{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:54:22Z","timestamp":1789181662296,"version":"build-2803163510"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Long-term survivors of childhood cancer may be at elevated risk for accelerated brain aging.<\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To determine the brain age gap estimation (BrainAGE), defined as the difference between estimated brain age and chronological age; the association between BrainAGE scores and poor neurocognitive outcomes; and the correlations of plasma biomarkers of oxidative stress, neuroinflammation, and cardiovascular health with older BrainAGE scores and previous exposure to central nervous system\u2013directed therapy in adult survivors of childhood cancer.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cross-sectional study analyzed participants in the St. Jude Lifetime Cohort Study. Included participants were survivors of childhood cancer (brain tumor, acute lymphoblastic leukemia, and Hodgkin lymphoma) and community controls (no history of childhood cancer) aged 18 years or older with a whole brain scan following a neurocognitive assessment. BrainAGE was calculated from January 2016 to February 2021 and analyzed from February 2022 to March 2025. Treatment information, plasma biomarkers, and neurocognitive outcomes were collected.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was estimated brain age (using previously trained machine learning pipelines) and associations of brain age with neurocognitive outcomes. Associations among BrainAGE scores, plasma biomarkers, and neurocognitive outcomes were examined using multivariable linear regression models and Spearman correlations.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 253 survivors of childhood cancer (127 males [50.2%]; mean [SD] age, 31.7 [8.6] years; mean [SD] time since diagnosis, 21.2 [9.8] years) and 43 community controls (24 females [55.8%]; mean [SD] age at evaluation, 31.4 [9.6] years) were included in analyses. Survivors had significantly higher mean BrainAGE scores than controls (6.6 [95% CI, \u201312.5 to 41.1] years vs 0.7 [95% CI, \u20131.0 to 2.4] years older than chronological age;\n P<\/jats:italic>\n &amp;lt; .001). A 10-year increase in BrainAGE score was associated with lower cognitive flexibility (\u03b2\u2009=\u2009\u22120.63; 95% CI, \u22120.82 to \u22120.45), processing speed (\u03b2\u2009=\u2009\u22120.49; 95% CI, \u22120.67 to \u22120.31), working memory (\u03b2\u2009=\u2009\u22120.28; 95% CI, \u22120.53 to \u22120.03) and visual memory (\u03b2\u2009=\u2009\u22120.40; 95% CI, \u22120.58 to \u22120.22), vocabulary (\u03b2\u2009=\u2009\u22120.33; 95% CI, \u22120.48 to \u22120.18), and reading (\u03b2\u2009=\u2009\u22120.31; 95% CI, \u22120.45 to \u22120.18)\n z<\/jats:italic>\n scores after adjusting for age at diagnosis and sex. Neurofilament light was correlated with BrainAGE score in female survivors (Spearman \u03c1\u2009=\u20090.24 [\n P<\/jats:italic>\n \u2009=\u2009.04]) and controls (Spearman \u03c1\u2009=\u2009\u22120.47 [\n P<\/jats:italic>\n \u2009=\u2009.03]). Female survivors who were younger than 10 years at cancer diagnosis and treated with 40 Gy or higher cranial radiation had mean BrainAGE scores higher than 30 years (37.34 [95% CI, 17.4-41.0] years) older than chronological age (\n P<\/jats:italic>\n \u2009=\u2009.004) and had lower sex hormone precursor correlated with higher BrainAGE score (Spearman \u03c1\u2009=\u2009\u22120.44 [\n P<\/jats:italic>\n \u2009=\u2009.01]) and higher cranial radiation dose (Spearman \u03c1\u2009=\u2009\u22120.48 [\n P<\/jats:italic>\n \u2009=\u2009.01]). Among male survivors, correlations of BrainAGE score and cranial radiation dose with malondialdehyde (Spearman \u03c1\u2009=\u2009\u22120.25 [\n P<\/jats:italic>\n \u2009=\u2009.04] and \u22120.26 [\n P<\/jats:italic>\n \u2009=\u2009.04]) and oxidized low-density lipoprotein (Spearman \u03c1\u2009=\u20090.24 [\n P<\/jats:italic>\n \u2009=\u2009.049] and 0.40 [\n P<\/jats:italic>\n \u2009=\u2009.001]) were identified.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion and Relevance<\/jats:title>\n This cross-sectional study found that accelerated brain aging was associated with poorer neurocognitive outcomes and correlated with cranial radiation, biomarkers of atherogenesis, neuronal damage, and sex hormone precursors. These findings can guide future research efforts to reduce the risk of vascular disease in this at-risk population.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.51865","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T16:30:29Z","timestamp":1767112229000},"page":"e2551865","source":"Crossref","is-referenced-by-count":4,"title":["Accelerated Brain Aging, Atherogenicity, and Neurocognition in Adult Survivors of Childhood Cancer"],"prefix":"10.1001","volume":"8","author":[{"given":"Nicholas S.","family":"Phillips","sequence":"first","affiliation":[{"name":"Departments of Psychology and Biobehavioral Science, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Psychology and Biobehavioral Science, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Baedke","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Oncology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah D.","family":"Sabin","sequence":"additional","affiliation":[{"name":"Department of Radiology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten K.","family":"Ness","sequence":"additional","affiliation":[{"name":"Department of Clinical Biomarkers Laboratory, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa M.","family":"Hudson","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"},{"name":"Department of Oncology, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Yasui","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Cancer Control, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebabrata","family":"Mahapatra","sequence":"additional","affiliation":[{"name":"Department of Clinical Biomarkers Laboratory, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenasri","family":"Kumbaji","sequence":"additional","affiliation":[{"name":"Clinical Biomarkers Laboratory, St Jude Children's Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth G.","family":"Tatevossian","sequence":"additional","affiliation":[{"name":"Department of Clinical Biomarkers Laboratory, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Scoggins","sequence":"additional","affiliation":[{"name":"Departments of Psychology and Biobehavioral Science, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AnnaLynn M.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Surgery, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin R.","family":"Krull","sequence":"additional","affiliation":[{"name":"Departments of Psychology and Biobehavioral Science, St Jude Children\u2019s Research Hospital, Memphis, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"issue":"1","key":"zoi251382r2","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nrc3634","article-title":"Survivors of childhood and adolescent cancer: life-long risks and responsibilities.","volume":"14","author":"Robison","year":"2014","journal-title":"Nat Rev Cancer"},{"issue":"6","key":"zoi251382r3","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1053\/j.seminoncol.2013.09.006","article-title":"Cognitive effects of cancer and its treatments at the intersection of aging: what do we know; what do we need to know?","volume":"40","author":"Mandelblatt","year":"2013","journal-title":"Semin Oncol"},{"issue":"5","key":"zoi251382r4","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.16077","article-title":"Late-onset cognitive impairment and modifiable risk factors in adult childhood cancer survivors.","volume":"6","author":"Phillips","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"11","key":"zoi251382r5","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1136\/jnnp-2016-314978","article-title":"Patterns of atrophy in pathologically confirmed dementias: a voxelwise analysis.","volume":"88","author":"Harper","year":"2017","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"zoi251382r6","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2022.103175","article-title":"Brain-age is associated with progression to dementia in memory clinic patients.","volume":"36","author":"Biondo","year":"2022","journal-title":"Neuroimage Clin"},{"issue":"1","key":"zoi251382r7","doi-asserted-by":"publisher","first-page":"12005","DOI":"10.1038\/s41598-022-14904-5","article-title":"Tissue volume estimation and age prediction using rapid structural brain scans.","volume":"12","author":"Hobday","year":"2022","journal-title":"Sci Rep"},{"issue":"5","key":"zoi251382r8","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1038\/mp.2017.62","article-title":"Brain age predicts mortality.","volume":"23","author":"Cole","year":"2018","journal-title":"Mol Psychiatry"},{"key":"zoi251382r9","doi-asserted-by":"publisher","first-page":"789","DOI":"10.3389\/fneur.2019.00789","article-title":"Ten years of BrainAGE as a neuroimaging biomarker of brain aging: what insights have we gained?","volume":"10","author":"Franke","year":"2019","journal-title":"Front Neurol"},{"issue":"9","key":"zoi251382r10","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.1158\/1078-0432.CCR-23-3709","article-title":"Systemic biological mechanisms of neurocognitive dysfunction in long-term survivors of childhood Hodgkin Lymphoma.","volume":"30","author":"Williams","year":"2024","journal-title":"Clin Cancer Res"},{"issue":"4","key":"zoi251382r11","doi-asserted-by":"publisher","DOI":"10.1093\/jncics\/pkad039","article-title":"Genetic variants, neurocognitive outcomes, and functional neuroimaging in survivors of childhood acute lymphoblastic leukemia.","volume":"7","author":"Gandy","year":"2023","journal-title":"J Natl Cancer Inst Cancer Spectr"},{"issue":"23","key":"zoi251382r12","doi-asserted-by":"publisher","first-page":"7270","DOI":"10.1182\/bloodadvances.2023010567","article-title":"Neurocognitive impairment associated with chronic morbidity in long-term survivors of Hodgkin lymphoma.","volume":"7","author":"Phillips","year":"2023","journal-title":"Blood Adv"},{"key":"zoi251382r13","doi-asserted-by":"publisher","first-page":"430","DOI":"10.3389\/fnagi.2017.00430","article-title":"Role of estrogen and other sex hormones in brain aging: neuroprotection and DNA repair.","volume":"9","author":"Z\u00e1rate","year":"2017","journal-title":"Front Aging Neurosci"},{"issue":"1","key":"zoi251382r14","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/ije\/dyaa203","article-title":"Cohort profile: the St. Jude Lifetime Cohort Study (SJLIFE) for paediatric cancer survivors.","volume":"50","author":"Howell","year":"2021","journal-title":"Int J Epidemiol"},{"issue":"5","key":"zoi251382r17","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1080\/23279095.2018.1559165","article-title":"Grooved pegboard test as a measure of executive functioning.","volume":"27","author":"Tolle","year":"2020","journal-title":"Appl Neuropsychol Adult"},{"issue":"2","key":"zoi251382r19","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/S0887-6177(03)00039-8","article-title":"Trail making test A and B: normative data stratified by age and education.","volume":"19","author":"Tombaugh","year":"2004","journal-title":"Arch Clin Neuropsychol"},{"key":"zoi251382r21","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.neuroimage.2017.07.059","article-title":"Predicting brain age with deep learning from raw imaging data results in a reliable and heritable biomarker.","volume":"163","author":"Cole","year":"2017","journal-title":"Neuroimage"},{"issue":"4","key":"zoi251382r22","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1002\/ana.24367","article-title":"Prediction of brain age suggests accelerated atrophy after traumatic brain injury.","volume":"77","author":"Cole","year":"2015","journal-title":"Ann Neurol"},{"issue":"3","key":"zoi251382r23","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.26632","article-title":"BrainAGE: Revisited and reframed machine learning workflow.","volume":"45","author":"Kalc","year":"2024","journal-title":"Hum Brain Mapp"},{"issue":"1","key":"zoi251382r24","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/s43587-024-00753-6","article-title":"Plasma proteomics identify biomarkers and undulating changes of brain aging.","volume":"5","author":"Liu","year":"2025","journal-title":"Nat Aging"},{"key":"zoi251382r25","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.1023651","article-title":"Oxidized low-density lipoprotein associates with cardiovascular disease by a vicious cycle of atherosclerosis and inflammation: a systematic review and meta-analysis.","volume":"9","author":"Hong","year":"2023","journal-title":"Front Cardiovasc Med"},{"key":"zoi251382r26","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.613780","article-title":"Overview of OxLDL and its impact on cardiovascular health: focus on atherosclerosis.","volume":"11","author":"Poznyak","year":"2021","journal-title":"Front Pharmacol"},{"issue":"4","key":"zoi251382r27","doi-asserted-by":"publisher","first-page":"605","DOI":"10.2165\/00003495-200262040-00005","article-title":"Drugs affecting homocysteine metabolism: impact on cardiovascular risk.","volume":"62","author":"Desouza","year":"2002","journal-title":"Drugs"},{"issue":"22","key":"zoi251382r28","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1016\/j.jacc.2017.04.010","article-title":"LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation.","volume":"69","author":"Pothineni","year":"2017","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"zoi251382r29","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/s41467-020-14612-6","article-title":"Serum neurofilament light levels in normal aging and their association with morphologic brain changes.","volume":"11","author":"Khalil","year":"2020","journal-title":"Nat Commun"},{"issue":"6","key":"zoi251382r30","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1002\/ana.24954","article-title":"Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis.","volume":"81","author":"Disanto","year":"2017","journal-title":"Ann Neurol"},{"key":"zoi251382r31","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102566","article-title":"Molecular mechanisms of neurofilament alterations and its application in assessing neurodegenerative disorders.","volume":"102","author":"Devarakonda","year":"2024","journal-title":"Ageing Res Rev"},{"issue":"8","key":"zoi251382r32","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1002\/acn3.51622","article-title":"Decreased neurofilament light chain levels in estriol-treated multiple sclerosis.","volume":"9","author":"Voskuhl","year":"2022","journal-title":"Ann Clin Transl Neurol"},{"issue":"25","key":"zoi251382r33","doi-asserted-by":"publisher","first-page":"2599","DOI":"10.1056\/NEJMoa040967","article-title":"Inflammatory markers and the risk of coronary heart disease in men and women.","volume":"351","author":"Pai","year":"2004","journal-title":"N Engl J Med"},{"key":"zoi251382r34","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1206541","article-title":"A novel therapeutic vaccine targeting the soluble TNFa receptor II to limit the progression of cardiovascular disease: AtheroVax\u2122.","volume":"10","author":"Iversen","year":"2023","journal-title":"Front Cardiovasc Med"},{"issue":"24","key":"zoi251382r35","doi-asserted-by":"publisher","first-page":"3858","DOI":"10.1200\/JCO.2006.05.9055","article-title":"Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate.","volume":"24","author":"Spiegler","year":"2006","journal-title":"J Clin Oncol"},{"key":"zoi251382r15","volume-title":"Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV)","author":"Wechsler","year":"2008"},{"key":"zoi251382r16","volume-title":"California Verbal Learning Test, 2nd edition: Adult Version Manual","author":"Delis","year":"2000"},{"key":"zoi251382r18","volume-title":"The Measurement and Appraisal of Adult Intelligence","author":"Wechsler","year":"1958","edition":"4th ed"},{"key":"zoi251382r20","volume-title":"Delis-Kaplan Executive Function System","author":"Delis","year":"2001"},{"key":"zoi251382r1","unstructured":"Howlader? N, Noone? AM, Krapcho? M, , eds. SEER Cancer Statistics Review, 1975-2017. National Cancer Institute; 2020. Accessed January 25, 2025. https:\/\/seer.cancer.gov\/csr\/1975_2017\/"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2843232\/phillips_2025_oi_251382_1766090483.58661.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T16:30:31Z","timestamp":1767112231000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2843232"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":35,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2025.51865","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,30]]}}}