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      Multiparameter MRI quantification of microstructural tissue alterations in multiple sclerosis

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          Conventional MRI is not sensitive to many pathological processes underpinning multiple sclerosis (MS) ongoing in normal appearing brain tissue (NABT). Quantitative MRI (qMRI) and a multiparameter mapping (MPM) protocol are used to simultaneously quantify magnetization transfer (MT) saturation, transverse relaxation rate R2* (1/T2*) and longitudinal relaxation rate R1 (1/T1), and assess differences in NABT microstructure between MS patients and healthy controls (HC).


          This prospective cross-sectional study involves 36 MS patients (20 females, 16 males; age range 22–63 years; 15 relapsing-remitting MS - RRMS; 21 primary or secondary progressive MS - PMS) and 36 age-matched HC (20 females, 16 males); age range 21–61 years). The qMRI maps are computed and segmented in lesions and 3 normal appearing cerebral tissue classes: normal appearing cortical grey matter (NACGM), normal appearing deep grey matter (NADGM), normal appearing white matter (NAWM). Individual median values are extracted for each tissue class and MR parameter. MANOVAs and stepwise regressions assess differences between patients and HC.


          MS patients are characterized by a decrease in MT, R2* and R1 within NACGM ( p < .0001) and NAWM ( p < .0001). In NADGM, MT decreases ( p < .0001) but R2* and R1 remain normal. These observations tend to be more pronounced in PMS. Quantitative MRI parameters are independent predictors of clinical status: EDSS is significantly related to R1 in NACGM and R2* in NADGM; the latter also predicts motor score. Cognitive score is best predicted by MT parameter within lesions.


          Multiparametric data of brain microstructure concord with the literature, predict clinical performance and suggest a diffuse reduction in myelin and/or iron content within NABT of MS patients.


          • We revisit microstructural alterations of NABT in MS patients by simultaneously quantifying three MRI parameters.
          • Data suggest reduction of MT/R2*/R1 in NABT of MS patients, suggesting a reduction in myelin and/or iron content.
          • Quantitative MRI parameters in NABT are independent predictors of clinical status.

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          Most cited references 50

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          Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

          New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011
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            Unified segmentation.

            A probabilistic framework is presented that enables image registration, tissue classification, and bias correction to be combined within the same generative model. A derivation of a log-likelihood objective function for the unified model is provided. The model is based on a mixture of Gaussians and is extended to incorporate a smooth intensity variation and nonlinear registration with tissue probability maps. A strategy for optimising the model parameters is described, along with the requisite partial derivatives of the objective function.
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              Cortical demyelination and diffuse white matter injury in multiple sclerosis.

              Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

                Author and article information

                Neuroimage Clin
                Neuroimage Clin
                NeuroImage : Clinical
                29 May 2019
                29 May 2019
                : 23
                [a ]GIGA – CRC in vivo Imaging, University of Liège, Liège, Belgium
                [b ]Clinical Neuroimmunology Unit, Neurology Department, CHU Liège, Belgium
                [c ]Psychology and Neurosciences of Cognition Research Unit, University of Liège, Belgium
                [d ]Neurosurgery Department, CHU Liège, Belgium
                [e ]GIGA – in silico Medicine, University of Liège, Liège, Belgium
                Author notes
                [* ]Corresponding author at: Department of Neurology, CHU Liège, Avenue Hippocrate, 4000 Liège 1, Belgium. elommers@
                S2213-1582(19)30229-3 101879
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (

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