RESUMEN
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.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Trastornos del Conocimiento/inducido químicamente , Metotrexato/efectos adversos , Ácido Palmítico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Ácidos Esteáricos , Análisis de Varianza , Niño , Cromatografía de Gases , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/metabolismo , Femenino , Humanos , Pruebas de Inteligencia , Masculino , NAD/antagonistas & inhibidores , NAD/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Ácido Palmítico/líquido cefalorraquídeo , Ácido Palmítico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Desempeño Psicomotor , Factores de Riesgo , Estadísticas no Paramétricas , Ácidos Esteáricos/líquido cefalorraquídeo , Ácidos Esteáricos/metabolismoRESUMEN
Free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) are recognized as markers of brain damage in animal studies. There is, however, relatively little information regarding FFA concentrations in human CSF in normal and pathological conditions. The present study examined FFA concentrations in CSF from 15 patients with traumatic brain injury (TBI) and compared the data with values obtained from 73 contemporary controls. Concentrations of specific FFAs from TBI patients, obtained within 48 h of the insult were significantly greater than those in the control group (arachidonic, docosahexaenoic and myristic, P<0.001; oleic, palmitic, P<0.01; linoleic, P<0.05). Higher concentrations of total polyunsaturated fatty acids (P<0.001) and of arachidonic, myristic and palmitic acids measured individually in CSF (P<0.01) obtained 1 week after the insult were associated with a worse outcome at the time of hospital discharge using the Glasgow Outcome Scale. This preliminary investigation suggests that CSF FFA concentrations may be useful as a predictive marker of outcome following TBI.
