Contributions
Abstract: P417
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Pathology
Introduction/Objectives: MS was traditionally considered to be a disease primarily affecting the white matter (WM), although the importance of grey matter (GM) demyelination has now been firmly established. Demyelination of cerebral WM is thought to drive neuronal degeneration and permanent neurological disability in individuals with MS. Brain magnetic resonance imaging (MRI) studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. This study investigated postmortem MS brains for pathological evidence of cortical neuronal loss that is independent of cerebral WM demyelination.
Methods: In our post-mortem MS cohort of 100 brains, we identified 12 brains that lacked cerebral WM demyelination. We matched these 12 brains with 12 typical MS (TMS) cases that included cerebral WM lesions. Cases were matched based on age, sex, disease duration, post-mortem interval, postmortem MRI protocol, and disability. Demyelination was quantified histologically in cerebral WM, cerebral cortex, and spinal cord and compared between the two groups. Neuronal densities in 5 cortical regions not directly connected to spinal cord were compared between the two groups and with aged-matched postmortem control brains. Cerebral MRI metrics were compared between the two groups and with controls. Pathological correlates of brain WM MRI abnormalities were investigated in the group lacking cerebral WM lesions.
Results: Cases without cerebral WM demyelination exhibited demyelination in spinal cord and cortex. Despite the lack of cerebral WM demyelination, cortical neuronal densities and cortical thickness were significantly decreased compared to control brains and similar to TMS brains. Surprisingly, cerebral WM MRI abnormalities were similar to those found in TMS. Swollen myelinated axons were the pathological correlate of cerebral WM MRI abnormalities found in the MS brains without cerebral WM demyelination.
Conclusions: A subtype of MS, which we call myelocortical multiple sclerosis (MCMS), is characterized by demyelination of the spinal cord and cerebral cortex, but not of the cerebral WM. Cortical neuronal loss occurs independent of cerebral WM demyelination in MCMS. Future studies should investigate mechanisms of primary neuronal degeneration in MS.
Disclosure: Jessica Dudman: Nothing to disclose
Bruce D. Trapp, PhD: Received grants from the National Multiple Sclerosis Society (NMSS) and from NIH/NINDS during the conduct of the study. In addition, he received grants from NIMH/NINDS, the State of Ohio, and the ALS Association, grants, personal fees and non-financial support from Sanofi Genzyme, grants and non-financial support from NMSS, personal fees and non-financial support from Genentech, Novartis, Biogen, Disarm Therapeutics, and Renovo Neural Inc., and personal fees from the Lunbeckfonden Foundation outside the submitted work.
Megan Vignos, PhD: Is currently an employee of Biogen.
Ansi Chang, MD: Nothing to disclose
Elizabeth Fisher, PhD: Received grants from NIH NINDS during the conduct of the study. She is currently an employee and stockholder of Biogen, Inc. Previously, she received grants and personal fees from Genzyme outside the submitted work. In addition, she has a patent Method and System for Brain Volume Analysis with royalties paid to Cleveland Clinic, a patent Automated Lesion Segmentation from MRI Images pending, and a patent Methods for Improved Measurements of Brain Volume and Changes in Brain Volume pending.
Susan M Staugaitis, MD, PhD: Nothing to disclose.
Harsha Battapady, MS: Is an employee of Renovo Neural Inc.
Sverre Mork, MD: Nothing to disclose.
Daniel Ontaneda, MD: Received grants and personal fees from Novartis, grants from Genentech, personal fees from Merck, grants and personal fees from Genzyme, and personal fees from Biogen, Inc. outside the submitted work.
Stephen E Jones, MD, PhD: Nothing to disclose.
Robert J Fox, MD: . Received personal fees from Actelion, personal fees and other from Biogen, personal fees from Genentech, grants and personal fees from Novartis, personal fees from Teva, personal fees from Mallinckrodt, and personal fees from Xenoport outside the submitted work.
Jacqueline Chen, PhD: Was supported by grants from the NIH/NCATS Clinical and Translational Science Collaborative of Cleveland, CTSC KL2 Training Program, during the conduct of the study.
Kunio Nakamura, PhD: Reports grants from NIH during the conduct of the study; grants and personal fees from Sanofi Genzyme, grants and personal fees from Biogen, and personal fees from NeuroRx Research outside the submitted work.
Richard A Rudick, MD: Is an employee of and holds stock in Biogen, Inc.
This work was supported by grants from the National Institutes of Health (P50NS38667 and R35NS09730 to Dr. Trapp) and National Multiple Sclerosis Society (RG 4348-A-7 to Dr. Trapp). Dr. Chen was funded by the NIH/NCATS Clinical and Translational Science Collaborative of Cleveland CTSC KL2 Training Program.
Abstract: P417
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Pathology
Introduction/Objectives: MS was traditionally considered to be a disease primarily affecting the white matter (WM), although the importance of grey matter (GM) demyelination has now been firmly established. Demyelination of cerebral WM is thought to drive neuronal degeneration and permanent neurological disability in individuals with MS. Brain magnetic resonance imaging (MRI) studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. This study investigated postmortem MS brains for pathological evidence of cortical neuronal loss that is independent of cerebral WM demyelination.
Methods: In our post-mortem MS cohort of 100 brains, we identified 12 brains that lacked cerebral WM demyelination. We matched these 12 brains with 12 typical MS (TMS) cases that included cerebral WM lesions. Cases were matched based on age, sex, disease duration, post-mortem interval, postmortem MRI protocol, and disability. Demyelination was quantified histologically in cerebral WM, cerebral cortex, and spinal cord and compared between the two groups. Neuronal densities in 5 cortical regions not directly connected to spinal cord were compared between the two groups and with aged-matched postmortem control brains. Cerebral MRI metrics were compared between the two groups and with controls. Pathological correlates of brain WM MRI abnormalities were investigated in the group lacking cerebral WM lesions.
Results: Cases without cerebral WM demyelination exhibited demyelination in spinal cord and cortex. Despite the lack of cerebral WM demyelination, cortical neuronal densities and cortical thickness were significantly decreased compared to control brains and similar to TMS brains. Surprisingly, cerebral WM MRI abnormalities were similar to those found in TMS. Swollen myelinated axons were the pathological correlate of cerebral WM MRI abnormalities found in the MS brains without cerebral WM demyelination.
Conclusions: A subtype of MS, which we call myelocortical multiple sclerosis (MCMS), is characterized by demyelination of the spinal cord and cerebral cortex, but not of the cerebral WM. Cortical neuronal loss occurs independent of cerebral WM demyelination in MCMS. Future studies should investigate mechanisms of primary neuronal degeneration in MS.
Disclosure: Jessica Dudman: Nothing to disclose
Bruce D. Trapp, PhD: Received grants from the National Multiple Sclerosis Society (NMSS) and from NIH/NINDS during the conduct of the study. In addition, he received grants from NIMH/NINDS, the State of Ohio, and the ALS Association, grants, personal fees and non-financial support from Sanofi Genzyme, grants and non-financial support from NMSS, personal fees and non-financial support from Genentech, Novartis, Biogen, Disarm Therapeutics, and Renovo Neural Inc., and personal fees from the Lunbeckfonden Foundation outside the submitted work.
Megan Vignos, PhD: Is currently an employee of Biogen.
Ansi Chang, MD: Nothing to disclose
Elizabeth Fisher, PhD: Received grants from NIH NINDS during the conduct of the study. She is currently an employee and stockholder of Biogen, Inc. Previously, she received grants and personal fees from Genzyme outside the submitted work. In addition, she has a patent Method and System for Brain Volume Analysis with royalties paid to Cleveland Clinic, a patent Automated Lesion Segmentation from MRI Images pending, and a patent Methods for Improved Measurements of Brain Volume and Changes in Brain Volume pending.
Susan M Staugaitis, MD, PhD: Nothing to disclose.
Harsha Battapady, MS: Is an employee of Renovo Neural Inc.
Sverre Mork, MD: Nothing to disclose.
Daniel Ontaneda, MD: Received grants and personal fees from Novartis, grants from Genentech, personal fees from Merck, grants and personal fees from Genzyme, and personal fees from Biogen, Inc. outside the submitted work.
Stephen E Jones, MD, PhD: Nothing to disclose.
Robert J Fox, MD: . Received personal fees from Actelion, personal fees and other from Biogen, personal fees from Genentech, grants and personal fees from Novartis, personal fees from Teva, personal fees from Mallinckrodt, and personal fees from Xenoport outside the submitted work.
Jacqueline Chen, PhD: Was supported by grants from the NIH/NCATS Clinical and Translational Science Collaborative of Cleveland, CTSC KL2 Training Program, during the conduct of the study.
Kunio Nakamura, PhD: Reports grants from NIH during the conduct of the study; grants and personal fees from Sanofi Genzyme, grants and personal fees from Biogen, and personal fees from NeuroRx Research outside the submitted work.
Richard A Rudick, MD: Is an employee of and holds stock in Biogen, Inc.
This work was supported by grants from the National Institutes of Health (P50NS38667 and R35NS09730 to Dr. Trapp) and National Multiple Sclerosis Society (RG 4348-A-7 to Dr. Trapp). Dr. Chen was funded by the NIH/NCATS Clinical and Translational Science Collaborative of Cleveland CTSC KL2 Training Program.