Overview

The prevalence of dementia and diabetes has increased in recent decades. The WHO forecasts an increase in the all-cause dementia prevalence to 152 million by 2050. Type 2 diabetes (T2D) is a well-known risk factor for dementia. The prevalence of T2D was estimated to be 6.28% (462 million people) worldwide, and 22% among people aged 70 years and older. Even pre-diabetes has been shown to be a risk factor for all-cause dementia, Alzheimer¿s disease (AD) and vascular dementia (VD).

There are various mechanisms by which T2D and dementia are connected. First, there are atherosclerotic consequences of T2D that favour VD. T2D is strongly associated with micro- and macrovascular diseases. This association is essentially determined by diabetes duration. Oxidative stress is the direct result of the imbalance between the production of reactive oxygen species (ROS) and intracellular antioxidant defences. It is involved in the onset of diabetes and neurological pathologies such as AD, Parkinson¿s disease, and amyotrophic lateral sclerosis. Therefore, as oxidative stress is a common pathway in diabetes and dementia, the evaluation of oxidative stress, using specific and direct biomarkers, is necessary to monitor the risk of dementia in patients with diabetes. Furthermore, it is important to study the mechanisms that lead to changes in the oxidative state, in order to define new therapeutic targets that allow delaying the eventual onset of dementia.

This project aims at defining how 1) soluble (s)NOX2-derived peptide(dp), a new direct biomarker of oxidative stress, could be used to stratify the risk of dementia in T2D patients; 2) if p47phox, a key cytosolic subunit that drives NOX2 activation, could be considered a therapeutic target to reduce oxidative stress-mediated dementia in T2D.

A clinical Aim will collect data of a T2D population to evaluate cognitive function, by the Multidimensional geriatric assessment (MGA) and cognitive biomarkers such as brain-derived neurotrophic factor (BDNF) and ß-amyloid 42/40 and oxidative stress by sNOX2dp.

A second Aim will explore the contribution of NOX2 activation in the thrombotic process and cognitive impairment in T2D patients by the evaluation of endothelial dysfunction, as a thrombogenic risk factor, and quantitative analysis of the thrombus formation process.

Finally, a preclinical Aim will test the hypothesis that p47phox could be a therapeutic target to prevent oxidative stress-mediated dementia in T2D. Specifically, we tested the effects of the p47phox inhibitor peptide both in vitro, in human umbilical vein endothelial cells (HUVEC), and in animal models (C57BL/6J) of high-fat diet (HFD)-induced diabetes.

Considering the prevalence of dementia in T2D and the uncertainty in their management, the proposed work is expected to generate results of immediate clinical significance.

Eligibility

Inclusion Criteria:

• Established diagnosis of T2D according to the 2019 ESC guidelines
• Written informed consent obtained from the patient before enrollment
• Antidiabetic drug-naive, or treated with one or two oral anti-diabetic drugs, or treated with human NPH insulin or longacting insulin analogue or pre-mixed insulin, alone or in combination with one or two oral anti-diabetic drugs
• Age \>50 years

Exclusion Criteria:

• \- Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening
• HbA1c \>10%
• History of chronic pancreatitis or idiopathic acute pancreatitis
• History of ischemic stroke or transient ischemic attack
• Acute coronary event within 30 days before enrolment
• Currently planned coronary, carotid or peripheral artery revascularization
• Chronic Heart Failure NYHA Class IV
• End-stage liver disease, defined as the presence of acute or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin \>2.0 mg/dL, albumin level \<3.5 g/dL, prothrombin time \>4 seconds prolonged, international normalised ratio (INR) \>1.7 or prior liver transplant
• End-stage chronic kidney disease (eGFR \<30 ml/min)
• Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years
• Life expectancy \<2 years (and in any case before the completion of the study)
• Low adherence to prescribed medications
• Female of childbearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods
• Use of oral anticoagulants (atrial fibrillation of venous thromboembolism)