Project

EGRET: the European Glaucoma Research Training Program

Goal: EGRET is the training environment for 15 highly talented Early Stage Researchers. The individual and collaborative outputs of their work contribute to the following aims: a) acquiring new, quantitative knowledge on glaucoma and the ageing visual system; and b) applying this new knowledge to boost innovation in glaucoma care in both the public and private sectors.

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Azzurra Invernizzi
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In glaucoma participants, both structural and functional brain changes have been observed, but we still have insufficient understanding of how these changes also affect the integrity of cortical functional networks, and how these changes relate to visual function. This is relevant, as functional network integrity may affect the applicability of future treatments, as well as the options for rehabilitation or training. Here, we compare global and local functional connectivity in local and global brain networks between glaucoma and control participants. Moreover, we study the relationship between functional connectivity and visual field (VF) loss. For our study, 20 subjects with primary open-angle glaucoma (POAG) and 24 age-similar healthy participants were recruited to undergo an ophthalmic assessment followed by two resting-state (RS) (f)MRI scans. For each scan and for each group, the ROIs with eigenvector centrality (EC) values higher than the 95th percentile were considered the most central brain regions ("hubs"). Hubs for which we found a significant difference in EC in both scans between glaucoma and healthy participants were considered to provide evidence for network changes. In addition, we tested the notion that a brain region's hub function in POAG might relate to the severity of a participant's VF defect, irrespective of which eye contributed mostly to this. To determine this, for each participant, eye-independent scores were derived for: (1) sensitivity of the worse eye-indicating disease severity, (2) sensitivity of both eyes combined-with one eye potentially compensating for loss in the other, or (3) difference in eye sensitivity-potentially requiring additional network interactions. By correlating each of these VF scores and the EC values, we assessed whether VF defects could be associated with centrality alterations in POAG. Our results show that no functional connectivity disruptions were found at the global brain level in POAG participants. This indicates that in glaucoma global brain network communication is preserved. Furthermore, for the Lingual Gyrus, identified as a brain hub, we found a Demaria et al. Network Function Changes in Glaucoma positive correlation between the EC value and the VF sensitivity of both eyes combined. The fact that reduced local network functioning is associated with reduced binocular VF sensitivity suggests the presence of local brain reorganization that has a bearing on functional visual abilities.
Catarina A R João
added 3 research items
Purpose: In glaucoma, visual field defects in the left and right eye may be non-overlapping, resulting in an intact binocular visual field. In clinical management, these patients are often considered to have normal vision. However, visual performance also relies on binocular processing. The aim of this study was to evaluate binocular visual functions in glaucoma patients with intact binocular visual field, normal visual acuity, and stereoscopy. Methods: We measured in 10 glaucoma patients and 12 age-similar controls: (1) monocular and binocular contrast sensitivity functions (CSF) using a modified quick CSF test to assess binocular contrast summation, (2) dominance during rivalry, and (3) contrast ratio at balance point with a binocular phase combination test. A mirror stereoscope was used to combine the left and right eye image (each 10° horizontally by 12° vertically) on a display. Results: Area under the monocular and binocular CSF was lower in glaucoma compared to healthy (P < 0.001), but the binocular contrast summation ratio did not differ (P = 0.30). For rivalry, the percentage of time of mixed percept was 9% versus 18% (P = 0.056), the absolute difference of the percentage of time of dominance between the two eyes 19% versus 10% (P = 0.075), and the rivalry rate 8.2 versus 12.1 switches per minute (P = 0.017) for glaucoma and healthy, respectively. Median contrast ratio at balance point was 0.66 in glaucoma and 1.03 in controls (P = 0.011). Conclusions: Binocular visual information processing deficits can be found in glaucoma patients with intact binocular visual field, normal visual acuity, and stereoscopy.
Nigus G. Asefa
added a research item
TITLE: Development and validation of myopia proxy using self-reported refractive error-related questions: the Lifelines cohort ABSTRACT BODY: Purpose: Ophthalmic examination in large population-based cohorts is challenging and time-consuming. To
Azzurra Invernizzi
added a research item
Connective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modeling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data. This is important since 3T scanners are much more abundant and more often used in clinical research compared to 7T scanners. Therefore in this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans, which were separated by the acquisition of visual field mapping data in 12 healthy participants. Our results show good agreement between RS- and visual field (VF)- based maps using either the standard or Bayesian CF approach. In addition to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter, beta, can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. Moreover, observations obtained using 3T scanners were qualitatively similar to those reported for 7T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies.
Anna Neustaeter
added a research item
Background Early detection of glaucoma is paramount to maintain patients’ eyesight, however glaucomatous vision loss tends to begin in the periphery with up to 50% of patients unaware they are affected. Because glaucomatous vision loss is permanent, screening appears attractive, but currently is not cost-effective. Therefore we aim to investigate the utility of genetic pre-screening for glaucoma in a population-based setting, called EyeLife. Methods EyeLife adopts a double blind prospective design with contrasting groups. Selected participants ( n = 1600) from the Lifelines cohort are 55 years of age or older, and of either the highest or lowest 20% of the genetic risk distribution for glaucoma. We obtained a highly curated list of genetic variants from the literature to obtain each participants’ genetic risk for glaucoma. Participants will undergo comprehensive ophthalmic screening. The primary outcome is the relative risk of glaucoma given a high genetic risk compared to a low genetic risk. Discussion If genetic pre-screening is successful, it will increase the yield of a glaucoma screening program by focusing on high-risk individuals. This, in turn, may improve long-term visual health of middle-aged and elderly people. Trial registration Ethics approval was obtained on January 31, 2019, and the study was retrospectively registered with the Netherlands Trial Register ( NL8718 ) on the 17th of June, 2020.
Hinke Noor Halbertsma
added an update
We are very excited to show you the after movie of EGRET(+)! In this extended program, we trained 25 enthusiastic and intelligent young researchers to become the next generation of glaucoma researchers. The result: a great network of amazing scientists that have shown not only to connect on a scientific but also on a social level. Check out the video below! https://youtu.be/WPz3XLXgq6w
 
Nigus G. Asefa
added 2 research items
Purpose : Genome-wide association studies (GWASs) have identified many genetic loci for glaucoma, which provide a starting point for functional follow-up studies. However, prioritization of the underlying causal genes and identification of their functional characteristics is largely lacking. The study aims to: (i) prioritize the most likely ‘causal’ genes, and (ii) identify underlying biological pathways and functional characteristics of candidate primary open-angle glaucoma (POAG) genes. Methods : We used the results of the most recent and largest GWAS based on 12,315 cases and 227,987 controls of UKB and GERA cohorts. First, we selected independent single nucleotide polymorphisms (SNPs) associated with POAG and performed gene-prioritization analyses based on: i) in-silico sequencing; ii) Data-driven expression prioritized integration for complex traits (DEPICT); iii) Summary statistics-based Mendelian Randomization (SMR); and iv) MetaXcan. Next, based on the resulting prioritized genes, we performed functional and tissue enrichment analysis. We also estimated the gene expression value of the prioritized genes in 10 ocular tissues. Results : In-silico sequencing of 50 independent variants yielded 50 nearest genes and nine non-synonymous linked SNPs (nsSNPs) (r2>0.5) mapping to seven genes. Three of these nsSNPs were found to have deleterious effects. DEPICT prioritized 72 additional genes at a false discovery-corrected (FDR) p-value <0.05. SMR analysis of blood and brain eQTL data, identified 18 genes as the most likely causal genes for POAG (HEIDI test p-value ≥ 2.78x10-3), of which TXNRD2, MVB12B, NR1H3 and LTBP3 were at top hits (p-value ≤7.79x10-8). Furthermore, MetaXcan analysis identified 12 significant genes of which eight showed acceptable evidence of colocalized signals with glaucoma. With 140 prioritized genes, Gene ontology and Ingenuity pathway enrichment analysis revealed 200 and 64 pathways associated with POAG, respectively. Cardiovascular related pathways, including cardiac muscle cell proliferation (GO:0060038), and blood vessel development (GO:0001568), were among the top hits (p-value ≤ 2.16x10-11, FDR ≤1.14x10-7). Glaucoma genes were overrepresented in optic nerve head, trabecular meshwork, genitalia, heart and blood vessel tissues. Conclusions : Our findings may help in understanding the molecular mechanisms underlying glaucoma pathogenesis.
Purpose: We investigated relationship of glaucoma with measurements related to autonomic dysfunction, including heart rate variability (HRV) and blood pressure (BP). Methods: Glaucoma was defined using a questionnaire-based algorithm for 86,841 LifeLines Cohort Study participants. Baseline HRV (root mean square of successive differences [RMSSD]) was calculated from resting electrocardiograms; systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) were oscillometric-based measurements. We used a generalized linear mixed model, adjusted for age, age square, sex, body mass index, and familial relationships to assess the relationship of baseline HRV and BP (continuous and quartiles), hypertension, and antihypertensive medication with glaucoma at follow up (median, 3.8 years). Results: The odds ratio (OR) of glaucoma was 0.95 (95% confidence interval [CI], 0.92-0.99) per unit increase in log-transformed RMSSD (in ms), indicating that autonomous dysfunction (low HRV) is associated with a higher risk of glaucoma. Per 10-mm Hg increase in BP, we found ORs of 1.03 (95% CI, 1.01-1.05; P = 0.015) for SBP, 1.01 (95% CI, 0.97-1.05; P = 0.55) for DBP, 1.03 (95% CI, 1.00-1.06; P = 0.083) for MAP, and 1.04 (95% CI, 1.01-1.07; P = 0.006) for PP. The OR for the lowest versus highest RMSSD quartile was 1.15 (95% CI, 1.05-1.27; P = 0.003). The ORs for the highest versus second quartile were 1.09 (95% CI, 0.99-1.19; P = 0.091) for SBP and 1.13 (95% CI, 1.02-1.24; P = 0.015) for PP. Glaucoma was more common among hypertensives (OR, 1.25; 95% CI, 1.16-1.35; P < 0.001); among those using angiotensin-converting enzyme (ACE) inhibitors (OR, 1.35; 95% CI, 1.18-1.55; P < 0.001); and among those using calcium-channel blockers (OR, 1.19; 95% CI, 1.01-1.40; P = 0.039). Conclusions: Low HRV, high SBP, high PP, and hypertension were associated with glaucoma. Longitudinal studies may elucidate if autonomic dysregulation and high BP also predict glaucoma incidence.
Birte Gestefeld
added a research item
There is a need for simple and effective ways to screen for visual field defects (VFD). Watching a movie is a simple task most humans are familiar with. Therefore we assessed whether it is possible to detect and reconstruct visual field defects based on free viewing eye movements, recorded while watching movie clips. Participants watched 90 movie clips of one minute, with and without simulated visual field defects (sVFD), while their eye movements were tracked. We simulated homonymous hemianopia (HH) (left and right sided) and glaucoma (small nasal arc, large nasal arc, and tunnel vision). We generated fixation density maps of the visual field and trained a linear support vector machine to predict the viewing conditions of each trial of each participant based on these maps. To reconstruct the visual field defect, we computed "viewing priority" maps and maps of differences in fixation density of the visual field of each participant. We were able to classify the simulated visual field condition with more than 85% accuracy. In simulated HH, the viewing priority distribution over the visual field indicated the location of the sVFD in the simulated HH condition. In simulated glaucoma the difference in fixation density to the control condition indicated the location of the sVFD. It is feasible to use natural viewing behavior to screen for and reconstruct (simulated) visual field defects. Movie clip viewing in combination with eye tracking may thus provide an alternative to or supplement standard automated perimetry, in particular in patients who cannot perform the latter technique.
Azzurra Invernizzi
added 2 research items
Previous studies demonstrated that alterations in functional MRI derived receptive field (pRF) properties in cortical projection zones of retinal lesions can erroneously be mistaken for cortical large-scale reorganization in response to visual system pathologies. We tested, whether such confounds are also evident in the normal cortical projection zone of the fovea for simulated peripheral visual field defects. We applied fMRI-based visual field mapping of the central visual field at 3 Tesla in eight controls to compare the pRF properties of the central visual field of a reference condition (stimulus radius: 14°) and two conditions with simulated peripheral visual field defect, i.e., with a peripheral gray mask, stimulating only the central 7° or 4° radius. We quantified, for the cortical representation of the actually stimulated visual field, the changes in the position and size of the pRFs associated with reduced peripheral stimulation using conventional and advanced pRF modeling. We found foveal pRF-positions (≤3°) to be significantly shifted towards the periphery (p<0.05, corrected). These pRF-shifts were largest for the 4° condition [visual area (mean eccentricity shift): V1 (0.9°), V2 (0.9°), V3 (1.0°)], but also evident for the 7° condition [V1 (0.5°), V2 (0.5°), V3 (0.9°)]. Further, an overall enlargement of pRF-sizes was observed. These findings indicate the dependence of foveal pRF parameters on the spatial extent of the stimulated visual field and are likely associated with methodological biases and/or physiological mechanisms. Consequently, our results imply that, previously reported similar findings in patients with actual peripheral scotomas need to be interpreted with caution and indicate the need for adequate control conditions in investigations of visual cortex reorganization.
Background: Eyemate® is a system for the continual monitoring of intraocular pressure (IOP), composed of an intraocular sensor, and a hand-held reader device. As the eyemate®-IO sensor communicates with the hand-held reader telemetrically, some patients might fear that the electronic devices that they use on a daily basis might somehow interfere with this communication, leading to unreliable measurements of IOP. In this study, we investigated the effect of electromagnetic radiation produced by a number of everyday electronic devices on the measurements made by an eyemate®-IO sensor in-vitro, in an artificial and controlled environment. Methods: The eyemate®-IO sensor was suspended in a sterile 0.9% sodium chloride solution and placed in a water bath at 37 °C. The antenna, connected to a laptop for recording the data, was positioned at a fixed distance of 1 cm from the sensor. Approximately 2 hrs of "quasi-continuous" measurements were recorded for the baseline and for a cordless phone, a smart-phone and a laptop. Repeated measures ANOVA was used to compare any possible differences between the baseline and the tested devices. Results: For baseline measurements, the sensor maintained a steady-state, resulting in a flat profile at a mean pressure reading of 0.795 ± 0.45 hPa, with no apparent drift. No statistically significant difference (p = 0.332) was found between the fluctuations in the baseline and the tested devices (phone: 0.76 ± 0.41 hPa; cordless: 0.787 ± 0.26 hPa; laptop: 0.775 ± 0.39 hPa). Conclusion: In our in-vitro environment, we found no evidence of signal drifts or fluctuations associated with the tested devices, thus showing a lack of electromagnetic interference with data transmission in the tested frequency ranges.
Birte Gestefeld
added a research item
My thesis will encompass two main research objectives: (1) Evaluation of eye tracking as a method to screen for visual field defects. (2) Investigating how vision rehabilitation therapy can be improved by employing eye tracking.
Nigus G. Asefa
added a research item
Introduction Glaucoma is the second leading cause of age-related vision loss worldwide; it is an umbrella term that is used to describe a set of complex ocular disorders with a multifactorial aetiology. Both genetic and lifestyle risk factors for glaucoma are well established. Thus far, however, systematic reviews on the heritability of glaucoma have focused on the heritability of primary open-angle glaucoma only. No systematic review has comprehensively reviewed or meta-analysed the heritability of other types of glaucoma, including glaucoma-related endophenotypes. The aim of this study will be to identify relevant scientific literature regarding the heritability of both glaucoma and related endophenotypes and summarise the evidence by performing a systematic review and meta-analysis. Methods and analysis This systematic review will follow the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols 2015 checklist, which provides a standardised approach for carrying out systematic reviews. To capture as much literature as possible, a comprehensive step-by-step systematic search will be undertaken in MEDLINE (PubMed), EMBASE, Web of Science and ScienceDirect, and studies published until 31 December 2017 will be included. Two reviewers will independently search the articles for eligibility according to predefined selection criteria. A database will be used for screening of eligible articles. The quality of the included studies will be rated independently by two reviewers, using the National Health Institute Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. A random-effects model will be used for the meta-analysis. This systematic review is registered with the International Prospective Register of Systematic Reviews with a registration number: CRD42017064504. Ethics and dissemination We will use secondary data from peer-reviewed published articles, and hence there is no requirement for ethics approval. The results of this systematic review will be disseminated through publication in a peer-reviewed scientific journal.
Birte Gestefeld
added a research item
Purpose: To test the usability of eye tracking and virtual reality during vision rehabilitation training of hemianopia patients. Methods: Individuals with hemianopia (n = 13) and normal-sighted controls (n = 4) performed various exercises that are commonly used in vision rehabilitation for mobility, while wearing a head-mounted eye tracker or a head-mounted virtual reality (VR) display. Occupational therapists (n = 4) guided them through the exercises. All participants (including therapists) filled out a questionnaire, assessing their experience with the used device. Individuals with hemianopia were split into three groups according to their stage in vision rehabilitation therapy and performed 1 (beginner), 2 (inter-mediate) or 3 (advanced) different exercises. Results: Individuals with hemianopia rated the mobile eye tracker with a score of 3.97 ± 0.5 points (beginner), 3.8 ± 0.5 points (inter-mediate) and 4 ± 0 points (advanced) the corresponding occupational therapists with a score of 3.6 ± 0.6, 3.4 ± 0.9 and 3.87 ± 0.6 points (out of a maximum of 4 points). The VR headset was rated with 3.9 ± 0.5 points by individuals with hemianopia, 3.8 ± 0.5 points by normal-sighted controls and 2.5 ± 1.4 points by the occupational therapist in a virtual hallway scenario. In a street-crossing scenario, it was rated with 3.7 ± 0.5 points by individuals with hemianopia, 3.7 ± 0.8 points by controls and 2.8 ± 1.2 by occupational therapists. In a walking along a pavement scenario the individual with hemianopia gave 4 ± 0 points and the controls 3.8 ± 0.4 points on average. Conclusions: Both devices were seen as useful additions to vision rehabilitation therapy, as they enable better feedback to patients and the opportunity to do different exercises at different levels of difficulty.
Nigus G. Asefa
added a research item
Purpose : Genome-wide association studies (GWASs) have identi ed many genetic loci for glaucoma, which provide a starting point for functional follow-up studies. However, prioritization of the underlying causal genes and identi cation of their functional characteristics is largely lacking. The study aims to: (i) prioritize the most likely 'causal' genes, and (ii) identify underlying biological pathways and functional characteristics of candidate primary open-angle glaucoma (POAG) genes. Methods : We used the results of the most recent and largest GWAS based on 12,315 cases and 227,987 controls of UKB and GERA cohorts. First, we selected independent single nucleotide polymorphisms (SNPs) associated with POAG and performed gene-prioritization analyses based on: i) in-silico sequencing; ii) Data-driven expression prioritized integration for complex traits (DEPICT); iii) Summary statistics-based Mendelian Randomization (SMR); and iv) MetaXcan. Next, based on the resulting prioritized genes, we performed functional and tissue enrichment analysis. We also estimated the gene expression value of the prioritized genes in 10 ocular tissues. Results : In-silico sequencing of 50 independent variants yielded 50 nearest genes and nine non-synonymous linked SNPs (nsSNPs) (r >0.5) mapping to seven genes. Three of these nsSNPs were found to have deleterious e ects. DEPICT prioritized 72 additional genes at a false discovery-corrected (FDR) p-value <0.05. SMR analysis of blood and brain eQTL data, identi ed 18 genes as the most likely causal genes for POAG (HEIDI test p-value ≥ 2.78x10), of which TXNRD2, MVB12B, NR1H3 and LTBP3 were at top hits (p-value ≤7.79x10). 2-3-8
Konstantinos Pappelis
added 3 research items
Purpose: To determine the intrasession repeatability (test-retest variability) of parafoveal and peripapillary perfused capillary density (PCD) and normalized flux index (NFI) as assessed with Canon OCT-HS100 angiography. Methods: Pairs of optical coherence tomography angiography (OCT-A) images were obtained from the parafoveal and peripapillary region of 30 eyes of 30 healthy subjects. PCD and NFI were calculated using generic image-processing software. Macular ganglion-cell complex thickness (GCC) and peripapillary retinal nerve fiber layer thickness (RNFLT) were also recorded. Bland-Altman analysis was performed and the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) were calculated. Correlations of parafoveal PCD/NFI with GCC and of peripapillary PCD/NFI with RNFLT were also computed. Results: Mean (standard deviation) parafoveal and peripapillary PCD were 40.0% (1.8%) and 44.5% (1.3%), respectively. Corresponding values for NFI were 151.2 (6.8) and 164.2 (3.9). For PCD, ICC was 0.76 for parafoveal and 0.79 for peripapillary measurements; corresponding CoRs were 2.7% and 1.8%. Corresponding values for NFI were 0.62 and 0.67 for ICC and 13.3 and 7.0 for CoR. Average measures ICC was 0.87/0.88 and 0.76/0.80 for the parafoveal/peripapillary PCD and NFI, respectively. PCD and NFI were weakly correlated with GCC (r = 0.39, P = 0.035; r = 0.33, P = 0.077) and moderately correlated with RNFLT (r = 0.43, P = 0.017; r = 0.55, P = 0.002). Conclusions: Repeatability of a commercially available OCT-A with generic image-processing software was good (NFI) to excellent (PCD). Our results indicate that changes surpassing the variability in healthy subjects should be easily detectable in a clinical setting. Translational relevance: Repeatability estimates provide information regarding the relevance of changes in retinal perfusion.
Purpose : Retinal vascular caliber is a potential biomarker of numerous ophthalmic and non-ophthalmic diseases. However, normative values obtained from population studies might not be directly comparable, due to the varying wavelength and optical properties of different instrumentation. This study aimed to test the hypothesis that the choice of imaging technique is a major determinant of vessel diameter estimation. Methods : 71 eyes from 71 ophthalmically healthy individuals (50-65y) were imaged twice with an SLO (Optos 200Tx) and twice with a FC (TRC-NW400), after pupil dilation. Central retinal artery and vein equivalents (CRAE, CRVE) and the arterio-venous ratio (AVR) were measured with the Knudtson-Parr-Hubbard algorithm and the Automated Retinal Image Analyzer (ARIA, Peter Bankhead). Bland-Altman analysis was performed; intra-device coefficients of repeatability (CR) and inter-device limits of agreement (LoA) were reported. Two-way mixed intraclass correlation coefficients (ICCs) for absolute agreement were also calculated. Paired t-tests were performed to assess discrepancies between the SLO and FC measurements. Results : Average (SD) CRAE, CRVE, and AVR values for the SLO were 158 (16) μm, 235 (19) μm, and 0.68 (0.06), respectively, versus 163 (15) μm, 230 (17) μm, and 0.71 (0.06) for the FC. CR for the intra-device SLO measurements were 9 μm (CRAE), 12 μm (CRVE), and 0.04 (AVR), while they were 10 μm, 11 μm, and 0.05 for the FC. LoA for the inter-device comparison were -20 μm to 12 μm (CRAE), -12 μm to 21 μm (CRVE), and -0.08 to 0.02 (AVR). Intra-device ICCs ranged between 0.93 and 0.96 (single measures) and between 0.97 and 0.98 (average measures), for both instruments; inter-device ICCs were 0.85, 0.87, and 0.79 (single measures) and 0.92, 0.93, and 0.88 (average measures) for CRAE, CRVE, and AVR, respectively. The lower CRAE, AVR and higher CRVE values reported by the SLO were highly significant (P<0.0001). Conclusions : These findings indicate that estimation of vascular caliber depends on the imaging modality. Compared to the FC, the SLO underestimates arteries and overestimates veins by 5 μm. These discrepancies could be possibly attributed to varying penetrating levels or to the hemoglobin absorption of different wavelengths. Hence, results among different studies should be interpreted with caution. This is a 2020 ARVO Annual Meeting abstract.
Purpose (1) To mathematically predict retinal vascular resistance and blood flow from minimal input; (2) to validate the model predictions in a healthy population using Laser Speckle Flowgraphy (LSF). Methods Fundus photographs, OCT and OCT‐angiography scans, and systolic/diastolic blood pressure (SBP/DBP) and intraocular pressure (IOP) measurements were performed in 32 healthy subjects. Predicted vascular resistance (PVR) was determined from the central retinal artery and vein equivalents, the fractal dimension of the vasculature, and population‐based hematocrit values, according to the Poiseuille law and an adapted version of the fractal model proposed by Takahashi et al. (2009). Predicted blood flow (PBF) was calculated as OPP/PVR, where OPP is the ocular perfusion pressure. For validation, the mean blur rate (MBR; measure of velocity) of large vessels inside the optic disc and waveform parameters (heart rate [HR], flow acceleration index [FAI], skew, acceleration time index, blowout score and time, fluctuation, rising rate, falling rate [FR]) were recorded by means of LSF. Linear models reduced by the Akaike Information Criterion were used to assess the relationship of PVR and PBF with the LSF parameters. Results In the reduced multivariable model, PVR was higher with higher DBP (p < 0.001), FAI (p < 0.001), and FR (p = 0.042), as well as with lower skew (p < 0.001), MBR (p = 0.001), and fluctuation (p = 0.103). PBF was higher with higher skew (p < 0.001) and MBR (p = 0.040), as well as with lower FAI (p < 0.001) and HR (p = 0.055). The R² of the models was 0.83 and 0.58, respectively. PVR correlated with retinal nerve fiber layer thickness (RNFLT), but not with macular volume (r = −0.53, p = 0.002; r = −0.218, p = 0.23). PBF correlated with macular volume, but not with RNFLT (r = 0.382, p = 0.031; r = 0.326, p = 0.068). Conclusions PVR can be used as a surrogate of vascular resistance. PBF provided a lesser fit with the LSF parameters and partially describes retinal blood flow. Reference Takahashi T, Nagaoka T, Yanagida H, et al. (2009). A mathematical model for the distribution of hemodynamic parameters in the human retinal microvascular network. J Biorheol 23:77‐86
Allison Loiselle
added a research item
The alternative mechanical theory of glaucoma, in which an increased pressure difference across the lamina cribrosa (difference between intraocular and intracranial pressure; IOP and ICP), rather than solely an elevated IOP, leads to structural and functional vision loss, is still controversial. If the theory is true, a drug that simultaneously lowers both the IOP and ICP may be ineffective. The aim of this study was to determine how acetazolamide (AAZ; a drug prescribed in glaucoma that aims to lower the IOP) affects both IOP and ICP in glaucoma patients and to compare the magnitude and time course of the induced pressure changes with those of healthy subjects not taking AAZ. IOP and noninvasive ICP (measured through emissions from the ear) were measured in 20 glaucoma patients taking 125 mg of AAZ twice daily. Measurements were taken for 30 minutes before taking the drug and for 2 hours post-ingestion. Comparisons were made with 13 age-similar controls. After 12 hours with no anti-glaucoma medication, AAZ did not further reduce IOP in glaucoma patients compared to controls (P = 0.58) but did reduce ICP compared to controls (P = 0.035), by approximately 4 mmHg. Our findings suggest that there are periods during the day when the pressure difference across the lamina cribrosa is larger in case of AAZ use. Future studies should focus on improving the noninvasive ICP testing, different doses and dosing schedules of AAZ, and the time course of IOP in glaucoma patients not taking AAZ.
Anna Neustaeter
added 2 research items
To improve upon self-reported glaucoma status in population-based cohorts by developing a questionnaire-based proxy incorporating self-reported status in conjunction with glaucoma-specific visual complaints. A vision specific questionnaire, including questions from the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) was administered to 79,866 Lifelines participants, a population-based cohort study in the Northern Netherlands. We compared NEI-VFQ-25 responses between ‘definite’ glaucoma cases (n = 90; self-reported surgical cases) and an age- and gender-matched subset of controls (n = 1,800) to uncover glaucoma-specific visual complaints, using a case–control logistic regression. We defined ‘probable glaucoma’ as both self-reported disease status and visual complaints, and ‘possible glaucoma’ as either. To evaluate the resulting proxy, we determined age-stratified glaucoma prevalences in the remaining cohort and compared the result to the literature. Per unit increase in the vision subscales (range 0–100) distance, peripheral and low luminance, we observed significantly increased odds of definite glaucoma (2% [P = 0.03], 4% [P = 1.2 × 10⁻⁸] and 2% [P = 0.02], respectively); the associated area under the curve was 0.73. We identified 300 probable and 3,015 (1,434 by self-report) possible glaucoma cases. Standardised prevalences of definite, probable and possible glaucoma for 55+ were 0.4%, 1.1% and 7.3%, respectively. For self-reported glaucoma (combining definite, probable and possible by self-report), this was 5.2%. The combination of self-reported glaucoma status and visual complaints can be used to capture glaucoma cases in population-based settings. The resulting prevalence of combined definite and probable glaucoma (1.5%) appears to be more consistent with previous reports than the prevalence estimate of 5.2% based only on self-report.
Purpose : To obtain the increased risk and additionally explained variance of endophenotypic variants added to a glaucoma genetic risk score, based on a glaucoma meta genome-wide association study (GWAS). Methods : We searched the literature for GWAS for glaucoma and related endophenotypes (intraocular pressure [IOP], central corneal thickness [CCT], and optic disc/cup parameters) in Caucasians. The summary statistics of a large glaucoma meta-GWAS were used to create a weighted glaucoma genetic risk score (GRS); variant effect-sizes were multiplied by genotype dosages and summed within a case-control cohort. Endophenotypic variants were weighted for the glaucoma meta-GWAS effect and subsequently added to the GRS. Cases (n=734) were obtained from the Groningen Longitudinal Glaucoma study, and controls (n=1,418) were obtained from the Groningen Expert Center for Kids with Obesity cohort. Adjusted odds ratios (ORs) per standard deviation increase in genetic risk were calculated, in addition to Nagelkerke’s Pseudo R2 and receiver operating characteristic (ROC) curves. Results : We obtained 47 genome-wide significant variants from the meta-GWAS, 4 additional glaucoma variants, 200 IOP variants, 13 CCT variants, and 4 disc/cup variants, totaling 268 variants of interest. Per standard deviation increase in genetic risk, the OR for glaucoma increased from 1.66, P=6.5*10-25 with glaucoma variants only, to 2.11 P=2.2*10-44 with endophenotypic variants added. The explained variance increased from 7.2% with only glaucoma variants to 14.1% with endophenotypic variants. Associated area under the curves (AUCs) ranged from 63.6% with glaucoma variants to 69.2% with endophenotypic variants added. Conclusions : The addition of endophenotypic variants to a glaucoma genetic risk score increases both the OR and variance explained. The inclusion of all informative variants for glaucoma genetic risk may improve future population-based genetic screening programs.
Allison Loiselle
added 2 research items
Purpose: To determine the association of statins, five classes of antihypertensive medications, and proton pump inhibitors with (1) primary open-angle glaucoma (POAG) progression and (2) conversion of POAG suspects to POAG. Methods: We retrospectively investigated the records of a cohort with POAG cases and suspects from the Groningen Longitudinal Glaucoma Study. To quantify visual field (VF) deterioration in cases, we used the rate of progression of the mean deviation (MD). Suspects were considered to have converted at the time point after which two consecutive VF tests for at least one eye were abnormal (glaucoma hemifield test outside normal limits). Progression and conversion were analyzed with quantile and logistic regression, respectively, with the systemic medications as predictors, controlling for age, sex, body mass index, pretreatment IOP, corneal thickness, and baseline MD. The multivariable models were built with and without IOP intervention. Results: No systemic medications were associated with POAG progression in the final IOP/treatment-adjusted or unadjusted model. However, angiotensin II receptor blockers (ARBs) appeared to slow progression in older patients (b = 0.014, P = 0.0001). Angiotensin-converting enzyme inhibitors (ACEIs) were significantly associated with a decrease in POAG suspect conversion in both the IOP/treatment-adjusted and -unadjusted model (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.07-0.79, P = 0.012; OR=0.24, 95% CI 0.07-0.78, P = 0.021, respectively), as were ARBs (OR 0.12, 95% CI 0.01-0.98, P = 0.014; OR 0.11, 95% CI 0.01-0.87, P = 0.005, respectively). Conclusions: No overall association of VF progression with systemic medication was found; ARBs delayed progression in older patients. ACEIs and ARBs were associated with lower risk of suspect conversion. The pathophysiology of this relationship is to be disentangled.
The purpose of this study was to determine if there is an association between tinnitus and glaucoma. We tested this by first completing a clinic-based cross-sectional questionnaire study in which we sent a series of tinnitus-related questions to glaucoma patients and healthy subjects, and then followed up with a large population-based cross-sectional study in which glaucoma and tinnitus were also assessed by questionnaire. For the clinical study, we received 209 responses from glaucoma patients and 109 responses from healthy subjects (primarily the spouses of the patients). For the population-based study, we evaluated 79,866 participants. Logistic regression models were used to test the relationship between glaucoma and tinnitus; the clinical study analysis was adjusted for age, gender, BMI, hypertension, and diabetes and the population-based study was adjusted for these same variables with the addition of socioeconomic status and subjective hearing loss. For the clinical study, glaucoma patients had an 85% increase in odds for tinnitus (adjusted OR 1.85, 95% CI 1.10 to 3.05). The effect did not depend on pretreatment intraocular pressure, and the associated symptoms were not pulsatile in nature. For the population-based study, glaucoma patients had a 19% increase in odds for tinnitus (adjusted OR 1.19, 95% CI 1.02 to 1.40). Overall, our results suggest that those with glaucoma are more likely to have tinnitus than those without glaucoma. These results provide hypotheses for a mechanism involved in both tinnitus and glaucoma. One possible mechanism could be vascular dysregulation due to impairment of nitric oxide production.
Azzurra Invernizzi
added a research item
The majority of neurons in the human brain process signals from neurons elsewhere in the brain. Therefore, it is critical to have methods that can describe this aspect of the brain’s circuitry. Connective Field (CF) modeling [1] allows characterizing the response of a population of neurons in term of the activity in another part of the brain. It translates the concept of the receptive field into the domain of connectivity by assessing the spatial dependency between signals in distinct cortical visual field areas. The standard CF method does not easily allow estimating parameter uncertainty. This somewhat limits its applicability, in particular when comparing alternative connective field models or studying connective plasticity e.g. in patient groups. To overcome this, we developed a Bayesian framework for the CF model based on Markov Chain Monte Carlo (MCMC) approach to estimate the underlying distribution and uncertainty associated with CF parameters.
Azzurra Invernizzi
added a research item
Purpose: Eyemate is a system for the continual monitoring of intraocular pressure (IOP), comprised of an intraocular sensor, and a hand-held reader device. The eyemate-IO sensor is surgically implanted in the eye during cataract surgery. Once implanted, the sensor communicates telemetrically with the hand-held device to activate and record IOP measurements. The aim of this study was to assess the possible influence of electromagnetic radiation emitted by daily-use electronic devices on the eyemate IOP measurements. Methods: The eyemate-IO sensor was placed in a plastic bag, immersed in a sterile sodium chloride solution at 0.9% and placed in a water bath at 37 C. The antenna, connected to a laptop for recording the data, was positioned at a fixed distance of 1 cm from the sensor. Approximately two hours of quasi-continuous measurements was recorded for the baseline and for cordless phone, smart-phone and laptop. Repeated measures ANOVA was used to compare any possible differences between the baseline and the tested devices. Results: For baseline measurements, the sensor maintained a steady-state. The same behavior was observed with the devices measurements during active and inactive states. Conclusion: We found no evidence of signal drifts or fluctuations associated with the tested devices, thus showing a lack of electromagnetic interference with data transmission. Patients who already have the eyemate-IO sensor implanted, or those considering it, can be informed that the electromagnetic radiation emitted by their daily-use electronic devices does not interfere with IOP measurements made by the eyemate-IO sensor.
Catarina A R João
added a research item
Purpose: Glaucoma affects many aspects of visual performance, including adaptation, and this may depend on ambient luminance. We determine the influence of glaucoma and luminance on temporal aspects of adaptation, specifically on contrast gain control and temporal modulation sensitivity (TMS). Methods: This case-control study included 12 glaucoma patients and 25 age-similar controls (50–70 years). Threshold perimetry was performed with a minimized testing grid (fovea and four peripheral locations). Stimuli (Goldmann size III 50 ms increment/decrement) were presented on a time-varying background with sinusoidally-modulated luminance (amplitude 60%; frequency 0–30 Hz; mean background luminance, 1 and 100 cd/m2). TMS (2.5–30 Hz) was measured in the same locations with a sinusoidally-modulated stimulus (Goldmann size IV, 334 ms) on a steady background (1 and 100 cd/m2). Results: In healthy subjects, contrast sensitivity decreased with increasing background modulation frequency and increased again at very high frequencies, indicating contrast gain control. Minimum sensitivity was located between 2.5 and 20 Hz, depending on luminance and eccentricity. In glaucoma patients, the same frequency dependency was found (P = 0.12) but with an overall reduced sensitivity (P = 1 × 10−5), independent of luminance (P = 0.20). Decrements differentiated better between glaucoma and healthy subjects than increments (P = 0.004). TMS was reduced in glaucoma (P = 5 × 10−6) across all frequencies and luminance levels, with complete loss for high frequencies at 1 cd/m2. Conclusions: Contrast gain control is largely unaffected in glaucoma, suggesting intact amacrine cell function. Perimetry with decrements or a high-frequency stimulus on a low-luminance background seems best to differentiate between glaucoma and healthy subjects.
Allison Loiselle
added a research item
The theory that glaucoma patients have a lower intracranial pressure (ICP) than healthy subjects is a controversial one. The aim of this study was to assess ICP noninvasively by determining the relationship between distortion product otoacoustic emission (DPOAE) phase and body position and to compare this relationship between patients with primary open angle glaucoma (POAG), patients with normal tension glaucoma (NTG), and controls. The relationship was also calibrated using published data regarding invasive measurements of ICP versus body position. DPOAEs were measured in 30 controls and 32 glaucoma patients (17 POAG, 15 NTG) at the following body positions (assuming 90° as upright): 45, 30, 20, 10, 0 (supine), -10, and -20°. DPOAE phase had a clear, nonlinear relationship with body position. The mean DPOAE phase shifts between the two most extreme body positions (45 to -20°) were 73.6, 80.7, and 66.3° for healthy, POAG, and NTG, respectively (P = 0.73), and the groups showed the same, nonlinear behaviour. This indicates that there is no evidence that glaucoma patients have a reduced ICP. When calibrated with invasive data, ICP and DPOAE phase were linearly related over an ICP of 3 mmHg. This suggests that, more broadly, DPOAEs could be used in the future to monitor changes in ICP in a clinical setting and to measure dynamic changes in ICP such as diurnal fluctuations or changes induced by certain medications.
Nigus G. Asefa
added a research item
We have systematically extracted all available heritability (h2) estimates of glaucoma and related endophenotypes from the literature and summarized the evidence by meta-analysis. Glaucoma endophenotypes were classified into 10 clusters: intraocular pressure, anterior chamber size, central corneal thickness, cup-to-disc ratio, disc size, cup size, corneal hysteresis, retinal nerve fiber layer thickness, cup shape, and peripapillary atrophy. Random-effects meta-analyses were performed for each cluster. For clusters with n ≥ 10 h2 estimates, we also performed subgroup and meta-regression analyses. The literature search yielded 53 studies. The h2 of primary open-angle glaucoma ranged from 0.17 to 0.81, and was 0.65 for primary angle-closure glaucoma in a single study. The pooled endophenotype h2 estimates were intraocular pressure, 0.43 (0.38-0.48); anterior chamber size, 0.67 (0.60-0.74); central corneal thickness, 0.81 (0.73-0.87); cup-to-disc ratio, 0.56 (0.44-0.68); disc size, 0.61 (0.37-0.81); cup size, 0.58 (0.35-0.78); corneal hysteresis, 0.40 (0.29-0.51); retinal nerve fiber layer thickness, 0.73 (0.42-0.91); cup shape, 0.62 (0.22-0.90); and peripapillary atrophy, 0.73 (0.70-0.75). We identified mean age, ethnicity, and study design as major sources of heterogeneity. Our results confirm the strong influence of genetic factors on glaucoma and its endophenotypes. These pooled h2 estimates provide the most accurate assessment to date of the total genetic variation that can ultimately be explained by gene-finding studies.
Asterios Chrysou
added a research item
Background Patients with Parkinson's disease experience visual symptoms, partially originating from retinal changes. Since 2011, multiple case-control studies using spectral-domain OCT, which allows for studying individual retinal layers, have been published. The aim of this study was to substantiate the occurrence, extent, and location of retinal degeneration in Parkinson's by meta-analysis. Methods Spectral-domain OCT case-control data were collected by performing a search in PubMed and Embase with terms: “optical coherence tomography” and “parkinson”, up to November 5th 2018. Studies with fewer than 10 patients or controls were excluded. We performed a random effects meta-analysis. Heterogeneity was evaluated with I2 statistics; publication bias with Egger's and Begg's tests. Results Out of 77 identified studies, 36 were included, totaling 1916 patients and 2006 controls. A significant thinning of the peripapillary retinal nerve fiber layer (d = −0.42; 95% confidence interval −0.54 to −0.29) and the combined ganglion cell and inner plexiform layers (d = −0.40; −0.72, to −0.07) was found. The inner nuclear layer and outer plexiform layer did not show significant changes. Heterogeneity ranged from 3 to 92%; no publication bias was found. Conclusions Parkinson's patients show significant thinning of the inner retinal layers, resembling changes found in glaucoma and other neurodegenerative diseases like Alzheimer's. Study of different cell layers in-vivo is possible by moving from time-to spectral domain OCT. Retinal degeneration may be affiliated with neurodegenerative pathology overall, and could serve as a biomarker in neurodegenerative disorders. Longitudinal research including clinical correlations is needed to determine usefulness in Parkinson's disease.
Hinke Noor Halbertsma
added a project goal
EGRET is the training environment for 15 highly talented Early Stage Researchers. The individual and collaborative outputs of their work contribute to the following aims: a) acquiring new, quantitative knowledge on glaucoma and the ageing visual system; and b) applying this new knowledge to boost innovation in glaucoma care in both the public and private sectors.