Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the remyelination process, where researchers are studying the effects of pharmacotherapy on myelin repair mechanisms. Multiple compounds are being tested for their potential to foster remyelination in different clinical settings through the application of less or more complex techniques to assess their efficacy. Objective: To review current methods and biomarkers to track myelin regeneration and recovery over time in people with MS (PwMS), with potential implications for promyelinating drug testing. Methods: Narrative review, based on a selection of PubMed articles discussing techniques to measure in vivo myelin repair and functional recovery in PwMS. Results: Non-invasive tools, such as structural Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), are being implemented to track myelin repair, while other techniques like evoked potentials, functional MRI, and digital markers allow the assessment of functional recovery. These methods, alone or in combination, have been employed to obtain precise biomarkers of remyelination and recovery in various clinical trials on MS. Conclusions: Combining different techniques to identify myelin restoration in MS could yield novel biomarkers, enhancing the accuracy of clinical trial outcomes for remyelinating therapies in PwMS.

Brain and Mind Center University of Sydney Sydney 2050 Australia

Department of Bioethics Medical University of Warsaw 02 091 Warsaw Poland

Department of Clinical Neurosciences University of Calgary Calgary AB T2N 1N4 Canada

Department of Neurology Hôpital Erasme Hôpital Universitaire de Bruxelles Université Libre de Bruxelles 1070 Brussels Belgium

Department of Neurology Medical Faculty Heinrich Heine University 40225 Düsseldorf Germany

Department of Neurology Palacky University Olomouc 779 00 Olomouc Czech Republic

Department of Neurology University of Warmia and Mazury 10 719 Olsztyn Poland

Department of Neurorehabilitation Sciences Casa di Cura Igea 20129 Milan Italy

Department of Neuroscience Biomedicine and Movement Science University of Verona 37129 Verona Italy

Experimental and Clinical Research Center Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin 12203 Berlin Germany

Experimental Neurophysiology Unit Institute of Experimental Neurology IRCCS San Raffaele Scientific Institute Università Vita Salute San Raffaele 20132 Milan Italy

Institute of Regional Health Research and Institute of Molecular Medicine University of Southern Denmark 5230 Odense Denmark

Multiple Sclerosis Center 2nd Department of Neurology Aristotle University of Thessaloniki 541 24 Thessaloniki Greece

Neuroimmunology Unit Department of Neurosciences Hospital Alemán Buenos Aires C1425FQB Argentina

Neuroinflammation Imaging Laboratory Institute of NeuroScience Université Catholique de Louvain 1348 Brussels Belgium

Neurology Clinic Clinical Centre of Montenegro 81000 Podgorica Montenegro

Neurology Department Pitié Salpêtrière Hospital APHP 75013 Paris France

Neurology Unit GHNE Paris Saclay Hospital 91400 Orsay France

Nuffield Departement of Clinical Neuroscience University of Oxford Oxford OX1 2JD UK

Paris Brain Institute ICM CNRS Inserm Sorbonne Université 75005 Paris France

The Center for Neurological Research Department of Neurology Næstved Slagelse Ringsted Hospitals 4200 Slagelse Denmark

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