August 10, 2021; 97 (6) Research ArticleOpen Access
Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis
View ORCID ProfilePietro Maggi, Jens Kuhle, Sabine Schädelin, Franziska van der Meer, View ORCID ProfileMatthias Weigel, View ORCID ProfileRiccardo Galbusera, Amandine Mathias, Po-Jui Lu, Reza Rahmanzadeh, View ORCID ProfilePascal Benkert, View ORCID ProfileFrancesco La Rosa, View ORCID ProfileMeritxell Bach Cuadra, Pascal Sati, Marie Théaudin, Caroline Pot, View ORCID ProfileVincent van Pesch, David Leppert, Christine Stadelmann, Ludwig Kappos, Renaud Du Pasquier, View ORCID ProfileDaniel S. Reich, Martina Absinta, Cristina Granziera
First published June 4, 2021, DOI: https://doi.org/10.1212/WNL.0000000000012326
Pietro Maggi
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Jens Kuhle
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Sabine Schädelin
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Franziska van der Meer
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Matthias Weigel
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Riccardo Galbusera
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Amandine Mathias
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Po-Jui Lu
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Reza Rahmanzadeh
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Pascal Benkert
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Francesco La Rosa
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Meritxell Bach Cuadra
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Pascal Sati
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Marie Théaudin
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Caroline Pot
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Vincent van Pesch
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
David Leppert
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Christine Stadelmann
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Ludwig Kappos
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Renaud Du Pasquier
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Daniel S. Reich
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Martina Absinta
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Cristina Granziera
From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis
Pietro Maggi, Jens Kuhle, Sabine Schädelin, Franziska van der Meer, Matthias Weigel, Riccardo Galbusera, Amandine Mathias, Po-Jui Lu, Reza Rahmanzadeh, Pascal Benkert, Francesco La Rosa, Meritxell Bach Cuadra, Pascal Sati, Marie Théaudin, Caroline Pot, Vincent van Pesch, David Leppert, Christine Stadelmann, Ludwig Kappos, Renaud Du Pasquier, Daniel S. Reich, Martina Absinta, Cristina Granziera
Neurology Aug 2021, 97 (6) e543-e553; DOI: 10.1212/WNL.0000000000012326
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Abstract
Objective To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.
Methods In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.
Results In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; p = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (βadd, 16.3; 95% confidence interval [CI], 4.6–28.0; p < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; βadd, 30.4; 95% CI, 15.6–45.2; p < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (βadd, 1.1; 95% CI, 0.3–1.9; p < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p = 0.004 and p = 0.0002, respectively).
Conclusion Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.
Glossary
- APP=
- amyloid precursor protein;
- AT=
- acquisition time;
- CI=
- confidence interval;
- DAB=
- 3,3'-diminobenzidine;
- DMT=
- disease-modifying treatment;
- EDSS=
- Expanded Disability Status Scale;
- EPI=
- echoplanar imaging;
- FA=
- flip angle;
- FLAIR=
- fluid-attenuated inversion recovery;
- Gd=
- gadolinium;
- IQR=
- interquartile range;
- MBP=
- myelin basic protein;
- MHC=
- major histocompatibility complex;
- MPRAGE=
- magnetization-prepared rapid gradient echo;
- MS=
- multiple sclerosis;
- MSSS=
- Multiple Sclerosis Severity Scale;
- NfL=
- neurofilament light chain;
- PMS=
- primary or secondary progressive multiple sclerosis;
- PRL=
- paramagnetic rim lesions;
- RRMS=
- relapsing-remitting multiple sclerosis;
- sNfL=
- serum neurofilament light chain;
- TE=
- echo time;
- TR=
- repetition time
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
The Article Processing Charge was funded by Swiss National Foundation
Editorial, page 257
- Received November 13, 2020.
- Accepted in final form May 5, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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