Healthy blood vessels are not only important for heart health. Vascular well-being is critical for brain health and potentially for combating age-related cognitive decline and neurodegenerative diseases such as Alzheimer’s disease, according to a new study led by Penn State researchers. The findings point to a previously understudied but potentially crucial role that the brain’s vascular network – or energy infrastructure – plays in the onset of neurodegenerative diseases. They published their work in Nature Communications.

Using advanced imaging techniques, the team created maps of the brains of mice that illustrate how vascular cells and structures such as blood vessels change with age and identified areas that are prone to deterioration. When blood vessels deteriorate, the nerve cells in the brain, known as neurons, are deprived of energy so that they no longer function properly or die. This can lead to a condition known as vascular dementia, the second most common cause of cognitive impairment in older adults, and symptoms such as sleep disturbance.

Detailed Map of the Vascular Network in the Brain Helps to Identify Those Areas that Selectively Degenerate in Old Age

“In something like Alzheimer’s disease, cell death has already occurred by the time you can see vascular changes and significant shrinkage of the brain on MRI. We need to understand how these cells and structures change before a major catastrophe occurs,” said Yongsoo Kim, associate professor of neural and behavioral sciences at Penn State College of Medicine and lead author of the study. This study provides early signs of neurodegenerative disorders that could lead to earlier diagnosis and clues on how to slow the aging process and cognitive changes. According to Kim, aging is one of the most important factors involved in neurodegenerative disorders. However, researchers do not know exactly how normal aging changes the brain and in particular the brain’s vasculature.

As the population ages, it is crucial to understand these changes, especially within the network of blood vessels. Blood vessels, specifically microvessels, regulate the delivery of oxygen and energy as well as the removal of waste products to and from neurons. Despite their importance, Kim says, most research focuses on how the structure and function of neurons degenerate over time, rather than on the vasculature. When researchers look at the brain’s vasculature, they primarily study larger blood vessels or focus on a single, easily accessible area of the brain, the somatosensory cortex. More importantly, typical imaging techniques such as MRI do not have high enough resolution to see what is happening in the tiny blood vessels, which experts say make up 80 to 85% of the brain’s vascular system.

Kim and his research team created a detailed map of the vascular network of the entire mouse brain using two high-resolution 3D mapping techniques: serial two-photon tomography – a technique that produces a series of stacked 2D images – and light-sheet fluorescence microscopy, which images intact 3D samples to visualize the entire brain at single-cell resolution. The scientists examined the brains of young and old mice to map the changes in the brain’s vasculature during the normal aging process.

Because they perform high-resolution mapping with sufficient resolution, the researchers can reconstruct the entire vascular structure and scan the entire brain to identify those areas that selectively degenerate with age. The experts found that the area that most people examine shows the least change, while profound changes take place in areas deep in the brain. The images showed that the changes in the vascular network are not equally pronounced everywhere in the brain. Rather, they were concentrated in the basal forebrain, the deep cortical layers and the hippocampal network, suggesting that these areas are more susceptible to vascular degeneration. These regions play a role in attention, sleep, memory processing and storage, among other functions.

Hope for Future Treatments for Neurodegenerative Disorders

As the brain ages, vascular length and branching density decrease by about 10%, suggesting that the blood distribution network is sparser. In addition, the arteries in older brains are more curved compared to those in younger brains, which may impede blood flow, especially in areas further away from the main arteries, such as the deep cortical layers. The team also looked at functional changes in the vessels and found that the system responds more slowly in older brains. This means that it cannot supply the neurons with energy as quickly and easily as the cells need it. There is also a loss of pericytes, a type of cell that regulates the blood supply and the permeability of blood vessels. As a result, the blood vessels become “leaky”, compromising the blood-brain barrier.

This study builds on previous research by the group in which they mapped the vasculature of a young mouse brain. Next, they will investigate how the changes in the brain caused by Alzheimer’s disease affect vascular health and neuron function. Ultimately, they hope their work will lead to treatments for neurodegenerative disorders.