Retinal vascular resistance is of interest in glaucoma research, as a potential link between retinal ganglion cell loss and observed phenomena including disrupted vascular autoregulation, altered biomechanical stiffness, and impaired neurovascular coupling. It can now be assessed in vivo, using laser speckle flowgraphy. However, continued progress in the field requires better understanding of its physiology. In this study, we test the hypothesis of homogeneity of vascular resistance indices between regions of the retina: specifically, between superior and inferior hemifields. The resistivity index (maximum flow minus minimum flow, as a proportion of the maximum) and pulsatility index (maximum minus minimum, as a proportion of the mean) were measured in major vessels within the optic nerve head, in the remaining tissue within the optic nerve head, and in peripapillary branch retinal arteries, separated in each case into superior and inferior quadrants. This was performed in 378 eyes of 189 participants with suspected, early or moderate glaucoma; and in 99 eyes of 50 participants without any ocular pathology. In the glaucoma cohort, the resistivity index was on average 9% higher superiorly than inferiorly in vessels within the optic nerve head; 8% higher superiorly in remaining tissue; and 8% higher superiorly in peripapillary vessels (all p < 0.001). The pulsatility index was on average 11% higher superiorly in all three locations (all p < 0.001). Average flow was slightly higher superiorly in major vessels in the nerve head, but higher inferiorly elsewhere. In the healthy control cohort, resistivity index was higher superiorly by 10% in vessels and 8% in tissue within the optic nerve head; pulsatility index was 12% and 10% higher superiorly respectively (all p < 0.001). The fact that these differences were similar between the two cohorts suggests that they are not caused by the disease process. However, it is notable that glaucomatous loss most frequently occurs first in the superior visual field, corresponding with the inferior retina. The finding that vascular resistance indices are consistently higher in the superior retina warrants further investigation, both for its causes and consequences.

Impaired retinal blood flow is associated with ocular diseases such as glaucoma, macular degeneration, and diabetic retinopathy. Among several ocular imaging techniques developed to measure retinal blood flow both invasively and non-invasively, adaptive optics (AO)-enabled scanning laser ophthalmoscopy (AO-SLO) resolves individual red blood cells and provides a high resolution with which to measure flow across retinal microvasculature. However, cross-validation of flow measures remains a challenge owing to instrument and patient-specific variability in each imaging technique. Hence, there is a critical need for a well-controlled clinical flow phantom for standardization and to establish blood-flow measures as clinical biomarkers for early diagnosis. Here, we present the design and validation of a simple, compact, portable, linear flow phantom based on a direct current motor and a conveyor-belt system that provides linear velocity tuning within the retinal microvasculature range (0.5-7 mm/s). The model was evaluated using a sensitive AO-SLO line-scan technique, which showed a <6% standard deviation from the true velocity. Further, a clinical SLO instrument showed a linear correlation with the phantom\'s true velocity (r2 > 0.997). This model has great potential to calibrate, evaluate, and improve the accuracy of existing clinical imaging systems for retinal blood flow and aid in the diagnosis of ocular diseases with abnormal blood flow.

OBJECTIVE: To evaluate retinal blood flow (RBF) regulation in response to RBF stress in maturity-onset diabetes of the young type 3 (MODY3) pigs.
METHODS: Case-control study.
METHODS: MODY3 pigs (diabetes mellitus [DM] group, n = 8) transfected with the human mutant hepatocyte nuclear factor-1⍺ and normal pigs of the same age (normal group, n = 8) were used as subjects. After confirming DM onset, the experiment was performed under inhalation anesthesia with isoflurane at 2 months of age before the cataract progressed. Ocular blood flow was assessed by calculating the optic papillary mean blur rate using laser speckle flowgraphy, modified for pig eye measurements. After baseline ocular blood flow measurements, flicker stimulation (12 Hz, 3 min) was applied, and ocular blood flow was measured over time.
RESULTS: Blood glucose was 81.8 ± 5.1 mg/dL in the normal group and 311.4 ± 23.1 mg/dL in the DM group (mean ± standard error). The percent change in ocular blood flow at 3 min after flicker stimulation was +31.0 ± 10.9% in the normal group and -6.6 ± 6.5% in the DM group compared to the preload value, and the difference was statistically significant (Mann-Whitney test, P = 0.015).
CONCLUSIONS: RBF response to flicker stimulation is reduced at 2 months of age in MODY3 pigs, suggesting that retinal neurovascular coupling is impaired from the early onset of DM.

Retinal oximetry could provide insights into the pathophysiology of optic nerve disease, including optic disc drusen (ODD). Vessel selection for oximetry analysis is based on morphological characteristics of arterioles and venules and supported by an overlay of estimated blood oxygen saturations. The purpose of this cross-sectional study was to determine the validity of this vessel selection procedure by comparing it with vessel selection supported by video fluorescein angiography (FA). The study included 36 eyes of 36 patients with ODD who underwent retinal oximetry (Oxymap retinal oximeter T1) followed by FA (Heidelberg Spectralis). Two trained graders selected vessel segments in a pre-defined measurement area around the optic disc. One of these graders additionally performed the vessel segment selection with the support of FA images. When performed by the same grader, FA-supported and non-FA-supported vessel selection did not lead to significant differences in total vessel segment length, estimated oxygen saturations or vessel diameters (all p > 0.05). Inter-grader differences were found for arterial and venous segment lengths and arterial saturation (p < 0.05). A similar tendency was found for the arteriovenous saturation difference (p = 0.10). In conclusion, identifying vessel segments for retinal oximetry analysis based on vessel morphology and supported by a color-coded saturation overlay appears to be a valid method without the need for invasive angiography. A numerically small inter-grader variation may influence oximetry results. Further studies of retinal oximetry in ODD are warranted.

OBJECTIVE: To assess intra- (repeatability) and inter-observer (reproducibility) variability of laser speckle flowgraphy (LSFG) for retinal blood flow (RBF) measurement in 20 eyes of wild type (C57BL/6J) mice and effect of intravitreal Aflibercept on RBF in optic nerve head (ONH) region of 10 eyes of Ins2 (Akita) diabetic mice.
METHODS: \'Mean blur rate (MBR)\' was measured for all quadrants of tissue area (MT), vessel (MV) and total area (MA) of ONH region. Changes in MT were analysed at each timepoint. Repeatability was evaluated by measuring MBR variability without changing mouse head position, and reproducibility after resetting mouse head position by another operator. Coefficient of repeatability (CR) through Bland-Altman plot method coefficient of variation (COV) and Intraclass correlation coefficient (ICC) was calculated. Intravitreal Aflibercept (1 μg) was administered to Akita eyes and intraocular pressure (IOP) was measured using a tonometer at baseline, day 7, 14, 21 and 28 post-injection. Hurvich and Tsai\'s criterion was used.
RESULTS: Coefficient of repeatability values of repeatability and reproducibility for all quadrants were within limits of agreement. Reliability was excellent (ICC 0.98-0.99) and reproducibility was moderate to excellent (ICC 0.64-0.96). There was a non-significant IOP increase in all Akita eyes at Day 28 (p > 0.05), and significant increase in MT in all quadrants at Day 21 and superior, inferior and temporal quadrants at Day 28 (p < 0.05).
CONCLUSIONS: Laser speckle flowgraphy demonstrates excellent repeatability and moderate to excellent reproducibility in measuring RBF. Intravitreal Aflibercept injection results in a significant increase in MT up to 28 days post-injection without significant increase in IOP.

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UNASSIGNED: The purpose of this study is to identify predictive activation biomarkers in retinal microvascular characteristics of non-exudative macular neovascularization (MNV) and avoid delayed treatment or overtreatment of subclinical MNV. The main objective is to contribute to the international debate on a new understanding of the role of retinal vessel features in the pathogenesis and progression of non-exudative MNV and age-related macular degeneration (AMD). A discussion on revising-related clinical protocols is presented.
UNASSIGNED: In this retrospective study, the authors included eyes with non-exudative MNV, eyes with exudative AMD, and normal eyes of age-matched healthy subjects. The parameters were obtained by optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA).
UNASSIGNED: In total, 21 eyes with exudative AMD, 21 eyes with non-exudative MNV, and 20 eyes of 20 age-matched healthy subjects without retinal pathology were included. Vessel density (VD) of the deep vascular complex (DVC) in eyes with non-exudative MNV was significantly greater than that in eyes with exudative AMD (p = 0.002), while for superficial vascular plexus (SVP) metrics, no VD differences among sectors were observed between eyes with non-exudative MNV and eyes with exudative AMD.
UNASSIGNED: The reduction in retinal vessel density, especially in the DVC, seems to be involved in or be accompanied by non-exudative MNV activation and should be closely monitored during follow-up visits in order to ensure prompt anti-angiogenic therapy. A discussion on applicable clinical protocols is presented aiming to contribute to new insights into ophthalmology service development which is directed to this specific type of patient and diagnosis.

To measure non-invasively retinal venous blood flow (RBF) in healthy subjects and patients with retinal venous occlusion (RVO).
The prototype named AO-LDV (Adaptive Optics Laser Doppler Velocimeter), which combines a new absolute laser Doppler velocimeter with an adaptive optics fundus camera (rtx1, Imagine Eyes®, Orsay, France), was studied for the measurement of absolute RBF as a function of retinal vessel diameters and simultaneous measurement of red blood cell velocity. RBF was measured in healthy subjects (n = 15) and patients with retinal venous occlusion (RVO, n = 6). We also evaluated two softwares for the measurement of retinal vessel diameters: software 1 (automatic vessel detection, profile analysis) and software 2 (based on the use of deep neural networks for semantic segmentation of vessels, using a M2u-Net architecture).
Software 2 provided a higher rate of automatic retinal vessel measurement (99.5 % of 12,320 AO images) than software 1 (64.9 %) and wider measurements (75.5 ± 15.7 μm vs 70.9 ± 19.8 μm, p < 0.001). For healthy subjects (n = 15), all the retinal veins in one eye were measured to obtain the total RBF. In healthy subjects, the total RBF was 37.8 ± 6.8 μl/min. There was a significant linear correlation between retinal vessel diameter and maximal velocity (slope = 0.1016; p < 0.001; r2 = 0.8597) and a significant power curve correlation between retinal vessel diameter and blood flow (3.63 × 10-5 × D2.54; p < 0.001; r2 = 0.7287). No significant relationship was found between total RBF and systolic and diastolic blood pressure, ocular perfusion pressure, heart rate, or hematocrit. For RVO patients (n = 6), a significant decrease in RBF was noted in occluded veins (3.51 ± 2.25 μl/min) compared with the contralateral healthy eye (11.07 ± 4.53 μl/min). For occluded vessels, the slope between diameter and velocity was 0.0195 (p < 0.001; r2 = 0.6068) and the relation between diameter and flow was Q = 9.91 × 10-6 × D2.41 (p < 0.01; r2 = 0.2526).
This AO-LDV prototype offers new opportunity to study RBF in humans and to evaluate treatment in retinal vein diseases.

Optic neuritis, a characteristic feature of multiple sclerosis (MS), involves the inflammation of the optic nerve and the degeneration of retinal ganglion cells (RGCs). Although previous studies suggest that retinal blood flow alterations occur during optic neuritis, the precise location, the degree of impairment, and the underlying mechanisms remain unclear. In this study, we utilized two emerging non-invasive imaging techniques, laser speckle flowgraphy (LSFG) and optical coherence tomography angiography (OCTA), to investigate retinal vascular changes in a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE). We associated these changes with leukostasis, RGC injury, and the overall progression of EAE. LSFG imaging revealed a progressive reduction in retinal blood flow velocity and increased vascular resistance near the optic nerve head in the EAE model, indicating impaired ocular blood flow. OCTA imaging demonstrated significant decreases in vessel density, number of junctions, and total vessel length in the intermediate and deep capillary plexus of the EAE mice. Furthermore, our analysis of leukostasis revealed a significant increase in adherent leukocytes in the retinal vasculature of the EAE mice, suggesting the occurrence of vascular inflammation in the early development of EAE pathology. The abovechanges preceded or were accompanied by the characteristic hallmarks of optic neuritis, such as RGC loss and reduced visual acuity. Overall, our study sheds light on the intricate relationship between retinal vascular alterations and the progression of optic neuritis as well as MS clinical score. It also highlights the potential for the development of image-based biomarkers for the diagnosis and monitoring of optic neuritis as well as MS, particularly in response to emerging treatments.

The Circle of Willis (CoW) is the main collateral system, and its morphological variants are more common in patients who have severe carotid artery stenosis. Earlier data suggest that optical coherence tomography angiography (OCTA) may help to assess the changes in cerebral vascular perfusion by imaging the retinal blood flow. In this single-center prospective clinical study, patients scheduled for carotid endarterectomy (CEA) underwent preoperative computed tomography angiography (CTA) of the extra- and intracranial cerebral circulation. OCTA imaging was performed one week before surgery and postoperatively one month later. The patients were divided into two subgroups based on CTA evaluation of CoW: compromised CoW or non-compromised CoW (containing hypoplastic and normal segments). The effect of the patient\'s age, OCTA scan quality (SQ), CoW morphology, laterality, and surgery on superficial capillary vessel density (VD) in the macula were assessed in multivariable regression models using linear mixed models. We found that VD significantly decreased with aging (-0.12%; 95%CI: -0.07--0.15; p < 0.001) and was significantly higher in patients with non-compromised CoW morphology (by 0.87% 95%CI (0.26-1.50); p = 0.005). After CEA, retinal blood flow significantly improved by 0.71% (95%CI: 0.18-1.25; p = 0.01). These results suggest that in the case of carotid artery occlusion, patients with non-compromised CoW have more preserved ocular blood flow than subjects with compromised CoW due to remodeling of the intra-orbital blood flow. Measuring the retinal blood flow might be used as a relevant and sensitive indicator of collateral cerebrovascular circulation.