Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications

Diabetic retinopathy; Inflammation; RetinaRetinopatia diabètica; Inflamació; RetinaRetinopatía diabética; Inflamación; RetinaThe etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects ICI20/00129 and PI22/01670 and co-funded by the European Union. Hugo Ramos is the recipient of a grant from the Ministerio de Economía y Competitividad (BES-2017-081690)

Genetics in Diabetic Retinopathy : Current Concepts and New Insights

There is emerging evidence which indicates the essential role of genetic factors in the development of diabetic retinopathy (DR). In this regard it should be highlighted that genetic factors account for 25-50% of the risk of developing DR. Therefore, the use of genetic analysis to identify those diabetic patients most prone to developing DR might be useful in designing a more individualized treatment. In this regard, there are three main research strategies: candidate gene studies, linkage studies and Genome-Wide Association Studies (GWAS). In the candidate gene approach, several genes encoding proteins closely related to DR development have been analyzed. The linkage studies analyze shared alleles among family members with DR under the assumption that these predispose to a more aggressive development of DR. Finally, Genome-Wide Association Studies (GWAS) are a new tool involving a massive evaluation of single nucleotide polymorphisms (SNP) in large samples. In this review the available information using these three methodologies is critically analyzed. A genetic approach in order to identify new candidates in the pathogenesis of DR would permit us to design more targeted therapeutic strategies in order to decrease this devastating complication of diabetes. Basic researchers, ophthalmologists, diabetologists and geneticists should work together in order to gain new insights into this issue

Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy

Retinopatía diabética; Neurodegeneración; Unidad neurovascularRetinopatia diabètica; Neurodegeneració; Unitat neurovascularDiabetic retinopathy; Neurodegeneration; Neurovascular unitThe concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.This research was funded by grants from the Instituto de Salud Carlos III (DTS18/0163, PI19/01215, and ICI20/00129). The funders had no role in the design of the study; in the collection, analyses, or the interpretation of the data; in the writing of the manuscript, or in the decision to publish the results

Circulating Biomarkers of Diabetic Retinopathy : An Overview Based on Physiopathology

Diabetic retinopathy (DR) is the main cause of working-age adult-onset blindness. The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR. Therefore, new pharmacological treatments for these early stages of the disease are required. In order to develop therapeutic strategies for early stages of DR new diagnostic tools are urgently needed. In this regard, circulating biomarkers could be useful to detect early disease, to identify those diabetic patients most prone to progressive worsening who ought to be followed up more often and who could obtain the most benefit from these therapies, and to monitor the effectiveness of new drugs for DR before more advanced DR stages have been reached. Research of biomarkers for DR has been mainly based on the pathogenic mechanism involved in the development of DR (i.e., AGEs, oxidative stress, endothelial dysfunction, inflammation, and proangiogenic factors). This review focuses on circulating biomarkers at both early and advanced stages that could be relevant for the prediction or detection of DR

Usefulness of eye fixation assessment for identifying type 2 diabetic subjects at risk of dementia

Type 2 diabetic (T2D) subjects have a significantly higher risk of developing mild cognitive impairment (MCI) and dementia than age-matched non-diabetic individuals. However, the accurate evaluation of cognitive status is based on complex neuropsychological tests, which makes their incorporation into the current standard of care for the T2D population infeasible. Given that the ability to maintain visual gaze on a single location (fixation) is hampered in Alzheimer's disease (AD), the aim of the present study was: (1) To assess whether the evaluation of gaze fixation during fundus-driven microperimetry correlated with cognitive status in T2D subjects; (2) to examine whether the addition of fixational parameters to the assessment of retinal sensitivity increased the predictive value of retinal microperimetry in identifying T2D subjects with MCI. For this purpose, fixation parameters and retinal sensitivity were compared in three age-matched groups of T2D subjects: normocognitive (n = 34), MCI (n = 33), and AD (n = 33). Our results showed that fixation is significantly more unstable in MCI subjects than normocognitive subjects, and even more altered in those affected by AD (ANOVA; p < 0.01). Moreover, adding fixation parameters to retinal sensitivity significantly increases the predictive value in identifying those subjects with MCI: ROC (Receiver Operating Characteristic) Area 0.68 with retinal sensitivity alone vs. ROC Area 0.86 when parameters of fixation are added to retinal sensitivity (p < 0.01). In conclusion, our results suggest that fixational eye movement parameters assessed by fundus-microperimetry represent a new tool for identifying T2D subjects at risk of dementia

Usefulness of liquid biopsy biomarkers from aqueous humor in predicting anti-VEGF response in diabetic macular edema : results of a pilot study

The objective was to investigate the usefulness of the "liquid biopsy" of aqueous humor (AH) to predict the clinical response after intravitreal injections (IVT) of anti-VEGF agents for treating diabetic macular edema (DME). For this purpose, AH samples obtained during the first anti-VEGF IVT from 31 type two diabetic patients were analyzed. Patients were classified into three groups according to their anti-VEGF response: rapid responders (n = 11), slow responders (n = 11), and non-responders (n = 9). In addition, patients (n = 7) who showed good response to corticosteroids but a delayed or no response to anti-VEGF therapy were analyzed. Levels of 17 different cytokines, chemokines, and growth factors in AH were measured using a multiplex immunoassay. We found higher concentrations of VEGF in rapid responders to anti-VEGF therapy compared to non-responders. In addition, slow responders to anti-VEGF treatment showed higher levels of inflammatory markers than rapid responders, but did not reach statistical significance. Finally, those patients who responded to corticosteroids but not to anti-VEGF therapy showed significantly lower levels of VEGF than patients with rapid response (p = 0.01). In conclusion, "liquid biopsy" of AH could be useful to determine whether the predominant pathogenic event is primarily angiogenic or inflammatory in nature. This approach would allow physicians to select a more rational and cost-effective treatment. Further studies to validate these preliminary results are warranted

Usefulness of Eye Fixation Assessment for Identifying Type 2 Diabetic Subjects at Risk of Dementia

Dementia; Diabetes; MicroperimetryDemència; Diabetis; MicroperimetriaDemencia; Diabetes; MicroperimetríaType 2 diabetic (T2D) subjects have a significantly higher risk of developing mild cognitive impairment (MCI) and dementia than age-matched non-diabetic individuals. However, the accurate evaluation of cognitive status is based on complex neuropsychological tests, which makes their incorporation into the current standard of care for the T2D population infeasible. Given that the ability to maintain visual gaze on a single location (fixation) is hampered in Alzheimer’s disease (AD), the aim of the present study was: (1) To assess whether the evaluation of gaze fixation during fundus-driven microperimetry correlated with cognitive status in T2D subjects; (2) to examine whether the addition of fixational parameters to the assessment of retinal sensitivity increased the predictive value of retinal microperimetry in identifying T2D subjects with MCI. For this purpose, fixation parameters and retinal sensitivity were compared in three age-matched groups of T2D subjects: normocognitive (n = 34), MCI (n = 33), and AD (n = 33). Our results showed that fixation is significantly more unstable in MCI subjects than normocognitive subjects, and even more altered in those affected by AD (ANOVA; p < 0.01). Moreover, adding fixation parameters to retinal sensitivity significantly increases the predictive value in identifying those subjects with MCI: ROC (Receiver Operating Characteristic) Area 0.68 with retinal sensitivity alone vs. ROC Area 0.86 when parameters of fixation are added to retinal sensitivity (p < 0.01). In conclusion, our results suggest that fixational eye movement parameters assessed by fundus-microperimetry represent a new tool for identifying T2D subjects at risk of dementi

Effects of the topical administration of semaglutide on retinal neuroinflammation and vascular leakage in experimental diabetes

Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL; 5 µL once/daily) or vehicle (PBS; 5 µL once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-κB), proinflammatory cytokines (IL-1β, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglu-tide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes. 092

Deep Learning of Retinal Imaging: A Useful Tool for Coronary Artery Calcium Score Prediction in Diabetic Patients

Retina fundus imaging; Deep learning; Medical imagingImatge del fons de la retina; Aprenentatge profund; Imatges mèdiquesImagen del fondo de la retina; Aprendizaje profundo; Imágenes médicasCardiovascular diseases (CVD) are one of the leading causes of death in the developed countries. Previous studies suggest that retina blood vessels provide relevant information on cardiovascular risk. Retina fundus imaging (RFI) is a cheap medical imaging test that is already regularly performed in diabetic population as screening of diabetic retinopathy (DR). Since diabetes is a major cause of CVD, we wanted to explore the use Deep Learning architectures on RFI as a tool for predicting CV risk in this population. Particularly, we use the coronary artery calcium (CAC) score as a marker, and train a convolutional neural network (CNN) to predict whether it surpasses a certain threshold defined by experts. The preliminary experiments on a reduced set of clinically verified patients show promising accuracies. In addition, we observed that elementary clinical data is positively correlated with the risk of suffering from a CV disease. We found that the results from both informational cues are complementary, and we propose two applications that can benefit from the combination of image analysis and clinical data.This research was funded by “RTI2018-095232-B-C22” grant from the Spanish Ministry of Science, Innovation and Universities (FEDER funds)