White matter compromise predicts poor intellectual outcome in survivors of pediatric low-grade glioma

Autor: Fang Liu, Chris Fryer, Frank Wang, Donald J. Mabbott, Isabelle Montour-Proulx, Douglas Strother, Suzanne Laughlin, Dina McConnell, Juliette Hukin, Uri Tabori, Eric Bouffet, Marie-Eve Brière, Daniel L. Keene, Nadia Scantlebury
Rok vydání: 2014
Předmět:
Zdroj: Neuro-Oncology. 17:604-613
ISSN: 1523-5866
1522-8517
DOI: 10.1093/neuonc/nou306
Popis: The relationship between white matter and cognitive outcome in pediatric brain tumor patients treated with cranial radiation is well documented.1–5 The reduction in intellectual function that occurs as a late effect of treatment with cranial radiation in childhood6–10 has been associated with changes to white matter structure.4,11,12 In contrast, there is a paucity of literature examining white matter structure in pediatric brain tumor patients not treated with cranial radiation. Indeed, the neurobiological predictors of adverse cognitive function in this group are understudied compared with those in patients requiring more intensive CNS-directed therapy.13 Considering that most patients treated without cranial radiation survive long after their diagnosis, it is critical to identify factors that may influence neurocognitive outcome. In particular, identifying the neural origin of cognitive deficit is essential for predicting outcome and mitigating long-term adverse effects in the group. Low-grade glioma accounts for 40%–45% of all childhood CNS neoplasms, with the vast majority of patients surviving their disease.14 Treatment for pediatric low-grade glioma (PLGG) is dependent on tumor location. Subtentorial PLGG (ie, cerebellar astrocytoma) is typically treated with maximal surgical resection alone.15,16 Supratentorial PLGG (ie, optic pathway, hypothalamic, thalamic, or third ventricle tumor) is often treated with subtotal resection/biopsy and adjuvant chemotherapy; in some cases multiple surgeries are required.17,18 Cranial radiation is used infrequently to treat PLGG, making this patient population ideal to examine late effects of white matter change in children treated for brain tumor without cranial radiation. Long-term outcome of patients treated for PLGG can be quite variable, ranging from minimal disability in some children to severe neuropsychological deficits and health issues in others.13 For many with PLGG, these complications of survival can lead to poor academic performance, reduced vocational attainment, and compromised quality of life.13,15,19–30 IQ scores below normative means have been observed within 2 years following PLGG diagnosis.15,20,31 Patients with subtentorial tumors do relatively well on global intellectual measures19,20 but display specific deficits in attention, memory, processing speed, and visual-spatial function.19,23 Supratentorial tumors are associated with greater cognitive disability, as well as hearing impairment, endocrine dysfunction, and seizure disorder.22,24,31 Younger age at diagnosis, presence of neurofibromatosis 1 (NF1), shunt placement, and chemotherapy predict lower intelligence scores in PLGG.24,25 Treatment with cranial radiation is associated with worse outcome.25 As yet, there is limited understanding of the neurobiological underpinning of these deficits. The scarcity of literature examining white matter structure in patients not treated with cranial radiation has precluded identification of the neurobiological predictors of adverse cognitive function in this group. In the single study we are aware of that examined white matter structure in pediatric brain tumor patients not treated with cranial radiation, patients with subtentorial astrocytoma demonstrated compromised supra- and subtentorial white matter structure compared with healthy children.32 In the present study, we examined intellectual ability and white matter structure in PLGG patients treated without cranial radiation and in healthy children. We used diffusion tensor imaging (DTI) to measure white matter structure. DTI allows for the visualization of different aspects of tissue microstructure based on water molecule displacement and directionality,33 particularly white matter structure. DTI yields voxelwise maps of several measures, including diffusivity of water movement, tissue anisotropy, and fiber directionality. These maps are based on 3 separate eigenvectors, λ1, λ2, and λ3, calculated by matrix diagonalization.33,34 The eigenvectors are combined to provide the quantitative DTI indices of fractional anisotropy (FA) and mean diffusivity (MD), as well as axial and radial diffusivity (AD and RD, respectively). FA reflects the principal diffusion direction within each voxel and is a ratio of λ1 divided by the sum of λ2 and λ3. FA is considered to reflect myelin structure, as myelin acts as a barrier to free water molecule movement.35 MD measures the magnitude of water diffusion and is the average of λ1, λ2, and λ3.33 MD is thought to reflect both axon and myelin structure.34 The first eigenvector (λ1) measures AD, reflecting diffusion parallel to the axonal fibers. The second and third eigenvectors (λ2 and λ3) represent diffusion perpendicular to axonal fibers.33 Radial diffusivity is the average of λ2 and λ3 and is an overall measure of this perpendicular diffusion.33 Measures of AD and RD are thought to reflect axon and myelin structure, respectively.34 Our first goal was to examine whether white matter compromise mediates poor intellectual outcome in patients with PLGG. We predicted that (i) lower IQ scores and compromised white matter structure would be observed in patients compared with healthy children and (ii) such structural compromise would mediate group effects in intellectual outcome (Fig. 1). Our second goal was to examine specific predictors of outcome in patients treated for PLGG. Hence, we examined the impact of tumor-related, treatment-related, host-related, and environmental variables on white matter. Fig. 1. Path analysis. Weights from multiple regression analyses were employed to estimate the strength of relations between variables for the hypothesized model. Treatment for PLGG was assumed to be causally independent of the other variables. We tested whether ...
Databáze: OpenAIRE
Externí odkaz: