Early Retinal Neurodegeneration As Risk Factor, Biomarker and Pharmacological Target of Diabetic Retinopathy

Overview

Despite the evidence that diabetic retinopathy (DR) remains the first cause of blindness among the working-age population, it lacks a specific preventive treatment. This is because early mechanisms leading to the development of DR have been, until recently, unknown. Recent studies have suggested that the early stages of DR could be preceded by neuronal abnormalities, in particular retinal ganglion cell death, coupled with widespread retinal inflammation. According to these studies, endothelial dysfunction and the development of microaneurysms, the classic hallmarks of DR, could be the consequence of these early abnormalities. This project will aim to verify whether neurodegeneration could represent at the same time: 1) a risk factor for subsequent development of DR (this will be investigated through a follow-up study in type 2 diabetic patients free of diabetic retinopathy). 2) a biomarker of the complication (if so, patients with long-standing diabetes in the absence of retinopathy should show no signs of neurodegeneration).

Detailed description

The project is centered on a clinical study aimed to clarify whether early, diabetes-driven neurodegeneration (something that has been demonstrated by several seminal studies) is related (possibly causative) to the subsequent development of DR (a concept that is presently far from being confirmed but that, in case, would probably pave the way to identify for the first time a treatment for this diabetic complication.

This project includes two substudies:

* LONGITUDINAL STUDY: the aim is to verify whether the presence of retinal neurodegeneration in type 2 diabetic patients without DR increases the risk of subsequent development of retinal microaneurisms, the classic first vascular sign of DR; will enroll 90 individuals affected by type 2 diabetes and 30 healthy controls. All the subjects will be recruited during the first 6 months of the study and followed for 24 months (baseline, month 6, month 12, month 18, and month 24). * CROSS-SECTIONAL STUDY: the aim is to verify the clinical evidence of retinal neurodegeneration in patients with type 2 diabetes diagnosed over 20 years and with overt diabetic retinopathy, compared to patients with type 2 diabetes diagnosed for over 20 years but no signs of diabetic retinopathy. Will be enrolled 30 individuals affected by type 2 diabetes with a duration of disease longer than 20 years and no clinical signs of DR and 30 individuals affected by type 2 diabetes with a duration of disease longer than 20 years and DR of any stage. All the subjects will be recruited during the first 6 months of the study and subjected to only one visit to the site.

Interventions

• Procedure Ophthalmological examination including imaging assessments
  Ophthalmological examination including imaging assessments (SD-OCT, Spectral Domain Optical Coherence Tomography, a procedure to study and quantify possible retinal neurodegeneration and OCT-A, Optical coherence tomography angiography, a procedure to study and quantify possible retinal vascular abnormalities)
• Procedure confocal analysis of cornea
  Confocal analysis of cornea: a procedure to study and quantify possible corneal nerve degeneration as a marker of involvement of diabetic neuropathy
• Procedure Dynamic Vessel Analyzer (DVA)
  Dynamic Vessel Analyzer (DVA), a device that measures the response of retinal arteries and veins to a standardized stimulus (flickering light) allowing direct quantification of the inflammatory status of the retinal vasculature
• Procedure tear sampling collection
  Collect and analyze tear samples to identify biomarkers in tears and at the endothelium of the ocular surface through impression conjunctival cytology and the quantitative/qualitative analysis of pro-inflammatory cytokines
• Procedure blood sampling collection
  collection and analysis of blood samples to identify diabetic retinopathy biomarkers and early abnormalities of the vascular retinal system.

Primary outcome measures

• imaging assessment (OCT, Optical coherence tomography; OCT-A, Optical Coherence Tomography Angiography and Dynamic Vessel Analyzer); confocal microscopy, blood sampling collection and conjunctival impression cytology [Time frame: 24 months]

Secondary outcome measures (1)

• imaging assessment (OCT, Optical coherence tomography; OCT-A, Optical Coherence Tomography Angiography and Dynamic Vessel Analyzer); confocal microscopy, blood sampling collection and conjunctival impression cytology [Time frame: 24 months]

Eligibility criteria

Inclusion Criteria - Longitudinal study (patients):

• Participant is willing and able to give informed consent for participation in the trial.
• Male or Female, aged 40 - 80 years;
• In good general health as evidenced by medical history or diagnosed with type 2 diabetes for less than 10 years without clinical signs of retinopathy and other diabetic complications;
• HbA1c level 7% or greater;

Inclusion Criteria - Longitudinal study (healthy controls)

• Participant is willing and able to give informed consent for participation in the trial;
• Male or Female, aged 40 - 80 years;
• In good general health as evidenced by medical history without diagnosis of type 2 diabetes;

Inclusion Criteria - Cross-sectional study

• Participant is willing and able to give informed consent for participation in the trial;
• Male or Female, aged 40 - 80 years;
• Patient with a diagnosis of type 2 diabetes for longer than 20 years in the absence or presence of clinical signs of retinopathy and other diabetic complications;
• HbA1c level 7% or greater.

Exclusion Criteria (longitudinal study and cross-sectional study)

An individual who meets any of the following criteria will be excluded from participation in this study:

• retinal or systemic diseases other than diabetes;
• hypertension (BP values greater than 140/90 mm Hg);
• anemia (hematocrit less than 35%);
• smoking;
• laser treatment and pregnancy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Italy · 2 centers

• Irccs Ospedale San Raffaele — Milan
• IRCCS Ospedale San Raffaele _O.U. Ophthalmology — Milan

Identifiers

NCT: NCT06582472 · PNRR-MAD-2022-12376008

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗