Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression

Abstract

Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be improved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or improve blood-brain barrier permeability and cerebral vasoreactivity.

Figure 1.. Detrimental effects of cerebral microvascular dysfunction

Type 2 diabetes-related microvascular dysfunction has various detrimental effects on the brain. It is related to inflammatory and immune responses, and may lead to increased blood-brain barrier permeability (A); perfusion defects, hypoxia and increased angiogenesis (B); and may impair neurovascular coupling (C) and cerebral autoregulation (D). A) Type 2 diabetes-related microvascular dysfunction is related to increased oxidative stress and inflammatory and immune responses, and increased blood-brain barrier permeability, resulting in leakage of proteins and other plasma constituents into the perivascular space B) Microvascular dysfunction may lead to perfusion defects, hypoxia and increased angiogenesis. Angiogenesis is associated with formation of capillaries that are leaky and poorly perfused, and that lack pericyte support C) Microvascular dysfunction may contribute to impaired neurovascular coupling, leading to compromised neuronal function. Neurovascular coupling is the mechanism that links transient local neural activity to the subsequent increase in blood flow D) Microvascular dysfunction may impair cerebral autoregulation, leading to greater vulnerability of brain tissue to the harmful effects of blood pressure changes. With impaired autoregulation, the normal autoregulation curve that expresses the relation-ship between cerebral blood flow and mean blood pressure (black curve) may become more linear and steeper, and perfusion becomes pressure--dependent (red curve)

Figure 2.. Presumed pathway by which type 2 diabetes-related cerebral microvascular dysfunction contributes to multiple brain diseases

In type 2 diabetes and prediabetes, drivers of cerebral microvascular dysfunction include hyperglycaemia, obesity and insulin resistance, as well as hypertension and arterial stiffening. Cerebral microvascular dysfunction and damage may lead to ischaemia, haemorrhage, abnormal neuronal function, neuronal cell death, and altered neuronal connectivity. Thereby, microvascular dysfunction may contribute to stroke, cognitive dysfunction, and depression.