Brain Age in Adult Survivors of Childhood Leukemia and CNS Tumor

摘要 儿童期癌症的长期幸存者可能会增加加速衰老和早发性癌症的风险 痴呆症，特别是接受治疗的白血病幸存者和中枢神经系统（CNS）肿瘤幸存者 神经毒性疗法我们最近发现白血病和中枢神经系统肿瘤中端粒长度较短， 比社区对照组和其他类型的儿童癌症更常见。我们还发现幸存者 白血病和中枢神经系统肿瘤患者在25 - 40岁之间进行性记忆衰退的风险最大 癌症诊断后的几年。儿童白血病和中枢神经系统肿瘤的成年幸存者有较低的脑白色 以及灰质体积和更小的小脑，符合痴呆症的特征。与非癌症相比 对照组中，这些幸存者表现出较低的颅顶容积与颅穹窿容积的比率，表明 在颅骨发育高峰后的脑组织体积。这个较低的比率与记忆问题有关 并可能表明大脑加速老化和早发性痴呆。CNS指导的癌症治疗在一个年轻的 年龄可以限制认知和脑储备的发展（即，对未来脑损伤的恢复力）和减少 在一般人群中，储备与痴呆症的风险增加有关。然而，全面 对儿童期癌症成年幸存者的脑老化评估尚未报道。我们建议计算 儿童癌症成年幸存者和社区对照的大样本的脑年龄。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名中枢神经系统白血病幸存者和197名儿童白血病幸存者的影像学扫描结果。 肿瘤患者和250名年龄、性别和种族相匹配的社区对照组。我们将比较大脑和大脑之间的差异 年龄和实足年龄的幸存者和控制，并检查脑年龄之间的关联 治疗、健康、功能状态和生物标志物测量的差异，包括无细胞线粒体 DNA，在SJLIFE队列中采集。这将是第一项直接研究加速认知和 儿童时期接受神经毒性治疗的儿童癌症成年幸存者队列的脑老化。这些 幸存者表现出记忆障碍的症状，与痴呆和/或阿尔茨海默病一致。 我们可以获得的全面纵向数据将为痴呆症的发作和进展提供信息， 幸存者的余生大脑加速老化的估计已经显示， 预测一般人群的痴呆症和死亡率，因此，该指标可作为有用的生物标志物 用于癌症幸存者的痴呆症和/或阿尔茨海默病的早期检测。这项研究的结果将有 了解慢性疾病中痴呆和阿尔茨海默病的病理学的主要影响， 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.