Long-term Treatment Related CNS Injury in Survivors of Childhood Cancer

描述（由申请人提供）：接受颅放射治疗儿童癌症的儿童有长期中枢神经系统（CNS）损伤的重大风险。我们的初步数据表明，长期记忆（延迟回忆）在这些成年幸存者中受到显着影响，类似于阿尔茨海默病老年人中的模式，引起了人们对这一人群可能有早期痴呆症风险的担忧。此外，已确定认知缺陷在暴露于CNS辐射后随着时间的推移而增加，然而，迄今为止，对该人群的大多数评价都发生在暴露后的前10年。目前尚不清楚认知状态（全量表IQ）是否超出该治疗后即刻阶段。持续的认知能力下降到成年会增加许多其他不良长期结果的风险。治疗诱导的CNS损伤的潜在机制及其与长期认知的关系知之甚少。我们提出了一项研究，以1）确定535名儿童急性淋巴细胞白血病成人幸存者中长期记忆缺陷的患病率，这些人接受了颅脑放射治疗，现在15-45岁。（平均30年）诊断和2）确定自最后一次治疗后检查以来认知功能的变化（平均6.9年的诊断）的145名成人幸存者的儿童ALL治疗颅放射治疗，现在11-37年（平均26年），从以前的检查。此外，我们将使用先进的、非侵入性的磁共振成像技术来探索长期记忆缺陷与1）使用先进的MRI体积分析的CNS结构和功能改变之间的关联，弥散张量成像和功能MRI与2）脑血管病（包括中风）在随机选择的140名幸存者的子集中，大血管和小血管的数量，提供了足够的统计能力来确定结构、功能和记忆结果。这项研究的结果将指导未来的筛查实践的神经认知缺陷和脑血管病的成年幸存者。如果在这项研究中证实了长期记忆缺陷，未来的纵向调查将是必要的，以确定痴呆症的长期风险以及预防或延迟痴呆症的干预策略。在圣裘德儿童研究医院接受治疗的4,000多名儿童癌症成年幸存者使这项研究变得可行。 公共卫生相关性：识别长期记忆丧失和认知状态恶化的证据将使幸存者和那些治疗儿童癌症幸存者的人受益。这项针对儿童期癌症辐射暴露成年幸存者的横断面研究的结果将直接为1）未来的结果研究提供信息，2）制定临床护理指南，包括筛查实践3）开发和测试干预策略。

DESCRIPTION (provided by applicant): Children who received cranial radiation for treatment of childhood cancer are at significant risk for long- term central nervous system (CNS) injury. Our preliminary data suggests long-term memory (delayed recall) is significantly impacted in these adult survivors similar to patterns seen in aging adults with Alzheimer's disease, raising concern that this population may be at risk for early dementia. Furthermore, it is established that cognitive deficits increase with time after exposure to CNS radiation, however, to date, most evaluations of this population have occurred in the first 10 years from exposure. It is unknown whether cognitive status (full scale IQ) worsens beyond this immediate post-treatment period. Ongoing cognitive decline into adulthood would increase risk for many other poor long-term outcomes. The underlying mechanisms of treatment-induced CNS injury and its relationship to long-term cognition are poorly understood. We propose a study to 1) determine the prevalence of long-term memory deficits among 535 adult survivors of childhood ALL treated with cranial radiotherapy and now 15-45 years (mean 30 years) from diagnosis and 2) identify change in cognitive function since the time of the last post-therapy examination (mean 6.9 year from diagnosis) among 145 adult survivors of childhood ALL treated with cranial radiotherapy and now 11-37 years (mean 26 years) from previous examination. In addition, we will use advanced, non-invasive, magnetic resonance imaging techniques to explore associations between long-term memory deficits and 1) alterations in CNS structure and function using advanced MRI volumetric analysis, diffusion tensor imaging and functional MRI and 2) cerbrovasculopathy (including stroke) of both large and small vessels in a randomly selected subset of 140 survivors providing sufficient statistical power to identify associations between structure, function and memory outcomes. The results of this study will guide future screening practices for both neurocognitive deficits and cerbrovasculopathy in adult survivors. If long-term memory deficits are confirmed in this study, future longitudinal investigation will be necessary to determine long-term risk for dementia as well as intervention strategies to prevent or delay dementia. Access to more than 4,000 adult survivors of childhood cancer treated at St. Jude Children's Research Hospital makes this study feasible. PUBLIC HEALTH RELEVANCE: Identifying long-term memory loss and evidence for worsening cognitive status will benefit survivors and those who treat survivors of childhood cancer. Results from this proposed cross-sectional study of radiation exposed adult survivors of childhood cancer will directly inform 1) future outcomes research, 2) formulation of clinical care guidelines, including screening practices 3) development and testing of intervention strategies.