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Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin
Open accessAbstract
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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“Preclinical studies in disease models that share numerous features with the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition (Ayoub et al., 2020; Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003; Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Ayoub et al., 2020
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Ming, G.-L., & Song, H. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.001 · Cited by 2,651
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Denoising of diffusion MRI using random matrix theory
Veraart, J., Novikov, D. S., Christiaens, D., Ades-aron, B., Sijbers, J., & Fieremans, E. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.08.016 · Cited by 1,905
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Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M.-H., Wood, J., O’Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.008 · Cited by 521
“…the cellular dysregulation observed here after mild respiratory COVID have identified anti-inflammatory and neuro-regenerative strategies that restore neural plasticity and rescue cognition (Ayoub et al., 2020; Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003; Villeda et al., 2011).”
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Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing
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“A double-blind, placebo-controlled crossover pilot study revealed that metformin was linked to better performance in the assessment of cognitive and neural recovery, with good safety and tolerance in survivors of pediatric brain tumors [149].”
BackgroundAmanollahi, M., Jameie, M., Heidari, A., & Rezaei, N. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03102-z · Cited by 207
“However, the cerebral blood flow investigation within the participants’ hippocampus revealed no significant difference between the treatment and placebo groups [99].”
BackgroundMethod
Metadata
- Authors
- Ayoub, R., Ruddy, R. M., Cox, E., Oyefiade, A., Derkach, D., Laughlin, S., Ades-aron, B., Shirzadi, Z., Fieremans, E., MacIntosh, B. J., de Medeiros, C. B., Skocic, J., Bouffet, E., Miller, F. D., Morshead, C. M., & Mabbott, D. J.
- Affiliations
- University of Toronto (CA)
- New York University (US)
- Hospital for Sick Children (CA)
- Corresponding author
- Morshead, Cindi M.
- Mabbott, Donald J.
- ORCID
- Venue
- Nature Medicine
- Published
- 2020-07-27
- Volume
- 26
- Issue
- 8
- Pages
- 1285-1294
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC8176964
- OpenAlex
- W3044625941
- Cited by
- 117
- References
- 77
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 22 · 2023: 28 · 2022: 21 · 2021: 16 · 2020: 4
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Garron Family Cancer Centre
- Fondation Brain Canada
- Stem Cell Network
- Ontario Institute for Regenerative Medicine
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- metformin, pediatric brain tumor survivors, cognitive recovery, neural progenitor cells, neurogenesis, dentate gyrus, hippocampus, white matter, working memory, declarative memory, drug safety and tolerability, sex differences
- MeSH terms
- Cancer Survivors, Adolescent, Adult, Brain, Brain Neoplasms, Child, Child, Preschool, Cognition, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Metformin, Pediatrics, Pilot Projects, Treatment Outcome, Neurogenesis, Young Adult, Cognitive Dysfunction
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