加拿大多伦多病童医院Donald J. Mabbott和多伦多大学Cindi M. Morshead研究组合作的最新研究，利用一项二甲双胍的临床试验评估了小儿脑肿瘤幸存者的认知和神经恢复。2020年7月27日出版的《自然-医学》发表了这项成果。
Title: Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin
Author: Ramy Ayoub, Rebecca M. Ruddy, Elizabeth Cox, Adeoye Oyefiade, Daniel Derkach, Suzanne Laughlin, Benjamin Ades-aron, Zahra Shirzadi, Els Fieremans, Bradley J. MacIntosh, Cynthia B. de Medeiros, Jovanka Skocic, Eric Bouffet, Freda D. Miller, Cindi M. Morshead, Donald J. Mabbott
Abstract: 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.