Diabetic Retinopathy Predicts Risk of Alzheimer’s Disease: A Danish Registry-Based Nationwide Cohort Study

Cognitive impairment; Diabetes mellitus; Diabetic retinopathyDiscapacidad cognitiva; Diabetes mellitus; Retinopatía diabéticaDiscapacitat cognitiva; Diabetis mellitus; Retinopatia diabèticaBackground: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). Objective: To investigate diabetes and DR as a risk marker of present and incident AD. Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59–0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81–0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08–1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18–1.53). Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.This work was supported by VELUX FONDEN (grant number 00028744) and Odense University Hospital PhD Foundation (grant number 4339)

Correlation between Retinal Vessel Calibre and Neurodegeneration in Patients with Type 2 Diabetes Mellitus in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR)

&lt;b&gt;&lt;i&gt;Purpose:&lt;/i&gt;&lt;/b&gt; To investigate the correlation between retinal vessel calibre and measurements of neurodegeneration in patients with type 2 diabetes (T2D) and no or early diabetic retinopathy (DR). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Baseline data on 440 patients with T2D from the EUROCONDOR clinical trial were used. DR was graded according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale, and patients with ETDRS levels 10-35 were included. Retinal vessel diameters were measured by semi-automatic software. Calibres were summarized into central retinal artery and vein equivalents (CRAE and CRVE). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Median age and diabetes duration were 64.0 and 10.3 years, respectively. ETDRS levels were 10 (42.3%), 20 (27.5%) and 35 (30.2%). The median CRAE and CRVE were 146.7 and 215.3 µm, respectively. CRAE did not differ according to ETRDS level (p = 0.12), but wider CRVE were found in patients with higher ETDRS levels (p = 0.04). In a multivariable linear regression model, CRAE was associated with macular ganglion cell layer thickness (coefficient 0.27 per micrometre, p &lt; 0.01), and CRVE was correlated with macular retinal thickness (coefficient -0.07 per micrometre, p = 0.04) and retinal nerve fibre layer thickness at the optic disc (coefficient 0.32 per micrometre, p &lt; 0.01). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Retinal vessel calibre was independently associated with structural changes of the neuroretina in patients with no or early DR.</jats:p

Retinal vascular fractals predict long-term microvascular complications in type 1 diabetes mellitus:the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987)

Diabetic neuropathy, nephropathy, and retinopathy cause significant morbidity in patients with type 1 diabetes, even though improvements in treatment modalities delay the appearance and reduce the severity of these complications. To prevent or further delay the onset, it is necessary to better understand common underlying pathogenesis and to discover preclinical biomarkers of these complications. Retinal vessel calibers have been associated with the presence of microvascular complications, but their long-term predictive value has only been sparsely investigated. We examined retinal vessel calibers as 16-year predictors of diabetic nephropathy, neuropathy, and proliferative retinopathy in a young population-based Danish cohort with type 1 diabetes. We used semiautomated computer software to analyze vessel diameters on baseline retinal photos. Calibers of all vessels coursing through a zone 0.5–1 disc diameter from the disc margin were measured and summarized as the central artery and vein equivalents. In multiple regression analyses, we found wider venular diameters and smaller arteriolar diameters were both predictive of the 16-year development of nephropathy, neuropathy, and proliferative retinopathy. Early retinal vessel caliber changes are seemingly early markers of microvascular processes, precede the development of microvascular complications, and are a potential noninvasive predictive test on future risk of diabetic retinopathy, neuropathy, and nephropathy.</jats:p

Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy:cross-sectional analyses of baseline data of the EUROCONDOR project

Cross-sectional study evaluating the relationship between: a) functional and structural measurements of neurodegeneration in initial stages of diabetic retinopathy (DR); and b) presence of neurodegeneration and early microvascular impairment. We analyzed baseline data of patients with type 2 diabetes (n=449) enrolled in the EUROCONDOR study (NCT01726075). Functional studies by multifocal ERG (mfERG) evaluated neurodysfunction and structural measurements using spectral domain optical-coherence tomography (SD-OCT) evaluated neurodegeneration. The mfERG P1 amplitude was more sensitive than the P1 implicit time (IT), and was lower in patients with ETDRS 20-35 than in patients with ETDRS <20 (p=0.005). In 58% of cases, mfERG abnormalities were present in the absence of visible retinopathy. Correspondence between SD-OCT thinning and mfERG abnormalities was shown in 67% of the eyes with ETDRS <20 and in 83% of the eyes with ETDRS 20-35. Notably, 32% of patients with ETDRS 20-35 presented no abnormalities in mfERG or SD-OCT. We conclude that there is a link between mfERG and SD-OCT measurements which increases with the presence of microvascular impairment. However, in our particular study population (ETDRS ≤ 35) a significant proportion of patients had normal GC-IPL thickness and normal mfERG findings. We raise the hypothesis that neurodegeneration may play a role in the pathogenesis of DR in many, but not in all type 2 diabetic patients

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy:Results of the EUROCONDOR Clinical Trial

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit