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

摘要 这项研究的目的是确定在6个月内每天服用美金刚是否与 安慰剂与4-18岁儿童12个月认知功能下降的减轻有关 原发性中枢神经系统肿瘤的头颅放射治疗及相关保护 美金刚对影像生物标志物的影响。放射治疗是一种公认的根治性治疗手段 原发脑肿瘤的治疗。然而，颅脑RT会导致显著的认知障碍。这个 辐射诱导损伤的机制导致的图像是小血管疾病的组合 可见于血管性痴呆症以及阿尔茨海默氏症等神经退行性疾病。缺血 损伤可以诱导过度的NMDA刺激并导致兴奋性毒性，临床前数据表明 选择性阻断NMDA受体可以恢复长时程增强和恢复学习 缺血模型和辐射损伤模型。美金刚是一种非竞争性、低亲和力、开放的 通道NMDA阻滞剂，已被证明在临床前模型中具有神经保护作用。在两个安慰剂中- III期对照试验，美金刚被证明是治疗阿尔茨海默氏症和血管疾病的有效药物 痴呆症，尤其是患有小血管疾病的患者。美金刚也被证明在减少 接受全脑放射治疗的脑转移瘤患者的认知功能障碍。美金刚延迟 认知衰退的时间，并降低记忆、执行功能和处理能力的衰退率 速度。重要的是，接受美金刚治疗的患者的认知功能即使在 美金刚被停用；这表明美金刚具有保护作用，而不仅仅是治疗 效果。在这项研究中，我们建议评估美金刚预防认知功能障碍的疗效。 儿童肿瘤学临床试验机制在儿童颅脑放射治疗中的应用 组。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 辐射后3个月、6个月和12个月)与简短的计算机化测试电池相关联 接受正式的认知测试以及长期认知功能(30个月和60个月)的评估 方法：研究方法。如果成功，这项研究将提供经过验证的早期认知评估时间点 晚期认知毒性，并导致加速研究设计的框架，该框架将允许早期 对未来神经保护剂试验的有效性进行评估。脑组织中剂量和体积依赖性的减少 体积是在放射治疗后出现的，与认知能力下降有关。我们假设 美金刚的神经保护也将保留相关的脑体积，这将与领域相关- 认知功能的具体改善。我们将使用定量容量磁共振分析来关联 美金刚对脑亚结构(白质、海马体、额叶等)体积的保护作用 随着时间的推移而变化，并与认知评估相关。放射分析将提供证据- 美金刚作用机制的原理以及可用于未来试验的生物标记物 放射防护剂，这对年轻患者或神经学上没有能力的患者尤其重要 完成认知评估，但谁可能从神经保护干预中受益最大。

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.