs. 99 IU/dl, P = 0.0004) were greater in ARMD subjects than the controls. Mean plasma fibrinogen and plasma viscosity levels were also higher in the subjects (both P < 0.0001). There were no significant differences in other indices between cases and controls. When "dry" (drusen, atrophy, n = 28) and "exudative" (n = 50) ARMD subjects were compared, there was no significant differences in VEGF, fibrinogen, viscosity, or von Willebrand factor levels. There were no significant correlations between the measured parameters. Stepwise multiple regression analysis did not demonstrate any significant clinical predictors (age, gender, smoking, body mass index, history of vascular disease, or hypertension) for plasma VEGF or fibrinogen levels, although smoking status was a predictor of plasma von Willebrand factor levels (P < 0.05). CONCLUSIONS: This study suggests an association between markers of angiogenesis (VEGF), hemorheologic factors, hemostasis, endothelial dysfunction, and ARMD. The interaction between abnormal angiogenesis and the components of Virchow's triad for thrombogenesis may in part contribute to the pathogenesis of ARMD.

A safety evaluation of ranibizumab in the treatment of age-related macular degeneration

Introduction: The use of intravitreal ranibizumab has transformed the outcomes for thousands of patients with wet age related macular degeneration (AMD), which is the leading cause of blindness in developed countries. Prior to its introduction, most patients with wet AMD would rapidly lose central vision. The use of intravitreal ranibizumab has been shown to reduce certifiable visual loss by about a half. Current treatment regimens with ranibizumab in wet AMD require multiple injections over several years and so it is highly relevant to review the safety record of this important drug.Areas covered: This review considers the important ocular and systemic adverse events (AE) that have been reported in the literature, particularly in the context of the pivotal clinical trials that have been performed. It also reviews the safety of other anti-VEGF drugs that are used in wet AMD, namely bevacizumab and aflibercept, and compares these drugs with ranibizumab.Expert opinion: Overall, intravitreal ranibizumab can be considered a safe and highly effective drug for patients with wet AMD. However recent concerns about retinal thinning following ranibizumab therapy, possible systemic AE associated with all anti-VEGF drugs and the occurrence of complications relating to drug preparation and delivery must be considered. © 2014 Informa UK, Ltd.

The effects of coloured light filter overlays on reading rates in age-related macular degeneration

Purpose: To determine the effect of coloured light filter overlays on reading rates for people with age-related macular degeneration (AMD). Method: Using a prospective clinical trial design, we examined the null hypothesis that coloured light filter overlays do not improve reading rates in AMD when compared to a clear filter. Reading rates for 12 subjects with non-exudative AMD, associated with a relative scotoma and central fixation (mean age 81 years, SD 5.07 years) were determined using the Rate of Reading Test® (printed, nonsense, lower case sans serif, stationary text) with 10 different, coloured light filter overlays (Intuitive Overlays®; figures in brackets are percentage transmission values); rose (78%), pink (78%), purple (67%), aqua (81%), blue (74%), lime-green (86%), mint-green (85%), yellow (93%), orange (83%) and grey (71%). A clear overlay (Roscolene # 00) (360 cdm-2) with 100% transmittance was used as a control. Results: ANOVA indicated that there was no statistically significant difference in reading rates with the coloured light filter overlays compared to the clear filter. Furthermore, chi-squared analysis indicated that the rose, purple and blue filters had a significantly poorer overall ranking in terms of reading rates compared to the other coloured and clear light filters. Conclusion: Coloured light filter overlays are unlikely to provide a clinically significant improvement in reading rates for people with non-exudative AMD associated with a relative scotoma and central fixation. Copyright © Acta Ophthalmol Scand 2004.

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.

Age-related macular degeneration patients' awareness of nutritional factors

Age-related macular degeneration (AMD) is the leading cause of visual impairment in older adults in the United Kingdom. This study sought to characterise AMD patients who seek the services of the Macular Society, and determine the level and source of their dietary knowledge. A questionnaire was designed, validated, and administered to 158 participants. The questions covered demographic data and knowledge of nutrition and supplementation. The mean age of participants was 79 years; 61% of them were female, and 27% were registered visually impaired. Only 55% of the participants thought diet was important for eye health, 63% felt that they had not received enough information about AMD. The participants reported that their information mainly came from non-professional support groups. Most participants identified healthy food, but could not say why, and were not able to identify carotenoid rich foods. The results of the study will inform design of education and dissemination methods regarding dietary information. © The Author(s) 2014.

Exploring attitudes towards dietary modification and nutritional supplementation in people with and without age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause for visual impairment and blindness registration in the developed world. Due to the large amounts of conflicting AMD research on the role of nutrition and antioxidant intake, it is difficult for patients and practitioners to determine which measures can be taken to slow down the disease progression. The aim of this research was to determine the beliefs and knowledge that patients with AMD have about nutrition, to identify whether their condition is preventing them from eating a healthy diet, and to discover what their diet consists of. For the initial study, 158 participants with AMD (mean age 79 ± 7.8 years) and 50 participants without AMD (mean age 67 ± 8 years) were recruited from the Macular Society helpline, or from optometric practice. Participants had a 25 minute telephone interview where a 36-question survey was completed. The survey elicited demographic information, and questions covered the knowledge that participants had on nutrition and their current diet. The results from this survey uncovered three major findings: 1) 100% of AMD participants felt that they do not have enough information and support from eye-care practitioners regarding nutrition, 2) AMD patients are confused over, and display a lack of knowledge of, which foods are beneficial for eye health and when and what nutritional supplements to take, evidenced by 65% of participants not taking the correct dosage 3) AMD patients are not eating enough nutrients that would be beneficial for their condition - consuming an average of 1.4mg of lutein and zeaxanthin rather than the recommended 10mg. A clinical decision-making aid was created as an intervention based upon these findings. The aim of the aid was to help eye-care practitioners give the correct nutritional advice to their patients. Founded on the AREDS 2 inclusion and exclusion criteria, practitioners are able to identify which patients could benefit from a nutritional supplement, and which patients could benefit from dietary modification. An evaluation of the aid with 72 qualified eye-care practitioners exhibited a statistically significant increase in confidence after using the aid for two weeks. An evaluation using 51 student optometrists showed a statistically significant increase in confidence and a statistically significant increase in appropriate management of patients after using the aid. This project has elicited findings that are significant for AMD patient education. It is hoped that through these studies, patients will receive consistent advice about the risk factors for AMD, the link between AMD and nutrition, and the importance of maintaining a healthy, well-balanced diet.

Cortical degeneration in frontotemporal lobar degeneration with TDP-43 proteinopathy caused by progranulin gene mutation

Familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is most commonly caused by progranulin (GRN) gene mutation. To characterize cortical degeneration in these cases, changes in density of the pathology across the cortical laminae of the frontal and temporal lobe were studied in seven cases of FTLD-TDP with GRN mutation using quantitative analysis and polynomial curve fitting. In 50% of gyri studied, neuronal cytoplasmic inclusions (NCI) exhibited a peak of density in the upper cortical laminae. Most frequently, neuronal intranuclear inclusions (NII) and dystrophic neurites (DN) exhibited a density peak in lower and upper laminae, respectively, glial inclusions (GI) being distributed in low densities across all laminae. Abnormally enlarged neurons (EN) were distributed either in the lower laminae or were more uniformly distributed across the cortex. The distribution of all neurons present varied between cases and regions, but most commonly exhibited a bimodal distribution, density peaks occurring in upper and lower laminae. Vacuolation primarily affected the superficial laminae and density of glial cell nuclei increased with distance across the cortex from pia mater to white matter. The densities of the NCI, GI, NII, and DN were not spatially correlated. The laminar distribution of the pathology in GRN mutation cases was similar to previously reported sporadic cases of FTLD-TDP. Hence, pathological changes initiated by GRN mutation, and by other causes in sporadic cases, appear to follow a parallel course resulting in very similar patterns of cortical degeneration in FTLD-TDP.

Corticobasal degeneration and dementia

Corticobasal degeneration is a rare, progressive neurodegenerative disorder which significantly impairs movement. The most common initial symptom is asymmetric limb clumsiness with or without accompanying rigidity or tremor. Subsequently, the disease progresses to affect gait and there is a slow progression to influence ipsilateral arms and legs. Apraxia and dementia are the most common cortical signs. Clinical diagnosis of the disorder is difficult as the symptoms resemble those of related neurodegenerative disorders. Histopathologically, there is widespread neuronal and glial pathology including tau-immunoreactive neuronal cytoplasmic inclusions, neuropil threads, oligodendroglial inclusions, astrocytic plaques, together with abnormally enlarged ‘ballooned’ neurons. Corticobasal degeneration has affinities both with the parkinsonian syndromes including Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy and with the fronto-temporal dementias. Treatment of corticobasal degeneration involves managing and reducing the effect of symptoms.

Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration

Background: The aim of this study was to describe bilateral visual outcomes and the effect of incomplete follow-up after 3 years of ranibizumab therapy for neovascular age-related macular degeneration. Secondarily, the demands on service provision over a 3-year period were described. Methods: Data on visual acuity, hospital visits, and injections were collected over 36 months on consecutive patients commencing treatment over a 9-month period. Visual outcome was determined for 1) all patients, using last observation carried forward for missed visits due to early discontinuation and 2) only those patients completing full 36-month follow-up. Results: Over 3 years, 120 patients cumulatively attended hospital for 1,823 noninjection visits and 1,365 injection visits. A visual acuity loss of <15 letters (L) was experienced by 78.2% of patients. For all patients (n=120), there was a mean loss of 1.68 L using last observation carried forward for missing values. Excluding five patients who died and 30 who discontinued follow-up, mean gain was 1.47 L. In bilateral cases, final acuity was on average 9 L better in second eyes compared to first eyes. Also, 91% of better-seeing eyes continued to be the better-seeing eye. Conclusion: We have demonstrated our approach to describing the long-term service provision and visual outcomes of ranibizumab therapy for neovascular age-related macular degeneration in a consecutive cohort of patients. Although there was a heavy burden with very frequent injections and clinic visits, patients can expect a good level of visual stability and a very high chance of maintaining their better-seeing eye for up to 3 years. © 2014 Chavan et al. This work is published by Dove Medical Press Limited.

Understanding the IT-related attitudes and needs of persons with age-related macular degeneration:a case study

In the UK, 20 per cent of people aged 75 years and over are living with sight loss; this percentage is expected to increase as the population ages (RNIB, 2011). Age-Related Macular Degeneration (AMD) is the UK’s leading cause of severe visual impairment amongst the elderly. It accounts for 16,000 blind/partial sight registrations per year and is the leading cause of blindness among people aged 55 years and older in western countries (Bressler, 2004). Our ultimate goal is to develop an assistive mobile application to support accurate and convenient diet data collection on which basis to then provide customised dietary advice and recommendations in order to help support individuals with AMD to mitigate their ongoing risk and retard the progression of the disease. In this paper, we focus on our knowledge elicitation activities conducted to help us achieve a deep and relevant understanding of our target user group. We report on qualitative findings from focus groups and observational studies with persons with AMD and interviews with domain experts which enable us to fully appreciate the impact that technology may have on our intended users as well as to inform the design and structure of our proposed mobile assistive application.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

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.

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

TDP-43-immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease (MND)

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD-TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP 'continuum' overlapping with FTLD-TDP disease subtypes 2 and 3. © 2012 Nova Science Publishers, Inc. All rights reserved.

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.