Contributions
Abstract: P1094
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Neurodegeneration
Background: Neurodegeneration in multiple sclerosis (MS) has been related to local grey matter (GM) demyelination and inflammation as well as to damage in remote connected white matter (WM) tracts. However, the relative contribution of 'local' vs 'remote' damage to neurodegeneration is not known. Therefore we combined postmortem MRI and histopathology to investigate the associations between cortical neurodegeneration and 1) local GM myelination and microglia density, and 2) remote WM tract integrity in MS and non-neurological controls (nNC).
Methods: Structural and diffusion weighted 3T MR images of the brain in situ were obtained postmortem from 16 MS (age: 65±13y; M/F: 5/11; postmortem delay [pmd]: 8.3±1.0h) and 10 nNC (age: 73±6y; M/F: 5/5; pmd: 9.8±3.4h) donors, collected by Netherlands Brain Bank and Normal Aging Brain Collection, VUmc. At subsequent autopsy, cortical GM regions were dissected in a standardized manner from 6 anatomical locations. Neuron density and volume, and axon density were determined as histopathological markers for cortical neurodegeneration. Similarly, myelin and microglia density were evaluated as markers for local GM damage. Tissue blocks were matched to cortical AAL atlas regions on MRI. Connected WM tract fractional anisotropy (FA), mean (MD), axial (AD) and radial (RD) diffusivities were determined from MRI as markers for remote damage. Linear mixed model analysis was performed to evaluate between-group differences and within-group relations between neurodegeneration and local or remote damage, while correcting for age, gender and pmd.
Results: Compared to nNC, MS donors displayed significant axonal loss (p=0.003) and a trend to lower GM myelin density (p=0.107). In connected tracts, MS donors showed increased normal appearing WM (NAWM) AD and MD (p=0.013; p=0.037; respectively) and whole tract AD (i.e., including lesions; p=0.018) compared to nNC. Axonal density was associated with myelin density in both nNC (β=0.63, p< 0.001) and MS (β=0.61, p< 0.001). Moreover, axonal density in MS was associated with NAWM AD, MD and RD (β=-0.41, p=0.033; β=-0.43, p=0.029; β=-0.42, p=0.025; respectively) and whole tract MD (β=-0.36, p=0.041).
Conclusion: Evident cortical neurodegeneration was observed in MS, predominantly characterized by axonal loss. In turn, axonal loss was associated with both local (cortical demyelination) and remote (WM tract disintegrity) damage.
Disclosure: S. Kiljan received research support from the Dutch MS Research Foundation, grant number MS14-358e.
P. Preziosa received speakers honoraria from Biogen Idec, Novartis, Merck Serono and Excemed.
L.E. Jonkman has nothing to disclose.
W.D.J. van de Berg was financially supported by a grant from Amsterdam Neuroscience, ZonMW Memorabel, Stichting Parkinson Fonds, Alzheimer Netherlands-LECMA, Roche Pharma and Lysosomal Therapeutics. She is a consultant for CHDR Leiden and Lysosomal Therapeutics.
G.J. Schenk has nothing to disclose.
M.A. Rocca received speakers honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono and Roche and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla.
M. Filippi is Editor-in-Chief of the Journal of Neurology; has received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).
J.J.G. Geurts is an editor of MS Journal. He serves on the editorial boards of Neurology and Frontiers of Neurology and is president of the Netherlands organization for health research and innovation. He has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme and Teva Pharmaceuticals.
M.D. Steenwijk has nothing to disclose.
Abstract: P1094
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Neurodegeneration
Background: Neurodegeneration in multiple sclerosis (MS) has been related to local grey matter (GM) demyelination and inflammation as well as to damage in remote connected white matter (WM) tracts. However, the relative contribution of 'local' vs 'remote' damage to neurodegeneration is not known. Therefore we combined postmortem MRI and histopathology to investigate the associations between cortical neurodegeneration and 1) local GM myelination and microglia density, and 2) remote WM tract integrity in MS and non-neurological controls (nNC).
Methods: Structural and diffusion weighted 3T MR images of the brain in situ were obtained postmortem from 16 MS (age: 65±13y; M/F: 5/11; postmortem delay [pmd]: 8.3±1.0h) and 10 nNC (age: 73±6y; M/F: 5/5; pmd: 9.8±3.4h) donors, collected by Netherlands Brain Bank and Normal Aging Brain Collection, VUmc. At subsequent autopsy, cortical GM regions were dissected in a standardized manner from 6 anatomical locations. Neuron density and volume, and axon density were determined as histopathological markers for cortical neurodegeneration. Similarly, myelin and microglia density were evaluated as markers for local GM damage. Tissue blocks were matched to cortical AAL atlas regions on MRI. Connected WM tract fractional anisotropy (FA), mean (MD), axial (AD) and radial (RD) diffusivities were determined from MRI as markers for remote damage. Linear mixed model analysis was performed to evaluate between-group differences and within-group relations between neurodegeneration and local or remote damage, while correcting for age, gender and pmd.
Results: Compared to nNC, MS donors displayed significant axonal loss (p=0.003) and a trend to lower GM myelin density (p=0.107). In connected tracts, MS donors showed increased normal appearing WM (NAWM) AD and MD (p=0.013; p=0.037; respectively) and whole tract AD (i.e., including lesions; p=0.018) compared to nNC. Axonal density was associated with myelin density in both nNC (β=0.63, p< 0.001) and MS (β=0.61, p< 0.001). Moreover, axonal density in MS was associated with NAWM AD, MD and RD (β=-0.41, p=0.033; β=-0.43, p=0.029; β=-0.42, p=0.025; respectively) and whole tract MD (β=-0.36, p=0.041).
Conclusion: Evident cortical neurodegeneration was observed in MS, predominantly characterized by axonal loss. In turn, axonal loss was associated with both local (cortical demyelination) and remote (WM tract disintegrity) damage.
Disclosure: S. Kiljan received research support from the Dutch MS Research Foundation, grant number MS14-358e.
P. Preziosa received speakers honoraria from Biogen Idec, Novartis, Merck Serono and Excemed.
L.E. Jonkman has nothing to disclose.
W.D.J. van de Berg was financially supported by a grant from Amsterdam Neuroscience, ZonMW Memorabel, Stichting Parkinson Fonds, Alzheimer Netherlands-LECMA, Roche Pharma and Lysosomal Therapeutics. She is a consultant for CHDR Leiden and Lysosomal Therapeutics.
G.J. Schenk has nothing to disclose.
M.A. Rocca received speakers honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono and Roche and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla.
M. Filippi is Editor-in-Chief of the Journal of Neurology; has received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).
J.J.G. Geurts is an editor of MS Journal. He serves on the editorial boards of Neurology and Frontiers of Neurology and is president of the Netherlands organization for health research and innovation. He has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme and Teva Pharmaceuticals.
M.D. Steenwijk has nothing to disclose.