This is a K23 award re-submission proposal for Dr. Mary Baron Nelson to provide her with the mentored support needed to accomplish the following goals: 1) become expert at using neuro-imaging research to determine mechanisms underlying injury to the brain; 2) further her understanding of neuroanatomy and physiology and neuropsychological assessment; 3) design and submit an R01 proposal; and 4) develop a career as an independent patient-oriented nurse researcher. Many childhood brain tumor survivors experience detrimental consequences, including neurocognitive deficits, physical disabilities and poor quality of life. Magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging (DTI) and tensor-based morphometry (TBM) allow for examination of structural integrity and volume in a non-invasive manner. Preliminary research of this investigator revealed evidence of chronic injury to multiple brain structures (pons, thalamus, mammillary bodies, caudate, putamen and globus pallidus) a mean of 5 years after treatment with systemic high dose chemotherapy in children with brain tumors. These structures are essential in transmitting information throughout the brain, and interaction between them is an inherent basis for cognition. The patients in the study also had deficits in executive functioning and poor quality of life (QOL). The purpose of this study is to further investigate this pattern o injury by comparing regional white and gray matter, specific brain structural volumes and diffusion indices between 50 children with posterior fossa brain tumors ages 10-16 years and 10 healthy sibling controls, and to determine the relationship of structural injury to neurocognitive, behavioral and QOL outcome. The patient group will consist of 20 patients who were treated with surgery, 10 treated with surgery and chemotherapy, and 20 treated with surgery/chemotherapy/cranial irradiation at least one year prior to study enrollment. All subjects will undergo brain MRI with DTI sequences, a full battery of neuropsychological, behavioral, emotional and QOL assessment. Individual DTI maps will be calculated, normalized and smoothed, and compared between patients and controls using analysis of covariance, with age at diagnosis and treatment as covariates. Post- processing multivariate tensor-based morphometry (mTBM) will compare white and gray matter volumes, and specific structural volumes. Additional analyses will be conducted among the 3 treatment groups to investigate differences in brain tissue injury patterns, neurocognitive and QOL outcomes, using multiple analysis of covariance, with age at diagnosis, current age and gender as covariates. This study will provide new information about patterns of injury and related outcomes in children with brain tumors treated with different modalities, creating a base of knowledge upon which to build interventional research.
One in 650 young adults in the U.S. is a survivor of childhood cancer. Due to neurocognitive deficits from the tumor and its treatment, brain tumor survivors are often unable to achieve social and financial independence and stable meaningful employment. Understanding the process and mechanism of chronic injury to the brain in this population will lead to interventions to improve cognition and quality of life.
