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Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise

Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas...

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Autores principales: Elliott, Colm, Momayyezsiahkal, Parya, Arnold, Douglas L, Liu, Dawei, Ke, Jun, Zhu, Li, Zhu, Bing, George, Ilena C, Bradley, Daniel P, Fisher, Elizabeth, Cahir-McFarland, Ellen, Stys, Peter K, Geurts, Jeroen J G, Franchimont, Nathalie, Gafson, Arie, Belachew, Shibeshih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453433/
https://www.ncbi.nlm.nih.gov/pubmed/34557664
http://dx.doi.org/10.1093/braincomms/fcab176
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author Elliott, Colm
Momayyezsiahkal, Parya
Arnold, Douglas L
Liu, Dawei
Ke, Jun
Zhu, Li
Zhu, Bing
George, Ilena C
Bradley, Daniel P
Fisher, Elizabeth
Cahir-McFarland, Ellen
Stys, Peter K
Geurts, Jeroen J G
Franchimont, Nathalie
Gafson, Arie
Belachew, Shibeshih
author_facet Elliott, Colm
Momayyezsiahkal, Parya
Arnold, Douglas L
Liu, Dawei
Ke, Jun
Zhu, Li
Zhu, Bing
George, Ilena C
Bradley, Daniel P
Fisher, Elizabeth
Cahir-McFarland, Ellen
Stys, Peter K
Geurts, Jeroen J G
Franchimont, Nathalie
Gafson, Arie
Belachew, Shibeshih
author_sort Elliott, Colm
collection PubMed
description Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis.
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spelling pubmed-84534332021-09-22 Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise Elliott, Colm Momayyezsiahkal, Parya Arnold, Douglas L Liu, Dawei Ke, Jun Zhu, Li Zhu, Bing George, Ilena C Bradley, Daniel P Fisher, Elizabeth Cahir-McFarland, Ellen Stys, Peter K Geurts, Jeroen J G Franchimont, Nathalie Gafson, Arie Belachew, Shibeshih Brain Commun Original Article Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis. Oxford University Press 2021-08-10 /pmc/articles/PMC8453433/ /pubmed/34557664 http://dx.doi.org/10.1093/braincomms/fcab176 Text en © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Elliott, Colm
Momayyezsiahkal, Parya
Arnold, Douglas L
Liu, Dawei
Ke, Jun
Zhu, Li
Zhu, Bing
George, Ilena C
Bradley, Daniel P
Fisher, Elizabeth
Cahir-McFarland, Ellen
Stys, Peter K
Geurts, Jeroen J G
Franchimont, Nathalie
Gafson, Arie
Belachew, Shibeshih
Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
title Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
title_full Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
title_fullStr Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
title_full_unstemmed Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
title_short Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
title_sort abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453433/
https://www.ncbi.nlm.nih.gov/pubmed/34557664
http://dx.doi.org/10.1093/braincomms/fcab176
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