The Role of Molecular Imaging as a Marker of Remyelination and Repair in Multiple Sclerosis.
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ABSTRACT:
SUBMITTER: Ben-Shalom I
PROVIDER: S-EPMC8745199 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundQuantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11 C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.MethodsPatients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11 C]PiB and magnetic resonance imaging. Voxel-wise maps of [11 C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination.ResultsAt baseline, there was a progressive reduction in [11 C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = -0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = -0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index.Interpretation[11 C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726-738.
| S-EPMC5006855 | biostudies-literature
Project description:Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures.
| S-EPMC4335693 | biostudies-literature
Project description:Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis (MS). Because demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.Postmortem brain tissue from 22 patients with MS (age 27-77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination.New oligodendrocytes that were actively forming myelin sheaths were identified in 30 of 42 remyelinated subpial cortical lesions, including lesions from 3 patients in their 70s. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes, and fewer reactive astrocytes. Astrocytes in the white matter, but not in cortical portions of these lesions, significantly upregulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination.Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.
| S-EPMC3535551 | biostudies-literature
Project description:Myelin sheaths in the central nervous system (CNS) insulate axons and thereby allow saltatory nerve conduction, which is a prerequisite for complex brain function. Multiple sclerosis (MS), the most common inflammatory autoimmune disease of the CNS, leads to the destruction of myelin sheaths and the myelin-producing oligodendrocytes, thus leaving behind demyelinated axons prone to injury and degeneration. Clinically, this process manifests itself in significant neurological symptoms and disability. Resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) are present in the adult brain, and can differentiate into mature oligodendrocytes which then remyelinate the demyelinated axons. However, for multiple reasons, in MS the regenerative capacity of these cell populations diminishes significantly over time, ultimately leading to neurodegeneration, which currently remains untreatable. In addition, microglial cells, the resident innate immune cells of the CNS, can contribute further to inflammatory and degenerative axonal damage. Here, we review the molecular factors contributing to remyelination failure in MS by inhibiting OPC and NSC differentiation or modulating microglial behavior.
| S-EPMC6721708 | biostudies-literature
Project description:Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons and eventual neurodegeneration. Current treatments approved for the treatment of relapsing forms of MS target the aberrant immune response and successfully reduce the severity of attacks and frequency of relapses. Therapies are still needed that can repair damage particularly for the treatment of progressive forms of MS for which current therapies are relatively ineffective. Remyelination can restore neuronal function and prevent further neuronal loss and clinical disability. Recent advancements in our understanding of the molecular and cellular mechanisms regulating myelination, as well as the development of high-throughput screens to identify agents that enhance myelination, have lead to the identification of many potential remyelination therapies currently in preclinical and early clinical development. One problem that has plagued the development of treatments to promote remyelination is the difficulty in assessing remyelination in patients with current imaging techniques. Powerful new imaging technologies are making it easier to discern remyelination in patients, which is critical for the assessment of these new therapeutic strategies during clinical trials. This review will summarize what is currently known about remyelination failure in MS, strategies to overcome this failure, new therapeutic treatments in the pipeline for promoting remyelination in MS patients, and new imaging technologies for measuring remyelination in patients.
| S-EPMC4674562 | biostudies-other
Project description:The greatest unmet need in multiple sclerosis (MS) are treatments that delay, prevent or reverse progression. One of the most tractable strategies to achieve this is to therapeutically enhance endogenous remyelination; doing so restores nerve conduction and prevents neurodegeneration. The biology of remyelination-centred on the activation, migration, proliferation and differentiation of oligodendrocyte progenitors-has been increasingly clearly defined and druggable targets have now been identified in preclinical work leading to early phase clinical trials. With some phase 2 studies reporting efficacy, the prospect of licensed remyelinating treatments in MS looks increasingly likely. However, there remain many unanswered questions and recent research has revealed a further dimension of complexity to this process that has refined our view of the barriers to remyelination in humans. In this review, we describe the process of remyelination, why this fails in MS, and the latest research that has given new insights into this process. We also discuss the translation of this research into clinical trials, highlighting the treatments that have been tested to date, and the different methods of detecting remyelination in people.
| S-EPMC7815564 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin and axons. All therapeutics used to treat MS have been developed to target an overactive immune response, with aims to reduce disease activity. Chronic demyelinated axons are further prone to irreversible damage and death, and it is imperative that new therapies address this critical issue. Remyelination, the generation of new myelin in the adult nervous system, is an endogenous repair mechanism that restores function of denuded axons and delays their deterioration. Although remyelination can be extensive in some patients, the majority of cases limit repair only to the acute phase of disease. A significant current drive in new MS therapeutics is to identify targets that can promote remyelination by boosting endogenous oligodendrocyte precursor cells to form new myelin. Also, a number of inhibitory pathways have been identified in chronic MS lesions that prevent oligodendrocyte precursor cells from being properly recruited to demyelinated lesions or interfere with their differentiation to myelin-forming oligodendrocytes. In this review, we introduce the phenomenon of remyelination from the view of experimental models and studies in MS patients, describe a potential role in remyelination for currently available MS mediations, and discuss many avenues that are being actively studied to promote remyelination. The next frontier in MS therapeutics will supplement immunomodulation with agents that directly foster myelin repair, with aims to delay disease progression and recover lost neurological functions.
| S-EPMC3557365 | biostudies-literature
Project description:We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the regenerative response, and we summarise progress on the development of new therapies to enhance remyelination aimed at reducing progressive accumulation of disability in MS. We discuss key target pathways identified in experimental models, as although most identified targets have not yet progressed to the stage of being tested in human clinical trials, they may provide treatment strategies for demyelinating diseases in the future. Finally, we discuss some of the problems associated with testing this class of drugs, where they might fit into the therapeutic arsenal and the gaps in our knowledge.
| S-EPMC3853368 | biostudies-literature
Project description:Current multiple sclerosis (MS) therapies are effective in reducing relapse rate, short-term measures of disability, and magnetic resonance imaging (MRI) measures of inflammation in relapsing remitting MS (RRMS), whereas in progressive/degenerative disease phases these medications are of little or no benefit. Therefore, the development of new therapies aimed at reversing neurodegeneration is of great interest. Remyelination, which is usually a spontaneous endogenous process, is achieved when myelin-producing oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs). Even though these precursor cells are abundant in MS brains, their regeneration capacity is limited. Enhancing the generation of myelin-producing cells is therefore a major focus of MS research. Here we present an overview of the different advancements in the field of remyelination, including suitable animal models for testing remyelination therapies, approved medications with a proposed role in regeneration, myelin repair treatments under investigation in clinical trials, as well as future therapeutics aimed at facilitating myelin repair.
| S-EPMC6389436 | biostudies-literature
Project description:Imaging Neurodegeneration in Multiple Sclerosis
| PRJNA827227 | ENA