Brain Age in Adult Survivors of Childhood Leukemia and CNS Tumor

摘要 儿童癌症的长期幸存者可能面临加速衰老和早发的风险增加 痴呆症，特别是白血病幸存者和接受治疗的中枢神经系统(CNS)肿瘤幸存者 用神经毒性疗法。我们最近证实白血病和中枢神经系统肿瘤的端粒长度较短 比社区控制和其他类型的儿童癌症更常见。我们还确认，幸存者 在25到40岁之间，白血病和中枢神经系统肿瘤的进行性记忆力下降的风险最大 在癌症确诊后的几年里。儿童白血病和中枢神经系统肿瘤的成年幸存者脑白质降低 灰质体积和较小的海马体，符合痴呆症的特征。与非癌症相比 与对照组相比，这些幸存者表现出较低的海马区与颅顶体积的比率，表明 颅骨发育高峰后的脑组织体积。这种较低的比率与内存问题有关 并可能预示着大脑加速老化和早发性痴呆。一位年轻人接受中枢神经系统指导的癌症治疗 年龄会限制认知和大脑储备的发展(即对未来脑损伤的恢复能力)，并降低 储备与普通人群中患痴呆症的风险增加有关。然而，全面的 儿童癌症成年幸存者的脑老化评估尚未见报道。我们建议计算 儿童癌症和社区控制的成年幸存者的大样本的大脑年龄。到目前为止，大脑 已经收集了793名儿童白血病成年幸存者，197名中枢神经系统幸存者的成像扫描 肿瘤和250名社区对照在年龄、性别和种族上匹配。我们将比较大脑和大脑之间的差异 幸存者和对照组的年龄和实际年龄，并检查脑年龄之间的关系 与治疗、健康、功能状态和生物标记物措施的差异，包括无细胞线粒体 DNA，在SJLIFE队列中收集的。这将是第一项直接检查加速认知和 儿童时期接受神经毒性治疗的成年癌症幸存者队列中的脑老化。这些 幸存者出现记忆障碍的症状，与痴呆症和/或阿尔茨海默病相一致。 我们可以获得的全面的纵向数据将为痴呆症的发生和发展提供信息，如下所述 我们队列中的幸存者在他们的余生中。关于大脑加速老化的估计显示 来预测普通人群中的痴呆症和死亡率，因此，这一指标可以作为一个有用的生物标记物 用于癌症幸存者的痴呆症和/或阿尔茨海默病的早期检测。这项研究的结果将会有 对理解慢性疾病中痴呆症和阿尔茨海默病的病理的主要启示 将提供有关风险预测和干预发展的宝贵信息。

Abstract Long-term survivors of childhood cancer may be at increased risk for accelerated aging and early-onset dementia, particularly survivors of leukemia and central nervous system (CNS) tumor survivors who are treated with neurotoxic therapies. We recently demonstrated shorter telomere length in leukemia and CNS tumors more frequently than community controls and other types of childhood cancer. We have also identified that survivors of leukemia and CNS tumors are at greatest risk for progressive memory decline during the interval of 25 to 40 years following cancer diagnosis. Adult survivors of childhood leukemia and CNS tumor have lower brain white and grey matter volume and smaller hippocampi, consistent with a dementia profile. Compared to non-cancer controls, these survivors demonstrate a lower ratio of hippocampi to cranial vault volume, suggesting loss of brain tissue volume after peak development of the cranium. This lower ratio is associated with memory problems and may indicate accelerated brain aging and early onset dementia. CNS-directed cancer treatment at a young age can limit development of cognitive and brain reserve (i.e., resilience to future brain injury) and reduced reserve is associated with increased risk for dementia in the general population. However, comprehensive assessment of brain aging in adult survivors of childhood cancer has not been reported. We propose to calculate the brain age of a large sample of adult survivors of childhood cancer and community controls. To date, brain imaging scans have already been collected on 793 adult survivors of childhood leukemia, 197 survivors of CNS tumor and 250 community controls matched on age, sex and race. We will compare discrepancies between brain age and chronological age in the survivors and controls and examine associations between brain age discrepancies with treatment, health, functional status and biomarker measures, including cell free mitochondrial DNA, collected in the SJLIFE cohort. This will be the first study to directly examine accelerated cognitive and brain aging in a cohort of adult survivors of childhood cancer treated with neurotoxic therapies as children. These survivors present with symptoms of memory impairment, consistent with dementia and/or Alzheimer's disease. The comprehensive longitudinal data available to us will inform dementia onset and progression, as we follow the survivors in our cohort for the remainder of their life's. Estimates of accelerated brain aging have been shown to predict dementia and mortality in the general population and thus, this metric may serve as a useful biomarker for early detection of dementia and/or Alzheimer's disease in cancer survivors. Results of this study will have major implications for understanding the pathology of dementia and Alzheimer's disease in chronic disease, and will provide invaluable information concerning risk prediction and intervention development.