Childhood Neurotoxicity and Brain Resilience to Adverse Events During Adulthood.

OBJECTIVE To use childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHC). METHODS Adult survivors of childhood cancer (n=2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical exam. Neurocognitive impairment was defined as age-adjusted Z-score <10th percentile. Participants impaired on ≥3 tests had global impairment. CHC were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1:mild, 2:moderate, 3:severe/disabling), 4:life-threatening), and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). 1,598 survivors received CNS directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2-4 conditions, stratified by CNS treatment. RESULTS CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p<0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high OR=2.24, 95%CI 1.42-3.53; very high OR=4.07, 95%CI 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors, who were impacted by neurologic conditions. INTERPRETATION Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. This article is protected by copyright. All rights reserved.