Neurobiologic Mechanisms of Cognitive Dysfunction and Decline in Medulloblastoma

描述（由申请人提供）：随着侵袭性脑肿瘤（如髓母细胞瘤（MB），这是第二种最常见的肿瘤类型）存活的儿童数量不断增加，这些肿瘤及其治疗的认知后遗症开始受到越来越多的关注。这种关注特别集中在这些认知障碍对患者及其家人造成的广泛，长期的残疾上。研究表明，抗癌治疗（化疗和颅部放疗）会增加儿童长期认知缺陷的风险，而且这些缺陷往往是渐进性的。因此，从生命周期的角度来看，干预改变这一轨迹的前景具有巨大的意义-可能影响学校服务、家庭动态、职业准备和社会服务支持。然而，尚未充分探讨MB或其他类型癌症儿童认知障碍风险的介导因素。该项目的总体目标是使用先进的多模态磁共振成像（MRI）技术，集中的遗传分析和认知行为评估，以阐明MB及其治疗对功能神经解剖学和认知行为结果的影响。具体目的是：1）检查MB儿童认知障碍和下降的神经解剖学和神经功能基础，2）阐明MB儿童认知结果中性别差异的神经生物学因素，3）确定遗传，人口统计学和医学变量在预测MB儿童认知轨迹中的相互作用。40名MB儿童和30名年龄和性别匹配的3-14岁健康对照儿童将在基线和12个月时接受全面的神经心理学和神经影像学评估。此外，将从所有受试者的唾液样本中提取DNA，并对儿茶酚-O-甲基转移酶（COMT）进行基因分型，认为COMT会影响脑损伤个体的认知结果。这项研究的最终目标是激发更具体和精确的干预措施的发展，以及更好地了解什么时候最需要干预和最有效。这里提出的研究也将有助于更广泛地更好地理解。相关性：这项研究的最终目标是激发为癌症儿童制定更具体、更精确的干预措施，并更好地了解何时最需要干预，何时最有效。这里提出的研究也将有助于更广泛地了解早期癌症相关的脑损伤如何影响人类的大脑发育和神经组织。

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.