Brain aging and neurocognitive outcomes in survivors of childhood cancer

While survival for most pediatric cancers has improved significantly, the impact of cancer and its treatment often extends well beyond childhood. Survivors of childhood cancer face a range of unique long-term health challenges related to both their disease and the therapies used to treat it. However, much remains to be understood about the full scope of these effects and the mechanisms underlying them.

Among these health challenges is accelerated aging, where a patient’s biological age exceeds their chronological age due to disease-related stress and treatment toxicity. In many cases, chronic health conditions, such as cardiovascular, metabolic, or cognitive issues, can develop in survivors much earlier than would be expected for their chronological age.

A study led by co-corresponding authors Kevin Krull, PhD, Department of Psychology & Biobehavioral Sciences chair, and Nicholas Phillips, MD, PhD, Department of Psychology & Biobehavioral Sciences, used a machine-learning method to determine the brain age gap estimation (BrainAGE), defined as the difference between the estimated brain age and chronological age, of survivors compared to community controls.

“This is the first study to demonstrate accelerated structural and functional brain aging in adult survivors of pediatric cancer,” Krull said. “It raises the concern that a significant proportion of these survivors may be at heightened risk for accelerated neurocognitive declines, though at the same time offers insight into potential interventions to mitigate this risk.”

This cross-sectional study, published in JAMA Network Open, included 253 adult survivors of childhood brain tumors, acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma enrolled in the St. Jude Lifetime Cohort Study, as well as a group of age-matched community controls. The researchers assessed treatment histories, blood biomarkers, and cognitive data, and used these assessments to calculate the BrainAGE score. This score represents the difference between estimated brain age and chronological age, obtained from magnetic resonance imaging (MRI) conducted at St. Jude.

BrainAGE scores were higher in adult survivors of childhood cancer compared to community controls, and survivors whose brains appeared older than expected (higher BrainAGE scores) were more likely to experience cognitive difficulties. Higher BrainAGE scores were also associated with elevated plasma biomarkers of oxidative stress, neuroinflammation, and cardiovascular dysfunction, as well as prior exposure to central nervous system–directed therapies. While these findings are based on a select group of survivors, they provide important insights, and additional research is needed to better understand how they apply across survivor populations.

The researchers found that many of the elevated biomarkers were related to vascular disease, suggesting that targeted interventions to improve vascular health and thus potentially protect neurocognitive health could be a fruitful area of future research.

“This study validates what we are hearing from our survivors,” Phillips said. “They are experiencing age-related memory loss and processing speed problems at a much younger age than their siblings. It also suggests that interventions that often support cerebrovascular health, such as physical exercise, healthy nutrition, sleep hygiene, and stress management, may reduce this risk and promote healthy brain aging.”