Contributions
Abstract: 22
Type: Young Scientific Investigators' Session
Abstract Category: Pathology and pathogenesis of MS - MRI and PET
Background: Cortical diffusivity abnormalities are associated with clinical and cognitive deterioration in patients with multiple sclerosis (PwMS). Interestingly, a higher fractional anisotropy (FA) has been found in cortical lesions (CLs) vs cortical normal-appearing gray matter (cNAGM). However, the pathological substrate of this finding has yet to be elucidated.
Aims: To define the histopathological substrate of diffusivity abnormalities in cNAGM and CLs of PwMS by performing a combined postmortem diffusion tensor (DT) MRI and histopathology study.
Methods: Sixteen PwMS and ten age- and gender-matched healthy controls (HC) underwent postmortem in situ 3T MRI with 3DT1 and DT sequences, followed by brain dissection. One hundred and ten paraffin embedded tissue blocks (54 from PwMS, 56 from HC) were collected from 6 standardized cortical regions. Tissue regions were matched to 3DT1 and co-registered to DT sequence to obtain regional FA and mean diffusivity. Using immunohistochemistry, cortical density of myelin and microglia, number of axons (total, parallel and perpendicular to cortical surface), number and size of neurons and glial cells were evaluated. Correlates of diffusivity alterations with histological markers were assessed through generalized estimating equation models for nested data.
Results: CLs (77% subpial) were found in 27 (50%) cortical regions from PwMS and none in HC. cNAGM of PwMS had a significantly lower FA vs HC (p=0.04), whereas in PwMS a higher FA was confirmed in CLs vs cNAGM (p=0.003). Compared to HC, cNAGM in PwMS showed a lower density of perpendicular and total axons (p from 0.006 to 0.02). In PwMS, CLs had a lower density of myelin, parallel and total axons vs cNAGM (p from 0.0003 to 0.02). Regarding the pathological substrate, HC cNAGM FA was positively associated with density of perpendicular, parallel and total axons (p from 0.003 to 0.009). In PwMS, cNAGM FA was positively associated with density of myelin, glial and total cells and perpendicular, parallel and total axons (p from 0.001 to 0.05), while CLs FA was positively associated with density of neurons and total cells and negatively with microglia density (p from 0.02 to 0.05).
Conclusions: Heterogeneous pathological processes, including demyelination, inflammation and variable loss of axons with different orientations, determine cortical microstructural abnormalities contributing to explain the different patterns of FA changes occurring in cNAGM and CLs of PwMS.
Disclosure: P. Preziosa received speakers honoraria from Biogen Idec, Novartis, Merck Serono and Excemed.
S. Kiljan received research support from the Dutch MS Research Foundation, grant number MS14-358e.
M.D. Steenwijk has nothing to disclose.
A.G.M. Meani 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.
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.
L.E. Jonkman has nothing to disclose.
Abstract: 22
Type: Young Scientific Investigators' Session
Abstract Category: Pathology and pathogenesis of MS - MRI and PET
Background: Cortical diffusivity abnormalities are associated with clinical and cognitive deterioration in patients with multiple sclerosis (PwMS). Interestingly, a higher fractional anisotropy (FA) has been found in cortical lesions (CLs) vs cortical normal-appearing gray matter (cNAGM). However, the pathological substrate of this finding has yet to be elucidated.
Aims: To define the histopathological substrate of diffusivity abnormalities in cNAGM and CLs of PwMS by performing a combined postmortem diffusion tensor (DT) MRI and histopathology study.
Methods: Sixteen PwMS and ten age- and gender-matched healthy controls (HC) underwent postmortem in situ 3T MRI with 3DT1 and DT sequences, followed by brain dissection. One hundred and ten paraffin embedded tissue blocks (54 from PwMS, 56 from HC) were collected from 6 standardized cortical regions. Tissue regions were matched to 3DT1 and co-registered to DT sequence to obtain regional FA and mean diffusivity. Using immunohistochemistry, cortical density of myelin and microglia, number of axons (total, parallel and perpendicular to cortical surface), number and size of neurons and glial cells were evaluated. Correlates of diffusivity alterations with histological markers were assessed through generalized estimating equation models for nested data.
Results: CLs (77% subpial) were found in 27 (50%) cortical regions from PwMS and none in HC. cNAGM of PwMS had a significantly lower FA vs HC (p=0.04), whereas in PwMS a higher FA was confirmed in CLs vs cNAGM (p=0.003). Compared to HC, cNAGM in PwMS showed a lower density of perpendicular and total axons (p from 0.006 to 0.02). In PwMS, CLs had a lower density of myelin, parallel and total axons vs cNAGM (p from 0.0003 to 0.02). Regarding the pathological substrate, HC cNAGM FA was positively associated with density of perpendicular, parallel and total axons (p from 0.003 to 0.009). In PwMS, cNAGM FA was positively associated with density of myelin, glial and total cells and perpendicular, parallel and total axons (p from 0.001 to 0.05), while CLs FA was positively associated with density of neurons and total cells and negatively with microglia density (p from 0.02 to 0.05).
Conclusions: Heterogeneous pathological processes, including demyelination, inflammation and variable loss of axons with different orientations, determine cortical microstructural abnormalities contributing to explain the different patterns of FA changes occurring in cNAGM and CLs of PwMS.
Disclosure: P. Preziosa received speakers honoraria from Biogen Idec, Novartis, Merck Serono and Excemed.
S. Kiljan received research support from the Dutch MS Research Foundation, grant number MS14-358e.
M.D. Steenwijk has nothing to disclose.
A.G.M. Meani 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.
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.
L.E. Jonkman has nothing to disclose.