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

摘要 本研究的目的是确定是否每天口服美金刚胺6个月，当比较 安慰剂与4-18岁儿童12个月时认知功能下降的减少有关 接受颅内放射治疗（RT）治疗原发性中枢神经系统肿瘤， 美金刚胺与成像生物标志物的作用。放射疗法是一种被证明有效的治疗工具， 原发性脑肿瘤的治疗然而，颅RT导致显著的认知发病率。的 放射性损伤的机制导致了小血管疾病 血管性痴呆和神经退行性疾病，如阿尔茨海默氏症。缺血 和损伤可诱导过度的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学习能力， 缺血模型和放射损伤模型。美金刚是一种非竞争性，低亲和力，开放性- 通道NMDA阻断剂，其已在临床前模型中显示出神经保护作用。在两个安慰剂- 对照III期试验，美金刚被证明是有效的治疗阿尔茨海默氏症和血管 痴呆症，尤其是小血管疾病患者。美金刚还被证明可以有效地减少 接受全脑放疗治疗脑转移的成人认知功能障碍。美金刚延迟 认知能力下降的时间，并降低记忆力、执行功能和处理能力下降的速度 速度重要的是，接受美金刚胺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作用 效果在这项研究中，我们建议评估美金刚在预防认知功能障碍的疗效， 通过儿童肿瘤学临床试验机制接受颅脑放射治疗的儿科患者 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、6和12个月）与简短的计算机化测试电池，我们将 正式认知测试以及长期认知功能（30和60个月）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， 并导致加速研究设计的框架， 评估未来神经保护剂试验的疗效。脑内剂量和体积依赖性减少 放射治疗暴露后可见体积，并与认知能力下降相关。我们假设 美金刚的神经保护作用也将保留相关的脑容量，这将与结构域相关， 认知功能的具体改善。我们将使用定量体积MRI分析来关联 美金刚对脑亚结构（白色物质、海马、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。放射学分析将提供证据- 美金刚作用机制的原理以及可用于未来试验的生物标志物 辐射防护剂，这是特别重要的年轻患者或患者没有神经功能的能力， 完成认知评估，但可能从神经保护干预中获益最多的人。

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.