International Journal of Molecular Sciences

Research

20 pages, 28463 KiB

Open AccessArticle

Evaluation of Disability Progression in Multiple Sclerosis via Magnetic-Resonance-Based Deep Learning Techniques

by Alessandro Taloni, Francis Allen Farrelly, Giuseppe Pontillo, Nikolaos Petsas, Costanza Giannì, Serena Ruggieri, Maria Petracca, Arturo Brunetti, Carlo Pozzilli, Patrizia Pantano and Silvia Tommasin

Int. J. Mol. Sci. 2022, 23(18), 10651; https://doi.org/10.3390/ijms231810651 - 13 Sep 2022

Cited by 4 | Viewed by 1761

Abstract

Short-term disability progression was predicted from a baseline evaluation in patients with multiple sclerosis (MS) using their three-dimensional T1-weighted (3DT1) magnetic resonance images (MRI). One-hundred-and-eighty-one subjects diagnosed with MS underwent 3T-MRI and were followed up for two to six years at two sites, [...] Read more.

Short-term disability progression was predicted from a baseline evaluation in patients with multiple sclerosis (MS) using their three-dimensional T1-weighted (3DT1) magnetic resonance images (MRI). One-hundred-and-eighty-one subjects diagnosed with MS underwent 3T-MRI and were followed up for two to six years at two sites, with disability progression defined according to the expanded-disability-status-scale (EDSS) increment at the follow-up. The patients’ 3DT1 images were bias-corrected, brain-extracted, registered onto MNI space, and divided into slices along coronal, sagittal, and axial projections. Deep learning image classification models were applied on slices and devised as ResNet50 fine-tuned adaptations at first on a large independent dataset and secondly on the study sample. The final classifiers’ performance was evaluated via the area under the curve (AUC) of the false versus true positive diagram. Each model was also tested against its null model, obtained by reshuffling patients’ labels in the training set. Informative areas were found by intersecting slices corresponding to models fulfilling the disability progression prediction criteria. At follow-up, 34% of patients had disability progression. Five coronal and five sagittal slices had one classifier surviving the AUC evaluation and null test and predicted disability progression (AUC > 0.72 and AUC > 0.81, respectively). Likewise, fifteen combinations of classifiers and axial slices predicted disability progression in patients (AUC > 0.69). Informative areas were the frontal areas, mainly within the grey matter. Briefly, 3DT1 images may give hints on disability progression in MS patients, exploiting the information hidden in the MRI of specific areas of the brain. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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16 pages, 2432 KiB

Open AccessArticle

Cytokine Secretion Dynamics of Isolated PBMC after Cladribine Exposure in RRMS Patients

by Rodica Balasa, Smaranda Maier, Adina Hutanu, Septimiu Voidazan, Sebastian Andone, Mirela Oiaga and Doina Manu

Int. J. Mol. Sci. 2022, 23(18), 10262; https://doi.org/10.3390/ijms231810262 - 6 Sep 2022

Viewed by 1539

Abstract

Cladribine (CLD) treats multiple sclerosis (MS) by selectively and transiently depleting B and T cells with a secondary long-term reconstruction of the immune system. This study provides evidence of CLD’s immunomodulatory role in peripheral blood mononuclear cells (PBMCs) harvested from 40 patients with [...] Read more.

Cladribine (CLD) treats multiple sclerosis (MS) by selectively and transiently depleting B and T cells with a secondary long-term reconstruction of the immune system. This study provides evidence of CLD’s immunomodulatory role in peripheral blood mononuclear cells (PBMCs) harvested from 40 patients with untreated relapsing-remitting MS (RRMS) exposed to CLD. We quantified cytokine secretion from PBMCs isolated by density gradient centrifugation with Ficoll–Paque using xMAP technology on a FlexMap 3D analyzer with a highly sensitive multiplex immunoassay kit. The PBMC secretory profile was evaluated with and without CLD exposure. PBMCs isolated from patients with RRMS for ≤12 months had significantly higher IL-4 but significantly lower IFN-γ and TNF-α secretion after CLD exposure. PBMCs isolated from patients with RRMS for >12 months had altered inflammatory ratios toward an anti-inflammatory profile and increased IL-4 but decreased TNF-α secretion after CLD exposure. CLD induced nonsignificant changes in IL-17 secretion in both RRMS groups. Our findings reaffirm CLD’s immunomodulatory effect that induces an anti-inflammatory phenotype. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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13 pages, 3971 KiB

Open AccessArticle

Ultrasound Neuromodulation Reduces Demyelination in a Rat Model of Multiple Sclerosis

by Feng-Yi Yang, Li-Hsin Huang, Meng-Ting Wu and Zih-Yun Pan

Int. J. Mol. Sci. 2022, 23(17), 10034; https://doi.org/10.3390/ijms231710034 - 2 Sep 2022

Cited by 5 | Viewed by 2246

Abstract

Microglia, astrocytes, and oligodendrocyte progenitor cells (OPCs) may serve as targets for remyelination-enhancing therapy. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to ameliorate myelin loss and inhibit neuroinflammation in animal models of brain disorders; however, the underlying mechanisms through which LIPUS stimulates remyelination [...] Read more.

Microglia, astrocytes, and oligodendrocyte progenitor cells (OPCs) may serve as targets for remyelination-enhancing therapy. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to ameliorate myelin loss and inhibit neuroinflammation in animal models of brain disorders; however, the underlying mechanisms through which LIPUS stimulates remyelination and glial activation are not well-understood. This study explored the impacts of LIPUS on remyelination and resident cells following lysolecithin (LPC)-induced local demyelination in the hippocampus. Demyelination was induced by the micro-injection of 1.5 μL of 1% LPC into the rat hippocampus, and the treatment groups received daily LIPUS stimulation for 5 days. The therapeutic effects of LIPUS on LPC-induced demyelination were assessed through immunohistochemistry staining. The staining was performed to evaluate remyelination and Iba-1 staining as a microglia marker. Our data revealed that LIPUS significantly increased myelin basic protein (MBP) expression. Moreover, the IHC results showed that LIPUS significantly inhibited glial cell activation, enhanced mature oligodendrocyte density, and promoted brain-derived neurotrophic factor (BDNF) expression at the lesion site. In addition, a heterologous population of microglia with various morphologies can be found in the demyelination lesion after LIPUS treatment. These data show that LIPUS stimulation may serve as a potential treatment for accelerating remyelination through the attenuation of glial activation and the enhancement of mature oligodendrocyte density and BDNF production. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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Graphical abstract

10 pages, 1713 KiB

Open AccessCommunication

The Dual Role of the β₂-Adrenoreceptor in the Modulation of IL-17 and IFN-γ Production by T Cells in Multiple Sclerosis

by Mikhail Melnikov, Vladimir Rogovskii, Anastasiya Sviridova, Anna Lopatina, Mikhail Pashenkov and Alexey Boyko

Int. J. Mol. Sci. 2022, 23(2), 668; https://doi.org/10.3390/ijms23020668 - 8 Jan 2022

Cited by 7 | Viewed by 1653

Abstract

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the β₂-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play [...] Read more.

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the β₂-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4⁺ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or β₂-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4⁺ T cells in both groups. Blockade of the β₂-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the β₂-adrenoreceptor agonist formoterol did not influence norepinephrine’s inhibitory effect on cytokine production in both groups. The blockade of the β₂-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, β₂-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4⁺ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4⁺ T cells in MS could be mediated via β₂-adrenoreceptor activation. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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Review

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26 pages, 761 KiB

Open AccessReview

Recent Progress in the Identification of Early Transition Biomarkers from Relapsing-Remitting to Progressive Multiple Sclerosis

by Smaranda Maier, Laura Barcutean, Sebastian Andone, Doina Manu, Emanuela Sarmasan, Zoltan Bajko and Rodica Balasa

Int. J. Mol. Sci. 2023, 24(5), 4375; https://doi.org/10.3390/ijms24054375 - 22 Feb 2023

Cited by 6 | Viewed by 2637

Abstract

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which [...] Read more.

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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34 pages, 1195 KiB

Open AccessReview

Proteomics in Multiple Sclerosis: The Perspective of the Clinician

by Dániel Sandi, Zsófia Kokas, Tamás Biernacki, Krisztina Bencsik, Péter Klivényi and László Vécsei

Int. J. Mol. Sci. 2022, 23(9), 5162; https://doi.org/10.3390/ijms23095162 - 5 May 2022

Cited by 16 | Viewed by 6964

Abstract

Multiple sclerosis (MS) is the inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. In the last decade, a new era was heralded in by a new phenotypic classification, a new diagnostic protocol and [...] Read more.

Multiple sclerosis (MS) is the inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. In the last decade, a new era was heralded in by a new phenotypic classification, a new diagnostic protocol and the first ever therapeutic guideline, making personalized medicine the aim of MS management. However, despite this great evolution, there are still many aspects of the disease that are unknown and need to be further researched. A hallmark of these research are molecular biomarkers that could help in the diagnosis, differential diagnosis, therapy and prognosis of the disease. Proteomics, a rapidly evolving discipline of molecular biology may fulfill this dire need for the discovery of molecular biomarkers. In this review, we aimed to give a comprehensive summary on the utility of proteomics in the field of MS research. We reviewed the published results of the method in case of the pathogenesis of the disease and for biomarkers of diagnosis, differential diagnosis, conversion of disease courses, disease activity, progression and immunological therapy. We found proteomics to be a highly effective emerging tool that has been providing important findings in the research of MS. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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23 pages, 1881 KiB

Open AccessReview

Exploring the Pro-Phagocytic and Anti-Inflammatory Functions of PACAP and VIP in Microglia: Implications for Multiple Sclerosis

by Margo I. Jansen, Sarah Thomas Broome and Alessandro Castorina

Int. J. Mol. Sci. 2022, 23(9), 4788; https://doi.org/10.3390/ijms23094788 - 26 Apr 2022

Cited by 6 | Viewed by 3721

Abstract

Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease of the central nervous system (CNS), characterised by the infiltration of peripheral immune cells, multifocal white-matter lesions, and neurodegeneration. In recent years, microglia have emerged as key contributors to MS pathology, acting as [...] Read more.

Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease of the central nervous system (CNS), characterised by the infiltration of peripheral immune cells, multifocal white-matter lesions, and neurodegeneration. In recent years, microglia have emerged as key contributors to MS pathology, acting as scavengers of toxic myelin/cell debris and modulating the inflammatory microenvironment to promote myelin repair. In this review, we explore the role of two neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), as important regulators of microglial functioning during demyelination, myelin phagocytosis, and remyelination, emphasising the potential of these neuropeptides as therapeutic targets for the treatment of MS. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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Other

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14 pages, 1381 KiB

Open AccessHypothesis

The Inflammatory Conspiracy in Multiple Sclerosis: A Crossroads of Clues and Insights through Mast Cells, Platelets, Inflammation, Gut Microbiota, Mood Disorders and Stem Cells

by Massimo Cocchi, Elisabetta Mondo, Marcello Romeo and Giovanna Traina

Int. J. Mol. Sci. 2022, 23(6), 3253; https://doi.org/10.3390/ijms23063253 - 17 Mar 2022

Cited by 4 | Viewed by 3101

Abstract

Multiple Sclerosis is a chronic neurological disease characterized by demyelination and axonal loss. This pathology, still largely of unknown etiology, carries within it a complex series of etiopathogenetic components of which it is difficult to trace the origin. An inflammatory state is likely [...] Read more.

Multiple Sclerosis is a chronic neurological disease characterized by demyelination and axonal loss. This pathology, still largely of unknown etiology, carries within it a complex series of etiopathogenetic components of which it is difficult to trace the origin. An inflammatory state is likely to be the basis of the pathology. Crucial elements of the inflammatory process are the interactions between platelets and mast cells as well as the bacterial component of the intestinal microbiota. In addition, the involvement of mast cells in autoimmune demyelinating diseases has been shown. The present work tries to hang up on that Ariadne’s thread which, in the molecular complexity of the interactions between mast cells, platelets, microbiota and inflammation, characterizes Multiple Sclerosis and attempts to bring the pathology back to the causal determinism of psychopathological phenomenology. Therefore, we consider the possibility that the original error of Multiple Sclerosis can be investigated in the genetic origin of the depressive pathology. Full article

(This article belongs to the Special Issue Advances in Mechanisms, Diagnosis and Therapy of Multiple Sclerosis and Other Demyelinating Diseases)

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