title: Methotrexate-induced alterations in beta-oxidation correlate with cognitive abilities in children with acute lymphoblastic leukemia.
abstract: Treatment advances, including central nervous system (CNS) treatment with methotrexate, have led to significant gains in disease-free survival from childhood acute lymphoblastic leukemia (ALL). However, methotrexate has been associated with neurological problems such as declines in cognitive and academic abilities. The purpose of this study was to investigate methotrexate-induced changes in beta-oxidation in children with ALL receiving methotrexate for CNS treatment. Specific aims were to investigate effects of methotrexate on beta-oxidation of the two most prevalent fatty acids (palmitic acid and stearic acid) in cerebrospinal fluid (CSF) samples and correlate the ratio of monounsaturation to saturation of these fatty acids with cognitive and academic abilities. The sample included 12 females and 14 males with low-risk (n = 7), standard-risk ( n = 13), or high-risk (n = 6) ALL. Mean age at diagnosis was 94.1 months (SD = 34.4). CSF samples were obtained in conjunction with diagnostic lumbar punctures; subsequent samples were obtained prior to intrathecal methotrexate administration during the induction, consolidation, and continuation phases of treatment. Fatty acids were analyzed by gas chromatography. Results showed a significant increase in the ratio of monounsaturation to saturation of both fatty acids, which was greatest during the most intensive phase of treatment. Ratios of monounsaturated to saturated fatty acids were negatively correlated with full-scale IQ, verbal IQ, and math calculations. Findings suggest that methotrexate alters beta-oxidation and that the resulting increase in fatty acid monounsaturation is related to declines in some domains of cognitive ability.
authors.affiliation: College of Nursing, University of Arizona, Tucson, AZ 85721-0203, USA. kmoore@nursing.arizona.edu
authors.forename: Ida M Ki
authors.initials: IM
authors.lastname: Moore
authors.forename: Petra
authors.initials: P
authors.lastname: Miketova
authors.forename: Marilyn
authors.initials: M
authors.lastname: Hockenberry
authors.forename: Kevin
authors.initials: K
authors.lastname: Krull
authors.forename: Alice
authors.initials: A
authors.lastname: Pasvogel
authors.forename: Marissa
authors.initials: M
authors.lastname: Carey
authors.forename: Kris
authors.initials: K
authors.lastname: Kaemingk
mesh_terms: D000704:Analysis of Variance; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D002648:Child; D002849:Chromatography, Gas; D003072:Cognition Disorders / Q000134:cerebrospinal fluid / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism; D005260:Female; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D009243:NAD / Q000037:antagonists & inhibitors / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D019308:Palmitic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy*; D011597:Psychomotor Performance; D012307:Risk Factors; D018709:Statistics, Nonparametric; D013229:Stearic Acids / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D013229:Stearic Acids; D009243:NAD; D019308:Palmitic Acid; D008727:Methotrexate