Retinal microvascular parameters are not significantly associated with mild cognitive impairment in the Northern Ireland Cohort for the Longitudinal Study of Ageing.

BACKGROUND: The retinal and cerebral microvasculature share similar embryological origins and physiological characteristics. Improved imaging technologies provide opportunistic non-invasive assessment of retinal microvascular parameters (RMPs) against cognitive outcomes. We evaluated baseline measures for associations between RMPs and mild cognitive impairment (MCI) from participants of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). METHODS: RMPs (central retinal arteriolar / venular equivalents, arteriole to venular ratio, fractal dimension and tortuosity) were measured from optic disc centred fundus images and analysed using semi-automated software. Associations between RMPs and MCI were assessed by multivariable logistic regression with adjustment for potential confounders including age, sex, alcohol consumption, smoking status, educational attainment, physical activity, cardiovascular disease (CVD), hypertension, mean arterial blood pressure, triglycerides, diabetes, body mass index, and high density lipoprotein levels. P < 0.05 was considered statistically significant. RESULTS: Data were available for 1431 participants, of which 156 (10.9%) were classified with MCI defined by a Montreal Cognitive Assessment (MoCA) score ≤ 26, with subjective cognitive decline, in the absence of depression or problems with activities of daily living. Participants had a mean age of 62.4 ± 8.5 yrs. and 52% were female. As expected, individuals with MCI had a lower MoCA score than those without (23.5 ± 2.6 versus 26.3 ± 2.7, respectively), were more likely to be female, have a lower level of educational attainment, be less physically active, more likely to have CVD, have higher levels of triglycerides and lower levels of high density lipoprotein. No significant associations between RMPs and MCI were detected in unadjusted, minimally adjusted or fully adjusted regression models or subsequent sensitivity analyses. CONCLUSION: Previous studies have reported both increased retinal venular calibre and reduced fractal dimension in association with mild cognitive impairment. Our study failed to detect any associations between RMPs and those individuals at an early stage of cognitive loss in an older community-based cohort.

Association of reduced retinal arteriolar tortuosity with depression in older participants from the Northern Ireland Cohort for the Longitudinal Study of Ageing.

INTRODUCTION: The retina shares similar anatomical and physiological features with the brain and subtle variations in retinal microvascular parameters (RMPs) may reflect similar vascular variation in the brain. The aim of this study was to assess associations between RMPs and measures of depression in the Northern Ireland Cohort for the Longitudinal Study of Ageing. METHODS: RMPs (arteriolar and venular caliber, fractal dimension and tortuosity) were measured from optic disc centred fundus images using semi-automated software. Depression was characterised by the Centre for Epidemiologic Studies Depression Scale (CES-D) in the absence of mild cognitive impairment or use of anti-depressive medications. Associations between depression and RMPs were assessed by regression analyses with adjustment for potential confounders. RESULTS: Data were available for 1376 participants of which 113 (8.2%) and 1263 (91.8%) were classified with and without depression. Participants had a mean age of 62.0 ± 8.4 yrs., 52% were female, and 8% were smokers. Individuals with depression had a higher CES-D score than those without (22.0 ± 6.2 versus 4.4 ± 3.9). Lower values of arteriolar tortuosity were significantly associated with depression, before and after adjustment for potential confounders (odds ratio = 0.79; 95% confidence intervals: 0.65, 0.96; P = 0.02). CONCLUSION: Decreased retinal arteriolar tortuosity, a measure of the complexity of the retinal microvasculature was associated with depression in older adults independent of potential confounding factors. Retinal measures may offer opportunistic assessment of microvascular health associated with outcomes of depression.

Association of retinal venular tortuosity with impaired renal function in the Northern Ireland Cohort for the Longitudinal Study of Ageing.

BACKGROUND: Previous studies have identified retinal microvascular features associated with renal dysfunction. Biopsies are necessary to confirm kidney microvascular damage and retinal imaging may enable evaluation of microangiopathic characteristics reflecting renal changes associated with chronic kidney disease (CKD). We evaluated retinal microvascular parameters (RMPs) for associations with renal function in a cross-sectional analysis of the Northern Ireland Cohort for the Longitudinal Study of Ageing. METHODS: RMPs (central retinal arteriolar/ venular equivalents [CRAE/CRVE], arteriolar to venular ratio [AVR], fractal dimension and tortuosity) were measured from optic disc centred fundus images using semi-automated software. Associations were assessed with multivariable regression analyses between RMPs and estimated glomerular filtration rate (eGFR) defined by serum creatinine (eGFRscr) and cystatin C (eGFRcys) and also CKD status characterised by eGFR < 60 mL/min/1.73m2. Regression models were adjusted for potential confounders including age, sex, diabetes, smoking status, educational attainment, cardiovascular disease, body mass index, antihypertensive medication, systolic blood pressure, triglycerides, high- and low-density lipoprotein levels. RESULTS: Data were included for 1860 participants that had measures of renal function and retinal fundus images of sufficient quality for analysis. Participants had a mean age of 62.0 ± 8.5 yrs. and 53% were female. The mean eGFR for scr and cys were 82.2 ± 14.9 mL/min/1.73m2 and 70.7 ± 18.6 mL/min/1.73m2 respectively. eGFRcys provided lower estimates than eGFRscr resulting in a greater proportion of participants categorised as having CKD stages 3-5 (eGFRcys 26.8%; eGFRscr 7.9%). Multivariable regression analyses showed that increased venular tortuosity (OR = 1.30; 95%CI: 1.10, 1.54; P < 0.01) was associated with CKD stages 3-5 characterised by eGFRscr < 60 mL/min/1.73 m2. No additional associations between CKD status characterised by eGFRscr or with eGFRcys, were detected (P > 0.05). Multivariable regression failed to detect associations between CRAE, CRVE, AVR, fractal dimension or tortuosity and eGFRscr or eGFRcys (P > 0.05). CONCLUSION: Increased retinal venular tortuosity was associated with CKD stages 3-5 defined by eGFRscr < 60 mL/min/1.73 m2, in an older population independent of potential confounding factors. These retinal measures may provide non-invasive microvascular assessment of associations with CKD.

Simple non-mydriatic retinal photography is feasible and demonstrates retinal microvascular dilation in Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is associated with an increased risk of myocardial infarction and stroke but it remains unclear how to identify microvascular changes in this population. OBJECTIVES: We hypothesized that simple non-mydriatic retinal photography is feasible and can be used to assess microvascular damage in COPD. METHODS: Novel Vascular Manifestations of COPD was a prospective study comparing smokers with and without COPD, matched for age. Non-mydriatic, retinal fundus photographs were assessed using semi-automated software. RESULTS: Retinal images from 24 COPD and 22 control participants were compared. Cases were of similar age to controls (65.2 vs. 63.1 years, p = 0.38), had significantly lower Forced Expiratory Volume in one second (FEV1) (53.4 vs 100.1% predicted; p < 0.001) and smoked more than controls (41.7 vs. 29.6 pack years; p = 0.04). COPD participants had wider mean arteriolar (155.6 ±15 uM vs. controls [142.2 ± 12 uM]; p = 0.002) and venular diameters (216.8 ±20.7 uM vs. [201.3± 19.1 uM]; p = 0.012). Differences in retinal vessel caliber were independent of confounders, odds ratios (OR) = 1.08 (95% confidence intervals [CI] = 1.02, 1.13; p = 0.007) and OR = 1.05 (CI = 1.01, 1.09; p = 0.011) per uM increase in arteriolar and venular diameter respectively. FEV1 remained significantly associated with retinal vessel dilatation r = -0.39 (p = 0.02). CONCLUSIONS: Non-mydriatic retinal imaging is easily facilitated. We found significant arteriole and venous dilation in COPD compared to age-matched smokers without COPD associated with lung function independent of standard cardiovascular risk factors. Retinal microvascular changes are known to be strongly associated with future vascular events and retinal photography offers potential to identify this risk. TRIAL REGISTRATION: clinicaltrials.gov NCT02060292.

An exploratory factor analysis of visual performance in a large population.

A factor analysis was performed on 25 visual and auditory performance measures from 1060 participants. The results revealed evidence both for a factor relating to general perceptual performance, and for eight independent factors that relate to particular perceptual skills. In an unrotated PCA, the general factor for perceptual performance accounted for 19.9% of the total variance in the 25 performance measures. Following varimax rotation, 8 consistent factors were identified, which appear to relate to (1) sensitivity to medium and high spatial frequencies, (2) auditory perceptual ability (3) oculomotor speed, (4) oculomotor control, (5) contrast sensitivity at low spatial frequencies, (6) stereo acuity, (7) letter recognition, and (8) flicker sensitivity. The results of a hierarchical cluster analysis were consistent with our rotated factor solution. We also report correlations between the eight performance factors and other (non-performance) measures of perception, demographic and anatomical measures, and questionnaire items probing other psychological variables.

Cost-effectiveness of community versus hospital eye service follow-up for patients with quiescent treated age-related macular degeneration alongside the ECHoES randomised trial.

OBJECTIVES: To assess the cost-effectiveness of optometrist-led follow-up monitoring reviews for patients with quiescent neovascular age-related macular degeneration (nAMD) in community settings (including high street opticians) compared with ophthalmologist-led reviews in hospitals. DESIGN: A model-based cost-effectiveness analysis with a 4-week time horizon, based on a 'virtual' non-inferiority randomised trial designed to emulate a parallel group design. SETTING: A virtual internet-based clinical assessment, conducted at community optometry practices, and hospital ophthalmology clinics. PARTICIPANTS: Ophthalmologists with experience in the age-related macular degeneration service; fully qualified optometrists not participating in nAMD shared care schemes. INTERVENTIONS: The participating optometrists and ophthalmologists classified lesions from vignettes and were asked to judge whether any retreatment was required. Vignettes comprised clinical information, colour fundus photographs and optical coherence tomography images. Participants' classifications were validated against experts' classifications (reference standard). Resource use and cost information were attributed to these retreatment decisions. MAIN OUTCOME MEASURES: Correct classification of whether further treatment is needed, compared with a reference standard. RESULTS: The mean cost per assessment, including the subsequent care pathway, was £411 for optometrists and £397 for ophthalmologists: a cost difference of £13 (95% CI -£18 to £45). Optometrists were non-inferior to ophthalmologists with respect to the overall percentage of lesions correctly assessed (difference -1.0%; 95% CI -4.5% to 2.5%). CONCLUSIONS: In the base case analysis, the slightly larger number of incorrect retreatment decisions by optometrists led to marginally and non-significantly higher costs. Sensitivity analyses that reflected different practices across eye hospitals indicate that shared care pathways between optometrists and ophthalmologists can be identified which may reduce demands on scant hospital resources, although in light of the uncertainty around differences in outcome and cost it remains unclear whether the differences between the 2 care pathways are significant in economic terms. TRIAL REGISTRATION NUMBER: ISRCTN07479761; Pre-results.

Design characteristic of randomised controlled trials for geographic atrophy in age-related macular degeneration: selection of outcomes and sample size calculation.

PURPOSE: The selection of suitable outcomes and sample size calculation are critical factors in the design of a randomised controlled trial (RCT). The goal of this study was to identify the range of outcomes and information on sample size calculation in RCTs on geographic atrophy (GA). METHODS: We carried out a systematic review of age-related macular degeneration (AMD) RCTs. We searched MEDLINE, EMBASE, Scopus, Cochrane Library, www.controlled-trials.com, and www.ClinicalTrials.gov. Two independent reviewers screened records. One reviewer collected data and the second reviewer appraised 10% of collected data. We scanned references lists of selected papers to include other relevant RCTs. RESULTS: Literature and registry search identified 3816 abstracts of journal articles and 493 records from trial registries. From a total of 177 RCTs on all types of AMD, 23 RCTs on GA were included. Eighty-one clinical outcomes were identified. Visual acuity (VA) was the most frequently used outcome, presented in 18 out of 23 RCTs and followed by the measures of lesion area. For sample size analysis, 8 GA RCTs were included. None of them provided sufficient Information on sample size calculations. CONCLUSIONS: This systematic review illustrates a lack of standardisation in terms of outcome reporting in GA trials and issues regarding sample size calculation. These limitations significantly hamper attempts to compare outcomes across studies and also perform meta-analyses.

Health professionals' and service users' perspectives of shared care for monitoring wet age-related macular degeneration: a qualitative study alongside the ECHoES trial.

OBJECTIVES: To explore the views of eye health professionals and service users on shared community and hospital care for wet or neovascular age-related macular degeneration (nAMD). METHOD: Using maximum variation sampling, 5 focus groups and 10 interviews were conducted with 23 service users and 24 eye health professionals from across the UK (consisting of 8 optometrists, 6 ophthalmologists, 6 commissioners, 2 public health representatives and 2 clinical eye care advisors to local Clinical Commissioning Groups). Data were transcribed verbatim and analysed thematically using constant comparative techniques derived from grounded theory methodology. RESULTS: The needs and preferences of those with nAMD appear to be at odds with the current service being provided. There was enthusiasm among health professionals and service users about the possibility of shared care for nAMD as it was felt to have the potential to relieve hospital eye service burden and represent a more patient-centred option, but there were a number of perceived barriers to implementation. Some service users and ophthalmologists voiced concerns about optometrist competency and the potential for delays with referrals to secondary care if stable nAMD became active again. The health professionals were divided as to whether shared care was financially more efficient than the current model of care. Specialist training for optometrists, under the supervision of ophthalmologists, was deemed to be the most effective method of training and was perceived to have the potential to improve the communication and trust that shared care would require. CONCLUSIONS: While shared care is perceived to represent a promising model of nAMD care, voiced concerns suggest that there would need to be greater collaboration between ophthalmology and optometry, in terms of interprofessional trust and communication. TRIAL REGISTRATION NUMBER: ISRCTN07479761.

A population study of binocular function.

As part of a genome-wide association study (GWAS) of perceptual traits in healthy adults, we measured stereo acuity, the duration of alternative percepts in binocular rivalry and the extent of dichoptic masking in 1060 participants. We present the distributions of the measures, the correlations between measures, and their relationships to other psychophysical traits. We report sex differences, and correlations with age, interpupillary distance, eye dominance, phorias, visual acuity and personality. The GWAS, using data from 988 participants, yielded one genetic association that passed a permutation test for significance: The variant rs1022907 in the gene VTI1A was associated with self-reported ability to see autostereograms. We list a number of other suggestive genetic associations (p<10(-5)).

Counterphase modulation flicker photometry: phenotypic and genotypic associations.

The OSCAR test, a clinical device that uses counterphase flicker photometry, is believed to be sensitive to the relative numbers of long-wavelength and middle-wavelength cones in the retina, as well as to individual variations in the spectral positions of the photopigments. As part of a population study of individual variations in perception, we obtained OSCAR settings from 1058 participants. We report the distribution characteristics for this cohort. A randomly selected subset of participants was tested twice at an interval of at least one week: the test-retest reliability (Spearman's rho) was 0.80. In a whole-genome association analysis we found a provisional association with a single nucleotide polymorphism (rs16844995). This marker is close to the gene RXRG, which encodes a nuclear receptor, retinoid X receptor γ. This nuclear receptor is already known to have a role in the differentiation of cones during the development of the eye, and we suggest that polymorphisms in or close to RXRG influence the relative probability with which long-wave and middle-wave opsin genes are expressed in human cones.

Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia.

Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. Here, we report a genome-wide association study of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642 758 single nucleotide polymorphism (SNP) markers. A significant association (P = 7.9 × 10(-9) ) was found with the SNP marker rs1797052, situated in the 5'-untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the α = 0.005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with N-methyl-d-aspartate receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements.

Heritability of the spatial distribution and peak density of macular pigment: a classical twin study.

PURPOSE: To elucidate the heritability of peak density and spatial width of macular pigment (MP) using a Classical Twin Study. METHODS: Fundus autofluorescence images were obtained at 488 nm from 86 subjects or 43 twin pairs (21 monozygotic (MZ) and 22 dizygotic (DZ)) (27 male, 59 female) aged from 55 to 76 years (mean 62.2 ± 5.3 years). The relative topographic distribution of MP was measured using a grey scale of intensity (0-255 units) in a 7° eccentricity around the fovea. Relative peak MP density (rPMPD) and relative spatial distribution of MP (rSDMP) were used as the main outcome measure in the statistical analysis. RESULTS: A significantly higher correlation was found within MZ pairs as compared with that within DZ pairs for rPMPD, (r=0.99, 95% confidence interval (95% CI) 0.93 to 1.00) and 0.22, 95% CI -0.34 to 0.71), respectively, suggesting strong heritability of this trait. When rSDMP was compared, there was no significant difference between the correlations within MZ pairs (r=0.48, 95% CI -0.02 to 0.83) and DZ pairs (r=0.63, 95% CI 0.32 to 0.83), thus rSDMP is unlikely to have a considerable heritable component. In addition, there was no difference between any MP parameter when normal maculae were compared with early age-related macular degeneration (AMD) (rPMPD 0.36 vs 0.34, t=1.18 P=0.243, rSDMP 1.75 vs 1.75, t=0.028 P=0.977). CONCLUSIONS: rPMPD is a strongly heritable trait whereas rSDMP has minimal genetic influence and a greater influence by environmental factors. The presence of macular changes associated with early AMD did not appear to influence any of these pigment parameters.

Investigation of the effect of simulated lens yellowing, transparency loss and refractive error on in vivo resonance Raman spectroscopy.

PURPOSE: To separately investigate the impact of simulated age-related lens yellowing, transparency loss and refractive error on measurements of macular pigment (MP) using resonance Raman spectroscopy. METHODS: Two healthy young subjects with clear media underwent Raman spectroscopy under the following conditions: age-related lens yellowing was simulated using seven broad-band yellow filters with transmittance at 488 nm ranging from 0.54 to 0.90; cataract was simulated using five white filters of increasing opacity (scatter filters), the transmittance of which ranged from 0.42 to 0.86, each of which reduced peak contrast sensitivity by approximately 0.1 log units over the previous filter. Refractive error up to +6.25 D was achieved using soft contact lenses. RESULTS: The Raman signal declined steadily to an average value of 43% of the starting value with the densest yellow filter in place. The white scatter filters produced a progressive linear reduction in signal resulting in almost complete signal loss with the densest filter. Refractive error resulted in an initial slight improvement in Raman count up to a value of +2.00 D followed by a decline thereafter. CONCLUSIONS: These results imply that lens yellowing and increasing scatter has an influence on the Raman signal and suggest that studies using this technology to estimate MP levels in older populations should carefully account for the status of the lens.

In vivo macular pigment measurements: a comparison of resonance Raman spectroscopy and heterochromatic flicker photometry.

AIM: To investigate whether two methods of measuring macular pigment-namely, heterochromatic flicker photometry (HFP) and resonance Raman spectroscopy (RRS)--yield comparable data. METHODS: Macular pigment was measured using HFP and RRS in the right eye of 107 participants aged 20-79 years. Correlations between methods were sought and regression models generated. RRS was recorded as Raman counts and HFP as macular pigment optical density (MPOD). The average of the top three of five Raman counts was compared with MPOD obtained at 0.5 degrees eccentricity, and an integrated measure (spatial profile; MPODsp) computed from four stimulus sizes on HFP. RESULTS: The coefficient of variation was 12.0% for MPODsp and 13.5% for Raman counts. MPODsp exhibited significant correlations with Raman counts (r = 0.260, p = 0.012), whereas MPOD at 0.5 degrees did not correlate significantly (r = 0.163, p = 0.118). MPODsp was not significantly correlated with age (p = 0.062), whereas MPOD at 0.5 degrees was positively correlated (p = 0.011). Raman counts showed a significant decrease with age (p = 0.002) and were significantly lower when pupil size was smaller (p = 0.015). CONCLUSIONS: Despite a statistically significant correlation, the correlations were weak, with those in excess of 90% of the variance between MPODsp and Raman counts remaining unexplained, meriting further research.

Visual function and dysfunction in early and late age-related maculopathy.

Late age-related maculopathy (ARM) is responsible for the majority of blind registrations in the Western world among persons over 50 years of age. It has devastating effects on quality of life and independence and is becoming a major public health concern. Current treatment options are limited and most aim to slow progression rather than restore vision; therefore, early detection to identify those patients most suitable for these interventions is essential. In this work, we review the literature encompassing the investigation of visual function in ARM in order to highlight those visual function parameters which are affected very early in the disease process. We pay particular attention to measures of acuity, contrast sensitivity (CS), cone function, electrophysiology, visual adaptation, central visual field sensitivity and metamorphopsia. We also consider the impact of bilateral late ARM on visual function as well as the relationship between measures of vision function and self-reported visual functioning. Much interest has centred on the identification of functional changes which may predict progression to neovascular disease; therefore, we outline the longitudinal studies, which to date have reported dark-adaptation time, short-wavelength cone sensitivity, colour-match area effect, dark-adapted foveal sensitivity, foveal flicker sensitivity, slow recovery from glare and slower foveal electroretinogram implicit time as functional risk factors for the development of neovascular disease. Despite progress in this area, we emphasise the need for longitudinal studies designed in light of developments in disease classification and retinal imaging, which would ensure the correct classification of cases and controls, and provide increased understanding of the natural course and progression of the disease and further elucidate the structure-function relationships in this devastating disorder.