In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis

  1. Maxime Donadieu
  2. Nathanael J Lee
  3. María I Gaitán
  4. Seung-Kwon Ha
  5. Nicholas J Luciano
  6. Snehashis Roy
  7. Benjamin V Ineichen
  8. Emily C Leibovitch
  9. Cecil C Yen
  10. Dzung L Pham
  11. Afonso C Silva
  12. Mac Johnson
  13. Steve Jacobson
  14. Pascal Sati  Is a corresponding author
  15. Daniel S Reich  Is a corresponding author
  1. National Institute of Neurological Disorders and Stroke, United States
  2. University of Pittsburgh, United States
  3. National Institute of Mental Health, United States
  4. Vertex Phamaceuticals Inc, United States
  5. Cedars-Sinai Medical Center, United States

Abstract

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In 6 animals followed with multisequence 7-tesla MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in 4 of 6 marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

Data availability

All of the 6 marmosets' serial in vivo MRI images, including all the sequences used for analysis and figure generation, were uploaded in an easily accessible format (NIFTI). The file names are titled with the corresponding animal # used in the manuscript, as well as the date of MRI acquisition. All the Iba1 and PLP immunohistochemistry stains have been uploaded as well.

Article and author information

Author details

  1. Maxime Donadieu

    Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  2. Nathanael J Lee

    Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  3. María I Gaitán

    Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  4. Seung-Kwon Ha

    Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  5. Nicholas J Luciano

    Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  6. Snehashis Roy

    Section on Neural Function, National Institute of Mental Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Benjamin V Ineichen

    Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  8. Emily C Leibovitch

    Viral Immunology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  9. Cecil C Yen

    Cerebral Microcirculation Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  10. Dzung L Pham

    Cerebral Microcirculation Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  11. Afonso C Silva

    Cerebral Microcirculation Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
  12. Mac Johnson

    Vertex Phamaceuticals Inc, Boston, United States
    Competing interests
    Mac Johnson, is a shareholder and employee of Vertex Pharmaceuticals, Inc..
  13. Steve Jacobson

    Viral immunology section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3127-1287
  14. Pascal Sati

    Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, United States
    For correspondence
    Pascal.Sati@cshs.org
    Competing interests
    No competing interests declared.
  15. Daniel S Reich

    Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, United States
    For correspondence
    reichds@ninds.nih.gov
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2628-4334

Funding

National Institutes of Health (Intramural Research Program)

  • Nathanael J Lee

Adelson Family Foundation

  • Maxime Donadieu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The study was performed under the guideline and in accordance with the National Institutes of Health IACUC. Specifically, the neuroethics committee of the National Institutes of Neurological Diseases and Stroke formally went through our manuscript prior to submission on salient topics including minimization of pain, justification of number of animals and the sex ratio, dosing of methylprednisone based on available human data. All procedures were performed under anesthesia to minimize discomfort and pain. Animals were housed in pairs or triplets to maximize social interactions and well-being. The institutional IACUC protocol number is #1308.

Reviewing Editor

  1. Jeannie Chin, Baylor College of Medicine, United States

Version history

  1. Received: September 10, 2021
  2. Preprint posted: October 28, 2021 (view preprint)
  3. Accepted: April 12, 2023
  4. Accepted Manuscript published: April 21, 2023 (version 1)
  5. Version of Record published: May 10, 2023 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Maxime Donadieu
  2. Nathanael J Lee
  3. María I Gaitán
  4. Seung-Kwon Ha
  5. Nicholas J Luciano
  6. Snehashis Roy
  7. Benjamin V Ineichen
  8. Emily C Leibovitch
  9. Cecil C Yen
  10. Dzung L Pham
  11. Afonso C Silva
  12. Mac Johnson
  13. Steve Jacobson
  14. Pascal Sati
  15. Daniel S Reich
(2023)
In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis
eLife 12:e73786.
https://doi.org/10.7554/eLife.73786

Share this article

https://doi.org/10.7554/eLife.73786

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