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）损伤的显著风险。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）受到显著影响，与老年阿尔茨海默病患者的模式相似，这引起了人们对这一人群可能存在早期痴呆风险的担忧。此外，已经确定认知缺陷在暴露于中枢神经系统辐射后随着时间的推移而增加，然而，迄今为止，对这一人群的大多数评估都发生在暴露后的前10年。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。成年后认知能力持续下降会增加许多其他不良长期后果的风险。治疗性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。我们提出了一项研究，1)确定535名接受颅放射治疗的儿童ALL成年幸存者中长期记忆缺陷的患病率，从诊断到现在15-45年（平均30年）；2)确定145名接受颅放射治疗的儿童ALL成年幸存者中自上次治疗后检查（平均6.9年）以来认知功能的变化，从上次检查到现在11-37年（平均26年）。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以下因素之间的联系：1)使用先进的MRI体积分析、弥散张量成像和功能MRI来改变中枢神经系统结构和功能；2)随机选择140名幸存者的大血管和小血管病变（包括中风），提供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在成年幸存者中神经认知缺陷和脑血管病的筛查实践。如果长期记忆缺陷在本研究中得到证实，未来的纵向调查将有必要确定痴呆的长期风险以及预防或延缓痴呆的干预策略。在圣犹达儿童研究医院接受治疗的4000多名儿童癌症成年幸存者使这项研究成为可能。

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.