OPEN Research Support

Frederik Nørregaard Pedersen
Department of Ophthalmology

Projekt styring
Projekt status    Open
Data indsamlingsdatoer
Start 16.11.2020  
Slut 01.03.2023  

Diabetic retinopathy as a marker of cognitive dysfunction and depression

Short summary

In recent years, retinal neurodegeneration has been recognised as an early event in diabetic retinopathy (DR), and DR has been linked with systemic neurological diseases like minimal cognitive impairment (MCI), Alzheimer's Disease (AD) and depression. This observation might raise an opportunity towards using retina as tool in detecting cognitive dysfunction and depression in an early stage. Through a clinical approach, we aim to evaluate non-invasive retinal markers to detect MCI and depression


Background Patients with type 2 diabetes (T2D) often face a variety of long-term micro- and macrovascular complications, of which diabetic retinopathy (DR) is the most common. In recent years, retinal neurodegeneration has been recognized as an early event in DR, and DR has been linked with systemic neurological diseases like minimal cognitive impairment (MCI), Alzheimer's disease (AD), and depression. Patients with diabetes have a higher risk of developing neurological diseases. Given that the eye and the brain share similar embryologic origin, anatomical features and physiological properties, observations could indicate that the retina offers a unique "window" to the brain. A European multinational, multicentre-study "Retinal and cognitive dysfunction in type 2 diabetes: unravelling the common pathways and identification of patients at risk of dementia - RECOGNISED" has just been launched in the Horizon 2020 programme. This study aims to assess whether retinal sensitivity is able to predict cognitive decline and progression to dementia in patients with T2D and MCI. This is important, given the higher risk of MCI in T2D as well as the annual conversion rate of 10-30% from MCI to dementia. In these terms, the interplay between retinal and systemic neurologic dysfunction is particularly important, given the possibilities to measure the retinal morphology non-invasively at an early stage. While this is somewhat explored in RECOGNISED, additional non-invasive testing of retinal metabolism and structure will lead to an improved understanding of the potential to include retinal markers to evaluate systemic neurological dysfunction in MCI and depression. Additionally, plasma biomarkers of endothelial dysfunction have been associated with increased risk of depression, which may support the hypothesis of vascular depression. This will further be investigated in order to examine whether depression might have an organic association. DIRMA will be performed in parallel with and partially embedded in the international, multicentre study RECOGNISED, which aims to evaluate retinal neurodegeneration in parallel to cerebral neurodegeneration, under the hypothesis that retina can be used as a tool to identify people who are at increased risk of cognitive dysfunction in an early stage. RECOGNISED will explore ocular and systemic biomarkers, retinal examinations, neuroimaging, mental health status, and cognitive dysfunction assessment. In RECOGNISED, a cross-sectional study is used to identify cases with non-proliferative DR and MCI along with controls without MCI, who will be followed in 30 months in order to investigate development of cognitive impairment in relation to DR. In DIRMA, we will perform additional retinal and psychological testing of patients attending RECOGNISED cross sectional study visit contributing to a Danish national cross-sectional study. In general the two studies share similarities regarding their cross-sectional study only differentiating within few retinal, laboratory and neuropsychological examinations. Subjects participating in RECOGNISED cross-sectional study at this clinical site will also participate, if willing so, in DIRMA. Aim: 1. To determine whether structural and/or metabolic retinal markers are able to differentiate people with MCI within the T2D population. 2. To determine whether structural and/or metabolic retinal markers are able to differentiate people with depressive symptoms within the T2D population.

Description of the cohort

Study population 200 patients from Funen Diabetes database (FDDB) will participate. Both eyes of each patient will be used to create approximately four groups of 100 eyes as stratified by level of DR (levels 0-3). Inclusion criteria: 1. Type 2 diabetes 2. 65 years and older 3. Diabetes duration of at least 5 years 4. None to moderate non-proliferative DR (NPDR), as determined by the evaluating ophthalmologists using fundus examination by slit-lamp biomicroscopy 5. Able to provide informed consent Exclusion criteria: 1. Previous history of stroke or neurodegenerative diseases. 2. Severe NPDR, Proliferative DR (PDR), Diabetic Macular Edema (DME) or other eye disorders affecting vision besides these complications of DR. 3. Previous laser photocoagulation. 4. Other diseases which may induce retinal neurodegeneration (e.g. glaucoma). 5. Subjects with a refractive error ≥ ± 6 D. 6. Media opacities that preclude retinal imaging. 7. Severe systemic illness or personal circumstances that would not make it possible for the patients to fulfil study protocols.

Data and biological material

History (Medical and ocular) The medical, psychiatric and ophthalmologic history and treatments previously given will be documented. Demographic: The following demographic information will be collected: • Age (year of birth) • Sex (gender) • Ethnicity • Education (years and international standard classification) • Occupation/retired Physical examination: Physical examination of the subject with determination of weight, height, body mass Index (BMI), waist circumference and blood pressure. Best corrected visual acuity (BCVA): Best corrected visual acuity will be obtained from both eyes of all participants using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts at 4 meters by an experienced optometrist, trained visual acuity technician or ophthalmologist. A protocol refraction will be used. Retinal oximetry: Retina oximetry will be obtained from each eye of each participant at the cross-sectional study visit by an experienced ophthalmic photographer using a commercially available instrument (Oxymap T1, Oxymap ehf., Reykjavik, Iceland). Fundus photography: Seven field ETDRS non-stereoscopic images will be obtained from both eyes of each participant. These will be analysed in order to determine the grade of retinopathy. Spectral Domain-Optical Coherence Tomography (SD-OCT): SD-OCT scans will be obtained from each eye of each participant. Measures of macular volume and central subfield retinal thickness (thickness in the central 1 mm of the retina), macular ganglion cell - inner plexiform layer (GC-IPL) and peripapillary retinal nerve fibre layer (RNFL) thickness, as automatically provided by the instrument, will be recorded. Optimal Coherence Tomography Angiography (OCT-A): OCT-A will be obtained from each eye of each participant. Measurements of capillary vessel density in superficial and deep capillary plexuses as well as the foveal avascular zone area will be determined. Montreal Cognitive Assessment (MoCA): The MoCA is used for screening MCI and has been successfully used in subjects with T2D and DR. The MoCA test is a one-page 30-point test administered in approximately 10 minutes. This instrument assesses several cognitive domains: short-term memory (delayed recall), visuospatial abilities/executive function, attention, working memory, language, and orientation (time and space). Scores range from 0 to 30; a score ≥26 is considered normal, whereas <26 is sensitive in detecting MCI. Geriatric Depression Scale (GDS-15): Cognitive performance can be influenced by several factors, especially the level of education and depression which is more frequent in the T2D population. We will therefore register the level of formal education in years and additionally in international standard classification (see demographics section, above). Likewise, depressive symptoms will be assessed using the 15-item self-reported Geriatric Depression Scale (GDS-15), which has a maximum score of 15. The GDS-15 is frequently used in clinical practice and research and is a valid and reliable screening instrument for depressive symptoms in older people. Inventory of Depressive Symptomatology (IDS-SR30): The IDS-SR-30 consist of 30 question regarding depressive symptoms. This is a self-administered questionnarie which can both be used as a screening depression tool but also mesuare severity of depressive symptoms. Scores between 0-84 describes depressive symptoms during the previous seven days. We will classify patients depressive symptoms according to standard classifications. Neuropsychological battery (NTB) For the formal diagnosis of MCI, clinical criteria and additional neuropsychological assessments beyond the MoCA are required (19). For this purpose, those participants scoring <26 in MoCA will undergo: Digit Symbol Substitution Test (DSST), Trail Making Test (TMT) part A and B, The Rey Auditory Verbal Learning Test (RAVLT), letter and category fluency test, the Rey-Osterrieth Complex Figure Test (ROCF), Boston Naming Test (BNT) and WAIS digit span (DS). With this neuropsychological battery of tests we will examine the following five cognitive domains: processing speed (DSST, TMT-A), attention and executive functioning (TMTB and fluency), memory (RAVLT, ROCF and DS), visuo-construction (ROCF) and language (BNT and fluency). These tests will be conducted according to the specific SOP. Laboratory tests: Full blood cell count, biochemistry (fasting glucose, lipids, liver and kidney function), HbA1c, and albumin excretion rate (in urine samples) will be assessed in all patients participating. These biosamples will be analysed after collection and biosamples will afterwards be disposed according to standard procedures.