INDIANAPOLIS — Researchers from the Indiana University School of Medicine have developed a highly sensitive diagnostic that predicts a person’s stage of dementia based on neurovascular and metabolic changes. They recently published their findings in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
Years before a person experiences the earliest symptoms of dementia or Alzheimer’s disease, scientists say there’s an imbalance in energy metabolism and blood flow in the brain — specifically within regions connected to memory, cognition and learning.
The IU research team — led by Paul Territo, PhD, professor of medicine, and Juan Antonio K. Chong Chie, PhD, postdoctoral research fellow — studied how cerebral perfusion, which is the flow of blood to the brain, and glucose metabolism, which is how the body breaks down and stores glucose for energy, change across dozens of brain regions in more than 400 human patients. They discovered that metabolism and perfusion in the brain may become dysregulated as early as 20 years prior to a clinical diagnosis of dementia or cognitive impairment changes.
The researchers previously developed this novel method to analyze perfusion and metabolism brain scans of animal models developed by the Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) center. They found that metabolism and perfusion were some of the first biological processes that become dysregulated in the progression of Alzheimer’s disease and dementia — potentially long before the accumulation of amyloid plaques and tau tangles, two major hallmarks of the neurodegenerative disorder.
In the recent study, the team investigated brain metabolism using PET scans and blood flow using MRI scans of 403 humans from the Alzheimer’s Disease Neuroimaging Initiative database and tracked the neurovascular and metabolic changes over the disease course. They confirmed these findings through gene signatures and clinical cognitive tests.
“Our data indicate that inflammation plays a major role early, which leads to metabolic and vascular damage,” Territo said. "This work confirmed that what we hypothesized in the mice occurs in humans as well. We’re able to see from the earliest phases of Alzheimer's disease and related dementia through to advanced disease.
“This approach permits assessment of disease progression and can be used for patient stratification and to monitor therapeutic response. If you analyze brain regions that have neuro-metabolic and vascular disruptions and then give a drug that mitigates those disruptions, we should see a regression of those processes along with fewer inflammatory signatures and improvements in cognition."
The group of patients the team studied was clinically diagnosed across the disease spectrum for dementia and memory conditions, which include cognitively normal, early mild cognitive impairment, mild cognitive impairment, late mild cognitive impairment and Alzheimer’s disease.
The lab developed a framework to assess the neuro-metabolic and vascular dysregulation in the brains of the patients — the same approach they used in animal models. This approach divides the process into four different phases of metabolism and perfusion changes that closely align with disease progression, Territo said. These range from decreased metabolism and increased blood flow at the earliest stage to decreases in metabolism and blood flow at the final stage of Alzheimer’s disease.
"What we observe in both animal models and humans is, as you progress across the entire spectrum of disease,” Territo said, “you fall into one of the four different neuro-metabolic and vascular states, and these states and their trajectories are specific for each region.”
Territo said the team discovered that among the 59 regions of the brain they evaluated in patients, some regions were more susceptible and progressed faster toward disease, while others were more resilient and progressed slower. Regions associated with memory, learning and cognition, he added, were impacted first and least tolerant of the neuro-metabolic and vascular dysregulation. They also found that disease progression varies by sex; females progress faster in disease compared to males.
Additionally, these changes aligned with gene signatures — specific sets of genes gathered through blood samples that classify diseases — and clinical cognitive tests of the patients, said Chong Chie, who also verified similarities with their animal model studies.
Researchers will next study how different regions of the brain communicate and connect after undergoing metabolic and vascular changes.
"Our analysis tells you that the brain undergoes these deficits, but what it doesn't tell you is how the brain is structured and how those structures change with disease," Territo said. "We'll next aim to answer those questions, and that will also allow us to help stratify the patient population. It's just a matter of looking at it in a unique way that others have not to date."
About the Indiana University School of Medicine
The IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability. According to the Blue Ridge Institute for Medical Research, the IU School of Medicine ranks No. 13 in 2024 National Institutes of Health funding among all public medical schools in the country.
Writer: Ben Middelkamp, bmiddel@iu.edu
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