Imaging chronic active lesions in multiple sclerosis: a consensus statement

Brain, Journal Year: 2024, Volume and Issue: 147(9), P. 2913 - 2933

Published: Jan. 16, 2024

Abstract Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery innovative MRI PET-derived biomarkers has made it possible to detect CAL, some extent quantify them, brain persons with sclerosis, vivo. Paramagnetic rim on susceptibility-sensitive sequences, MRI-defined slowly expanding T1-weighted T2-weighted scans, 18-kDa translocator protein-positive PET promising candidate CAL. While partially overlapping, these do not equivalent sensitivity specificity histopathological Standardization use available imaging measures CAL identification, quantification monitoring is lacking. To fast-forward clinical translation North American Imaging Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance radiological definition measurement The proposed manuscript presents this summarizes multistep process leading it, identifies remaining major gaps knowledge.

Language: Английский

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Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(1), P. 1 - 20

Published: April 3, 2024

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of disease underlies progression disability, which proceeds relentlessly independently clinical radiological relapses (PIRA). The complex system pathological events driving "chronic" worsening likely linked with early accumulation compartmentalized inflammation within central nervous as well insufficient repair phenomena mitochondrial failure. These mechanisms are partially lesion-independent differ those causing formation new focal demyelinating lesions; they lead to neuroaxonal dysfunction death, myelin loss, glia alterations, finally, neuronal network outweighing (CNS) compensatory mechanisms. This review aims provide an overview state art neuropathological, immunological, knowledge about underlying activity, focusing on possible biomarkers their translation into practice. ANN NEUROL 2024;96:1-20.

Language: Английский

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B cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(6), P. 615 - 624

Published: May 15, 2024

Language: Английский

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Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability

Drugs, Journal Year: 2024, Volume and Issue: 84(3), P. 285 - 304

Published: March 1, 2024

Currently, there are four monoclonal antibodies (mAbs) that target the cluster of differentiation (CD) 20 receptor available to treat multiple sclerosis (MS): rituximab, ocrelizumab, ofatumumab, and ublituximab. B-cell depletion therapy has changed therapeutic landscape MS through robust efficacy on clinical manifestations MRI lesion activity, currently anti-CD20 mAb therapies for use in a cornerstone highly effective disease-modifying treatment. Ocrelizumab is only with regulatory approval primary progressive MS. There few data regarding relative these therapies, though several trials ongoing. Safety concerns applicable this class therapeutics relate primarily immunogenicity mechanism action, include infusion-related or injection-related reactions, development hypogammaglobulinemia (leading increased infection malignancy risk), decreased vaccine response. Exploration alternative dose/dosing schedules might be an strategy mitigating risks. Future biosimilar medications make more readily available. Although have led significant improvements disease outcomes, CNS-penetrant still needed effectively address compartmentalized inflammation thought play important role disability progression.

Language: Английский

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Programming tissue-sensing T cells that deliver therapies to the brain

Science, Journal Year: 2024, Volume and Issue: 386(6726)

Published: Dec. 5, 2024

To engineer cells that can specifically target the central nervous system (CNS), we identified extracellular CNS-specific antigens, including components of CNS matrix and surface molecules expressed on neurons or glial cells. Synthetic Notch receptors engineered to detect these antigens were used program T induce expression diverse payloads only in brain. CNS-targeted induced chimeric antigen receptor efficiently cleared primary secondary brain tumors without harming cross-reactive outside Conversely, locally delivered immunosuppressive cytokine interleukin-10 ameliorated symptoms a mouse model neuroinflammation. Tissue-sensing represent strategy for addressing disorders an anatomically targeted manner.

Language: Английский

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Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis

Neurology Neuroimmunology & Neuroinflammation, Journal Year: 2024, Volume and Issue: 11(4)

Published: May 24, 2024

The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or combination, central vein sign (CVS), paramagnetic rim lesion (PRL), cortical (CL), as well their association with outcomes.

Language: Английский

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Comparative CNS Pharmacology of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis

Drugs in R&D, Journal Year: 2024, Volume and Issue: 24(2), P. 263 - 274

Published: June 1, 2024

Tolebrutinib is a covalent BTK inhibitor designed and selected for potency CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied translational approach evaluate three inhibitors Phase 3 clinical development MS with respect their relative block the METHODS: used vitro kinase cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) non-human primate cynomolgus estimate ability these candidates (evobrutinib, fenebrutinib, tolebrutinib) inside CNS.

Language: Английский

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A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 21, 2024

Introduction Despite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers disability progression that insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing metformin for PMS. The objective this clinical trial is evaluate whether metformin, as add-on treatment, superior placebo delaying disease Methods analysis MACSiMiSE-BRAIN multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled trial, conducted at five sites Belgium. Enrollment 120 PMS planned. Each participant will undergo screening visit assessment baseline magnetic resonance imaging (MRI), tests, questionnaires, safety laboratory assessment. Following randomization, participants be assigned either the (metformin) or group. Subsequently, they 96-week follow-up period. primary outcome change walking speed, measured Timed 25-Foot Walk Test, from 96 weeks. Secondary measures include neurological (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) hand function (9-Hole Peg test). Annual brain MRI performed assess evolution volumetry diffusion metrics. As may not progress all domains, composite outcome, Overall Response Score additionally evaluated an exploratory outcome. Other outcomes consist paramagnetic rim lesions, 2-minute test health economic analyses well both patient- caregiver-reported like EQ-5D-5L, Multiple Sclerosis Impact Scale Caregiver Strain Index. Ethics dissemination Clinical authorization regulatory agencies [Ethical Committee Federal Agency Medicines Health Products (FAMHP)] was obtained after submission centralized European Trial Information System. results disseminated scientific conferences, peer-reviewed publications, patient associations general public. registration ClinicalTrials.gov Identifier: NCT05893225, EUCT number: 2023-503190-38-00.

Language: Английский

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Targeting cytokine networks in neuroinflammatory diseases

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(11), P. 862 - 879

Published: Sept. 11, 2024

Language: Английский

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Bruton tyrosine kinase inhibitors in multiple sclerosis: evidence and expectations

Current Opinion in Neurology, Journal Year: 2024, Volume and Issue: 37(3), P. 237 - 244

Published: March 27, 2024

Despite availability of high-efficacy therapies for multiple sclerosis (MS), many patients experience significant disability worsening due to limited effects currently available drugs on central nervous system (CNS)-compartmentalized inflammation. Bruton tyrosine kinase (BTK) is an intracellular signaling molecule involved in regulation maturation, survival, migration, and activation B cells microglia, which are players the immunopathogenesis progressive MS. Therefore, CNS-penetrant BTK inhibitors may better prevent disease progression by targeting immune both sides blood-brain barrier. This review gives overview preliminary results clinical trials.

Language: Английский

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