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Cited by 110Multiple Sclerosis Research StudiesBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

The formation of inflammatory demyelinated lesions in cerebral white matter

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Maggi, Pietro, Macri, Sheila M. Cummings, Gaitán, María I., Leibovitch, Emily, Wholer, Jillian E., Knight, Heather L., Ellis, Mary, Wu, Tianxia +5 more·2014·Annals of Neurology
DOI 10.1002/ana.24242PMC PMC4723108
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Abstract

Objective: Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. Methods: By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2‐weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood–brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. Results: On average, BBB permeability increased 3.5‐fold ( p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood‐derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died ( p < 0.0001). Interpretation: This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood‐derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions. Ann Neurol 2014;76:594–608

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  • In the experimental autoimmune encephalomyelitis marmoset model, high-field MRI detected a 3.5-fold increase in blood-brain barrier permeability 4 weeks before the onset of multiple sclerosis lesions.

    “Increased BBB permeability has been also detected early in the EAE model in marmosets using high-field MRI indicating a 3.5-fold increase in BBB permeability 4 wk before the onset of MS lesions (382).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [382]

    The Abstract Results report a 3.5-fold increase in BBB permeability over the four weeks preceding lesion appearance in marmoset EAE. The Results section says permeability was roughly stable before week −4 and then rose; it does not say the 3.5-fold increase had already occurred four weeks before lesions appeared. (LLM, conf=0.88)

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Authors
Maggi, P., Macri, S. M. C., Gaitán, M. I., Leibovitch, E., Wholer, J. E., Knight, H. L., Ellis, M., Wu, T., Silva, A. C., Massacesi, L., Jacobson, S., Westmoreland, S., & Reich, D. S.
Affiliations
  • National Institutes of Health (US)
  • Harvard University (US)
Corresponding author
Maggi, Pietro
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2014-08-21
Volume
76
Issue
4
Pages
594-608
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.24242
PMC
PMC4723108
OpenAlex
W1916428876
Cited by
110
References
4
Citations by year
2025: 10 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 12 · 2017: 6 · 2016: 10 · 2015: 10 · 2014: 3
FWCI
7.19
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion, other-oa)
  • Digital Access to Libraries (submittedVersion, other-oa)
Funders
National Institute of Neurological Disorders and Stroke
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
inflammatory demyelination, cerebral white matter lesions, blood-brain barrier permeability, vascular permeability, experimental autoimmune encephalomyelitis, multiple sclerosis, Callithrix jacchus, microglial activation, macrophages, T cells, early lesion detection, 7T MRI
MeSH terms
Analysis of Variance, Animals, Blood-Brain Barrier, Callithrix, Cerebral Cortex, Contrast Media, Disease Models, Animal, Encephalitis, Encephalomyelitis, Autoimmune, Experimental, Female, Glial Fibrillary Acidic Protein, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Microfilament Proteins, 2',3'-Cyclic-Nucleotide Phosphodiesterases, Leukocyte L1 Antigen Complex, White Matter

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