Contributions
Abstract: P528
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Imaging
Introduction: Magnetisation transfer ratio (MTR) is an MRI technique commonly used to assess tissue integrity. MTR in MS lesions correlates with demyelination and axonal damage. Longitudinally, changes in MTR suggest changes in myelin status, axonal health, and/or inflammatory activity. We hypothesised that changes in lesion MTR over long-term follow-up are associated with changes in chronic active lesions, whereas stable MTR within pre-existing lesions is indicative of chronic inactive lesions. We tested these hypotheses in post-mortem brain tissue from an MS patient who had participated in our longitudinal MRI study for 11 years.
Methods: Brain tissue from a 51-year-old male with SPMS (disease duration=23 years; cause of death=acute myocardial infarction) was procured through the Cleveland Clinic MS rapid autopsy protocol. We used the last 4 years of annual imaging data to classify T2 white matter (WM) lesion voxels into 6 possible categories based on the initial MTR level (low or high) and the pattern of MTR change over 4 years (decreasing, increasing, or stable) using voxel-wise linear regression. Thresholds for initial MTR level and MTR change were based on concurrently acquired WM MTR values from 14 healthy controls. We identified 11 regions-of-interest (ROI) based on MRI/MTR including normal-appearing WM (NAWM) and 4 MTR lesion categories. Histopathologically, we evaluated myelin status, axonal diameter and loss and inflammatory activity in these ROIs.
Results: NAWM was myelinated, with a mean axonal diameter of 0.74 um and axonal density of 23.4%. In comparison, high and stable MTR regions were myelinated, with no swollen axons and some axonal loss (density=16.1%). Two ROIs with low and stable MTR had swollen axons and intermediate axonal loss (density=19.9%) compared to NAWM: one was myelinated; the other was a demyelinated, chronic inactive lesion. Regions with low and changing MTR (increasing or decreasing) were demyelinated with many swollen axons and axonal loss (density=14.9%), corresponding to chronic active lesions. There were no remyelinating lesions in the identified ROIs.
Conclusions: Longitudinal MTR-based classification of T2 lesions showed different pathologies on histology: chronic active demyelinated lesions, chronic inactive demyelinated lesions, and myelinated but axonal loss with or without swollen axons. Our approach may be useful to quantify the extent of specific types of tissue damage and help in understanding MS pathogenesis.
Disclosure: This study was supported by the NIH NINDS P01-NS38667 and the National Multiple Sclerosis Society RG-3099.
Dr. Rudick and Dr. Fisher are employees and stockholders of Biogen.
Yufan Zheng: nothing to disclose.
Dr. Nakamura: Consultant (NeuroRx Research); Research support (Biogen, Sanofi Genzyme).
Dr. Trapp: receives grant support from NIH, State of Ohio, ALS Association, Sanofi Genzyme, and the NMSS. He also receives speaking fees from EMD Serono, Genentech, Sanofi Genzyme, and Novartis. He is founder and Chief Scientific Officer of Renovo Neural.
Abstract: P528
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Imaging
Introduction: Magnetisation transfer ratio (MTR) is an MRI technique commonly used to assess tissue integrity. MTR in MS lesions correlates with demyelination and axonal damage. Longitudinally, changes in MTR suggest changes in myelin status, axonal health, and/or inflammatory activity. We hypothesised that changes in lesion MTR over long-term follow-up are associated with changes in chronic active lesions, whereas stable MTR within pre-existing lesions is indicative of chronic inactive lesions. We tested these hypotheses in post-mortem brain tissue from an MS patient who had participated in our longitudinal MRI study for 11 years.
Methods: Brain tissue from a 51-year-old male with SPMS (disease duration=23 years; cause of death=acute myocardial infarction) was procured through the Cleveland Clinic MS rapid autopsy protocol. We used the last 4 years of annual imaging data to classify T2 white matter (WM) lesion voxels into 6 possible categories based on the initial MTR level (low or high) and the pattern of MTR change over 4 years (decreasing, increasing, or stable) using voxel-wise linear regression. Thresholds for initial MTR level and MTR change were based on concurrently acquired WM MTR values from 14 healthy controls. We identified 11 regions-of-interest (ROI) based on MRI/MTR including normal-appearing WM (NAWM) and 4 MTR lesion categories. Histopathologically, we evaluated myelin status, axonal diameter and loss and inflammatory activity in these ROIs.
Results: NAWM was myelinated, with a mean axonal diameter of 0.74 um and axonal density of 23.4%. In comparison, high and stable MTR regions were myelinated, with no swollen axons and some axonal loss (density=16.1%). Two ROIs with low and stable MTR had swollen axons and intermediate axonal loss (density=19.9%) compared to NAWM: one was myelinated; the other was a demyelinated, chronic inactive lesion. Regions with low and changing MTR (increasing or decreasing) were demyelinated with many swollen axons and axonal loss (density=14.9%), corresponding to chronic active lesions. There were no remyelinating lesions in the identified ROIs.
Conclusions: Longitudinal MTR-based classification of T2 lesions showed different pathologies on histology: chronic active demyelinated lesions, chronic inactive demyelinated lesions, and myelinated but axonal loss with or without swollen axons. Our approach may be useful to quantify the extent of specific types of tissue damage and help in understanding MS pathogenesis.
Disclosure: This study was supported by the NIH NINDS P01-NS38667 and the National Multiple Sclerosis Society RG-3099.
Dr. Rudick and Dr. Fisher are employees and stockholders of Biogen.
Yufan Zheng: nothing to disclose.
Dr. Nakamura: Consultant (NeuroRx Research); Research support (Biogen, Sanofi Genzyme).
Dr. Trapp: receives grant support from NIH, State of Ohio, ALS Association, Sanofi Genzyme, and the NMSS. He also receives speaking fees from EMD Serono, Genentech, Sanofi Genzyme, and Novartis. He is founder and Chief Scientific Officer of Renovo Neural.