A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I
A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I
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DOI：
10.1002/acn3.288
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发表时间：
2016-04-01
影响因子：
5.3
通讯作者：
Silva, Alcino J.
中科院分区：
文献类型：
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作者：
Bearden, Carrie E.;Hellemann, Gerhard S.;Silva, Alcino J.
研究表明，ovastatin可以逆转1型神经纤维瘤病（NF1）小鼠模型的学习缺陷，NF1是一种由Ras-MAPK通路突变引起的常见单基因疾病，与学习障碍相关。我们进行了一项随机双盲安慰剂对照试验，以评估洛伐他汀对NF1患者认知和行为的影响。方法44例NF1患者（平均年龄25.7±11.6岁，64%为女性）被随机分配到14周的洛伐他汀组（N = 23，成人最大剂量为80mg /天，儿童最大剂量为40mg /天）或安慰剂组（N = 21）。根据小鼠模型的研究结果，主要结果测量是非语言学习和工作记忆。次要结果测量包括言语记忆、注意力、自我/父母报告的行为问题，以及药物耐受性。参与者还在基线和14周时接受了神经影像学评估，以确定神经生物标志物是否与治疗反应相关。线性混合模型评估了差异治疗对结果测量的影响。12名参与者在完成前退出研究（8名安慰剂，4名洛伐他汀），导致32名完成者（15名安慰剂，17名洛伐他汀）。洛伐他汀耐受性良好，无严重不良事件。洛伐他汀治疗在一个主要指标（工作记忆；效应量f(2) = 0.70, P < 0.01）和两个次要指标(言语记忆，f（2) = 0.19, P = 0.02，和成人自我报告的内化问题，f(2) = 0.26, P = 0.03）上有差异改善。探索性调节分析显示，额叶区域较高的基线神经活动与较大的治疗效果相关。这些初步结果表明洛伐他汀对NF1患者的一些学习和记忆功能以及内化症状有有益作用。
ObjectiveLovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1.MethodForty-four NF1 patients (mean age 25.7+/-11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent-reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures.ResultsTwelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f(2) = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f(2) = 0.19, P = 0.02, and adult self-reported internalizing problems, f(2) = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects.InterpretationThese preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.