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Micro-diffusely abnormal white matter: An early multiple sclerosis lesion phase with intensified myelin blistering

Antonio Luchicchi1,2, Gema Muñoz-Gonzalez1,2, Saar T Halperin1,2

  • 1Department of Anatomy and Neurosciences, Amsterdam University Medical Centers, location VU Medical Center, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Annals of Clinical and Translational Neurology
|March 1, 2024
PubMed
Abstract

Insights

Researchers identified a new early phase of multiple sclerosis (MS) lesion formation, termed micro-diffusely abnormal white matter (mDAWM). This prelesional stage shows myelin degeneration without Wallerian pathology, suggesting a novel pathway in MS pathogenesis.

Area of Science:

  • Neuroscience
  • Pathology
  • Immunology

Background:

  • Multiple sclerosis (MS) is a chronic central nervous system disease with debated white matter lesion origins.
  • Subtle changes in normal-appearing white matter (NAWM) in MS, including myelin blisters and citrullination, suggest early degenerative processes.
  • The relevance of these early changes to subsequent myelin degeneration in MS requires further investigation.

Purpose of the Study:

  • To investigate the prevalence of early myelin and axonal changes in micro-diffusely abnormal white matter (mDAWM) regions in MS.
  • To clarify the role of mDAWM in the initial stages of MS myelin degeneration.
  • To compare pathological features in mDAWM with normal-appearing white matter (NAWM) in MS.

Main Methods:

  • Utilized in-depth immunohistochemistry on brain tissue from 27 MS donors and 5 controls with histological mDAWM.
  • Employed an antibody panel targeting degenerative markers to analyze myelin and axonal aberrations.
  • Compared findings in mDAWM regions with NAWM from the same cases, slices, and regions.

Main Results:

  • mDAWM areas displayed ill-defined borders, lacked Wallerian degeneration, and were associated with visible veins.
  • mDAWM showed increased myelin blister frequency, polar myelin phospholipids, citrullination, and myelin basic protein (MBP) degradation compared to NAWM.
  • Enhanced microglial and macrophage reactivity against citrullinated MBP was observed in mDAWM.

Conclusions:

  • A new, histologically defined early phase of MS lesion formation, mDAWM, characterized by myelin blistering and degradation without Wallerian pathology, has been identified.
  • These findings support the prelesional nature of mDAWM, indicating it precedes overt MS lesion development.
  • The evolution to MS lesions likely involves myelin degeneration (myelin blistering) and subsequent immune activation by released myelin components.

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