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

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。 癌症。在分子靶向治疗的时代，预计60%以上的脑瘤儿童 成为长期的幸存者。然而，生存并不是没有并发症，大多数患者都遭受着 神经认知缺陷，直接影响他们的教育程度和工作就业。尽管 分子个体化治疗方案，放射治疗仍然是儿童癌症治疗的主要手段 与脑瘤有关，被认为是神经认知功能障碍的最重要的危险因素。 放射治疗会导致细胞损伤，从而加速大脑中铁的沉积。使用磁共振成像 定量易感性图谱(QSM)正在改变神经退行性疾病的面貌，如 帕金森氏症，铁最近被确定为疾病负担的生物标志物以及 以螯合疗法的形式进行的疾病治疗。类似于神经退行性疾病的患者，我们的 QSM的初步磁共振成像数据显示，我们的脑部患者铁沉积加速 接受颅脑放射治疗(CRT)的肿瘤。这项初步研究的目的是收集新的成像 和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辐射对大脑的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 结果与患者相比，大脑中铁的积累更高(通过QSM在体内进行量化) 无CRT病史，脑铁质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：确定颅脑放射治疗是否影响脑内铁的积累。 儿童后颅窝肿瘤患者的横断面队列研究。 目的2：探讨铁沉积与神经心理功能障碍的关系。 儿童后颅窝肿瘤。 目前，神经肿瘤学家和他们治疗这种疾病的优先顺序之间存在脱节。 延长生存期与神经心理学家及其识别和管理后遗症的尝试 辐射导致幸存者的神经认知缺陷。这项探索性研究是否应该为 辐射对大脑的损伤，铁的积累和认知功能障碍之间的直接联系，这 断开连接可能会被桥接。这最终将导致早期识别高危患者。 放射损伤与癌症风险适应性治疗的实施及探讨 神经保护性治疗的选择，如铁螯合疗法，以减少这些人的神经认知缺陷 患者的一生中。

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.