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

Nature Medicine volume 26, pages 1285–1294 (2020)Cite this article

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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.

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Fig. 1: Pilot trial design and procedures.
Fig. 2: Cranial radiation leads to cellular and cognitive deficits and metformin is able to rescue these deficits in females.
Fig. 3: Pilot trial adverse events and adherence.
Fig. 4: Baseline and outcome data points for LSWM, average reaction time on the CANTAB tests and immediate recall on the CAVLT-2/RAVLT.
Fig. 5: Baseline and outcome data points for AWF within the corpus callosum.

Data availability

Requests for data related to the rodent studies should be directed to, and will be fulfilled by, senior corresponding author C.M.M. Requests for resources from the pilot clinical trial, including a copy of the trial protocol and aggregate data, should be directed to, and will be fulfilled by, senior corresponding author D.J.M. Data from individual participants in the pilot trial are not available owing to privacy and confidentiality and participants did not explicitly consent for their data to be shared.

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Acknowledgements

We wish to thank A. Willan, Clinical Trials Methodologist, Ontario Child Health Support Unit, Research Institute, The Hospital for Sick Children, for consulting on and developing our analytic approach while blind to the trial data. We also wish to thank the research personnel and clinical staff who made this trial possible, particularly V. Ramaswamy, U. Bartels, U. Tabori and A. Huang, as well as N. Sarvaria, D. Thomas, E. Barlev, J. Dutton, J. Gammon, L. Lauer, A. Decker, A. Ferkul, D. McRae, T. Rayner, R. Weiss and M. Lalancette. We would also like to thank J. Wang, D. Kaplan and P. Frankland for frequent discussions and advice during the course of this work. Finally, we wish to thank J. Tseng for her technical support in improving the presentation of our figures. This work was supported by grants from Brain Canada (F.D.M., D.J.M., C.M.M.), the Stem Cell Network (F.D.M., D.J.M., C.M.M.), the Ontario Institute for Regenerative Medicine (F.D.M., D.J.M., C.M.M.), Medicine By Design (CFREF), and the Garron Family Cancer Centre (D.J.M., E.B.). R.M.R. was supported by a CIHR graduate student fellowship.

Author information

Author notes

  1. These authors contributed equally: Ramy Ayoub, Rebecca M. Ruddy.

Authors and Affiliations

  1. Neurosciences and Mental Health Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada

    Ramy Ayoub, Elizabeth Cox, Adeoye Oyefiade, Cynthia B. de Medeiros, Jovanka Skocic, Freda D. Miller & Donald J. Mabbott

  2. Department of Psychology, University of Toronto, Toronto, Ontario, Canada

    Ramy Ayoub, Elizabeth Cox, Adeoye Oyefiade & Donald J. Mabbott

  3. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Rebecca M. Ruddy, Daniel Derkach, Freda D. Miller & Cindi M. Morshead

  4. Diagnostic Imaging, Hospital for Sick Children, Toronto, Ontario, Canada

    Suzanne Laughlin

  5. Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada

    Suzanne Laughlin

  6. Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, USA

    Benjamin Ades-aron & Els Fieremans

  7. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Zahra Shirzadi & Bradley J. MacIntosh

  8. Hurvitz Brain Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada

    Zahra Shirzadi & Bradley J. MacIntosh

  9. Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada

    Eric Bouffet

  10. Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada

    Eric Bouffet

  11. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Freda D. Miller

  12. Department of Physiology, University of Toronto, Toronto, Ontario, Canada

    Freda D. Miller

  13. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

    Cindi M. Morshead

  14. Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    Cindi M. Morshead

Authors
  1. Ramy Ayoub
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  2. Rebecca M. Ruddy
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  3. Elizabeth Cox
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  4. Adeoye Oyefiade
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  16. Donald J. Mabbott
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Contributions

Conceptualization, R.M.R., E.B., F.D.M., C.M.M. and D.J.M.; methodology, R.A., R.M.R., E.B., C.M.M. and D.J.M.; software, B.A., Z.S., E.F. and B.J.M.; formal analysis, R.A., R.M.R., E.C., A.O., D.D., C.B.d.M., E.B., C.M.M. and D.J.M.; investigation, R.M.R., C.B.d.M., J.S., E.B., C.M.M. and D.J.M.; resources, S.L., B.A., Z.S., E.F., B.J.M., E.B., C.M.M. and D.J.M.; data curation, R.A., R.M.R., D.D., C.B.d.M. and J.S.; writing—original draft, R.A., R.M.R., F.D.M., C.M.M. and D.J.M.; writing—review and editing, R.A., R.M.R., E.C., A.O., D.D., B.A., Z.S., E.F., B.J.M., C.B.d.M., J.S., E.B., F.D.M., C.M.M. and D.J.M.; supervision, C.M.M. and D.J.M.; project administration, C.B.d.M., J.S. and D.J.M.; funding acquisition, F.D.M., C.M.M. and D.J.M.

Corresponding authors

Correspondence to Cindi M. Morshead or Donald J. Mabbott.

Ethics declarations

Competing interests

E.F. is a co-inventor and the New York University Grossman School of Medicine is owner of the denoising technology used in this manuscript as part of the routine data image processing pipeline; a patent application has been filed and is pending. E.F., B.A. and the New York University Grossman School of Medicine are shareholders and have advisory roles at Microstructure Imaging, Inc. The remaining authors do not have any competing interests to declare.

Additional information

Peer review information Kate Gao and Javier Carmona were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Metformin in the absence of injury has no significant effect on the number of neurospheres or on behavioural assays.

a, b, Fold change in the number of neurospheres from the (a) SVZ (n = 21 Ctrl, 19 Met mice over 10 independent experiments; t(38) = 0.10, p = 0.92) and (b) DG (n = 12 Ctrl, 10 Met mice over 5 independent experiments; t(20) = 0.90, p = 0.38) 5 weeks post-radiation. c, Spontaneous alternation performance measured using the Y maze at P43 (n = 38 Ctrl, 31 Met mice over 14 independent experiments; t(67) = 0.34, p = 0.74). d, Percentage of time spent exploring objects in a novel place measured using the novel place recognition task from P44-46 (n = 34 Ctrl, 27 Met over 13 independent experiments; t(59) = 0.70, p = 0.48). Two-sided unpaired t-test was used for all analyses. Data is presented as mean ± SEM.

Extended Data Fig. 2 Metformin’s effects on NSC pool recovery following juvenile cranial radiation are not sex-dependent.

a, b, Fold change in the number of neurospheres from the SVZ 5 weeks post-radiation in (a) females (n = 8 Ctrl, 9 IR, 6 IR + Met mice over 6 independent experiments; F(2,20) = 0.56, p = 0.58) and (b) males (n = 9 Ctrl, 7 IR, 12 IR+Met mice over 6 independent experiments; F(2,25) = 0.03, p = 0.97). (c-d) Fold change in the number of neurospheres from the DG 5 weeks post-radiation in (c) females (n = 6 Ctrl, 5 IR, 6 IR+Met mice over 4 independent experiments; F(2,14) = 3.47, p = 0.06; Ctrl vs. IR, p = 0.0496) and (d) males (n = 4 Ctrl, 5 IR, 4 IR+Met over 4 independent experiments; F(2,10) = 6.47, p = 0.02; Ctrl vs. IR, p = 0.04; IR vs. IR+Met, p = 0.02). *p < 0.05, one-way ANOVA with Tukey’s test was used for all analyses. Data is presented as mean ± SEM.

Extended Data Fig. 3 Cranial radiation does not lead to impairments in the open field test or in the elevated plus maze.

a, Experimental paradigm. IR=cranial radiation. b, c, Path length travelled over 10 minutes in an open arena by (b) females (n = 17 Ctrl, 15 IR, 13 IR+Met mice over 13 independent experiments; F(2,42) = 0.62, p = 0.54) and (c) males (n = 17 Ctrl, 19 IR, 19 IR+Met mice over 13 independent experiments; F(2,52) = 0.40, p = 0.67). d, e, Percentage of time spent in the open arms of the elevated plus maze over 10 minutes by (d) females (n = 5 Ctrl, 5 IR, 6 IR+Met mice over 4 independent experiments; F(2,13) = 1.26, p = 0.32) and (e) males (n = 5 Ctrl, 5 IR, 6 IR+Met mice over 4 independent experiments; F(2,13) = 0.78, p = 0.48). One-way ANOVA with Tukey’s test was used for all analyses. Data is presented as mean ± SEM.

Extended Data Fig. 4 Consort table.

Eligible participants were identified via database review. Randomization was conducted by the Research Support Pharmacy and all research personnel remained blind to treatment assignment until all participants had completed the trial and data processing and scoring was completed. Initially, due to the pilot nature of the trial, neuroimaging and neuropsychological assessments were acquired at three time points (Baseline 1 and 2; Outcome 2). With an amendment to the study protocol, subsequent participants were assessed at four time points (Baseline 1 and 2; Outcome 1 and 2). Therefore, fewer Outcome 1 than Outcome 2 data points were acquired. Linear mixed modeling can be used in the context of such missing data. The single participant who consented but did not complete the trial was not included in the analyses.

Extended Data Fig. 5 Estimated marginal means for linear mixed models of cognitive and WMTI outcomes.

Data are presented as estimated marginal means from seperate general linear mixed models (two sided) with two sets of outcomes (Outcome 1 and 2 corresponding to the end of the first and second 12-week treatment cycles, respectively). We examined the fixed effects of cycle (the first versus second 12-week treatment cycle), treatment (metformin versus placebo), and sequence (metformin first, placebo second [AB] versus placebo first, metformin second [BA]). Bar graphs show estimated means+/- SEMs from the following model: Outcome measure = cycle + treatment + sequence + covariate (Baseline measure) + (1| participant ID)+ε, where cycle, treatment, and sequence are independent fixed effects and where the measures are: a) total correct on the LSWM (n = 23); b) CANTAB mean latency (n = 22); c) total number of words recall for immediate recall (n = 23); and d) AWF. Standard error bars are shown for each estimated mean. All models were corrected for multiple comparisons (False Discovery Rate (FDR) q < .10): * p < 0.05, ** q < 0.10 from the linear mixed models (Panel a-c, qs = 0.09; Panel d, q = 0.08).

Extended Data Fig. 6 Voxel wise analyses of treatment effects.

We used a longitudinal voxel wise approach to test for clusters of significant changes in AWF and De,⊥ following metformin in all participants using Tract Based Spatial Statistics (TBSS). For 2 sided comparisons across treatment conditions, individual difference maps for AWF and De,⊥ (post-metformin minus pre-metformin) were projected onto the skeleton and tested for voxels where change was significantly different from zero using threshold-free cluster enhancement (TFCE). For these analyses, the null distribution of the cluster-size statistic was built up over 5000 random permutations. Cluster size was thresholded at P < 0.05, which is family wise fully corrected for multiple comparisons across space. Images are presented in the axial frame in radiological convention within Montreal Neurological Institute (MNI) Z-coordinates. The white matter skeleton is displayed in blue. No significant clusters of change were evident for AWF (p = .90) or De,⊥ (p = .47) across the white matter skeleton.

Extended Data Fig. 7 Arterial Spin Labelling and Cerebral Blood Flow within the Hippocampus as a function of cycle, treatment, and sequence effects for the right and left hippocampi and adjusted for baseline hippocampal CBF.

a, Axial T1-weighted image with FreeSurfer hippocampus segmentation shown. b, PASL image processing pipeline shown in the axial plane, including PASL Control, PASL Labeled image, Perfusion weighted Image and Cerebral Blood Flow Map. c, Segmented hippocampi registered to the CBF map. Boxplots showing all data points at baseline and outcome assessment with the mean (dashed line) and median (solid line) sequence group observations for CBF (ml/100 g/min) for: the left hippocampus at d) Cycle 1 and e) Cycle 2; and the right hippocampus at f) Cycle 1 and g) Cycle 2. Metformin treatment condition is shown in red and placebo in blue. The upper and lower limits of the box plots are the third and first quartiles (75th and 25th percentile), respectively. The whiskers extend up to 1.5 times the interquartile range from the top (bottom) of the box to the furthest datum within that distance: Data beyond this distance are represented individually as points.

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Ayoub, R., Ruddy, R.M., Cox, E. et al. Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin. Nat Med 26, 1285–1294 (2020). https://doi.org/10.1038/s41591-020-0985-2

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