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

摘要 新的证据表明，儿童癌症幸存者在没有中枢神经系统(CNS)的情况下接受治疗 定向治疗有很大的神经认知障碍的风险，这与社交能力下降有关。 获得和提高生活质量。然而，神经认知障碍的潜在生物学机制 人们对这一群体知之甚少，这限制了我们预防或减轻这些不利后果的能力。长- 儿童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 对照表明癌症治疗可能会加速生理和生物衰老过程，这可能 会导致神经认知障碍。在普通人群中的研究表明，全身炎症和 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有关。 炎症和氧化应激也是端粒长度和表观遗传学变化的重要调节因素 与老年非癌症人群的神经认知障碍有关。这些生物标志物 尚未在没有接受中枢神经系统定向治疗的儿童癌症幸存者中进行广泛检查。这个 本K99R00的目的是确定与衰老相关的神经认知障碍的生物学预测因子和 随后下降，以便利用现有数据和生物谱为未来干预措施的设计提供信息 来自圣犹大终身队列中的300名HL幸存者和200名社区对照人员。具体来说，K99阶段 旨在研究炎症标记物、氧化应激、 免疫衰老和细胞老化(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。R00阶段将首先对这些发现进行扩展 描述长期HL幸存者的神经认知功能下降的轨迹，然后通过纵向检查 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 提供可修改的风险因素(如锻炼、吸烟、营养)对这些生物标记物的影响的数据 告知未来干预措施的发展，以减轻癌症幸存者的神经认知障碍。Dr。 威廉姆斯是一位新兴的转化型癌症控制流行病学家，专注于潜在的病理生理学和 癌症幸存者神经认知功能的生物学机制。K99R00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针对HL的治疗方面的专业知识，2)与衰老相关的生物标记物和 分子流行病学，3)复杂的统计方法，4)临床和行为干预试验。Dr。 威廉姆斯的指导团队在神经认知评估、神经病理学、分子生物学等方面拥有广泛的专业知识 流行病学、儿童癌症和统计学方法。圣犹大儿童研究医院是一家 在癌症控制和生存方面处于国际领先地位，为Dr提供资源丰富的培训环境。 威廉姆斯。联合培训和研究计划将确保威廉姆斯博士通过以下方式过渡到独立 提供技能和初步数据，以成功竞争未来的R01级资助。

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.