Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin

被引：102

作者：

Ayoub, Ramy ^{[1
,2
]}

Ruddy, Rebecca M. ^{[3
]}

Cox, Elizabeth ^{[1
,2
]}

Oyefiade, Adeoye ^{[1
,2
]}

Derkach, Daniel ^{[3
]}

Laughlin, Suzanne ^{[4
,5
]}

Ades-aron, Benjamin ^{[6
]}

Shirzadi, Zahra ^{[7
,8
]}

Fieremans, Els ^{[6
]}

MacIntosh, Bradley J. ^{[7
,8
]}

de Medeiros, Cynthia B. ^{[1
]}

Skocic, Jovanka ^{[1
]}

Bouffet, Eric ^{[9
,10
]}

Miller, Freda D. ^{[1
,3
,11
,12
]}

Morshead, Cindi M. ^{[3
,13
,14
]}

Mabbott, Donald J. ^{[1
,2
]}

机构：

[1] Hosp Sick Children, Res Inst, Neurosci & Mental Hlth Program, Toronto, ON, Canada

[2] Univ Toronto, Dept Psychol, Toronto, ON, Canada

[3] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[4] Hosp Sick Children, Diagnost Imaging, Toronto, ON, Canada

[5] Univ Toronto, Dept Med Imaging, Toronto, ON, Canada

[6] NYU, Dept Radiol, Grossman Sch Med, Ctr Biomed Imaging, 560 1St Ave, New York, NY 10016 USA

[7] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[8] Univ Toronto, Sunnybrook Res Inst, Hurvitz Brain Sci, Toronto, ON, Canada

[9] Hosp Sick Children, Div Haematol Oncol, Toronto, ON, Canada

[10] Univ Toronto, Dept Paediat, Toronto, ON, Canada

[11] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[12] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[13] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON, Canada

[14] Univ Toronto, Dept Surg, Div Anat, Toronto, ON, Canada

来源：

NATURE MEDICINE | 2020年 / 26卷 / 08期

关键词：

HIPPOCAMPAL NEUROGENESIS; WHITE-MATTER; STEM-CELLS; ADULT NEUROGENESIS; DENTATE GYRUS; MOUSE MODEL; MEMORY; CHILDREN; IRRADIATION; IMPAIRMENT;

D O I：

10.1038/s41591-020-0985-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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,) 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.

引用

页码：1285 / +

页数：22

共 78 条

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Evaluation of the accuracy and precision of the diffusion parameter EStImation with Gibbs and NoisE removal pipeline [J].