Brain iron accumulation as an in vivo quantifiable biomarker of neurocognitive dysfunction in pediatric brain tumor survivors

脑铁积累作为儿科脑肿瘤幸存者神经认知功能障碍的体内可量化生物标志物

• 批准号: 10285786
• 负责人: Benita Tamrazi
• 金额: $ 23.77万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285786
• 关键词: Affect; Age-associated memory impairment; Alzheimer' s Disease; Biological Markers; Brain; Brain Neoplasms; Cause of Death; Cell Nucleus; Cerebellum; Chelation Therapy; Child; Childhood Brain Neoplasm; Clinical; Cognitive deficits; Cohort Effect; Cranial Irradiation; Data; Dentate nucleus; Deposition; Disease; Early identification; Employment; Endothelium; Functional disorder; Globus Pallidus; Hemorrhage; Histology; Image; Imaging Techniques; Impaired cognition; Infratentorial Neoplasms; Injury; Institution; Iron; Lead; Link; Long-Term Effects; Long-Term Survivors; Longevity; Longitudinal cohort study; Magnetic Resonance Imaging; Measurement; Measures; Mediator of activation protein; Modernization; Molecular; Morbidity - disease rate; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuroglia; Neuropsychology; Oncologist; Parkinson Disease; Pathologic; Patients; Pediatric cohort; Pilot Projects; Play; Predisposition; Primary Brain Neoplasms; Process; Radiation; Radiation Injuries; Radiation therapy; Recording of previous events; Registries; Reporting; Research Personnel; Risk; Risk Factors; Role; Scanning; Secondary to; Sickle Cell Anemia; Solid Neoplasm; Survivors; Time; TimeLine; Treatment Protocols; Work; aging population; base; brain dysfunction; burden of illness; cancer therapy; cell injury; childhood cancer mortality; cognitive ability; cohort; executive function; falls; follow-up; high risk; imaging biomarker; improved; in vivo; individualized medicine; iron chelation therapy; molecular subtypes; molecular targeted therapies; neurocognitive test; novel; pediatric patients; personalized medicine; processing speed; prospective; radiation adverse effect; radiation-induced injury; recruit; standard of care; targeted treatment; treatment group

Primary brain tumors are the most common solid tumors and the leading cause of death from childhood cancer. In the era of molecular targeted therapy, greater than 60% of children with brain tumors are expected to become long-term survivors. Survival however is not without morbidity, with the majority of patients suffering from neurocognitive deficits that directly impact their educational attainment and work employment. Despite molecular tailored treatment regimens, radiation therapy remains a mainstay of cancer treatment in children with brain tumors and is considered the single most important risk factor for neurocognitive dysfunction. Radiation therapy leads to cellular injury that accelerates iron deposition in the brain. MR imaging with quantitative susceptibility mapping (QSM) is changing the landscape of neurodegenerative diseases such as Parkinson’s, where iron has been recently identified as a biomarker for disease burden as well as a target for disease therapy in the form of chelation therapy. Similar to patients with neurodegenerative disorders, our preliminary MR imaging data with QSM demonstrates accelerated iron deposition in our patients with brain tumors that received cranial radiation therapy (CRT). The purpose of this pilot study is to collect novel imaging and neuropsychological data in pediatric brain tumor survivors, exploring the continuum of short and long term effects of radiation therapy in order to investigate the direct association between radiation injury to the brain, iron accumulation and cognitive deficits. Our central hypothesis is that CRT in pediatric brain tumor survivors results in higher accumulation of iron in the brain (as quantified in vivo by QSM) as compared to patients without history of CRT, with increased brain iron independently correlating with worsening neurocognitive function. In this context, we advance the following specific aims: Specific Aim 1: To determine if cranial radiation therapy affects iron accumulation in the brain in a cross- sectional cohort of pediatric patients with posterior fossa tumors. Specific Aim 2: To explore the correlation between iron deposition and neuropsychological dysfunction in children with posterior fossa tumors. Currently, there is a disconnect between neuro-oncologists and their priority of curing the disease and prolonging survival versus neuropsychologists and their attempts of identifying and managing sequel of radiation induced neurocognitive deficits in survivors. Should this exploratory study provide evidence for the direct association between radiation injury to the brain, iron accumulation and cognitive dysfunction, this disconnect can potentially be bridged. This will ultimately lead to early identification of high-risk patients with radiation-induced injury and the implementation of risk-adaptive cancer therapy as well as the exploration of neuro-protective treatment options, such as iron chelation therapy, to reduce neurocognitive deficits in these patients throughout their lifespan.

原发性脑肿瘤是最常见的实体肿瘤，也是儿童死亡的主要原因 癌在分子靶向治疗时代，大于60%的儿童脑肿瘤有望 成为长期的幸存者。然而，生存并非没有发病率，大多数患者患有 神经认知缺陷直接影响他们的教育程度和工作就业。尽管 分子定制的治疗方案，放射治疗仍然是儿童癌症治疗的主要手段 脑肿瘤，被认为是神经认知功能障碍的最重要的风险因素。 放射治疗导致细胞损伤，加速铁在大脑中的沉积。MR成像 定量易感性绘图（QSM）正在改变神经退行性疾病的前景， 帕金森氏症，其中铁最近被确定为疾病负担的生物标志物以及治疗的目标。 螯合疗法形式的疾病治疗。与神经退行性疾病患者相似，我们的 QSM的初步MR成像数据表明，我们的脑梗死患者铁沉积加速 接受颅放射治疗（CRT）的肿瘤。这项初步研究的目的是收集新的成像 儿童脑肿瘤幸存者的神经心理学数据，探索短期和长期的连续性， 放射治疗的效果为了研究放射性脑损伤之间的直接联系， 铁积累和认知缺陷。我们的中心假设是儿童脑肿瘤幸存者的CRT 与患者相比， 无CRT史，脑铁增加与神经认知功能恶化独立相关 功能在这方面，我们提出以下具体目标： 具体目标1：确定颅放射治疗是否影响交叉脑内铁蓄积， 儿童后颅窝肿瘤患者的分层队列研究。 目的2：探讨铁沉积与神经心理功能障碍的相关性。 儿童后颅窝肿瘤 目前，神经肿瘤学家和他们治疗疾病的优先权之间存在脱节， 延长生存与神经心理学家和他们的尝试，确定和管理的后果， 辐射诱发幸存者的神经认知缺陷。这项探索性研究是否应该为 大脑辐射损伤、铁积累和认知功能障碍之间存在直接联系，这一点 可以潜在地桥接断开。这将最终导致早期发现高危患者， 放射性损伤与癌症风险适应性治疗的实施， 神经保护性治疗选择，如铁螯合疗法，以减少这些患者的神经认知缺陷。 患者的一生。