Neurobiologic Mechanisms of Cognitive Dysfunction and Decline in Medulloblastoma

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DESCRIPTION (provided by applicant): With the rising number of children who survive invasive brain tumors such as medulloblastoma (MB) which is the second most common tumor type, cognitive sequelae of these neoplasms and their treatments have begun to receive increased attention. This attention is particularly focused on the extensive, long-term disabilities that these cognitive impairments pose for patients and their families. Studies indicate that anti- cancer treatments (chemotherapy and cranial radiation) increase the risk for long-term cognitive deficits in children and that these impairments are often progressive. The prospect of intervening to change this trajectory thus has tremendous significance from a lifespan perspective - potentially affecting school services, family dynamics, vocational readiness and social services support. However, factors mediating the risk for cognitive impairments in children with MB or other types of cancer have not been adequately explored. The overarching aim of this project is to use advanced, multi-modal magnetic resonance imaging (MRI) techniques, focused genetic analyses and cognitive-behavioral assessment to elucidate the effects of MB and its treatments on functional neuroanatomy and cognitive-behavioral outcome. The specific aims are 1) to examine the neuroanatomical and neurofunctional substrates of cognitive impairment and decline in children with MB, 2) elucidate neurobiologic factors subserving gender differences in cognitive outcome among children with MB, and 3) determine the interaction of genetic, demographic and medical variables in predicting the cognitive trajectory of children with MB. Forty children with MB and 30 age and gender matched healthy controls age 3-14 years will undergo comprehensive neuropsychological and neuroimaging assessments at baseline and 12 months. Additionally, DNA will be extracted from saliva samples from all subjects and genotyped for catechol-O-methyltransferase (COMT) which is believed to influence cognitive outcome in individuals with brain injury. The ultimate goal of this research is to inspire the development of more specific and precise interventions, as well as to better understand when intervention is most needed and most effective. The research proposed here also will contribute more broadly to a better understanding. RELEVANCE : The ultimate goal of this research is to inspire the development of more specific and precise interventions for children with cancer, as well as to better understand when intervention is most needed and most effective. The research proposed here also will contribute more broadly to a better understanding of how early cancer- related brain injury affects brain development and neural organization in humans.