title: Systemic Chemotherapy and White Matter Integrity in Tracts Associated with Cognition Among Children With Neurofibromatosis Type 1.
abstract: BACKGROUND
  Children with neurofibromatosis type 1 (NF1) are predisposed to both brain tumors and cognitive deficits. While changes in white matter integrity after multimodal therapy are associated with cognitive dysfunction, the effect of isolated chemotherapy in NF1 is unknown. To determine whether chemotherapy is associated with white matter microstructural changes, we examined diffusion tensor imaging (DTI) in NF1 subjects.
  
  
  METHODS
  We reviewed DTI measures in tracts associated with cognition but free from tumor in 24 children with NF1-associated optic pathway gliomas unexposed to surgery or radiation. Twelve age-matched pairs were identified based on exposure to chemotherapy. A paired t-test was used to compare fractional anisotropy (FA) in tracts of interest between subjects with and without chemotherapy exposure.
  
  
  RESULTS
  On paired t-test, FA was significantly lower in the corpus callosum (P = 0.015) and cerebellothalamic (P = 0.038) tracts of subjects exposed to chemotherapy. There was no effect of age or time from chemotherapy on the difference between groups. In multivariable analysis, FA of these tracts was associated with chemotherapy exposure after adjusting for age, tumor location, and DTI acquisition. In longitudinal measures, FA decreased after chemotherapy exposure while FA increased with age in unexposed subjects.
  
  
  CONCLUSIONS
  Exposure to low-intensity chemotherapy in NF1 is associated with changes in white matter microstructure in tracts associated with cognition. Future studies should determine whether these changes are associated with cognitive decline. While chemotherapy may spare cognition relative to radiation and surgery, children with NF1 exposed to chemotherapy may benefit from early cognitive testing to allow for earlier intervention.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Peter Matthew Kennedy
authors.initials: PM
authors.lastname: de Blank
authors.affiliation: Department of Radiology, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Berman
authors.affiliation: Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael Jay
authors.initials: MJ
authors.lastname: Fisher
mesh_terms: D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D003071:Cognition; D003337:Corpus Callosum / Q000473:pathology*; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000473:pathology*; D012189:Retrospective Studies; D066127:White Matter / Q000473:pathology*
keywords: chemotherapy; cognition; diffusion tensor imaging; low-grade glioma; neurofibromatosis type 1