Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis.

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

Longitudinal imaging of microvascular remodelling in proliferative diabetic retinopathy using adaptive optics scanning light ophthalmoscopy.

PURPOSE: To characterise longitudinal changes in the retinal microvasculature of type 2 diabetes mellitus (T2DM) as exemplified in a patient with proliferative diabetic retinopathy (PDR) using an adaptive optics scanning light ophthalmoscope (AOSLO). METHODS: A 35-year-old T2DM patient with PDR treated with scatter pan-retinal photocoagulation at the inferior retina 1 day prior to initial AOSLO imaging along with a 24-year-old healthy control were imaged in this study. AOSLO vascular structural and perfusion maps were acquired at four visits over a 20-week period. Capillary diameter and microaneurysm area changes were measured on the AOSLO structural maps. Imaging repeatability was established using longitudinal imaging of microvasculature in the healthy control. RESULTS: Capillary occlusion and recanalisation, capillary dilatation, resolution of local retinal haemorrhage, capillary hairpin formation, capillary bend formation, microaneurysm formation, progression and regression were documented over time in a region 2° superior to the fovea in the PDR patient. An identical microvascular network with same capillary diameter was observed in the control subject over time. CONCLUSIONS: High-resolution serial AOSLO imaging enables in vivo observation of vasculopathic changes seen in diabetes mellitus. The implications of this methodology are significant, providing the opportunity for studying the dynamics of the pathological process, as well as the possibility of identifying highly sensitive and non-invasive biomarkers of end organ damage and response to treatment.

FELLOW EYE CHANGES IN PATIENTS WITH NONISCHEMIC CENTRAL RETINAL VEIN OCCLUSION: Assessment of Perfused Foveal Microvascular Density and Identification of Nonperfused Capillaries.

PURPOSE: Eyes fellow to nonischemic central retinal vein occlusion (CRVO) were examined for abnormalities, which might explain their increased risk for future occlusion, using adaptive optics scanning light ophthalmoscope fluorescein angiography. METHODS: Adaptive optics scanning light ophthalmoscope fluorescein angiography foveal microvascular densities were calculated. Nonperfused capillaries adjacent to the foveal avascular zone were identified. Spectral domain optical coherence tomography, ultrawide field fluorescein angiographies, and microperimetry were also performed. RESULTS: Ten fellow eyes of nine nonischemic CRVO and 1 nonischemic hemi-CRVO subjects and four affected eyes of three nonischemic CRVO and one nonischemic hemi-CRVO subjects were imaged. Ninety percent of fellow eyes and 100% of affected eyes demonstrated at least 1 nonperfused capillary compared with 31% of healthy eyes. Fellow eye microvascular density (35 ± 3.6 mm(-1)) was significantly higher than that of affected eyes (25 ± 5.2 mm(-1)) and significantly lower than that of healthy eyes (42 ± 4.2 mm(-1)). Compared with healthy controls, spectral domain optical coherence tomography thicknesses showed no significant difference, whereas microperimetry and 2/9 ultrawide field fluorescein angiography revealed abnormalities in fellow eyes. CONCLUSION: Fellow eye changes detectable on adaptive optics scanning light ophthalmoscope fluorescein angiography reflect subclinical pathology difficult to detect using conventional imaging technologies. These changes may help elucidate the pathogenesis of nonischemic CRVO and help identify eyes at increased risk of future occlusion.

Outer retinal structure after closed-globe blunt ocular trauma.

PURPOSE: To evaluate outer retinal structural abnormalities in patients with visual deficits after closed-globe blunt ocular trauma. METHODS: Nine subjects with visual complaints after closed-globe blunt ocular trauma were examined between 1 month after trauma and 6 years after trauma. Spectral domain optical coherence tomography was used to assess the outer retinal architecture, whereas adaptive optics scanning light ophthalmoscopy was used to analyze the photoreceptor mosaic integrity. RESULTS: Visual deficits ranged from central scotomas to decreased visual acuity. Spectral domain optical coherence tomography defects included focal foveal photoreceptor lesions, variable attenuation of the interdigitation zone, and mottling of the outer segment band, with one subject having normal outer retinal structure. Adaptive optics scanning light ophthalmoscopy revealed disruption of the photoreceptor mosaic in all subjects, variably manifesting as foveal focal discontinuities, perifoveal hyporeflective cones, and paracentral regions of selective cone loss. CONCLUSION: We observe persistent outer retinal disruption in subjects with visual complaints after closed-globe blunt ocular trauma, albeit to a variable degree. Adaptive optics scanning light ophthalmoscopy imaging allows the assessment of photoreceptor structure at a level of detail not resolvable using spectral domain optical coherence tomography or other current clinical imaging tools. Multimodal imaging seems to be useful in revealing the cause of visual complaints in patients after closed-globe blunt ocular trauma. Future studies are needed to better understand how photoreceptor structure changes longitudinally in response to various traumas.

Imaging vitreous cortex hyalocyte response to paracentral acute middle maculopathy (PAMM) using En Face OCT.

INTRODUCTION: Vitreous cortex hyalocytes (VCH) are resident macrophage cells that provide immunosurveillance, respond to tissue injury and inflammation, and help maintain the transparency of the media. In this case report we demonstrate the use of en face optical coherence tomography (OCT) to image VCH in vivo in a patient presenting with PAMM secondary to antiphospholipid syndrome. CASE DESCRIPTION: A 38-year-old female with no known medical history presented with complaints of visual disturbances in the right eye. OCT revealed hyperreflective bands in the IPL and INL nasal to the fovea. A diagnosis of PAMM was made. Work-up revealed elevated titers of antiphospholipid antibodies. En face OCT revealed a decline in the inflammatory activation over a seven-month period as evidenced by changes in VCH distribution and morphology. CONCLUSIONS: Our findings suggest that monitoring changes in the distribution and morphology of VCH could have a potential clinical utility for assessing disease severity, predicting recovery, and early recognition of treatment response in various inflammatory ocular pathologies such as PAMM.

Modified Endolaser Instrument for Chandelier Scleral Buckling.

Purpose: To report a new modification of an illuminated endolaser to facilitate safe endophotocoagulation during chandelier-assisted scleral buckling surgery. Methods: This case series comprised phakic patients with rhegmatogenous retinal detachments (RRDs) who had primary scleral buckling with chandelier endoillumination, external drainage, and endophotocoagulation using the modified endolaser instrument. Results: All 6 patients had successful outcomes after primary scleral buckling for RD repair without significant intraoperative or postoperative complications. Conclusions: The new modified endolaser instrument can be safely used in a nonvitrectomized eye during chandelier scleral buckling.

Retinal Surface Macrophage Changes in Thyroid Eye Disease before and after Treatment with Teprotumumab.

Retinal surface macrophages play key roles in the regulation of immune response, maintenance of vitreous clarity, and tissue repair. We examined the variation of parafoveal surface macrophages in a thyroid eye disease (TED) patient before and after treatment with teprotumumab (Tepezza, Horizon therapeutics). Pre- and posttreatment parafoveal surface macrophages were imaged using clinical en face OCT, and their density was assessed using a novel cell density mapping technique. Pretreatment, surface macrophage cell density was high. Macrophages had a nonuniform spatial distribution, and their appearance was round with few protrusions, consistent with an "activated" state. Posttreatment, cell density decreased. The macrophages were regularly spaced and had a ramified appearance and filopodia-like processes, consistent with a "quiescent" state. Surface macrophage density decreased as the Clinical Activity Score (CAS) decreased with teprotumumab treatment, suggesting a potential association of these cells with an underlying intraocular and retinal inflammatory process previously not described in TED.

3-D OCT angiographic evidence of Anti-VEGF therapeutic effects on retinal capillary hemangioma.

PURPOSE: To report the impact of intravitreal anti-vascular endothelial growth factor (VEGF) therapy on a retinal capillary hemangioma (RCH) using clinical OCT angiography (OCT-A) in addition to standard imaging modalities. OBSERVATIONS: A 25-year-old male patient with Von Hippel-Lindau (VHL) disease presented with a history of bilateral RCH. No view was present in the right eye. Examination of the left eye revealed six peripheral RCH, the smallest of which was temporal to the macula with active exudation. This RCH was thought to be the source of cystoid macular edema (CME) involving the fovea, and therefore, the source of vision decline. 11 injections of 1.25mg of Bevacizumab EA across 14-month was given. Comparison of the pre- and post-treatment OCT-A at the temporal RCH showed a reduction of CME and regression of RCH. CONCLUSION: Anti-VEGF therapy appeared to stabilize the visual acuity and produce partial regression of RCH. It offers a safe option when visual acuity is threatened. OCT and OCT-A have the ability to document the impact of antiangiogenic therapy on RCH. 3D renderings of OCT-A offer enhanced sensitivity to recognition of structural and functional changes of RCH which may prove useful for monitoring treatment response.

Insights into Sickle Cell Disease through the Retinal Microvasculature: Adaptive Optics Scanning Light Ophthalmoscopy Correlates of Clinical OCT Angiography.

Purpose: Clinical OCT angiography (OCTA) of the retinal microvasculature offers a quantitative correlate to systemic disease burden and treatment efficacy in sickle cell disease (SCD). The purpose of this study was to use the higher resolution of adaptive optics scanning light ophthalmoscopy (AOSLO) to elucidate OCTA features of parafoveal microvascular compromise identified in SCD patients. Design: Case series of 11 SCD patients and 1 unaffected control. Participants: A total of 11 eyes of 11 SCD patients (mean age, 33 years; range, 23-44; 8 female, 3 male) and 1 eye of a 34-year-old unaffected control. Methods: Ten sequential 3 × 3 mm parafoveal OCTA full vascular slab scans were obtained per eye using a commercial spectral domain OCT system (Avanti RTVue-XR; Optovue). These were used to identify areas of compromised perfusion near the foveal avascular zone (FAZ), designated as regions of interest (ROIs). Immediately thereafter, AOSLO imaging was performed on these ROIs to examine the cellular details of abnormal perfusion. Each participant was imaged at a single cross-sectional time point. Additionally, 2 of the SCD patients were imaged prospectively 2 months after initial imaging to study compromised capillary segments across time and with treatment. Main Outcome Measures: Detection and characterization of parafoveal perfusion abnormalities identified using OCTA and resolved using AOSLO imaging. Results: We found evidence of abnormal blood flow on OCTA and AOSLO imaging among all 11 SCD patients with diverse systemic and ocular histories. Adaptive optics scanning light ophthalmoscopy imaging revealed a spectrum of phenomena, including capillaries with intermittent blood flow, blood cell stasis, and sites of thrombus formation. Adaptive optics scanning light ophthalmoscopy imaging was able to resolve single sickled red blood cells, rouleaux formations, and blood cell-vessel wall interactions. OCT angiography and AOSLO imaging were sensitive enough to document improved retinal perfusion in an SCD patient 2 months after initiation of oral hydroxyurea therapy. Conclusions: Adaptive optics scanning light ophthalmoscopy imaging was able to reveal the cellular details of perfusion abnormalities detected using clinical OCTA. The synergy between these clinical and laboratory imaging modalities presents a promising avenue in the management of SCD through the development of noninvasive ocular biomarkers to prognosticate progression and measure the response to systemic treatment.

Efficacy of CRISPR-Based Gene Editing in a Sickle Cell Disease Patient as Measured through the Eye.

Sickle cell disease (SCD) exists on a phenotypic spectrum with variable genetic expressivity, making it difficult to assess an individual patient's risk of complications at any particular point in time. Current and emerging SCD treatments, including CRISPR-based gene editing, result in a variable proportion of affected red blood cells (RBCs) still vulnerable to sickling. Clinical serological indicators of disease such as hemoglobin, indirect bilirubin, and reticulocyte count and clinical metrics including number of emergency department visits and hospitalizations over time often fall short in their ability to objectively quantify ischemic disease activity and efficacy of treatments. Clearly, better clinical biomarkers are needed. The rapidly developing field of oculomics leverages the transparent nature of the ocular tissue to directly study the retinal microvasculature in order to characterize the status of systemic diseases. In this case report, we demonstrate the ability of optical coherence tomography angiography (OCT-A) to detect and measure micro-occlusive events within the retinal capillary bed before and after RBC exchange transfusion and following CRISPR-based gene editing, as an indicator of systemic ischemic disease activity and measure of treatment efficacy. The implications of these findings are discussed.

Hemi- and Central Retinal Vein Occlusion Associated with COVID-19 Infection in Young Patients without Known Risk Factors.

PURPOSE: Venous thromboembolic complications have been reported in association with coronavirus disease 2019 (COVID-19) infection. We raised awareness regarding a potential temporal association between COVID-19 infection and retinal vein occlusion (RVO). DESIGN: Multicenter, retrospective, nonconsecutive case series. SUBJECTS: Patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection, were included. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. METHODS: This was a multicenter, retrospective, nonconsecutive case series including patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. MAIN OUTCOME MEASURES: Ophthalmic findings, including presenting and final visual acuity (VA), imaging findings, and clinical course. RESULTS: Twelve eyes of 12 patients with CRVO (9 of 12) or HRVO (3 of 12) after COVID-19 infection were included. The median age was 32 years (range, 18-50 years). Three patients were hospitalized, but none were intubated. The median time from COVID-19 diagnosis to ophthalmic symptoms was 6.9 weeks. The presenting VA ranged from 20/20 to counting fingers, with over half (7 of 12) having a VA of ≥20/40. OCT revealed macular edema in 42% of the eyes; of these, 80% (4 of 5) were treated with anti-VEGF injections. Ninety-two percent (11 of 12) had partial or complete resolution of ocular findings at final follow-up. Four eyes (33%) had retinal thinning, as determined using OCT, by the end of the study interval. The final VA ranged from 20/20 to 20/60, with 11 of the 12 (92%) eyes achieving a VA of ≥20/40 at a median final follow-up period of 13 weeks (range, 4-52 weeks). CONCLUSIONS: Although we acknowledge the high seroprevalence of COVID-19 and that a causal relationship cannot be established, we reported this series to raise awareness regarding the potential risk of retinal vascular events due to a heightened thromboinflammatory state associated with COVID-19 infection.

A Pilot Study of Subclinical Non-Capillary Peripapillary Perfusion Changes in Thyroid-Related Orbitopathy Detected Using Optical Coherence Tomography Angiography.

Purpose: Hemodynamic changes surrounding the optic nerve head are known to occur in thyroid-related orbitopathy (TRO). This pilot study explores the capillary and non-capillary peripapillary perfusion changes of the retina in TRO eyes without dysthyroid optic neuropathy (DON) using optical coherence tomography angiography (OCT-A). Methods: Non-capillary and capillary peripapillary perfusion densities were calculated using single 4.5 × 4.5mm en face "RPC layer" OCT-A scans of 8 TRO patients without DON (8 eyes, mean age 40.6 years, range 23-69 years). Results were compared to a previously published dataset of 133 healthy controls (133 eyes, mean 41.5 years, range 11-83 years). The strength of association was measured between OCT-A perfusion densities and clinical measures of TRO. Results: Non-capillary peripapillary perfusion density in TRO eyes was found to be significantly decreased compared to healthy controls (TRO group 15.4 ± 2.9% vs controls 21.5 ± 3.1%; p < 0.0001). Capillary peripapillary perfusion densities showed no significant difference (TRO group 42.5 ± 1.8% vs controls 42.5 ± 1.5%; p = 1.0). Clinical measures of disease did not correlate well with OCT-A perfusion densities (p>0.05). Conclusion: These findings may represent decreased blood flow and subclinical ischemia to the optic nerve. We discuss possible pathogenic mechanisms of thyroid-related vasculopathy, including vessel wall thickening due to immunologically-induced media enlargement.

Quantification of intermittent retinal capillary perfusion in sickle cell disease.

Pathophysiology of sickle cell disease (SCD) features intermittent vaso-occlusion of microcirculatory networks that facilitate ischemic damage. Past research has, however, relied on static images to characterize this active disease state. This study develops imaging metrics to more fully capture dynamic vascular changes, quantifying intermittent retinal capillary perfusion in unaffected controls and SCD patients using sequential optical coherence tomography angiography (OCT-A) scans. The results reveal significant dynamic variation of capillary perfusion in SCD patients compared to controls. This measurement of vaso-occlusive burden in patients would provide utility in monitoring of the disease state and in evaluating treatment efficacy.

Acute Vitreous and Intraretinal Hemorrhage with Multifocal Subretinal Fluid in Juvenile X-Linked Retinoschisis.

PURPOSE: To report a rare case of spontaneous vitreous and intraretinal hemorrhage in a patient with juvenile X-linked retinoschisis which was managed conservatively. METHODS: Single patient case report. INTRODUCTION: Juvenile X-linked retinoschisis (JXLR) most often occurs as a result of a genetic defect in the retinoschisin (RS1) gene, causing a separation between the ganglion cell layer and the nerve fiber layer. Spontaneous vitreous hemorrhage has been reported as an uncommon secondary consequence of JXLR. We present a case of spontaneous vitreous and diffuse macular intraretinal hemorrhages in a patient with JXLR which resolved with medical management alone. RESULTS: A 23-year-old man with a history of juvenile X-linked retinoschisis presented to the ophthalmic emergency room complaining of acute onset of floaters in his right eye. On examination, the patient was found to have a new vitreous hemorrhage with diffuse intraretinal hemorrhages in his right eye, without new retinal tears or detachment. SD-OCT demonstrated multifocal pockets of subretinal fluid. The genetic testing panel revealed a hemizygous mutation in the RS-1 gene. He was managed conservatively on oral acetazolamide, with the resolution of the subretinal fluid and with both visual and symptomatic improvement. CONCLUSIONS: Spontaneous vitreous hemorrhage may rarely occur in patients with JXLR, even in the absence of acute retinal tear or detachment. This case demonstrates an atypical presentation of vitreous hemorrhage with diffuse intraretinal hemorrhage and new multifocal areas of subretinal fluid which improved without surgical intervention. Good outcomes may be achieved in these patients with conservative management alone, even in atypical presentations.

Novel Development of Parafoveal Capillary Density Deviation Mapping using an Age-Group and Eccentricity Matched Normative OCT Angiography Database.

PURPOSE: We evaluate the impact of age and signal strength index (SSI) on foveal avascular zone (FAZ) metrics and parafoveal capillary density measured using optical coherence tomography angiography (OCT-A), and propose a deviation mapping approach that accounts for age-group, SSI, eccentricity, and variation in FAZ size. METHODS: Parafoveal OCT-A with full vascular layer was obtained for 261 controls and four patients with retinal abnormalities. Parafoveal capillary densities were measured within eight consecutive 200-µm wide annuli from the FAZ border. In controls, the impacts of age and SSI on FAZ metrics and parafoveal capillary density were evaluated. Deviation maps highlighting regions with density at the lower and upper tails of the age-group and eccentricity matched distribution were generated. RESULTS: Linear regressions showed significant correlations between age, SSI, and mean parafoveal capillary density. There was a significant difference in FAZ metrics and parafoveal capillary densities with different age groups after controlling for SSI using univariate analysis. However, the effect of age on parafoveal capillary density disappeared after controlling for SSI using multivariate linear regression analysis. Our deviation mapping approach was able to identify regions with abnormal density in four patients. CONCLUSIONS: Our findings suggest that the relationship between parafoveal capillary density and age is confounded by SSI. Parafoveal capillary density is SSI- and eccentricity-dependent. An age-group and eccentricity matched normative database was used as the basis for a parafoveal capillary density deviation mapping technique, providing an intuitive way to assess the status of parafoveal capillary density in individual eyes. TRANSLATIONAL RELEVANCE: Understanding the impact of age and SSI on parafoveal capillary density is critical for providing accurate interpretation of OCT-A. We demonstrate an age-group and eccentricity matched deviation mapping technique for an intuitive assessment of retinal regions with abnormal density.

Earliest Evidence of Preclinical Diabetic Retinopathy Revealed Using Optical Coherence Tomography Angiography Perfused Capillary Density.

PURPOSE: To compare perfused capillary density (PCD) in diabetic patients and healthy controls using optical coherence tomography angiography (OCTA). METHODS: Forty controls, 36 diabetic subjects without clinical retinopathy (NoDR), 38 with nonproliferative retinopathy (NPDR), and 38 with proliferative retinopathy (PDR) were imaged using spectral-domain optical coherence tomography. A 3 × 3-mm full-thickness parafoveal OCTA scan was obtained from each participant. Following manual delineation of the foveal avascular zone (FAZ), FAZ area, perimeter, and acircularity index were determined. Seven consecutive equidistant 200-µm-wide annular segments were drawn at increasing eccentricities from the FAZ margin. Annular PCD (%) was defined as perfused capillary area divided by the corresponding annulus area after subtraction of noncapillary blood vessel areas. Nonparametric Kruskal-Wallis testing with Bonferroni correction was performed in pairwise comparisons of group PCD values. RESULTS: The NoDR group demonstrated consistently higher PCD compared to the control group in all 7 annuli, reaching statistical significance (36.6% ± 3.30% vs 33.6% ± 3.98%, P = .034) at the innermost annulus (FAZ margin to 200 µm out). The NPDR and PDR groups demonstrated progressively decreasing PCD. Differences in FAZ metrics between the NoDR and control groups did not reach statistical significance. CONCLUSIONS: Relative to healthy controls, increased PCD values in the NoDR group likely represent an autoregulatory response to increased metabolic demand, while the decrease in PCD that follows in NPDR and PDR results largely from an incremental loss of capillary segments. These findings, consistent with previous studies, demonstrate the potential of OCTA as a clinical tool for earlier objective detection of preclinical diabetic retinopathy. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Noninvasive Detection of Mitochondrial Dysfunction in Ocular Hypertension and Primary Open-angle Glaucoma.

PURPOSE: To assess mitochondrial dysfunction in vivo in ocular hypertension (OHT) and primary open-angle glaucoma (POAG) using retinal metabolic analysis. PATIENTS AND METHODS: This was an observational, cross-sectional study performed from November 2015 to October 2016 at the New York Eye and Ear Infirmary of Mount Sinai. Thirty-eight eyes with varying stages of POAG, 16 eyes with OHT, and 32 control eyes were imaged on a custom fundus camera modified to measure full retinal thickness fluorescence at a wavelength optimized to detect flavoprotein fluorescence (FPF). Optical coherence tomography was used to measure the retinal ganglion cell-plus layer (RGC+) thickness. Macular FPF and the ratio of macular FPF to RGC+ thickness were the primary outcome variables and were compared among the three groups using an age-adjusted linear regression model. A mixed-effects model was used to assess correlations between FPF variables and clinical characteristics. RESULTS: Both macular FPF and the macular FPF/RGC+ thickness ratio were significantly increased in OHT compared with control eyes (P<0.05 and <0.01, respectively). In POAG eyes, macular FPF was not significantly increased compared with controls (P=0.24). However, the macular FPF/RGC+ thickness ratio in POAG eyes was significantly increased compared with controls (P<0.001). FPF was significantly correlated to age in POAG eyes. CONCLUSIONS: Despite lacking clinical evidence of glaucomatous deterioration, OHT eyes displayed significantly elevated macular FPF, suggesting that mitochondrial dysfunction may be detected before structural changes visible on current clinical imaging. Our preliminary results suggest that macular FPF analysis may prove to be a useful tool in assessing and evaluating OHT and POAG eyes.

A method for age-matched OCT angiography deviation mapping in the assessment of disease- related changes to the radial peripapillary capillaries.

PURPOSE: To present a method for age-matched deviation mapping in the assessment of disease-related changes to the radial peripapillary capillaries (RPCs). METHODS: We reviewed 4.5x4.5mm en face peripapillary OCT-A scans of 133 healthy control eyes (133 subjects, mean 41.5 yrs, range 11-82 yrs) and 4 eyes with distinct retinal pathologies, obtained using spectral-domain optical coherence tomography angiography. Statistical analysis was performed to evaluate the impact of age on RPC perfusion densities. RPC density group mean and standard deviation maps were generated for each decade of life. Deviation maps were created for the diseased eyes based on these maps. Large peripapillary vessel (LPV; noncapillary vessel) perfusion density was also studied for impact of age. RESULTS: Average healthy RPC density was 42.5±1.47%. ANOVA and pairwise Tukey-Kramer tests showed that RPC density in the ≥60yr group was significantly lower compared to RPC density in all younger decades of life (p<0.01). Average healthy LPV density was 21.5±3.07%. Linear regression models indicated that LPV density decreased with age, however ANOVA and pairwise Tukey-Kramer tests did not reach statistical significance. Deviation mapping enabled us to quantitatively and visually elucidate the significance of RPC density changes in disease. CONCLUSIONS: It is important to consider changes that occur with aging when analyzing RPC and LPV density changes in disease. RPC density, coupled with age-matched deviation mapping techniques, represents a potentially clinically useful method in detecting changes to peripapillary perfusion in disease.

Genetic variance contributes to naltrexone-induced inhibition of sucrose intake in inbred and outbred mouse strains.

The study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid receptor-deficient or lacking either pre-pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01-5 mg/kg) and time-dependent (5-120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid "floor effects" of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5-36.5 fold range of greater effects in the ID(50) of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35-40%) in 129P3/J and SJL/J mice, moderate ( approximately 50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70-80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.

Peripapillary perfused capillary density in primary open-angle glaucoma across disease stage: an optical coherence tomography angiography study.

AIMS: To assess peripapillary perfused capillary density (PCD) in primary open-angle glaucoma (POAG) across stage of disease. METHODS: In this observational, cross-sectional study, 60 eyes with varying stages of POAG and 24 control eyes were imaged on a spectral domain optical coherence tomography angiography system (AngioVue, Optovue, Fremont, California, USA) generating images centred on the optic nerve head. Major blood vessels were removed using custom automated software. PCD was calculated as a percentage as the ratio of pixels associated with perfused capillaries to the total number of pixels in the corresponding region-of-interest (ROI). Analysis of covariance was used to compare PCD among the subject groups and control for possible covariates. Area under the receiver operating characteristic curve (AROC) and sensitivity at 95% specificity were calculated to assess the capability of PCD to distinguish mild glaucoma from control. The Pearson's product-moment correlation coefficient was used to assess correlations between PCD and circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and visual field mean deviation (MD). RESULTS: PCD demonstrated a progressive stepwise decrease from control eyes throughout worsening POAG stage at all ROIs. PCD demonstrated AROC and sensitivity values comparable to cpRNFLT and visual field parameters and exhibited significant correlations with cpRNFLT and MD at all corresponding ROIs. CONCLUSIONS: PCD displayed significant correlations with morphological and functional indices and exhibited diagnostic capabilities comparable to currently employed clinical variables. Our preliminary results suggest that PCD analysis may prove to be a useful tool in monitoring POAG across stage and identifying early POAG.