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Purpose of Review: The introduction some 30 years ago of β-interferon, followed by a panel of immunomodulators and immunosuppressants has led to a remarkable improvement in the management of multiple sclerosis (MS) patients. Despite these noticeable progresses, which lower the number of relapses and thereby ameliorate patients' quality of life, preventing long-term progression of disability is still an unmet need, highlighting the necessity to develop therapeutic strategies aimed at repairing demyelinated lesions and protecting axons from degeneration. The capacity of human brain to self-regenerate demyelinated lesion has opened a field of research aimed at fostering this endogenous potential., Recent Findings: The pioneer electron microscopic evidence by Périer and Grégoire [Périer O, Grégoire A. Electron microscopic features of multiple sclerosis lesions. Brain 1965; 88:937-952] suggesting the capacity of human brain to self-regenerate demyelinated lesion has opened a field of research aimed at fostering this endogenous potential. Here we review some recently identified mechanisms involved in the remyelination process, focusing on the role of electrical activity and the involvement of innate immune cells. We then provide an update on current strategies promoting endogenous myelin repair., Summary: Identification of therapeutic targets for remyelination has opened an active therapeutic field in MS. Although still in early phase trials, with heterogenous efficacy, the door for myelin regeneration in MS is now opened., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages., Recent Findings: In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS., Summary: Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection.

Purpose of Review: Despite major progress in multiple sclerosis (MS) treatment, to date, accumulation of irreversible clinical disability is not sufficiently prevented with immunotherapies. In this context, repair strategies aimed at reducing axonal damage are becoming a very active field of preclinical and clinical research., Recent Findings: Improved understanding of the cellular and molecular mechanisms of myelin repair, together with the emergence of new therapeutic candidates are paving the way for novel therapeutic strategies in MS. In parallel, there is a very active development of imaging methods to assess lesions ongoing remyelination that are crucially needed to evaluate therapeutic efficacy., Summary: The current development of a very dynamic and multidisciplinary research on remyelination should accelerate the development of myelin repair strategies in MS, to prevent disability progression.

Purpose of Review: Following the establishment of a number of successful immunomodulatory treatments for multiple sclerosis, current research focuses on the repair of existing damage., Recent Findings: Promotion of regeneration is particularly important for demyelinated areas with degenerated or functionally impaired axons of the central nervous system's white and gray matter. As the protection and generation of new oligodendrocytes is a key to the re-establishment of functional connections, adult oligodendrogenesis and myelin reconstitution processes are of primary interest. Moreover, understanding, supporting and promoting endogenous repair activities such as mediated by resident oligodendroglial precursor or adult neural stem cells are currently thought to be a promising approach toward the development of novel regenerative therapies., Summary: This review summarizes recent developments and findings related to pharmacological myelin repair as well as to the modulation/application of stem cells with the aim to restore defective myelin sheaths.

Purpose of Review: Despite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy., Recent Findings: Several hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels., Summary: Despite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.