Neurometabolic correlates of accelerated aging and neurocognitive late effects in long-term survivors of pediatric hodgkin lymphoma and acute lymphoblastic leukemia

Adult survivors of pediatric cancers are at elevated risk for neurocognitive late effects, but how these effects relate to metabolic perturbations in the brain remains unclear. To address this knowledge gap, the present study explored associations between neurometabolite levels and neurocognitive function in adult survivors of Hodgkin lymphoma (HL) and acute lymphocytic leukemia (ALL). Data were collected from a single-center observational study conducted at St. Jude Children's Research Hospital (SJCRH) between October 2022 and November 2024. Adult survivors of HL (<i>N</i>=11 [5 females]; ≥5 years post-diagnosis; mean [SD] current age 34 [9.5] years) and ALL (<i>N</i>=24 [16 females]; ≥5 years post-diagnosis; current age 40 [12.6] years) and community controls (<i>N</i>=35 [17 females]; current age 40 [11] years) completed standardized neurocognitive tests of memory, attention, executive function, and processing speed. Participants also underwent proton magnetic resonance spectroscopy (¹H MRS) to quantify neurometabolite levels in the left dorsolateral prefrontal cortex (dlPFC), left hippocampus, and left cerebellum. Analyses used regression models to examine differences in the slope of the relationship between neurometabolite and neurocognitive function or between neurometabolite and age. When comparing HL survivors vs controls, significant interactions were identified for group × age on the ratio of myo-inositol to N-Acetyl aspartic acid (mI/NAA; <i>p</i>=0.007) and group × Gamma-Aminobutyric Acid (GABA) on processing speed (<i>p</i>=0.04) in the left dlPFC. When comparing ALL survivors vs controls, significant interactions were identified for group × myo-inositol on verbal fluency in the left hippocampus (<i>p</i>=0.01) and group × GABA on cognitive flexibility in the left cerebellum (<i>p</i>=0.01). These preliminary findings suggest that neuroinflammation may be a mechanistic underpinning of age-associated neurocognitive impairment in pediatric cancer survivors.