TY - JOUR
T1 - Micro-diffusely abnormal white matter
T2 - An early multiple sclerosis lesion phase with intensified myelin blistering
AU - Luchicchi, Antonio
AU - Muñoz-Gonzalez, Gema
AU - Halperin, Saar T.
AU - Strijbis, Eva
AU - van Dijk, Laura H. M.
AU - Foutiadou, Chrisa
AU - Uriac, Florence
AU - Bouman, Piet M.
AU - Schouten, Maxime A. N.
AU - Plemel, Jason
AU - 't Hart, Bert A.
AU - Geurts, Jeroen J. G.
AU - Schenk, Geert J.
N1 - Publisher Copyright: © 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024/4
Y1 - 2024/4
N2 - Objective: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM). Methods: We used an in-depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. Results: mDAWM-defined areas exhibit ill-defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. Interpretation: We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo-myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.
AB - Objective: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM). Methods: We used an in-depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. Results: mDAWM-defined areas exhibit ill-defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. Interpretation: We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo-myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.
UR - http://www.scopus.com/inward/record.url?scp=85186599819&partnerID=8YFLogxK
U2 - 10.1002/acn3.52015
DO - 10.1002/acn3.52015
M3 - Article
C2 - 38425098
SN - 2328-9503
VL - 11
SP - 973
EP - 988
JO - Annals of clinical and translational neurology
JF - Annals of clinical and translational neurology
IS - 4
ER -