Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.
Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.
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DOI：
10.1038/s41591-020-0985-2
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发表时间：
2020-08
期刊：
影响因子：
82.9
通讯作者：
Mabbott DJ
中科院分区：
文献类型：
--
作者：
Ayoub R;Ruddy RM;Cox E;Oyefiade A;Derkach D;Laughlin S;Ades-Aron B;Shirzadi Z;Fieremans E;MacIntosh BJ;de Medeiros CB;Skocic J;Bouffet E;Miller FD;Morshead CM;Mabbott DJ
我们询问内源性神经前体细胞（NPC）的药理学刺激是否可以促进认知恢复和脑修复，重点是药物二甲双胍，在平行的啮齿动物和人类辐射损伤研究。在啮齿类动物脑辐射模型中，我们发现二甲双胍可增强齿状回中NPC的恢复，对神经发生和认知具有性别依赖性影响。在接受过颅骨放疗的儿童脑肿瘤幸存者中进行了一项先导性双盲、安慰剂对照交叉试验（ClinicalTrials.gov，NCT 02040376）。安全性、可行性、认知测试和白色物质和海马的MRI测量作为终点进行评价。24名参与者同意并被随机分配以AB或BA序列完成12周周期的二甲双胍（A）和安慰剂（B）治疗，交叉时有10周的洗脱期。进行抽血以监测安全性。可行性评估为招募率、药物依从性和程序依从性。线性混合模型用于检查认知和MRI结果作为周期，序列和治疗的函数。我们未发现与二甲双胍相关的临床相关安全性问题和严重不良事件。在我们的线性混合模型中，观察到所有认知结果的序列效应。对于第1周期有完整数据的受试者子集，二甲双胍在陈述性和工作记忆测试中的表现优于安慰剂。我们提供的证据表明，在儿科脑肿瘤的长期幸存者中进行二甲双胍对认知和脑结构影响的临床试验是可行的，并且二甲双胍在该人群中使用安全且耐受。这项初步试验并不是为了测试二甲双胍对认知恢复和大脑生长的疗效，但初步结果令人鼓舞，需要在一项大型多中心III期试验中进一步研究。
We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.
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