Brain Insulin Resistance in Mild Cognitive Impairment

Alzheimer´s disease (AD) and other diseases causing dementia have become increasingly important causes of disability in elderly people worldwide. Mainly due to a rise in life-expectancy, the prevalence of dementia is estimated to double during the next 15 years.

Despite the acknowledgement of the global burden of persons with dementia and intensive research in the field, no curing treatment is yet available for AD or the less common forms of dementia. It seems that insulin resistance would be an important link between diabetes and dementia. Thus, research focusing on the cognitive and the neuropathological changes associated with insulin resistance is needed to evaluate if insulin resistance is an independent risk factor for cognitive decline and dementia, and more specifically, AD. Insulin has many important functions in the central nervous system (CNS). Insulin is actively transported through the blood-brain barrier (BBB) by a transporter in a saturable manner. In addition to transporting insulin from the blood flow to the CNS, the insulin-binding sites act as receptors and activate intra-cellular signaling cascades that alter the functions of the BBB cells in numerous ways.

Insulin resistance has been traditionally thought to occur mainly in the muscles, the liver, and in adipocytes. The brain has been considered an insulin insensitive organ, mainly because glucose uptake in the brain is thought to be mostly independent of insulin. In recent years, however, evidence of insulin resistance occurring also in the CNS has started to accumulate. In obese rodents the binding of insulin to the endothelium of the BBB was reduced when compared to lean animals, and plasma insulin levels correlated negatively to specific insulin binding in the BBB. A similar inverse relationship was found between higher plasma insulin and a lower number of insulin receptors in the liver, suggesting that peripheral hyperinsulinemia downregulates the expression of insulin receptors at the BBB in a similar way as in the peripheral tissues. A magnetoencephalographic study showed that in obese humans the cerebrocortical response to infused insulin during a hyperinsulinemic euglycemic clamp was reduced when compared to lean individuals. These results indicate that peripheral hyperinsulinemia leads to a reduced insulin response in the brain, probably due to lower insulin concentrations in the CNS as a result of insulin transporter down-regulation at the BBB.

In addition to the direct effects of insulin resistance on AD neuropathology, insulin resistance has negative effects on cerebrovascular function. The metabolic syndrome - of which insulin resistance is the key feature - is associated with an increased risk of stroke and brain white matter lesions. The brain is highly dependent of adequate microvascular blood flow, which is maintained by vascular reactivity, and mediated by nitric oxide and endothelial function. Individuals with insulin resistance have been shown to have lower cerebral blood flow in the cortex than normal controls. The vascular injuries associated with insulin resistance might promote the neuropathological changes of AD by, for example, disturbing Aβ transportation between the CNS and periphery. In turn, Aβ deposits in the blood vessel wall can induce inflammation thereby damaging the endothelium. To summarize, insulin resistance is linked to vascular cognitive impairment through brain vascular lesions which, in turn, might be a "second hit" that contributes to the clinical symptoms of AD in the presence of AD neuropathological changes, i.e. Aβ and neurofibrillary tangles.

Measuring brain insulin resistance The definition of systemic insulin resistance is based on tissue-level studies whereseveral molecular defects have been established. For obvious reasons, such studies cannot be performed in the human brain in vivo to define central insulin resistance (IR). To date, there is no consensus on how to measure insulin resistance in the central nervous system in humans. Considering that both systematic and CNS IR have been linked to cognitive decline and AD, many groups have attempted to demonstrate IR in the human brain with different methods.