Retinal Blood Flow Research Articles

Effects of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms on Retinal Tissue Perfusion in Mild Diabetic Retinopathy Patients Receiving the Medical Food, Ocufolin®.

We evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on retinal tissue perfusion in patients with mild diabetic retinopathy (DR + PM) taking the medical food, Ocufolin®, for 6 months. Prospective, case-controlled study. Eight early diabetic retinopathy patients with common reduced function MTHFR polymorphisms (DR+PM) and 15 normal controls (NC) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The medical food is intended to address ocular ischemia with high doses of vitamin B-complexes and antioxidants, including L-methylfolate, methylcobalamin, zinc, copper, lutein, vitamins C, D, E, and n-acetylcysteine. The subjects were provided with a medical food for a period of 6 months. BCVA and vascular indices of DR + PM patients at baseline were initially below those of NC and improved after medical food. Compared to baseline, DR + PM patients after the medical food had significantly improved BCVA during the follow-up period (P < 0.05). In comparison, overall RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05). The changes varied with MTHFR subtypes. In patients with the C677T and the C677T/A1298C compound mutations, RTP was increased at 6 months as compared to that at baseline and 4 months (P < 0.05). In patients with only the A1298C mutation, all microcirculation metrics were increased from baseline at 4 and 6 months, but with less improvement at 6 months than at 4 months (P < 0.05). Medical food was effective in improving both visual acuity and retinal tissue perfusion in DR + PM patients. The degree of improvement of retinal microcirculation varied among MTHFR subtypes.

Analysis of Blood Flow in the Macula and Optic Nerve Head in Healthy Young Volunteers Using Laser Speckle Flowgraphy.

To assess optic nerve head (ONH) and macular blood flow in young healthy volunteers using laser speckle flowgraphy (LSFG). This is a prospective single-center study conducted at the Department of Ophthalmology, University Hospital Zurich from May to November 2021. Young, healthy men aged ≥ 18 years without ocular or systemic diseases were included. A corrected visual acuity (VA) of 0.0 logMAR or better in both eyes and an intraocular pressure (IOP) of 21 mmHg or lower were required for inclusion. Subjects exceeding a spherical equivalent (SE) of ± 6 diopters (dpt) were excluded. Blood flow in the macula and the ONH was recorded using the Nidek LSFG RetFlow device (Nidek Company, Ltd., Hirioshi-cho, Japan). Laser power was set to 0.5 Millivolts (mV). Mean blur rate (MBR) was recorded as a parameter for blood flow. MBR is a calculated parameter that represents relative blood flow velocity correlated with the real anatomical blood flow rate. Colored heat maps of the recorded retinal area were generated automatically by the RetFlow device. Final analyses included 83 eyes of 43 male volunteers. Mean age was 21.9 years (SD ± 1.5, range: 20 to 29). Mean corrected VA was - 0.1 logMAR (SD ± 0.05, range: - 0.2 to 0.0), mean IOP was 15.4 mmHg (SD ± 2.5, range: 8.5 to 18.5), and mean SE was - 0.3 dpt (SD ± 1.2, range: - 5.0 to 1.2). Mean ONH MBR was 37.44 (SD ± 7.9, range: 22.5 to 53.5) and mean macular MBR was 27.8 (SD ± 9.7, range: 6.4 to 57.7). Pearson's Test showed a strong correlation between macular and papillary blood flow (p < 0.05, coefficient: 0.647). This study provides both ONH and macular blood flow data in a healthy young male population, showing a strong correlation between ONH and macular blood flow in the examined eyes. Further investigations are required to assess the validity of MBR as a parameter for the combined evaluation of retinal blood flow at the macula and ONH in healthy volunteers and patients with various diseases.

TRPV4 channels promote vascular permeability in retinal vascular disease

This study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4), a calcium (Ca2+)-permeable cation channel, in the pathophysiology of retinal vascular disease. The retinal vein occlusion (RVO) murine model was created by irradiating retinal veins using lasers. TRPV4 expression and localization were evaluated in RVO mice retinas. In addition, we examined the effects of TRPV4 antagonists (RQ-00317310, HC-067047, GSK2193874, and GSK2798745) on retinal edema, blood flow, and ischemic areas in RVO mice. Furthermore, changes in the retinal expression of tumor necrosis factor (TNF)-α and aquaporin4 (AQP4) by RQ-00317310 were analyzed using Western blot. We also assessed the barrier integrity of epithelial cell monolayers using trans-endothelial electrical resistance (TEER) in Human Retinal Microvascular Endothelial Cells (HRMECs). The expression of TRPV4 was significantly increased and co-localized with glutamine synthetase (GS), a Müller glial marker, in the ganglion cell layer (GCL) of the RVO mice. Moreover, RQ-00317310 administration ameliorated the development of retinal edema and ischemia in RVO mice. In addition, the up regulation of TNF-α and down-regulation of AQP4 were lessened by the treatment with RQ-00317310. Treatment with GSK1016790A, a TRPV4 agonist, increased vascular permeability, while RQ-00317310 treatment decreased vascular endothelial growth factor (VEGF)- or TRPV4-induced retinal vascular hyperpermeability in HRMECs. These findings suggest that TRPV4 plays a role in the development of retinal edema and ischemia. Thus, TRPV4 could be a new therapeutic target against the pathological symptoms of retinal vascular diseases.

Relationship Between Retinal Microcirculation and Renal Function in Patients with Diabetes and Chronic Kidney Disease by Laser Speckle Flowgraphy

This study investigated the effect of renal dysfunction categorized by the stage of chronic kidney disease (CKD) on the retinal microcirculation assessed by laser speckle flowgraphy (LSFG) and retinal artery caliber measured by adaptive optics imaging in diabetic patients particularly the early stage of retinopathy and nephropathy. We divided the patients with diabetes into three groups based on the CKD stage (non-CKD (n = 54); CKD stage 1 + 2 (n = 20); CKD stage 3 (n = 41)). The mean blur rate (MBR) of the stage 3 CKD group was significantly lower than that of the no-CKD group (p < 0.015). The total retinal flow index (TRFI) in the stage 3 CKD group was significantly lower than that of the no-CKD group (p < 0.002). Multiple regression analysis demonstrated that CKD stage was independently associated with MBR (β = -0.257, p = 0.031) and TRFI (β = -0.316, p = 0.015). No significant differences were observed in external diameter, lumen diameter, wall thickness, and wall to lumen ratio among the groups. These results indicated that the ONH MBR and TRFI as assessed by LSFG decreases in diabetic patients with stage 3 CKD, but the arterial diameter measured by adaptive optics imaging does not change, suggesting that impaired renal function may be associated with decreased retinal blood flow in early-stage diabetic retinopathy.

Alterations in Retinal Vascularity in Severe Psoriasis

ABSTRACT Purpose To evaluate the changes in retinal vascularity in patients with severe psoriasis. Materials and Methods Patients with severe psoriasis [psoriasis area-severity index (PASI) >10] who did not get any systemic treatment in the last year and do not have any ocular diseases were included. All patients underwent detailed ophthalmological examination, including optical coherence tomography (OCT) and OCT angiography (OCTA). Vessel densities (VD) of Superficial (SCP) and deep (DCP) capillary plexus, foveal avascular zone (FAZ) diameter, central retinal thickness (CRT) were analyzed and compared with age-sex matched healthy adults. Results Fifty-three patients (13 F, 40 M) and 56 controls (16 F, 40 M) were included in the study. VD of SCP (50.4%±3.9 vs. 51.4%±3.2) and DCP (52.6%±6.4 vs. 55.4%±5.7) were lower in psoriasis group compared to controls (p < .05). Presence of psoriatic arthritis was related with an increased CRT (p = .000), larger FAZ and decreased foveal VD in SCP (p = .01, p = .02, respectively). Conclusion Severe psoriasis causes a decrease in retinal blood flow and presence of psoriatic arthritis is related with decreased foveal VD.

Metabolic blood flow regulation in a hybrid model of the human retinal microcirculation

The retinal vascular network supplies perfusion to vital visual structures, including retinal ganglion cells responsible for vision. Impairments in retinal blood flow and oxygenation are involved in the progression of many ocular diseases, including glaucoma. In this study, an established theoretical hybrid model of a retinal microvascular network is extended to include the effects of local blood flow regulation on oxygenation. A heterogeneous representation of the arterioles based on confocal microscopy images is combined with a compartmental description of the downstream capillaries and venules. A Green’s function method is used to simulate oxygen transport in the arterioles, and a Krogh cylinder model is applied to the capillary and venular compartments. Acute blood flow regulation is simulated in response to changes in pressure, shear stress, and metabolism. Model results predict that both increased intraocular pressure and impairment of blood flow regulation can cause decreased tissue oxygenation, indicating that both mechanisms represent factors that could lead to impaired oxygenation characteristic of ocular disease. Results also indicate that the metabolic response mechanism reduces the fraction of poorly oxygenated tissue but that the pressure- and shear stress-dependent response mechanisms may hinder the vascular response to changes in oxygenation. Importantly, the heterogeneity of the vascular network demonstrates that traditionally reported average values of tissue oxygen levels hide significant localized defects in tissue oxygenation that may be involved in disease processes, including glaucoma. Ultimately, the model framework presented in this study will facilitate future comparisons to sectorial-specific clinical data to better assess the role of impaired blood flow regulation in ocular disease.

Methods to measure blood flow and vascular reactivity in the retina.

Disturbances of retinal perfusion are involved in the onset and maintenance of several ocular diseases, including diabetic retinopathy, glaucoma, and retinal vascular occlusion. Hence, knowledge on ocular vascular anatomy and function is highly relevant for basic research studies and for clinical judgment and treatment. The retinal vasculature is composed of the superficial, intermediate, and deep vascular layer. Detection of changes in blood flow and vascular diameter especially in smaller vessels is essential to understand and to analyze vascular diseases. Several methods to evaluate blood flow regulation in the retina have been described so far, but no gold standard has been established. For highly reliable assessment of retinal blood flow, exact determination of vessel diameter is necessary. Several measurement methods have already been reported in humans. But for further analysis of retinal vascular diseases, studies in laboratory animals, including genetically modified mice, are important. As for mice, the small vessel size is challenging requiring devices with high optic resolution. In this review, we recapitulate different methods for retinal blood flow and vessel diameter measurement. Moreover, studies in humans and in experimental animals are described.

Effect of silicone oil on retinal microcirculation after vitrectomy for rhegmatogenous retinal detachment evaluated by OCT angiography: a literature review.

Silicone oil (SO) has been widely used as intravitreal tamponade agent for rhegmatogenous retinal detachment (RRD) and has been occasionally associated with incomplete retinal structural and functional recovery. The use of Optical Coherence Tomography Angiography (OCT-A) has recently attracted significant attention for detailed analysis of retinal capillary plexus and blood flow changes as predicting factors for postoperative outcomes. A detailed literature search was performed in PubMed database until October 2022. The following keywords were used: rhegmatogenous retinal detachment, silicone oil, optical coherence tomography angiography, macular microvasculature, peripapillary capillary plexus, vessel density, and foveal avascular zone. We identified and reviewed 19 studies referring to microcirculation alterations of the retinal capillary plexus as seen on OCT-A in eyes treated by vitrectomy with intravitreal SO for RRD. A comprehensive update revealed variability of microcirculation characteristics of the retinal capillary plexus including the macular and the peripapillary capillaries. Further studies are warranted to clarify the OCT-A values in an attempt to identify the potential effect of SO on retinal tissue in clinical practice. A review of the existing literature sheds light on the effect of SO on retinal capillary plexus and the potential impact on functional outcomes after vitrectomy for RRD. This article discusses important aspects of key publications on the topic, highlights the importance to identify distinct alterations of the microvasculature status, and proposes the need for further future research in this field.

Akimba Proliferative Diabetic Retinopathy Model: Understanding Molecular Mechanism and Drug Screening for the Progression of Diabetic Retinopathy.

As the prevalence of diabetes has reached epidemic proportions worldwide, diabetic retinopathy incidence is increasing rapidly. An advanced diabetic retinopathy (DR) stage can lead to a sight-threatening form. There is growing evidence showing diabetes causes a range of metabolic changes that subsequently lead to pathological modifications in the retina and retinal blood vessels. To understand the complex mechanism of the pathophysiology of DR, a precise model is not readily available. By crossbreeding the Akita and Kimba strains, a suitable proliferative DR model was acquired. This new Akimba strain manifests marked hyperglycemia and vascular changes, which resemble the early and advanced stage of DR.Here, we describe the breeding method, colony screening for experiments, and imaging techniques widely used to investigate the DR progression in this model. We elaborate step-by-step protocols to set up and perform fundus, fluorescein angiography, optical coherence tomography, and optical coherence tomography-angiogram to study retinal structural changes and vascular abnormalities. In addition, we show a method to label the leukocytes with fluorescence and laser speckle flowgraphy to examine the inflammation in the retina and retinal vessel blood flow speed, respectively. Lastly, we describe electroretinogram to evaluate the functional aspect of the DR transformations.

Correlations between Visual Performance and Chorioretinal Variables after Vitrectomy for the Idiopathic Macular Hole.

To investigate the relationships between visual function and the retinal and choroid microstructure in idiopathic macular hole patients after surgery. A prospective study investigated changes in the fundus structure and visual function in 16 macular hole patients before and after surgery. Patients' best-corrected visual acuity (BCVA) and retinal sensitivity were measured by an EDTRS visual chart and microperimetry (MP1), respectively. The thickness of the retina and the blood supply to the retina and superficial choroid were detected by OCTA, and the choroidal capillary blood flow density was analysed with MATLAB. The thickness of the choroid and the aperture size of the macular hole were detected by Heidelberg OCT. Compared with before surgery and one month after surgery, the BCVA (3 months: 0.47 ± 0.27, before: 1.02 ± 0.22, 1 month: 0.66 ± 0.27, and P < 0.05) and the central sensitivity of the retina (3 months: 14.88 ± 2.87 dB, before: 8.76 ± 3.27 dB, 1 month: 12.22 ± 3.30 dB, and P < 0.05) were significantly improved three months after surgery. The change in BCVA was significantly correlated with the basal diameter (r = 0.677 and P = 0.004), the minimum diameter (r = 0.585 and P = 0.017), the macular hole cystoid height area index (r = -0.618 and P = 0.011), the central macular hole index (r = -0.727 and P = 0.001), the peripheral macular hole index (r = -0.758 and P = 0.001), the central tractional hole index (r = -0.717 and P = 0.002), the peripheral tractional hole index (r = -0.725 and P = 0.001), and changes in the peripheral blood vessel density of the choroid capillary layer (r = 0.585 and P = 0.0017). The change in central retinal sensitivity was correlated with the change in the superficial foveal avascular zone (FAZ; r = 0.520 and P = 0.039), change in the retinal superficial peripheral blood flow density (r = -0.503 and P = 0.047), change in the deep FAZ (r = 0.599 and P = 0.014), and change in the retinal deep peripheral blood flow density (r = -0.601 and P = 0.014). The morphology of the macular hole as well as changes to the retinal and choroidal microstructure contributes to the recovery of visual function after surgery.

The Endothelial Glycocalyx and Retinal Hemodynamics.

Previous studies suggest that the endothelial glycocalyx adds to vascular resistance, inhibits thrombosis, and is critical for regulating homogeneous blood flow and ensuring uniform red blood cell (RBC) distribution. However, these functions and consequences of the glycocalyx have not been examined in the retina. We hypothesize that the endothelial glycocalyx is a critical regulator of retinal hemodynamics and perfusion and decreases the propensity for retinal thrombus formation. Hyaluronidase and heparinase, which are endothelial glycocalyx-degrading enzymes, were infused into mice. Fluorescein isothiocyanate-dextran (2000 kDa) was injected to measure lumen diameter, while RBC velocity and distribution were measured using fluorescently labeled RBCs. The diameters and velocities were used to calculate retinal blood flow and shear rates. Mean circulation time was calculated by measuring the difference between arteriolar and venular mean transit times. Rose Bengal dye was infused, followed by illumination with a green light to induce thrombosis. The acute infusion of hyaluronidase and heparinase led to significant increases in both arteriolar (7%) and venular (16%) diameters in the retina, with a tendency towards increased arteriolar velocity. In addition, the degradation caused a significant decrease in the venular shear rate (14%). The enzyme infusion resulted in substantial increases in total retinal blood flow (26%) and retinal microhematocrit but no changes in the mean circulation time through the retina. We also observed an enhanced propensity for retinal thrombus formation with the removal of the glycocalyx. Our data suggest that acute degradation of the glycocalyx can cause significant changes in retinal hemodynamics, with increases in vessel diameter, blood flow, microhematocrit, pro-thrombotic conditions, and decreases in venular shear rate.

Retinal protection by fungal product theissenolactone B in a sodium iodate-induced AMD model through targeting retinal pigment epithelial matrix metalloproteinase-9 and microglia activity

Age-related macular degeneration (AMD) is the leading cause of low vision and blindness for which there is currently no cure. Increased matrix metalloproteinase-9 (MMP-9) was found in AMD and potently contributes to its pathogenesis. Resident microglia also promote the processes of chronic neuroinflammation, accelerating the progression of AMD. The present study investigates the effects and mechanisms of the natural compound theissenolactone B (LB53), isolated from Theissenia cinerea, on the effects of RPE dysregulation and microglia hyperactivation and its retinal protective ability in a sodium iodate (NaIO3)-induced retinal degeneration model of AMD. The fungal component LB53 significantly reduces MMP-9 gelatinolysis in TNF-α-stimulated human RPE cells (ARPE-19). Similarly, LB53 abolishes MMP-9 protein and mRNA expression in ARPE-19 cells. Moreover, LB53 efficiently suppresses nitric oxide (NO) production, iNOS expression, and intracellular ROS levels in LPS-stimulated TLR 4-activated microglial BV-2 cells. According to signaling studies, LB53 specifically targets canonical NF-κB signaling in both ARPE-19 and BV-2 microglia. In an RPE-BV-2 interaction assay, LB53 ameliorates LPS-activated BV-2 conditioned medium-induced MMP-9 activation and expression in the RPE. In NaIO3-induced AMD mouse model, LB53 restores photoreceptor and bipolar cell dysfunction as assessed by electroretinography (ERG). Additionally, LB53 prevents retinal thinning, primarily the photoreceptor, and reduces retinal blood flow from NaIO3 damage evaluated by optic coherence tomography (OCT) and laser speckle flowgraphy (LSFG), respectively. Our results demonstrate that LB53 exerts neuroprotection in a mouse model of AMD, which can be attributed to its anti-retinal inflammatory effects by impeding RPE-mediated MMP-9 activation and anti-microglia.

Nomogram model predicts the risk of visual impairment in diabetic retinopathy: a retrospective study

To develop a model for predicting the risk of visual impairment in diabetic retinopathy (DR) by a nomogram. Patients with DR who underwent both optical coherence tomography angiography (OCTA) and fundus fluorescein angiography (FFA) were retrospectively enrolled. FFA was conducted for DR staging, swept-source optical coherence tomography (SS-OCT) of the macula and 3*3-mm blood flow imaging by OCTA to observe retinal structure and blood flow parameters. We defined a logarithm of the minimum angle of resolution visual acuity (LogMAR VA) ≥0.5 as visual impairment, and the characteristics correlated with VA were screened using binary logistic regression. The selected factors were then entered into a multivariate binary stepwise regression, and a nomogram was developed to predict visual impairment risk. Finally, the model was validated using the area under the receiver operating characteristic (ROC) curve (AUC), calibration plots, decision curve analysis (DCA), and clinical impact curve (CIC). A total of 29 parameters were included in the analysis, and 13 characteristics were used to develop a nomogram model. Finally, diabetic macular ischaemia (DMI) grading, disorganization of the retinal inner layers (DRIL), outer layer disruption, and the vessel density of choriocapillaris layer inferior (SubVD) were found to be statistically significant (P < 0.05). The model was found to have good accuracy based on the ROC (AUC = 0.931) and calibration curves (C-index = 0.930). The DCA showed that risk threshold probabilities in the (3-91%) interval models can be used to guide clinical practice, and the proportion of people at risk at each threshold probability is illustrated by the CIC. The nomogram model for predicting visual impairment in DR patients demonstrated good accuracy and utility, and it can be used to guide clinical practice. Chinese Clinical Trial Registry, ChiCTR2200059835. Registered 12 May 2022, https://www.chictr.org.cn/edit.aspx?pid=169290&htm=4.

Ocular blood flow and myopia

AbstractPurpose: It has previously been found that imposing positive defocus changes axial length and choroidal thickness after only 30 minutes. In the present study, we investigated whether these changes may result from an altered choroidal blood flow.Methods: Eighteen young adult subjects watched a movie from a large screen (65 inch) in a dark room at 2 m distance. A fifteen‐minute wash‐out period was followed by 30 minutes of watching the movie with a monocular positive defocus (+2.5D). Changes in axial length and ocular blood flow were measured before and after the defocus, by using low‐coherent interferometer (LS 900, Haag‐Streit, Switzerland) and a laser speckle flowgraphy (LSFG) RetFlow unit (Nidek Co., LTD, Japan), respectively. Three regions were analysed: (1) the macular area, where choroidal blood flow can be measured, (2) the optic nerve head (ONH), and (3) retinal vessel segments.Results: Changes in choroidal blood flow were significantly and negatively correlated with changes in axial length that followed positive defocus in exposed eyes (R = −0.67, p &lt; 0.01). The absolute values of changes in choroidal blood flow in the defocused eyes were significantly larger than in the fellow control eyes. ONH and retinal blood flow were not associated with the induced changes in axial length.Conclusions: Positive defocus selectively alters choroidal, but not retinal or ONH blood flow in young human subjects after short‐term visual exposure. The results suggest that blood flow modulation is involved in the mechanism of choroidal responses to optical defocus.

Retinal blood flow and oxygen metabolism in diabetes

AbstractDiabetic retinopathy is the leading cause for blindness in the Western countries and its prevalence is constantly increasing. In the last years, evidence has accumulated that alterations in the retinal microcirculation and changes in retinal oxygen metabolism play a key role in the disease process. In particular, tissue hypoxia seems to be a major trigger of neovascularization and macular edema in the retina of patients with diabetes.Recently, new methods to assess the retinal vasculature, such as Doppler Optical Coherence Tomography (OCT) or OCT angiography have become available, providing valuable findings in patients with diabetes. Combining these methods with techniques such as the assessment of retinal oxygen saturation, more information about retinal oxygen metabolism can be obtained.The present talk will summarize the current knowledge on retinal blood flow and oxygen metabolism in patients with diabetes.Acknowledgements: Part of the work presented was funded by the Austrian Science Fund (FWF), Projects No. KLI 721 and P26157.

Impaired retinal capillary function in patients with clinical Alzheimer’s disease

AbstractBackgroundExtensive evidence indicates that vasculopathy, especially the level of microcirculation, contributes to neurodegeneration in AD. However, it is not easy to direct monitor cerebral microcirculation. The retinal microvasculature has been used as a surrogate to study cerebral vascular changes. Indeed, decreased retinal microvascular network densities were reported in patients with AD. The goal of this project is to determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) in patients with Alzheimer’s disease (AD).MethodTwenty patients (age 60‐84, mean ± SD: 72.8 ± 7.7 yrs) with AD and 14 age‐matched cognitive normal controls (CN, age 62‐81, mean ± SD: 68.6 ± 6.7 yrs) were recruited. There were no differences in vascular risk factors including smoking, hypertension, hyperlipidemia, type 2 diabetes, and cardiovascular disease between groups (Chi‐square test, all P &gt; 0.05). One eye of each subject in both groups was imaged. Retinal blood flow (RBF) was measured using a Retinal Function Imager and retinal capillary density (RCD, expressed as fractal dimension Dbox) was measured using optical coherence tomography angiography. RCF was defined as the ratio of RBF to RCD.ResultRCF was 1.62 ± 0.56 nl/s/Dbox (mean ± SD) in the AD group, which was significant lower than that (2.56 ± 0.25 nl/s/Dbox, P = 0.0001) in the CN group. The change of RCF in the AD group represented 28% lower than the CN group. RCF was significantly related to RBF in the AD group (r = 0.98, P &lt; 0.05) and the CN group (r = 0.65, P &lt; 0.05).ConclusionOur study is the first to demonstrate the impaired retinal capillary function in patients with AD. The alteration of RCF was mainly due to decreased retinal blood flow, which the capillary network can transfer. The RCF may be developed as a biomarker to study cerebral microcirculation in patients with AD.

Ex vivo model of spontaneous neuroretinal degeneration for evaluating neuroprotection

AbstractEx vivo neuroretina models are considered adequate tools for improving the knowledge of retinal physiology and pathobiology. Neuroretina explant cultures closely resemble in vivo conditions, thus, preserving complex in vivo neuronal connections and retaining the functionality of non‐neuronal cells of the retina. Furthermore, immunohistochemistry, electrophysiology and molecular biology techniques can be applied over retinal explant cultures.Although several cell culture‐based techniques have been developed to investigate retinal function, such as retinal cells primary cultures, co‐cultures with retinal pigment epithelium (RPE) cells, or 3D aggregates cultures, ex vivo models provide a better alternative to animal experimentation and are inexpensive and easy to develop. Limitations of these ex vivo systems include the absence of choroidal and retinal blood flow, the lack of vitreous and RPE, and the axotomy of the ganglion cells, which considerably limit the evaluation of the inner retina modifications. However, these limitations are also critical for the retina to degenerate spontaneously and progressively as the culture progresses.Neuroretina culture systems began to develop in the 1920 s, using chicken embryos' retinas and posteriorly mammalian retinas. In 1954, Trowell developed the membrane culture method, in which the retina was placed with the vitreous surface in contact with a supporting porous membrane and maintained at an air‐medium interface. In 1989, Caffé et al. cultured the neuroretina with the photoreceptors layer facing downward over porous membrane, the technique that is currently considered the gold standard. Since then, ex vivo mammal neuroretina cultures from rats, mice, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows or primate, have been used to describe the differentiation processes of post‐natal retinas; to provide valuable insights into retinal diseases processes; to test potential therapeutic substances; to examine the role of growth factors over retinal cells' dynamics; to assess nanostructured scaffolds and their potential cytotoxicity, and to evaluate potential advanced therapies.Although mammal neuroretina is an excellent alternative to the dependency on post‐mortem human eyes, ex vivo human neuroretina cultures have also been characterized. They have improved the current knowledge about photoreceptors, ganglion cells, glial cells and microglia dynamics. Furthermore, human tissues are theoretically better suited for translational research than animal cells and perhaps even animal models, which exponentially increases the usefulness of the neuroretina cultures, and the extrapolation of the results obtained, marking a promising future for the screening and evaluation of potential neuroprotectors.

Retinal blood flow and oxygen saturation in patients previously infected with COVID‐19

AbstractPurpose: The SARS‐CoV‐2 pandemic has affected all countries in the world and is still ongoing. Although respiratory symptoms are the main manifestation of acute infection, there is also increasing evidence that neurological and vascular symptoms occur, and it is unknown whether residuals remain after patients have recovered. We therefore set out to investigate whether ocular vascular alterations remain after patients have recovered.Methods: Patients that had recovered from COVID‐19 infection within the last 6 months before inclusion and healthy age‐ and sex‐matched controls were recruited. Main inclusion criteria for patients were confirmed positive PCR test for SARS‐CoV‐2 in the medical history and positive testing for SARS‐CoV‐2 seroprevalence while controls had no history of COVID‐19 infection. Arteriovenous (AV) difference in oxygen saturation was calculated out of retinal arterial and venous oxygen saturation, which were measured with a commercially available Dynamic Vessel Analyser (DVA, Imedos, Germany). Retinal vessel diameters and arteriovenous ratio (AVR) were assessed using the same device. In addition, mean blur rate in the tissue area of the optic nerve head (MT) was quantified using laser speckle flowgraphy (LSFG, Nidek, Japan).Results: 29 patients that had recovered from moderate to severe COVID‐19 requiring hospitalization (mean age 35 ± 17 years) and 11 control subjects (mean age 36 ± 12 years) were included in the present study. No differences between groups regarding sex or concomitant diseases in the medical history were found. Body mass index (BMI) was significantly higher in patients that had recovered from COVID‐19 (27.5 ± 5.6 vs. 24.5 ± 2.8 m2/kg, p = 0.036). AVR as well as AV difference in oxygen saturation was significantly lower in patients compared to healthy controls (p = 0.021 for AVR and p = 0.023 for AV difference in oxygen saturation). MT in the optic nerve head also was significantly lower in patients (23.4 ± 10.1 a.u.) than in control subjects (47.3 ± 26.6 a.u., p &lt; 0.001).Conclusions: The results of this study imply that retinal metabolism is still altered in patients after recovering from COVID‐19 infection. Longitudinal studies are required to investigate whether these changes in retinal vessels as well as optic nerve head blood flow are temporary or remain.

Impairments of retinal hemodynamics and oxygen metrics in ocular hypertension-induced ischemia-reperfusion.

Ischemia-reperfusion (I/R) is an established model for retinal neurodegeneration. However, there is limited knowledge of retinal physiological metrics and their relationships to retinal function and morphology in the I/R model. The purpose of the study was to test the hypotheses that retinal hemodynamic and oxygen metrics are impaired and associated with visual dysfunction, retinal thinning, and retinal ganglion cell (RGC) loss due to I/R injury. Intraocular pressure (IOP) was increased in one eye of 10 rats for 90min followed by reperfusion. Fellow eyes served as controls. After one week of reperfusion, multimodal imaging was performed to quantify total retinal blood flow (TRBF) and retinal vascular oxygen contents. Retinal oxygen delivery (DO2) and metabolism (MO2) were calculated. Pattern-evoked electroretinography (PERG) and optical coherence tomography were performed to measure RGC function and retinal thicknesses, respectively. RGCs were counted from retina whole mounts. After one week of reperfusion, TRBF was lower in study eyes than in control eyes (p<0.0003). Similarly, DO2 and MO2 were reduced in study eyes compared to control eyes (p<0.003). PERG amplitude, TRT, IRT, ORT, and RGCs were also lower in study eyes (p≤0.01). DO2 and MO2 were correlated with PERG amplitude, TRT, IRT, and ORT (r≥0.6, p≤0.005). The findings improve knowledge of physiological metrics affected by I/R injury and have the potential for identifying biomarkers of injury and outcomes for evaluating experimental treatments.

Applications of Artificial Intelligence in Optical Coherence Tomography Angiography Imaging

Optical coherence tomography angiography (OCTA) and artificial intelligence (AI) are two emerging fields that complement each other. OCTA enables the noninvasive, in vivo, 3D visualization of retinal blood flow with a micrometer resolution, which has been impossible with other imaging modalities. As it does not need dye-based injections, it is also a safer procedure for patients. AI has excited great interest in many fields of daily life, by enabling automatic processing of huge amounts of data with a performance that greatly surpasses previous algorithms. It has been used in many breakthrough studies in recent years, such as the finding that AlphaGo can beat humans in the strategic board game of Go. This paper will give a short introduction into both fields and will then explore the manifold applications of AI in OCTA imaging that have been presented in the recent years. These range from signal generation over signal enhancement to interpretation tasks like segmentation and classification. In all these areas, AI-based algorithms have achieved state-of-the-art performance that has the potential to improve standard care in ophthalmology when integrated into the daily clinical routine.