Multi-parametric quantitative MRI of normal appearing white matter in multiple sclerosis, and the effect of disease activity on T2
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White matter (WM) lesions with a distinct lesion-tissue contrast are the main radiological hallmark of multiple sclerosis (MS) in standard magnetic resonance imaging (MRI). Pathological WM changes beyond lesion development lack suitable contrasts, rendering the investigation of normal appearing WM (NAWM) more challenging. In this study, repeat quantitative MRI (qMRI) was collected in 9 relapsing remitting MS patients with mild disease over nine months. The relaxation times T1 and T2, the proton density (PD), and the magnetization transfer ratio (MTR) were analysed in the NAWM. For each parameter, both the mean value and the standard deviation were determined across large NAWM regions. The resulting 8-dimensional multi-parameter space includes parameter non-uniformities as additional descriptors of NAWM inhomogeneity. The goals of the study were to investigate (1) which of the eight parameters differ significantly between NAWM and normal WM, (2) if parameter time courses differ between patients with and without radiological disease activity, and (3) if a suitable biomarker can be derived from the multi-parameter space, allowing for NAWM characterization and differentiation from controls. On a group level, all parameters investigated except mean T1 values were significantly affected in MS NAWM. Group classification accuracy using a multi-parametric support vector machine approach in NAWM was 66.7 %. In addition, mean T2 values increased significantly with time for patients with radiological disease activity, but not for patients without radiological activity. In conclusion, our data demonstrate the potential of qMRI for investigating MS pathology in NAWM. T2 measurements in NAWM may enable monitoring of disease activity outside of overt lesions.
KeywordsQuantitative MRI (qMRI) Normal appearing white matter (NAWM) Multiple sclerosis (MS) Relapsing remitting multiple sclerosis (RRMS)
This study was supported by the Bundesministerium für Bildung und Forschung (Brain Imaging Center Frankfurt, DLR 01GO0203), and the Deutsche Forschungsgemeinschaft (DFG CRC-TR 128).
Compliance with ethical standards
Disclosures of potential conflicts of interest
The authors report no conflicts of interest relevant to this study.
Dr. RM Gracien went to a MS related training to London in 2013 sponsored by Roche.
Dr. F Zipp has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation fees from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma. She has received travel compensation from the aforementioned companies.
Dr. JC Klein received speaker honoraria and travel reimbursement from Medtronic, AstraZeneca, Abbott Laboratories and AbbVie.
Dr. H Steinmetz has received honoraria from Bayer, Sanofi, Boehringer Ingelheim.
Dr. U Ziemann has received honoraria from Biogen Idec Deutschland GmbH, Bayer Vital GmbH, CorTec GmbH, Medtronic and Servier for advisory work, and a grant from Biogen Idec for an investigator initiated trial.
Human and animals Rights
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
No animals were involved.
Written informed consent was given by all participants and the study was approved by the ethics committee of the State Medical Board of Rhineland-Palatine.
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