Contributions
Abstract: 240
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Background: Magnetization transfer ratio (MTR) has been used as an imaging outcome in clinical trials in MS, because it is thought to reflect tissue demyelination and axonal loss. Previous pathology-MTR correlation studies involved a limited set of histological stains and regions-of-interest (ROIs). We performed a comprehensive analysis of the pathological correlates of MTR in normal-appearing white matter (NAWM), normal-appearing grey matter (NAGM) and lesions in the WM and GM, in order to estimate the impact of different pathological processes on the MTR values.
Methods: MTR maps and conventional sequences were acquired at 3T from 14 fixed brain slices of respective MS patients. 71 histological cassettes were immunostained and quantified by using Definiens software for neuronal structure (HE, NF200, SMI94), lymphocyte activity (CD20, CD3, CD8), microglia activation (CD68, IBA1), astrocyte reaction (GFAP), and mitochondrial activity (COX4, VDAC). The following ROIs were defined on digitized histological sections co-registered to MTR maps: NAWM, cortical NAGM, WM lesions, and cortical GM lesions. Multilevel linear regression models with MTR as dependent variable were used, including the hierarchical structure of data (cassettes nested within patients); covariates were age, gender, interval death-to-fixation, and ROI size.
Results: In NAWM, MTR was associated with NF200 (β=0.472; p=0.016), which explained 30.8% of MTR variability (R2=0.308).
In WM lesions, MTR was associated with CD68 (β=-0.071; p=0.049). which explained 18.5% of MTR variability (R2=0.185).
In NAGM, MTR was associated with three stains: GFAP (β=-0.767; 95%CI=-1.504--0.030; p=0.041), IBA1 (β=-0.531; p=0.009), and COX4 (β=0.963; p=0.004). Together, these stains explained 11.0% of MTR variability (R2=0.110).
Finally, in GM lesions, MTR was associated with five stains: NF200 (β=0.930; p=0.029), SMI94 (β=0.923; p=0.025), GFAP (β=-1.004; p=0.023), IBA1 (β=-0.770; p=0.005), COX4 (β=1.058; p=0.032), and VDAC (β=0.625; p=0.039). These stains only explained 9.4% of MTR variability (R2=0.094).
Conclusion: MTR reflects axonal pathology in NAWM, and microglia activation in WM lesions. Additional processes, including microglia/astrocyte activity and energy metabolism, correlate with MTR in the NAGM and GM lesions. Overall, the MTR values are only partially explained by the quantified pathological processes (particularly in GM), the interpretation of which depends on brain area.
Disclosure: Marcello Moccia has received grant from the ECTRIMS-MAGMNISM fellowship program, honoraria and travel support form Almirall, Coloplast, Genzyme, and Merck-Serono.
Steven van de Pavert has nothing to disclose.
Arman Eshaghi has nothing to disclose.
Jonas Pichat has nothing to disclose.
Marc Modat has received funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), the NIHR Biomedical Research Unit (Dementia) at UCL, the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative).
Yi Wang has nothing to disclose.
Alan Thompson has received honoraria and support for travel from Eisai and EXCEMED. He received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief of MSJ.
Frederik Barkhof has received funding from the Dutch MS Society, and honoraria from Bayer-Schering Pharma, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme, and IXICO.
Olga Ciccarelli has received research funding from UK MS Society, National MS Society, Rosetrees trust and NIHR UCLH BRC. OC serves as a consultant for Biogen, Novartis, Roche, Genzyme, Teva and GE healthcare.
Abstract: 240
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Background: Magnetization transfer ratio (MTR) has been used as an imaging outcome in clinical trials in MS, because it is thought to reflect tissue demyelination and axonal loss. Previous pathology-MTR correlation studies involved a limited set of histological stains and regions-of-interest (ROIs). We performed a comprehensive analysis of the pathological correlates of MTR in normal-appearing white matter (NAWM), normal-appearing grey matter (NAGM) and lesions in the WM and GM, in order to estimate the impact of different pathological processes on the MTR values.
Methods: MTR maps and conventional sequences were acquired at 3T from 14 fixed brain slices of respective MS patients. 71 histological cassettes were immunostained and quantified by using Definiens software for neuronal structure (HE, NF200, SMI94), lymphocyte activity (CD20, CD3, CD8), microglia activation (CD68, IBA1), astrocyte reaction (GFAP), and mitochondrial activity (COX4, VDAC). The following ROIs were defined on digitized histological sections co-registered to MTR maps: NAWM, cortical NAGM, WM lesions, and cortical GM lesions. Multilevel linear regression models with MTR as dependent variable were used, including the hierarchical structure of data (cassettes nested within patients); covariates were age, gender, interval death-to-fixation, and ROI size.
Results: In NAWM, MTR was associated with NF200 (β=0.472; p=0.016), which explained 30.8% of MTR variability (R2=0.308).
In WM lesions, MTR was associated with CD68 (β=-0.071; p=0.049). which explained 18.5% of MTR variability (R2=0.185).
In NAGM, MTR was associated with three stains: GFAP (β=-0.767; 95%CI=-1.504--0.030; p=0.041), IBA1 (β=-0.531; p=0.009), and COX4 (β=0.963; p=0.004). Together, these stains explained 11.0% of MTR variability (R2=0.110).
Finally, in GM lesions, MTR was associated with five stains: NF200 (β=0.930; p=0.029), SMI94 (β=0.923; p=0.025), GFAP (β=-1.004; p=0.023), IBA1 (β=-0.770; p=0.005), COX4 (β=1.058; p=0.032), and VDAC (β=0.625; p=0.039). These stains only explained 9.4% of MTR variability (R2=0.094).
Conclusion: MTR reflects axonal pathology in NAWM, and microglia activation in WM lesions. Additional processes, including microglia/astrocyte activity and energy metabolism, correlate with MTR in the NAGM and GM lesions. Overall, the MTR values are only partially explained by the quantified pathological processes (particularly in GM), the interpretation of which depends on brain area.
Disclosure: Marcello Moccia has received grant from the ECTRIMS-MAGMNISM fellowship program, honoraria and travel support form Almirall, Coloplast, Genzyme, and Merck-Serono.
Steven van de Pavert has nothing to disclose.
Arman Eshaghi has nothing to disclose.
Jonas Pichat has nothing to disclose.
Marc Modat has received funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), the NIHR Biomedical Research Unit (Dementia) at UCL, the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative).
Yi Wang has nothing to disclose.
Alan Thompson has received honoraria and support for travel from Eisai and EXCEMED. He received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief of MSJ.
Frederik Barkhof has received funding from the Dutch MS Society, and honoraria from Bayer-Schering Pharma, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme, and IXICO.
Olga Ciccarelli has received research funding from UK MS Society, National MS Society, Rosetrees trust and NIHR UCLH BRC. OC serves as a consultant for Biogen, Novartis, Roche, Genzyme, Teva and GE healthcare.