Utility of memantine in preventing cognitive dysfunction in children receiving cranial radiotherapy

美金刚在预防接受颅脑放疗的儿童认知功能障碍中的作用

• 批准号: 10020353
• 负责人: Nadia N Laack
• 金额: $ 28.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10020353
• 关键词: Adult; Adverse effects; Affect; Affinity; Age; Alzheimer' s Disease; Amino Acid Neurotransmitters; Animal Model; Attention; Behavioral; Biological Markers; Brain; Brain Neoplasms; Brain imaging; Brain region; Cell Line; Central Nervous System Neoplasms; Cephalic; Child; Childhood; Childhood Brain Neoplasm; Clinical Data; Clinical Trials; Cognition; Cognitive; Combined Modality Therapy; Complex; Complication; Cranial Irradiation; Data; Dementia; Development; Diagnostic radiologic examination; Dose; Drug usage; Education; Employment; Evaluation; Excitatory Amino Acids; Functional disorder; Future; Glutamates; Health; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Injury; Intervention; Ischemia; Lead; Learning; Long-Term Potentiation; Magnetic Resonance Imaging; Maintenance; Marriage; Measurement; Measures; Memantine; Memory; Metastatic malignant neoplasm to brain; Methods; Microvascular Dysfunction; Modeling; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neonatal; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neuropsychology; Oral; Outcome; Participant; Pathologic; Patients; Pediatric Neoplasm; Pediatric Oncology Group; Phase; Physiological; Placebos; Population; Pre-Clinical Model; Primary Brain Neoplasms; Radiation; Radiation Injuries; Radiation therapy; Radio; Randomized; Rattus; Research Design; Research Personnel; Research Priority; Risk; Role; Severities; Social Adjustment; Structure; Supratentorial Brain; Survivors; Testing; Therapeutic Effect; Thinking; Time; Toxic effect; Vascular Dementia; base; brain volume; cognitive function; cognitive testing; computerized; curative treatments; dosimetry; effective therapy; efficacy study; emotional distress; excitotoxicity; executive function; frontal lobe; imaging biomarker; improved; in vivo; ischemic injury; neuroprotection; novel; pediatric patients; phase III trial; pre-clinical; preservation; prevent; processing speed; protective effect; radiation-induced injury; receptor; survivorship; tool; white matter; young adult

ABSTRACT The purpose of this study is to determine whether oral memantine daily for 6 months, when compared to placebo, is associated with reduction in decline of cognitive function at 12 months in children ages 4-18 receiving cranial radiotherapy (RT) for primary central nervous system tumors and to correlate protective effects of memantine with imaging biomarkers. Radiotherapy is a proven curative therapeutic tool in the treatment of primary brain tumors. However, cranial RT results in significant cognitive morbidity. The mechanisms of radiation-induced injury result in a picture that is a combination of the small vessel disease seen with vascular dementia as well as neurodegenerative diseases like Alzheimer’s dementia. Ischemia and injury can induce excessive NMDA stimulation and lead to excitotoxicity, and pre- clinical data suggests that selective blocking of the NMDA receptor can restore long-term potentiation and restore learning in both models of ischemia as well as models of radiation injury. Memantine is a non- competitive, low-affinity, open- channel NMDA blocker, which has been shown to be neuroprotective in pre- clinical models. In two placebo- controlled phase III trials, memantine proved to be effective treatment for Alzheimer’s and vascular dementia, especially for patients with small-vessel disease. Memantine has also proven effective in reducing cognitive dysfunction in adults receiving whole-brain radiotherapy for brain metastases. Memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function and processing speed. Importantly, cognitive function in patients receiving memantine remained stable even after memantine was discontinued; suggesting memantine had a protective effect rather than simply a therapeutic effect. In this study, we propose evaluating the efficacy of memantine in preventing cognitive dysfunction in pediatric patients receiving cranial radiation through the clinical trial mechanism of the Children’s Oncology Group. This study is novel in that children will undergo early cognitive evaluations (baseline prior to radiation, 3, 6, and 12 months post-radiation) with a brief computerized testing battery that we will correlate with formal cognitive testing as well with long-term cognitive function (30 and 60 months) assessed with both methods. If successful, this study will provide validated early cognitive assessment time points that correlate with late cognitive toxicity and result in an framework for accelerated study design that will allow for early assessment of efficacy for future neuro-protectant trials. Dose- and volume-dependent reduction in brain volume is seen after radiotherapy exposure and is associated with cognitive decline. We hypothesize that neuroprotection with memantine will also preserve relevant brain volume and this will correlate with domain- specific improvements in cognitive function. We will use quantitative volumetric MRI analysis to correlate protective effects of memantine with brain substructure (white matter, hippocampus, frontal lobes etc) volume changes over time and correlate with cognitive assessments. Radiographic analysis will provide proof-of- principle for the mechanism of action of memantine as well as a biomarker that can be utilized in future trials of radio-protectants, which is especially important for young patients or patients not neurologically capable of completing cognitive assessments but who may benefit the most from neuroprotective interventions.

抽象的 这项研究的目的是确定与与 安慰剂，与4-18岁儿童12个月的认知功能下降有关 接受原发性中枢神经系统肿瘤的颅放疗（RT）并相关受保护 美容与成像生物标志物的影响。放射疗法是一种经过证明的治疗性治疗工具 治疗原发性脑肿瘤。但是，颅骨RT导致了明显的认知发病率。这 辐射引起的损伤的机制导致图片是小血管疾病的组合 患有血管性痴呆以及如阿尔茨海默氏痴呆的神经退行性疾病。缺血 损伤会引起过多的NMDA模拟并导致兴奋性毒性，并且预临床数据表明 NMDA受体的选择性阻断可以恢复长期潜力，并恢复两者的学习 缺血模型以及辐射损伤模型。美容是一种非竞争，低亲和力，开放的 通道NMDA阻滞剂，已显示在临床模型中具有神经保护作用。在两个安慰剂中 - 对受控的III期试验，纪念碑被证明是对阿尔茨海默氏症和血管的有效治疗 痴呆症，特别是对于小血管疾病的患者。美容也已证明有效减少 在接受全脑放射疗法的成年人中的认知功能障碍。美容延迟 认知能力下降并降低记忆力，执行功能和处理的时间 速度。重要的是，即使在 纪念品被停产；暗示美容具有保护作用，而不是仅仅是治疗 影响。在这项研究中，我们提出了评估纪念碑在防止认知功能障碍中的有效性 通过儿童肿瘤学的临床试验机制接受颅辐射的儿科患者 团体。这项研究是新颖的，因为儿童将接受早期认知评估（基线之前 放射后的辐射，3、6和12个月），用简短的计算机测试电池我们将相关联 以及正式认知测试以及长期认知功能（30和60个月）的评估 方法。如果成功，这项研究将提供有效的早期认知评估时间点，以相关 具有晚期认知毒性，并为加速研究设计带来了框架 评估未来神经保护剂试验的效率。大脑的剂量和体积依赖性减少 放射疗法暴露后观察到体积，并与认知能力下降有关。我们假设这一点 神经保护与美灵的神经保护也将保留相关的大脑体积，这将与结构域相关 认知功能的具体改进。我们将使用定量体积MRI分析来相关 美金刚与大脑子结构（白质，海马，额叶爱等）的保护作用 随着时间的变化，与认知评估相关。射线照相分析将提供证明 纪念碑的作用机理以及可以在以后的试验中使用的生物标志物的原理 无线电保护剂，这对于年轻患者或没有神经学的患者尤其重要 完成认知评估，但谁可能从神经保护干预措施中受益最大。