Brain insulin resistance is a significant feature of dementia.

Dementia is a group of neurological and vascular disorders that are characterized by cognitive impairment that is severe enough to interfere with one's daily function. Brain insulin resistance is a significant feature of dementia. In fact, greater than 80% of patients with dementia are also insulin resistant. The Lansdell laboratory studies the role of insulin signaling in regulating cerebral microvascular and cognitive function.

Chronic cerebral hypoperfusion is a major cause of vascular dementia.

Chronic cerebral hypoperfusion (CCH) is a condition in which cerebral blood flow gradually decreases, eventually leading to injury of neuronal tissue and the development of vascular dementia. Cardiovascular diseases including hypertension, and carotid artery stenosis are thought to cause dementia due to CCH. It remains to be determined how pathological states, such as hypertension, carotid artery stenosis, and diabetes affect PA structure and function.

Hypertension: Nearly half the adult population in the U.S. has hypertension. Hypertension often goes undiagnosed and/or untreated. This population is at risk for developing dementia.

Carotid artery stenosis: Over 30% of the U.S. population has some degree of carotid artery stenosis. Screening for asymptomatic carotid artery stenosis is generally not recommended. However, work from our lab suggests that this population is at risk for developing dementia.

Parenchymal arterioles are the “bottleneck” to perfusion of the brain.

Parenchymal arterioles (PAs) are high resistance blood vessels that diverge from pial arteries. These arterioles dive deep into the brain parenchyma and perfuse discrete columns of neuronal tissue. Because PAs are long and relatively unbranched, they form a bottle neck of perfusion to the brain. Impairment of one PA can result in the loss of perfusion to an entire column of brain tissue. There is a significant gap in our understanding of insulins effects on PA function.

Does insulin resistance impair endothelial-dependent dilation of PAs?

It is evident that impaired vasodilation occurs in the peripheral vasculature in models of insulin resistance. In healthy large cerebral arteries, insulin induces endothelium-dependent dilation. Bilateral carotid artery stenosis results in impaired endothelium-dependent dilation of PAs in rats. We previously showed that these rats also develop insulin resistance. We are currently investigating the role of CCH-induced insulin resistance in insulin signaling and endothelium-dependent dilation of PAs.

My lab’s overarching goal is to discover pathological changes in the mechanisms of endothelial-dependent dilation in cerebral PAs under conditions that cause CCH. We use rodent models of CCH to understand the cellular mechanisms underpinning PA dysfunction and associated cognitive impairment. It is our hope that discoveries found through our work can be used to develop new treatments for patients with atherosclerosis or hypertension that will prevent or mitigate the development of dementia.

Sponsored Projects

Alzheimer’s Association Research Fellowship 22-9746618; Cerebral Hypoperfusion Induces Insulin Resistance and Exacerbates Dementia. Principal Investigator Dr. Teri Lansdell