TY - JOUR
T1 - Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis
T2 - Evidence from a combined MRI-histopathology study
AU - Kiljan, Svenja
AU - Preziosa, Paolo
AU - Jonkman, Laura E.
AU - van de Berg, Wilma D.J.
AU - Twisk, Jos
AU - Pouwels, Petra J.W.
AU - Schenk, Geert J.
AU - Rocca, Maria A.
AU - Filippi, Massimo
AU - Geurts, Jeroen J.G.
AU - Steenwijk, Martijn D.
N1 - Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch MS Research Society (Grant No. 14-358e MS). Funding Information: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.K., W.D.J.v.d.B., J.T., P.J.W.P., G.J.S., and M.D.S. report no disclosures. P.P. reports personal fees from Biogen Idec, Novartis, and ExceMED. L.E.J. reports grants from Alzheimer’s Association. M.A.R. reports personal fees from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono, and Roche. M.F. reports personal fees from Biogen Idec, Merck-Serono, Novartis, and Teva Pharmaceutical Industries; grants from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, and Roche; and is Editor-in-Chief of the Journal of Neurology . J.J.G.G. reports grants from Biogen, Novartis, and Sanofi Genzyme. Publisher Copyright: © The Author(s), 2020. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - Background: Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS). Objective: To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS. Methods: Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models. Results: The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices (p < 0.001 and p = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD (p = 0.003; p = 0.02, respectively), and NAWM MD and AD (p = 0.04; p = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity (p = 0.002), explaining 34.4% of axonal loss variance. Conclusion: Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.
AB - Background: Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS). Objective: To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS. Methods: Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models. Results: The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices (p < 0.001 and p = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD (p = 0.003; p = 0.02, respectively), and NAWM MD and AD (p = 0.04; p = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity (p = 0.002), explaining 34.4% of axonal loss variance. Conclusion: Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.
KW - Multiple sclerosis
KW - axonal loss
KW - histopathology
KW - magnetic resonance imaging
KW - post mortem
KW - progressive
UR - http://www.scopus.com/inward/record.url?scp=85084803640&partnerID=8YFLogxK
U2 - https://doi.org/10.1177/1352458520918978
DO - https://doi.org/10.1177/1352458520918978
M3 - Article
C2 - 32390507
VL - 27
SP - 380
EP - 390
JO - Multiple sclerosis (Houndmills, Basingstoke, England)
JF - Multiple sclerosis (Houndmills, Basingstoke, England)
SN - 1352-4585
IS - 3
ER -