A new USC-led study links abnormal immature astroglia, star-shaped cells that support brain function, to lower fluid intelligence, or the ability to solve new problems, in older adults with epilepsy. Researchers from the USC Stem Cell lab of Michael Bonaguidi, PhD , and their collaborators found that older epilepsy patients tended to have more abnormal immature astroglia in their brains, and that higher numbers of these cells were associated with poorer fluid intelligence. This ability to solve new problems declines with age and becomes impaired in Parkinson's disease, frontotemporal dementia and multiple sclerosis.
The study, supported in part by the National Institutes of Health and published in the journal Frontiers in Cellular Neuroscience, is one of the first to link astroglia numbers to human cognition. Astroglia have traditionally been seen as support cells that help neurons communicate and promote a healthy overall brain environment. Past research on the role of these cells in cognition has mainly relied on animal models or indirect tests, such as measures of gene activity. The new study, by contrast, looks directly at human tissue removed during brain surgery and quantifies astroglia numbers.
The findings come from epilepsy patients, but could have implications well beyond this population, the researchers said. Astroglia could represent a new target for drugs and other treatments aimed at preserving cognitive function as we age.
"Aging is something we're all familiar with and all impacted by—it's a matter of when, not if. What this study provides is a new therapeutic target that could someday help us slow down or potentially even reverse age-related declines in our ability to solve new problems," said Bonaguidi, the study's co-corresponding author, who is an associate professor of stem cell biology and regenerative medicine, gerontology, biomedical engineering and neurological surgery, and assistant director of the USC Neurorestoration Center.
A rare research opportunity
Studying the link between cell types and human brain function is a challenge. Non-invasive technologies used to measure brain function, including electroencephalography and magnetic resonance imaging, do not typically provide enough resolution to study individual cells. Analyzing brain tissue under a microscope can provide more detailed information, but researchers rarely have access to tissue samples from living patients.
The study was a rare exception. Researchers from USC Stem Cell and the USC Neurorestoration Center had the opportunity to analyze tissue samples from 29 patients with mesial temporal lobe epilepsy, which can involve seizures and cognitive decline. The tissue was surgically removed from the hippocampus, a brain region involved in learning and memory, to help treat severe, drug-resistant seizures.
Before surgery, patients completed a series of detailed tests of cognition, including reasoning, memory, attention, language and fine motor coordination. After surgery, researchers examined tissue from each patient under a microscope to identify and count immature astroglia in selected areas of the hippocampus. They then compared the number of immature astroglia with results from the cognitive tests.
"We found that older patients tended to have more abnormal immature astroglia—and that higher numbers of these cells were also associated with poorer performance on tests of fluid intelligence," said the study's first author Aswathy Ammothumkandy, PhD , assistant professor of research in the Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC. "These findings suggest that astroglia could be a shared therapeutic target for accelerated age-related cognitive decline in people with epilepsy, as well as for seizure control, as indicated by our previous research."
Targeting astroglia
Astroglia are not a major focus of drug development, but this study could change that. Although more research is needed to determine whether abnormal immature astroglia contribute directly to cognitive decline, the findings offer an early clue that these cells may play an important role in human cognition.
Ammothumkandy is now searching for molecular differences in immature astroglia that could point to new drug targets. By comparing cells taken from people with epilepsy with control samples, she aims to better understand astroglia and identify ways to restore them to a healthier state.
In addition to drug discovery, future research might also explore ways to boost healthy astroglia function, including through neuromodulation, which uses electrical or magnetic stimulation to alter nervous system activity.
The patients advancing brain science
The rare insights afforded by the study were made possible in part by the USC Neurorestoration Center's integrated approach to studying and restoring brain function, which brings together expertise from clinicians, neuroscientists and engineers.
Past work led by the center has explored innovative approaches to brain imaging , a new way to treat seizures and a potential way to improve memory through electrical stimulation.
"Understanding processes like cognitive decline, which can be accelerated in people with epilepsy, could help us improve these patients' lives while also shedding light on broader questions about brain function that affect us all," said the study's co-author Charles Liu, MD, PhD , professor of clinical neurological surgery, surgery, urology, psychiatry and the behavioral sciences, biokinesiology and physical therapy, and biomedical engineering, and director of the USC Neurorestoration Center. "This group of patients has already made an extraordinary contribution to our understanding of how the brain works."
About this research
In addition to Bonaguidi, Ammothumkandy and Liu, the study's other authors are Luis Corona, Nadia A. Atai, Aidin Abedi, Lina M. D'Orazio, Alisha Cayce, Mohammad Shariq, Ryan McGinn, Darrin Lee, Brian Lee, Christianne Heck and Jonathan J. Russin from USC; Michelle Armacost from USC and Rancho Los Amigos National Rehabilitation Center; Nora Jimenez from Los Angeles General Medical Center; Virginia Zuverza-Chavarria from the Rancho Los Amigos National Rehabilitation Center; and Jason A.D. Smith from USC and the University of South Carolina.
This research was supported by the National Institutes of Health (grant R01AG076956), , the , the Cure Alzheimer's Fund, The Eli and Edythe Broad Foundation, the USC Neurorestoration Center, the Rudi Schulte Research Institute, the American Epilepsy Society, the California Institute for Regenerative Medicine (grant EDUC4-12756), and CURE Epilepsy Taking Flight.
