The retina shares similar embryologic origin, anatomical features and physiological properties with the brain and hence offers a unique and accessible "window" to study the correlates and consequences of subclinical pathology in patients with cognitive impairment. Our hypothesis is that the neurodegeneration of the retina will run in parallel to the neurodegeneration of the brain and, therefore, the signs of neurodysfunction in the retinal assessment will be more evident in those patients with rapid cognitive decline. Microangiopathy will also participate in cognitive decline and its specific role, as well as usefulness of retinal imaging, will be also examined.

This is a multinational and multicentre cross-sectional study and prospective, longitudinal cohort observational study.

The study consists of two main parts: a cross-sectional part and a longitudinal part, aimed at a) to determine whether functional and/or structural retinal biomarkers or circulating biomarkers are able to differentiate people with mild cognitive impairment (MCI) within the type 2 diabetes (T2D) population (the investigators will be able to do in the cross-sectional study, and, thus, use retina and/or blood biomarkers as a potential proxy to events taking place in the brain); b)to determine whether functional and/or structural retinal biomarkers or circulating biomarkers can be used to determine the speed of cognitive decline in people with T2D and MCI and those at higher risk of developing dementia.

The cross-sectional study will allow characterization of a large group of individuals with T2D (720 participants) and establish correlations between the various functional and structural retinal endpoints obtained and the presence/absence of mild cognitive impairment (MCI) and dementia. The cross-sectional study will allow identification of T2D patients with MCI; of these a group of 168 T2D patients with MCI and a group of T2D patients without MCI (n=63), which will act as a control group, will be then followed prospectively in the longitudinal cohort study to evaluate end points predictive of cognitive decline and dementia.

The primary objective is: to assess whether retinal sensitivity measured by microperimetry is able to predict cognitive decline and progression to dementia in MCI T2D patients.

The secondary objectives are:

1. To assess whether retinal sensitivity, measured by microperimetry, can identify individuals with MCI among people with T2D.
2. To assess whether eye fixation, measured by microperimetry, can identify individuals with MCI among people with T2D.
3. To assess whether eye fixation measured by microperimetry is able to predict rapid cognitive decline in T2D patients with MCI.
4. To define a T2D phenotype at high risk of developing dementia based on retinal imaging and functional retinal assessments.
5. To determine whether retinal imaging and functional retinal assessments may identify individuals with MCI among people with T2D.
6. To define a T2D phenotype at high risk to develop cognitive decline and dementia based on retinal imaging plus brain imaging.
7. To define a T2D phenotype at high risk to develop dementia based on retinal imaging plus brain imaging plus circulating biomarkers.
8. To establish a score to predict cognitive decline or progression from MCI to dementia based on the variables included in the study.

Inclusion Criteria:

1. Type 2 diabetes
2. 65 years and older
3. Diabetes duration of at least 5 years
4. No overt retinopathy on fundus examination or fundus images, as determined by the evaluating ophthalmologist, in one or both eyes, and people with mild to moderate non-proliferative diabetic retinopathy (NPDR) as determined by the evaluating phthalmologists using fundus examination by slit-lamp biomicroscopy.
5. Able to provide informed consent

Prospective study:

In addition to the above, participants enrolled in the prospective longitudinal cohort study should fulfilled the following criteria:

1. Diagnosis of MCI confirmed by a neuropsychological test battery (NTB) and a specialized physician. For the control group the absence of MCI will also be confirmed by a neuropsychological test battery (NTB) and a specialized physician.
2. Diagnosis of no overt or mild to moderate NPDR (ETDRS DR level 20 to 47) confirmed by the reading centre.

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 diabetic retinopathy (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. HbA1C > 10% (86 mmol/mol).
8. Severe systemic illness or personal circumstances that would not make it possible for patients to fulfil study protocols.

Prospective study:

In addition to the above, participants enrolled in the prospective longitudinal cohort study should fulfilled the following criteria:

1. Established dementia.

Subjects with type 2 diabetes, older than 65 years of age.