Modeling the effect of white matter lesions on grey matter atrophy in MS based on data from the human connectome project
ECTRIMS Online Library. Bussas M. 09/13/19; 279567; 309
Matthias Bussas
Matthias Bussas
Contributions
Abstract

Abstract: 309

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - MRI and PET

M. Bussas1, S. Grahl1, C. Gasperi1, V. Pongratz1, A. Berthele1, J. Kirschke2, C. Zimmer2, B. Hemmer1, M. Mühlau1

1Neurology, 2Neuroradiology, Technical University Munich, Klinikum rechts der Isar, München, Germany

Background: White matter (WM) lesions and grey matter (GM) atrophy are the most established MRI-based parameters to track activity and progression of multiple sclerosis (MS). It is well known that both measures develop heterogeneously across patients, however the causal interplay between these measures is incompletely understood. We combined individual WM lesion maps with Human Connectome Project data to predict areas of GM atrophy both cross-sectionally and longitudinally.
Methods: We included 1138 patients (EDSS = 1.90 +/- 1.87) with clinically isolated syndrome (14%), relapsing remitting MS (76%), secondary progressive MS (6%) and primary progressive MS (4%). 757 of these patients were scanned more than once and included into a longitudinal study (time between scans = 3.8 +/- 2.4 years). 3D T1-weighted and FLAIR images were coregistered, normalized and segmented, resulting in WM lesion maps and modulated GM maps. We further made use of two Connectomes provided by Horn et al. (Neuroimage 2016) and, most recently, by Yeh et al. (Neuroimage 2018) in the context of the Human Connectome Project. For each patient, we overlaid the Connectomes and the WM lesion map. Voxels of WM lesions were followed along WM fibres to identify potentially disconnected GM regions, leading to individual disconnectivity maps. In a cross-sectional analysis, disconnection maps were correlated with GM maps in a voxel-wise manner across subjects. A longitudinal analysis compared changes in the disconnection map with GM maps of two timepoints and atrophy between both time points.
Results: We found a strong correlation of disconnection maps with local GM atrophy (maximal r values: in the deep GM = .75, p < .001; in the cortex = .3, p < .001) using both Connectome maps. In the longitudinal analysis, the change in disconnection was unrelated to GM atrophy at the baseline scan but correlated significantly with the atrophy at the follow up scan (p < .001).
Conclusion: Atrophy of GM is related to the projections of fibres passing through WM lesions which is compatible with the idea that WM lesions contribute considerably to GM atrophy through axonal pathology. In line with this concept we demonstrate that local GM atrophy occurs in close temporal relation to new WM lesions within topically projecting fibres.
Disclosure: This work was funded by the 'German Competence Network Multiple Sclerosis' (German Ministry for Research and Education, grant 01GI1604A).
M. Bussas has nothing to disclose.
S. Grahl has nothing to disclose.
C. Gasperi has nothing to disclose.
V. Pongratz has received research support from Novartis (Oppenheim Förderpreis) and intramural funding from the Technical University of Munich (KKF grant).
A. Berthele reports compensations for clinical trials received by his institution from Alexion Pharmaceuticals, Biogen, Novartis Pharmaceuticals, Roche, Sanofi Genzyme, Teva Pharmaceuticals, and personal fees and non-financial support from Bayer Healthcare, Biogen, Merck Serono, Mylan, Novartis Pharmaceuticals, Roche, and Sanofi Genzyme
J. Kirschke has received travel support from Kaneka Europe as well as speaker honoraria from Philips Healthcare; all not related to this work.
C. Zimmer has nothing to disclose.
B. Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, and Bayer AG; he has served as DMSC member for AllergyCare and TG Therapeutics; he or his institution have received speaker honoraria from Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.
M. Mühlau has nothing to disclose.

Abstract: 309

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - MRI and PET

M. Bussas1, S. Grahl1, C. Gasperi1, V. Pongratz1, A. Berthele1, J. Kirschke2, C. Zimmer2, B. Hemmer1, M. Mühlau1

1Neurology, 2Neuroradiology, Technical University Munich, Klinikum rechts der Isar, München, Germany

Background: White matter (WM) lesions and grey matter (GM) atrophy are the most established MRI-based parameters to track activity and progression of multiple sclerosis (MS). It is well known that both measures develop heterogeneously across patients, however the causal interplay between these measures is incompletely understood. We combined individual WM lesion maps with Human Connectome Project data to predict areas of GM atrophy both cross-sectionally and longitudinally.
Methods: We included 1138 patients (EDSS = 1.90 +/- 1.87) with clinically isolated syndrome (14%), relapsing remitting MS (76%), secondary progressive MS (6%) and primary progressive MS (4%). 757 of these patients were scanned more than once and included into a longitudinal study (time between scans = 3.8 +/- 2.4 years). 3D T1-weighted and FLAIR images were coregistered, normalized and segmented, resulting in WM lesion maps and modulated GM maps. We further made use of two Connectomes provided by Horn et al. (Neuroimage 2016) and, most recently, by Yeh et al. (Neuroimage 2018) in the context of the Human Connectome Project. For each patient, we overlaid the Connectomes and the WM lesion map. Voxels of WM lesions were followed along WM fibres to identify potentially disconnected GM regions, leading to individual disconnectivity maps. In a cross-sectional analysis, disconnection maps were correlated with GM maps in a voxel-wise manner across subjects. A longitudinal analysis compared changes in the disconnection map with GM maps of two timepoints and atrophy between both time points.
Results: We found a strong correlation of disconnection maps with local GM atrophy (maximal r values: in the deep GM = .75, p < .001; in the cortex = .3, p < .001) using both Connectome maps. In the longitudinal analysis, the change in disconnection was unrelated to GM atrophy at the baseline scan but correlated significantly with the atrophy at the follow up scan (p < .001).
Conclusion: Atrophy of GM is related to the projections of fibres passing through WM lesions which is compatible with the idea that WM lesions contribute considerably to GM atrophy through axonal pathology. In line with this concept we demonstrate that local GM atrophy occurs in close temporal relation to new WM lesions within topically projecting fibres.
Disclosure: This work was funded by the 'German Competence Network Multiple Sclerosis' (German Ministry for Research and Education, grant 01GI1604A).
M. Bussas has nothing to disclose.
S. Grahl has nothing to disclose.
C. Gasperi has nothing to disclose.
V. Pongratz has received research support from Novartis (Oppenheim Förderpreis) and intramural funding from the Technical University of Munich (KKF grant).
A. Berthele reports compensations for clinical trials received by his institution from Alexion Pharmaceuticals, Biogen, Novartis Pharmaceuticals, Roche, Sanofi Genzyme, Teva Pharmaceuticals, and personal fees and non-financial support from Bayer Healthcare, Biogen, Merck Serono, Mylan, Novartis Pharmaceuticals, Roche, and Sanofi Genzyme
J. Kirschke has received travel support from Kaneka Europe as well as speaker honoraria from Philips Healthcare; all not related to this work.
C. Zimmer has nothing to disclose.
B. Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, and Bayer AG; he has served as DMSC member for AllergyCare and TG Therapeutics; he or his institution have received speaker honoraria from Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.
M. Mühlau has nothing to disclose.

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