Aging-Related Biomarkers of Neurocognitive Function in Long-term Hodgkin Lymphoma Survivors

摘要 新出现的证据表明，在没有中枢神经系统（CNS）的情况下治疗的儿童癌症幸存者 定向治疗有显著的神经认知障碍风险， 成就和生活质量。然而，神经认知障碍的潜在生物学机制， 对这一人群了解甚少，限制了我们预防或减轻这些不良后果的能力。长- 儿童期癌症的长期幸存者比兄弟姐妹有更高的虚弱和慢性健康状况的频率 控制表明癌症治疗可能加速生理和生物衰老过程，这可能 导致神经认知障碍。在一般人群中的研究表明，全身性炎症和 氧化应激随着年龄的增长而增加，并与发病率、死亡率和认知能力下降的增加有关。 炎症和氧化应激也是端粒长度和表观遗传变化的重要调节因子， 与老年非癌症人群的神经认知障碍有关。这些生物标志物具有 在没有接受中枢神经系统定向治疗的儿童癌症幸存者中还有待广泛研究。的 本K99 R 00的目的是确定神经认知障碍的衰老相关生物学预测因子， 随后的下降，以便为使用现有数据和生物标本的未来干预措施的设计提供信息 来自St. Jude Lifetime队列的300名HL幸存者和200名社区对照。K99阶段 旨在检查炎症，氧化应激， 免疫衰老和细胞衰老（端粒长度和表观遗传年龄加速）与神经认知 长期霍奇金淋巴瘤幸存者（HL）的损害。R 00阶段将首先在这些发现的基础上进行扩展， 描述长期HL幸存者神经认知能力下降的轨迹，然后通过检查纵向 这些生物标志物与随后的神经认知衰退之间的关联。此外，这些研究将 提供关于可改变的风险因素（如运动、吸烟、营养）对这些生物标志物影响的数据， 为未来发展干预措施提供信息，以减轻癌症幸存者的神经认知障碍。博士 威廉姆斯是一个新兴的翻译癌症控制流行病学家，专注于潜在的病理生理和 癌症幸存者神经认知功能的生物学机制。K99 R 00允许威廉姆斯博士开发 在1）神经生物学和癌症生物学以及HL特异性治疗方面的专业知识，2）衰老相关生物标志物， 分子流行病学，3）复杂的统计方法和4）临床和行为干预试验。博士 威廉姆斯的指导团队在神经认知评估、神经病理学、分子生物学和神经功能缺损方面拥有丰富的专业知识。 流行病学、儿童癌症和统计方法。圣裘德儿童研究医院是一家 国际领先的癌症控制和生存，并提供了一个资源丰富的培训环境，博士。 威廉姆斯。联合培训和研究计划将确保威廉姆斯博士过渡到独立， 提供技能和初步数据，以成功竞争未来的R 01级赠款。

Abstract Emerging evidence suggests that childhood cancer survivors treated without central nervous system (CNS) directed therapies are at significant risk for neurocognitive impairment that is associated with decreased social attainment and quality of life. However, the underlying biological mechanisms of neurocognitive impairment in this population are poorly understood limiting our ability to prevent or alleviate these adverse outcomes. Long- term survivors of childhood cancer have a higher frequency of frailty and chronic health conditions than sibling controls suggesting cancer therapy may accelerate the physiological and biological aging process, which may lead to neurocognitive impairment. Studies in the general population indicate systemic inflammation and oxidative stress increase with age and are associated with increased morbidity, mortality, and cognitive decline. Inflammation and oxidative stress are also important regulators of telomere length and epigenetic changes which have been associated with neurocognitive impairment in aging non-cancer populations. These biomarkers have yet to be extensively examined in childhood cancer survivors treated without CNS directed therapies. The objective of this K99R00 is to identify aging-related biological predictors of neurocognitive impairment and subsequent decline in order to inform the design of future interventions using existing data and biospecimens from 300 HL survivors and 200 community controls in the St. Jude Lifetime cohort. Specifically, the K99 phase aims to examine cross-sectional associations between markers of inflammation, oxidative stress, immunosenescence, and cellular aging (telomere length and epigenetic age acceleration) with neurocognitive impairment in long-term Hodgkin lymphoma survivors (HL). The R00 phase will expand on these findings by first describing the trajectory of neurocognitive decline in long-term HL survivors and then by examining longitudinal associations between these biomarkers and subsequent neurocognitive decline. Further, these studies will provide data on the influence of modifiable risk factors (e.g. exercise, smoking, nutrition) on these biomarkers to inform future development of interventions to mitigate neurocognitive impairment in cancer survivors. Dr. Williams is an emerging translational cancer control epidemiologist focused on underlying pathophysiologic and biologic mechanisms of neurocognitive function in cancer survivors. The K99R00 allows Dr. Williams to develop expertise in 1) neurobiology and cancer biology and treatment specific to HL, 2) aging-related biomarkers and molecular epidemiology, 3) complex statistical methods and 4) clinical and behavioral intervention trials. Dr. Williams' mentoring team has extensive expertise in neurocognitive assessments, neuropathology, molecular epidemiology, childhood cancer, and statistical methods. St. Jude Children's Research Hospital is an international leader in cancer control and survivorship and provides a resource-rich training environment for Dr. Williams. The combined training and research plan will ensure Dr. Williams' transition to independence by providing the skills and preliminary data to successfully compete for future R01-level grants.