Improved brain mapping reveals subtle cognitive changes in older adults with preclinical Alzheimer’s disease

Neuroscientists at the Medical University of South Carolina (MUSC) report in brain connectivity that they detected subtle differences in brain function in older people with preclinical Alzheimer’s disease (AD).

Adults with preclinical AD show early signs of the disease, such as amyloid-beta protein buildup in their brains. However, they show no noticeable symptoms of cognitive decline.

The research team, led by Andreana Benitez, Ph.D., and Stephanie Fountain-Zaragoza, Ph.D., used a new brain imaging analysis technique to construct individualized maps of brain function. They then investigated whether there were links between subtle changes in brain function and lower cognitive performance, assessed using behavior-based tests. This approach could improve the ability to study the preclinical phase of AD.

Previous studies have not found an association between brain function and behavior in preclinical AD. Using these individualized maps of brain function, we found a potential brain-based reason for very subtle cognitive changes in this early phase of the disease.”

Andreana Benitez, Ph.D.

Detect subtle changes in brain function through enhanced brain mapping

Research on the preclinical phase of AD could help us understand how the disease begins and progresses. However, early changes in brain function are very subtle, making them difficult to study. With funding from a pilot project from the South Carolina Clinical & Translational Research Institute, MUSC researchers used a new form of brain mapping to detect these subtle effects.

They examined brain activity using a functional connectome – a type of brain map that measures how different regions of the brain communicate with each other. Think of the brain as a big city, Fountain-Zaragoza said, where brain regions are clustered in neighborhoods connected by highways. The functional connectome is like looking at the activity across this city – how much is happening in each neighborhood and how much traffic is flowing between them.

The researchers relied on a more recent and very sensitive form of image analysis to assess the functioning of these neighborhoods in individuals. The technique – the Individualized Functional Connectome – was developed by their collaborator Hesheng Liu, Ph.D.

Traditional functional connectomes use an average of many people’s brains as a map of functional brain regions. In contrast, Liu’s method can show unique patterns of brain function for each individual.

“We all have the same functional parts of our brains, but they’re positioned slightly differently, much like a fingerprint,” Fountain-Zaragoza said. “This method creates an individualized brainprint that more accurately reflects where different functional regions are located in each individual’s brain.”

Connecting subtle changes in brain function to behavior

The researchers used this new brainprinting technique to look for subtle changes in brain function in 149 participants between the ages of 45 and 85 without signs of cognitive decline. All participants underwent PET scans of their brains and were divided into two groups – those with and without PET evidence of early beta-amyloid protein accumulation. The participants also underwent MRI scans, which were used to generate brain fingerprints.

The researchers then tested the performance of participants in each group on behavior-based information-processing tests. They found that certain changes in brain imprinting were associated with poorer information processing in participants with beta-amyloid accumulation or preclinical Alzheimer’s disease.

In participants with preclinical AD, information processing was worse in those who had higher than normal inter-network connectivity or too much activity on brain highways. In contrast, information processing was better in those who had higher intra-network connectivity or more brain activity in important areas of the brain.

“A healthy brain typically has a balance of connectivity within and between its networks,” Fountain-Zaragoza said. “We found that in preclinical AD – when amyloid buildup is present in the brain – this balance can be disrupted, which can lead to information not being processed as efficiently.”

What the study tells us

The study shows that individualized functional connectomes can detect subtle variations in brain function that might be missed with other conventional brain imaging analysis techniques.

It also suggests that the early stages of beta-amyloid accumulation could affect the function of brain networks even before symptoms of cognitive decline become noticeable.

Finally, it reveals that changes in connectivity within and between specific brain networks may indicate early information processing problems. This connectivity imbalance could therefore be a good target for therapies aimed at improving outcomes for patients with AD.

Next steps

With renewed grants from the National Institute of Aging, Benitez and Fountain-Zaragoza plan to continue their work on preclinical AD. They hope to focus more on how brain changes affect disease progression and also explore new treatments, such as brain stimulation, that can help slow it down.

“There’s a lot of great work out there aimed at helping us understand the early signs and symptoms of Alzheimer’s disease,” Fountain-Zaragoza said. “This area of ​​work is important for understanding the full spectrum of the disease and identifying who might be at risk of developing it.”