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September 2019; 6 (5) ArticleOpen Access

Lesion activity and chronic demyelination are the major determinants of brain atrophy in MS

Chenyu Wang, Michael H. Barnett, Con Yiannikas, Joshua Barton, John Parratt, Yuyi You, Stuart L. Graham, Alexander Klistorner
First published July 16, 2019, DOI: https://doi.org/10.1212/NXI.0000000000000593
Chenyu Wang
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Michael H. Barnett
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Con Yiannikas
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Joshua Barton
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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John Parratt
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Yuyi You
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Stuart L. Graham
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Alexander Klistorner
From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.
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Citation
Lesion activity and chronic demyelination are the major determinants of brain atrophy in MS
Chenyu Wang, Michael H. Barnett, Con Yiannikas, Joshua Barton, John Parratt, Yuyi You, Stuart L. Graham, Alexander Klistorner
Neurol Neuroimmunol Neuroinflamm Sep 2019, 6 (5) e593; DOI: 10.1212/NXI.0000000000000593

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Abstract

Objective To evaluate the combined effect of lesion activity and pathologic processes occurring in both chronically demyelinated lesions and normal-appearing white matter (NAWM) on brain atrophy in MS.

Methods Pre- and post-gadolinium T1, fluid attenuation inversion recovery, and diffusion tensor imaging images were acquired from 50 consecutive patients with relapsing-remitting MS (all, but one, on disease-modifying therapy) at baseline and 5 years. Brain atrophy was measured using structural image evaluation, using normalization of atrophy percent brain volume change (PBVC) analysis.

Results During follow-up, brain volume diminished by 2.0% ± 1.1%. PBVC was not associated with patient age, disease duration, sex, or type of treatment. PBVC moderately correlated with baseline lesion load (r = −0.38, p = 0.016), but demonstrated strong association with new lesion activity (r = −0.63, p < 0.001). Brain atrophy was also strongly linked to the increase of water diffusion within chronic MS lesions (r = −0.62, p < 0.001). In normal-appearing white matter (NAWM), PBVC demonstrated a significant correlation with both baseline and longitudinal increase of demyelination as measured by radial diffusivity (RD, r = −0.44, p = 0.005 and r = −0.35, p = 0.026, respectively). Linear regression analysis explained 62% of the variance in PBVC. It confirmed the major role of new lesion activity (p = 0.002, standardized beta-coefficient −0.42), whereas change in diffusivity inside chronic lesions and NAWM RD at baseline also contributed significantly (p = 0.04 and 0.02, standardized beta-coefficient −0.31 and −0.29, respectively), increasing predictive power of the model by 55%.

Conclusion In addition to new lesion activity, progressive loss of demyelinated axons in chronic lesions and the degree of demyelination in NAWM significantly contribute to accelerated loss of brain tissue in patients with MS receiving immunomodulatory therapy.

Glossary

AD=
axial diffusivity;
DTI=
diffusion tensor imaging;
EDSS=
Expanded Disability Status Scale;
FLAIR=
fluid attenuation inversion recovery;
FSL=
Functional MRI of the Brain Software Library;
GAD=
gadolinium;
MD=
mean diffusivity;
NAWM=
normal-appearing white matter;
PBVC=
percent brain volume change;
RD=
radial diffusivity;
ROI=
region of interest;
RRMS=
relapsing-remitting MS

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the NMSS.

  • Received November 27, 2018.
  • Accepted in final form May 7, 2019.
  • Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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