U-shaped effect of blood pressure on structural OCT metrics and retinal perfusion in ophthalmologically healthy subjects

PURPOSE: We wanted to investigate the association of blood pressure (BP) status with the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thickness of nonglaucomatous eyes and to elucidate whether this effect is related to vascular metrics proxying retinal perfusion. METHODS: For this case-control study, we prospectively included 96 eyes of 96 healthy subjects (age 50–65) from a large-scale population-based cohort in the northern Netherlands (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We measured macular GCIPL and RNFL (mRNFL) and peripapillary RNFL (pRNFL) thicknesses with optical coherence tomography (OCT). We estimated retinal blood flow (RBF), retinal vascular resistance (RVR), and autoregulatory reserve (AR) from quantitative OCT-angiography, fundus imaging, BP, and intraocular pressure. We compared structural and vascular metrics across groups and performed mediation analysis. RESULTS: Compared to controls, GCIPL was thinner in the low BP group (P = 0.013), treated hypertensives (P = 0.007), and untreated hypertensives (P = 0.007). Treated hypertensives exhibited the thinnest mRNFL (P = 0.001), temporal pRNFL (P = 0.045), and inferior pRNFL (P = 0.034). The association of GCIPL thickness with BP was mediated by RBF within the combined low BP group and controls (P = 0.003), by RVR and AR within the combined treated hypertensives and controls (P = 0.001, P = 0.032), and by RVR within the combined untreated antihypertensives and controls (P = 0.022). CONCLUSIONS: Inner retinal thinning was associated with both tails of the BP distribution and with ineffective autoregulation. Longitudinal studies could clarify whether these defects can explain the reported glaucomatous predisposition of these population groups

Retinal Oxygen Delivery and Extraction in Ophthalmologically Healthy Subjects With Different Blood Pressure Status

PURPOSE: To compare retinal oxygen delivery (DO(2)) and oxygen extraction (VO(2)) in ophthalmologically healthy subjects with different blood pressure (BP) status. METHODS: In this case-control study, we prospectively included 93 eyes of 93 subjects (aged 50–65 years) from a Dutch cohort (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We estimated vascular calibers from fundus images and fractal dimension from optical coherence tomography angiography scans. We combined calibers, fractal dimension, BP, and intraocular pressure measurements in a proxy of retinal blood flow (RBF), using a Poiseuille-based model. We measured arterial and venous oxygen saturations (S(a)O(2), S(v)O(2)) with a scanning laser ophthalmoscope. We calculated the DO(2) and VO(2) from the RBF, S(a)O(2), and S(v)O(2). We compared the DO(2) and VO(2) between groups and investigated the DO(2)–VO(2) association. RESULTS: DO(2) and VO(2) were different between groups (P = 0.009, P = 0.036, respectively). In a post hoc analysis, the low BP group had lower DO(2) than the untreated AHT group (P = 4.9 × 10(−4)). The low BP group and the treated AHT group had a lower VO(2) than the untreated AHT group (P = 0.021 and P = 0.034, respectively). There was a significant DO(2)–VO(2) correlation (R(obs) = 0.65, b(obs) = 0.51, P = 2.4 × 10(−12)). After correcting for shared measurement error, the slope was not significant. CONCLUSIONS: The DO(2) and VO(2) were altered in ophthalmologically healthy subjects with different BP status. Future studies could elucidate whether these changes can explain the increased risk of ophthalmic pathologies in those subjects. TRANSLATIONAL RELEVANCE: Understanding the baseline interplay between BP, retinal perfusion, and oxygenation allows for improved evaluation of retinal disease manifestation

Retinal layer thicknesses retrieved with different segmentation algorithms from optical coherence tomography scans acquired under different signal-to-noise ratio conditions

Glaucomatous damage can be quantified by measuring the thickness of different retinal layers. However, poor image quality may hamper the accuracy of the layer thickness measurement. We determined the effect of poor image quality (low signal-to-noise ratio) on the different layer thicknesses and compared different segmentation algorithms regarding their robustness against this degrading effect. For this purpose, we performed OCT measurements in the macular area of healthy subjects and degraded the image quality by employing neutral density filters. We also analysed OCT scans from glaucoma patients with different disease severity. The algorithms used were: The Canon HS-100's built-in algorithm, DOCTRAP, IOWA, and FWHM, an approach we developed. We showed that the four algorithms used were all susceptible to noise at a varying degree, depending on the retinal layer assessed, and the results between different algorithms were not interchangeable. The algorithms also differed in their ability to differentiate between young healthy eyes and older glaucoma eyes and failed to accurately separate different glaucoma stages from each other. (c) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreemen

Retinal layers in Parkinson's disease::A meta-analysis of spectral-domain optical coherence tomography studies

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

Microcirculatory model predicts blood flow and autoregulation range in the human retina:in vivo investigation with laser speckle flowgraphy

In this study, we mathematically predict retinal vascular resistance (RVR) and retinal blood flow (RBF), we test predictions using laser speckle flowgraphy (LSFG), we estimate the range of vascular autoregulation, and we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, optical coherence tomography (OCT), and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained float 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregula tion limits (LARL/HARL), using retinal vessel calibers, fractal dimen- sion, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R-2 =0.77/P = 6.9.10(-9)) and RBF (R-2 =0.65/P = 1.0.10(-6)), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P = 4.0.10(-4)) and GCC (P = 0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies. NEW & NOTEWORTHY We describe and test a new approach to quantify retinal blood flow, based on standard clinical examinations and imaging techniques, linked together with a physiological model. We use these findings to generate individualized estimates of the autoregulation range. We provide evidence that healthy subjects are closer to the lower autoregulation limit than thought before. This suggests that some retinas are less prepared to withstand hypoperfusion, even after small intraocular pressure rises or blood pressure drops

Investigating changes in axonal density and morphology of glaucomatous optic nerves using fixel-based analysis

PURPOSE: To characterize neurodegeneration of glaucomatous optic nerves (ONs) in terms of changes in axonal density and morphology using fixel-based analysis (FBA), a novel framework for analyzing diffusion-weighted MRI (DWI). Furthermore, we aimed to explore the potential of FBA measures as biomarkers of glaucomatous ON degeneration. METHODS: DWI scans were obtained from 15 glaucoma patients and 15 controls. ONs were tracked and segmented into their three anatomical segments; intraorbital (IO), intracanalicular (ICAN) and intracranial (ICRAN). For each segment, FBA measures were computed, which included fiber density (FD; a measure of axonal density), fiber-bundle cross-section (FC; an estimate of morphological changes), and fiber density and cross-section (FDC). Peripapillary retinal nerve fiber layer (pRNFL) thickness and visual field mean deviation (VFMD) were assessed for glaucoma patients. ANCOVA was used to compare FBA values between the two groups, and Spearman's correlation analysis was used to test the correlation between FBA measures and pRNFL thickness and VFMD. RESULTS: All glaucomatous ON segments showed a significant loss of FD and FDC compared to the controls, while a loss of FC was found in the IO and ICRAN segments only. FD and FDC values of the IO and ICAN segments of glaucomatous ONs showed significant correlations with pRNFL thickness and VFMD. CONCLUSIONS: Glaucomatous ONs exhibit lower FD and FC compared to controls, indicating axonal loss and gross atrophy. The correlation between FBA measures of glaucomatous ONs and established clinical tests of glaucoma demonstrates the potential of FBA measures as biomarkers of glaucomatous ON degeneration

Progression of Visual Pathway Degeneration in Primary Open-Angle Glaucoma:A Longitudinal Study

Background: Primary open-angle glaucoma (POAG) patients exhibit widespread white matter (WM) degeneration throughout their visual pathways. Whether this degeneration starts at the pre- or post-geniculate pathways remains unclear. In this longitudinal study, we assess the progression of WM degeneration exhibited by the pre-geniculate optic tracts (OTs) and the post-geniculate optic radiations (ORs) of POAG patients over time, aiming to determine the source and pattern of spread of this degeneration. Methods: Diffusion-weighted MRI scans were acquired for 12 POAG patients and 14 controls at two time-points 5.4 +/- 2.1 years apart. Fiber density (FD), an estimate of WM axonal density, was computed for the OTs and ORs of all participants in an unbiased longitudinal population template space. First, FD was compared between POAG patients and the controls at time-point 1 (TP1) and time-point 2 (TP2) independently. Secondly, repeated measures analysis was performed for FD change in POAG patients between the two time-points. Finally, we compared the rate of FD change over time between the two groups. Results: Compared to the controls, POAG patients exhibited significantly lower FD in the left OT at TP1 and in both OTs and the left OR at TP2. POAG patients showed a significant loss of FD between the time-points in the right OT and both ORs, while the left OR showed a significantly higher rate of FD loss in POAG patients compared to the controls. Conclusions: We find longitudinal progression of neurodegenerative WM changes in both the pre- and post-geniculate visual pathways of POAG patients. The pattern of changes suggests that glaucomatous WM degeneration starts at the pre-geniculate pathways and then spreads to the post-geniculate pathways. Furthermore, we find evidence that the trans-synaptic spread of glaucomatous degeneration to the post-geniculate pathways is a prolonged process which continues in the absence of detectable pre-geniculate degenerative progression. This suggests the presence of a time window for salvaging intact post-geniculate pathways, which could prove to be a viable therapeutic target in the future

Glaucoma in large-scale population-based epidemiology:a questionnaire-based proxy

Purpose: 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. Methods: 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. Results: 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%. Conclusions: 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

Binocular Interactions in Glaucoma Patients With Nonoverlapping Visual Field Defects:Contrast Summation, Rivalry, and Phase Combination

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