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Neurocognitive impairment was defined as age\u2010adjusted <jats:italic>z<\/jats:italic> score\u2009&lt;\u200910th percentile. Participants impaired on \u22653 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe\/disabling; 4, life\u2010threatening) and were combined into a severity\/burden score by frequency and grade (none\/low, medium, high, and very high). A total of 1,598 survivors received CNS\u2010directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity\/burden score and grade 2 to 4 conditions, stratified by CNS treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CNS\u2010treated survivors performed worse than non\u2013CNS\u2010treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, <jats:italic>p<\/jats:italic> &lt;\u20090.001). After adjusting for demographic and treatment factors, there was a dose\u2013response association between severity\/burden score and global neurocognitive impairment, but only among CNS\u2010treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] =\u20091.42\u20133.53; very high OR = 4.07, 95% CI = 2.30\u20137.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS\u2010treated but not non\u2013CNS\u2010treated survivors who were impacted by neurologic conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Reduced cognitive\/brain reserve associated with CNS\u2010directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534\u2013545<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25981","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T10:26:37Z","timestamp":1607077597000},"page":"534-545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood"],"prefix":"10.1002","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7042-5851","authenticated-orcid":false,"given":"AnnaLynn M.","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Cancer Control St Jude Children's Research Hospital  Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin Ting","family":"Cheung","sequence":"additional","affiliation":[{"name":"School of Pharmacy Faculty of Medicine, Chinese University of Hong Kong  Hong Kong 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