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

长期霍奇金淋巴瘤幸存者神经认知功能的衰老相关生物标志物

• 批准号: 10701034
• 负责人: AnnaLynn Williams
• 金额: $ 15.71万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701034
• 关键词: Acceleration; Adolescent and Young Adult; Aftercare; Age; Aging; Attention; Automobile Driving; Behavior Therapy; Biological; Biological Aging; Biological Markers; Brain; CD4/CD8 ratio procedure; Cancer Biology; Cancer Control; Cancer Survivor; Cancer Survivorship; Cell Aging; Central Nervous System; Childhood Hodgkin' s Lymphoma; Chronic; Chronology; Clinical; Cognitive aging; Communities; Complex; Data; Development; Development Plans; Ensure; Environment; Epidemiologist; Epigenetic Process; Exercise; Exposure to; Frequencies; Future; General Population; Grant; Health; Hodgkin Lymphoma survivors; Immune; Impaired cognition; Impairment; Inflammaging; Inflammation; Inflammation Mediators; Interleukin-6; International; Intervention; Intervention Trial; Length; Long-Term Survivors; Malignant Childhood Neoplasm; Malignant Neoplasms; Malondialdehyde; Mediating; Memory; Mentors; Modeling; Modification; Molecular; Molecular Epidemiology; Morbidity - disease rate; Mortality Decline; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Neuropsychology; Oxidative Stress; Patient Self-Report; Pediatric Neoplasm; Phase; Physiological; Population; Positioning Attribute; Predisposition; Premature aging syndrome; Process; Quality of life; Recovery; Research; Research Personnel; Resources; Risk; Risk Factors; Saint Jude Children' s Research Hospital; Siblings; Smoking; Statistical Methods; Survivors; TNF gene; Time; Training; adverse outcome; blood-brain barrier crossing; cancer therapy; career development; childhood cancer survivor; cognitive reserve; cohort; comorbidity; critical period; cytokine; design; effective intervention; experience; frailty; glial activation; glutathione peroxidase; high risk population; immunosenescence; inflammatory marker; mild cognitive impairment; modifiable risk; mortality; neurocognitive test; neuroinflammation; neuropathology; nutrition; oxidized low density lipoprotein; premature; prevent; recruit; reduce symptoms; senescence; skills; social; systemic inflammatory response; telomere; therapy development

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.

抽象的 新的证据表明儿童癌症幸存者没有接受中枢神经系统 (CNS) 治疗 定向治疗存在与社交能力下降相关的神经认知障碍的显着风险 成就和生活质量。然而，神经认知障碍的潜在生物学机制 对这一人群知之甚少，限制了我们预防或减轻这些不良后果的能力。长的- 儿童癌症足月幸存者比兄弟姐妹更容易出现虚弱和慢性健康问题 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 导致神经认知障碍。对普通人群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增加相关。 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。这些生物标志物具有 尚未在未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 K99R00 的目标是确定与衰老相关的神经认知障碍的生物预测因素和 随后的下降，以便利用现有数据和生物样本为未来干预措施的设计提供信息 来自 St. Jude Lifetime 队列中 300 名 HL 幸存者和 200 名社区对照者。具体来说，K99阶段 旨在检查炎症标志物、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 霍奇金淋巴瘤长期幸存者（HL）的损害。 R00 阶段将首先扩展这些发现 描述长期 HL 幸存者的神经认知衰退轨迹，然后通过纵向检查 这些生物标志物与随后的神经认知能力下降之间的关联。此外，这些研究将 提供有关可改变的风险因素（例如运动、吸烟、营养）对这些生物标志物的影响的数据，以 为未来制定减轻癌症幸存者神经认知障碍的干预措施提供信息。博士。 威廉姆斯是一位新兴的转化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 使 Williams 博士能够开发 1) 神经生物学和癌症生物学以及针对 HL 的治疗的专业知识，2) 衰老相关生物标志物和 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、分子生物学等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 癌症控制和生存方面的国际领先者，并为 Dr. 提供了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。