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

描述（由申请人提供）：接受颅脑放射治疗儿童癌症的儿童面临长期中枢神经系统 (CNS) 损伤的显着风险。我们的初步数据表明，这些成年幸存者的长期记忆（延迟回忆）受到显着影响，类似于患有阿尔茨海默病的老年人的模式，引起人们对这一人群可能面临早期痴呆风险的担忧。此外，已经确定认知缺陷随着暴露于中枢神经系统辐射后的时间而增加，然而，迄今为止，对该人群的大多数评估都是在暴露后的头 10 年内进行的。目前尚不清楚认知状态（全面智商）是否会在治疗后立即恶化。成年后持续的认知能力下降会增加许多其他不良长期结果的风险。治疗引起的中枢神经系统损伤的潜在机制及其与长期认知的关系尚不清楚。我们提出一项研究，目的是 1) 确定 535 名接受颅脑放射治疗的儿童 ALL 成人幸存者中长期记忆缺陷的患病率，距诊断后 15-45 年（平均 30 年）；2) 确定 145 名接受颅脑放射治疗的儿童 ALL 成年幸存者自上次治疗后检查（距诊断后平均 6.9 年）以来认知功能的变化，距诊断年龄 11-37 年（平均 26 年）。年）从上次检查。此外，我们将使用先进的非侵入性磁共振成像技术来探索长期记忆缺陷与 1) 使用先进 MRI 体积分析、扩散张量成像和功能 MRI 改变中枢神经系统结构和功能之间的关联，以及 2) 随机选择的 140 名幸存者子集中大小血管的脑血管病变（包括中风），从而提供足够的统计能力来识别结构、功能和记忆结果之间的关联。这项研究的结果将指导未来对成年幸存者神经认知缺陷和脑血管病的筛查实践。如果本研究证实存在长期记忆缺陷，则有必要进行未来的纵向调查，以确定痴呆症的长期风险以及预防或延缓痴呆症的干预策略。接触到圣裘德儿童研究医院治疗的 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：确定长期记忆丧失和认知状态恶化的证据将使幸存者和儿童癌症幸存者的治疗者受益。这项拟议的针对儿童癌症辐射暴露成年幸存者的横断面研究结果将直接为 1) 未来结果研究、2) 临床护理指南的制定，包括筛查实践 3) 干预策略的制定和测试提供信息。

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.