Editorial

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Open AccessEditorial

Pathophysiology and Imaging Diagnosis of Demyelinating Disorders

by Evanthia Bernitsas

Brain Sci. 2018, 8(3), 44; https://doi.org/10.3390/brainsci8030044 - 14 Mar 2018

Cited by 3 | Viewed by 3734

The spectrum of “demyelinating disorders” is broad and it includes various disorders with central nervous system (CNS) demyelination[...] Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

Research

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Open AccessArticle

Structural and Neuronal Integrity Measures of Fatigue Severity in Multiple Sclerosis

by Evanthia Bernitsas, Kalyan Yarraguntla, Fen Bao, Rishi Sood, Carla Santiago-Martinez, Rajkumar Govindan, Omar Khan and Navid Seraji-Bozorgzad

Brain Sci. 2017, 7(8), 102; https://doi.org/10.3390/brainsci7080102 - 12 Aug 2017

Cited by 31 | Viewed by 5548

Abstract

Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty-three Relapsing Remitting MS (RRMS) patients with MS-related [...] Read more.

Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty-three Relapsing Remitting MS (RRMS) patients with MS-related fatigue (Fatigue Severity Scale (FSS) range: 1–7) and Expanded Disability Status Scale (EDSS) ≤ 4, were divided into high fatigue (HF, FSS ≥ 5.1) and low fatigue groups (LF, FSS ≤ 3). We measured T2 lesion load using a semi-automated technique. Cortical thickness, volume of sub-cortical nuclei, and brainstem structures were measured using Freesurfer. Cortical Diffusion Tensor Imaging (DTI) parameters were extracted using a cross modality technique. A correlation analysis was performed between FSS, volumetric, and DTI indices across all patients. HF patients showed significantly lower volume of thalamus, (p = 0.02), pallidum (p = 0.01), and superior cerebellar peduncle ((SCP), p = 0.002). The inverse correlation between the FSS score and the above volumes was significant in the total study population. In the right temporal cortex (RTC), the Radial Diffusivity ((RD), p = 0.01) and Fractional Anisotropy ((FA), p = 0.01) was significantly higher and lower, respectively, in the HF group. After Bonferroni correction, thalamic volume, FA-RTC, and RD-RTC remained statistically significant. Multivariate regression analysis identified FA-RTC as the best predictor of fatigue severity. Our data suggest an association between fatigue severity and volumetric changes of thalamus, pallidum, and SCP. Early neuronal injury in the RTC is implicated in the pathogenesis of MS-related fatigue. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Open AccessArticle

Evaluation of Visual-Evoked Cerebral Metabolic Rate of Oxygen as a Diagnostic Marker in Multiple Sclerosis

by Nicholas A. Hubbard, Yoel Sanchez Araujo, Camila Caballero, Minhui Ouyang, Monroe P. Turner, Lyndahl Himes, Shawheen Faghihahmadabadi, Binu P. Thomas, John Hart, Hao Huang, Darin T. Okuda and Bart Rypma

Brain Sci. 2017, 7(6), 64; https://doi.org/10.3390/brainsci7060064 - 11 Jun 2017

Cited by 3 | Viewed by 6789

Abstract

A multiple sclerosis (MS) diagnosis often relies upon clinical presentation and qualitative analysis of standard, magnetic resonance brain images. However, the accuracy of MS diagnoses can be improved by utilizing advanced brain imaging methods. We assessed the accuracy of a new neuroimaging marker, [...] Read more.

A multiple sclerosis (MS) diagnosis often relies upon clinical presentation and qualitative analysis of standard, magnetic resonance brain images. However, the accuracy of MS diagnoses can be improved by utilizing advanced brain imaging methods. We assessed the accuracy of a new neuroimaging marker, visual-evoked cerebral metabolic rate of oxygen (veCMRO₂), in classifying MS patients and closely age- and sex-matched healthy control (HC) participants. MS patients and HCs underwent calibrated functional magnetic resonance imaging (cfMRI) during a visual stimulation task, diffusion tensor imaging, T₁- and T₂-weighted imaging, neuropsychological testing, and completed self-report questionnaires. Using resampling techniques to avoid bias and increase the generalizability of the results, we assessed the accuracy of veCMRO₂ in classifying MS patients and HCs. veCMRO₂ classification accuracy was also examined in the context of other evoked visuofunctional measures, white matter microstructural integrity, lesion-based measures from T₂-weighted imaging, atrophy measures from T₁-weighted imaging, neuropsychological tests, and self-report assays of clinical symptomology. veCMRO₂ was significant and within the top 16% of measures (43 total) in classifying MS status using both within-sample (82% accuracy) and out-of-sample (77% accuracy) observations. High accuracy of veCMRO₂ in classifying MS demonstrated an encouraging first step toward establishing veCMRO₂ as a neurodiagnostic marker of MS. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Review

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Open AccessReview

Role of Immunological Memory Cells as a Therapeutic Target in Multiple Sclerosis

by Tanima Bose

Brain Sci. 2017, 7(11), 148; https://doi.org/10.3390/brainsci7110148 - 07 Nov 2017

Cited by 13 | Viewed by 4978

Abstract

Pharmacological targeting of memory cells is an attractive treatment strategy in various autoimmune diseases, such as psoriasis and rheumatoid arthritis. Multiple sclerosis is the most common inflammatory disorder of the central nervous system, characterized by focal immune cell infiltration, activation of microglia and [...] Read more.

Pharmacological targeting of memory cells is an attractive treatment strategy in various autoimmune diseases, such as psoriasis and rheumatoid arthritis. Multiple sclerosis is the most common inflammatory disorder of the central nervous system, characterized by focal immune cell infiltration, activation of microglia and astrocytes, along with progressive damage to myelin sheaths, axons, and neurons. The current review begins with the identification of memory cell types in the previous literature and a recent description of the modulation of these cell types in T, B, and resident memory cells in the presence of different clinically approved multiple sclerosis drugs. Overall, this review paper tries to determine the potential of memory cells to act as a target for the current or newly-developed drugs. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Open AccessReview

Pattern Recognition of the Multiple Sclerosis Syndrome

by Rana K. Zabad, Renee Stewart and Kathleen M. Healey

Brain Sci. 2017, 7(10), 138; https://doi.org/10.3390/brainsci7100138 - 24 Oct 2017

Cited by 20 | Viewed by 13081

Abstract

During recent decades, the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD), once broadly classified under the umbrella of multiple sclerosis (MS), has been extended to include autoimmune inflammatory conditions of the central nervous system (CNS), which are now diagnosable with serum serological tests. [...] Read more.

During recent decades, the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD), once broadly classified under the umbrella of multiple sclerosis (MS), has been extended to include autoimmune inflammatory conditions of the central nervous system (CNS), which are now diagnosable with serum serological tests. These antibody-mediated inflammatory diseases of the CNS share a clinical presentation to MS. A number of practical learning points emerge in this review, which is geared toward the pattern recognition of optic neuritis, transverse myelitis, brainstem/cerebellar and hemispheric tumefactive demyelinating lesion (TDL)-associated MS, aquaporin-4-antibody and myelin oligodendrocyte glycoprotein (MOG)-antibody NMOSD, overlap syndrome, and some yet-to-be-defined/classified demyelinating disease, all unspecifically labeled under MS syndrome. The goal of this review is to increase clinicians’ awareness of the clinical nuances of the autoimmune conditions for MS and NMSOD, and to highlight highly suggestive patterns of clinical, paraclinical or imaging presentations in order to improve differentiation. With overlay in clinical manifestations between MS and NMOSD, magnetic resonance imaging (MRI) of the brain, orbits and spinal cord, serology, and most importantly, high index of suspicion based on pattern recognition, will help lead to the final diagnosis. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Melanocortins, Melanocortin Receptors and Multiple Sclerosis

by Robert P. Lisak and Joyce A. Benjamins

Brain Sci. 2017, 7(8), 104; https://doi.org/10.3390/brainsci7080104 - 14 Aug 2017

Cited by 21 | Viewed by 7143

Abstract

The melanocortins and their receptors have been extensively investigated for their roles in the hypothalamo-pituitary-adrenal axis, but to a lesser extent in immune cells and in the nervous system outside the hypothalamic axis. This review discusses corticosteroid dependent and independent effects of melanocortins [...] Read more.

The melanocortins and their receptors have been extensively investigated for their roles in the hypothalamo-pituitary-adrenal axis, but to a lesser extent in immune cells and in the nervous system outside the hypothalamic axis. This review discusses corticosteroid dependent and independent effects of melanocortins on the peripheral immune system, central nervous system (CNS) effects mediated through neuronal regulation of immune system function, and direct effects on endogenous cells in the CNS. We have focused on the expression and function of melanocortin receptors in oligodendroglia (OL), the myelin producing cells of the CNS, with the goal of identifying new therapeutic approaches to decrease CNS damage in multiple sclerosis as well as to promote repair. It is clear that melanocortin signaling through their receptors in the CNS has potential for neuroprotection and repair in diseases like MS. Effects of melanocortins on the immune system by direct effects on the circulating cells (lymphocytes and monocytes) and by signaling through CNS cells in regions lacking a mature blood brain barrier are clear. However, additional studies are needed to develop highly effective MCR targeted therapies that directly affect endogenous cells of the CNS, particularly OL, their progenitors and neurons. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Open AccessReview

Multiple Sclerosis: Immunopathology and Treatment Update

by Narges Dargahi, Maria Katsara, Theodore Tselios, Maria-Eleni Androutsou, Maximilian De Courten, John Matsoukas and Vasso Apostolopoulos

Brain Sci. 2017, 7(7), 78; https://doi.org/10.3390/brainsci7070078 - 07 Jul 2017

Cited by 185 | Viewed by 23695

Abstract

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies [...] Read more.

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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The Role of Peripheral CNS‐Directed Antibodies in Promoting Inflammatory CNS Demyelination

by Silke Kinzel and Martin S. Weber

Brain Sci. 2017, 7(7), 70; https://doi.org/10.3390/brainsci7070070 - 22 Jun 2017

Cited by 14 | Viewed by 6609

Abstract

In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This [...] Read more.

In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti-aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS-autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Open AccessReview

Contribution of the Degeneration of the Neuro-Axonal Unit to the Pathogenesis of Multiple Sclerosis

by Hannah E. Salapa, Sangmin Lee, Yoojin Shin and Michael C. Levin

Brain Sci. 2017, 7(6), 69; https://doi.org/10.3390/brainsci7060069 - 18 Jun 2017

Cited by 19 | Viewed by 7632

Abstract

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. In recent years, it has become more evident that neurodegeneration, including neuronal damage and axonal injury, underlies permanent disability in MS. This manuscript reviews some of the mechanisms that could [...] Read more.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. In recent years, it has become more evident that neurodegeneration, including neuronal damage and axonal injury, underlies permanent disability in MS. This manuscript reviews some of the mechanisms that could be responsible for neurodegeneration and axonal damage in MS and highlights the potential role that dysfunctional heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and antibodies to hnRNP A1 may play in MS pathogenesis. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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Open AccessReview

Is Decompressive Surgery for Cervical Spondylotic Myelopathy Effective in Patients Suffering from Concomitant Multiple Sclerosis or Parkinson’s Disease?

by Taylor E. Purvis, Daniel Lubelski and Thomas E. Mroz

Brain Sci. 2017, 7(4), 39; https://doi.org/10.3390/brainsci7040039 - 10 Apr 2017

Cited by 9 | Viewed by 5155

Abstract

A subset of patients with a demyelinating disease suffer from concurrent cervical spondylotic myelopathy, both of which evince similar symptomatology. Differentiating the cause of these symptoms is challenging, and little research has been done on patients with coexisting diseases. This review explores the [...] Read more.

A subset of patients with a demyelinating disease suffer from concurrent cervical spondylotic myelopathy, both of which evince similar symptomatology. Differentiating the cause of these symptoms is challenging, and little research has been done on patients with coexisting diseases. This review explores the current literature on the appropriate surgical management of patients with concurrent multiple sclerosis (MS) and cervical spondylotic myelopathy (CSM), and those with both Parkinson’s disease (PD) and CSM. MS and CSM patients may benefit from surgery to reduce pain and radiculopathy. Surgical management in PD and CSM patients has shown minimal quality-of-life improvement. Future studies are needed to better characterize demyelinating disease patients with concurrent disease and to determine ideal medical or surgical treatment. Full article

(This article belongs to the Special Issue Pathophysiology and Imaging Diagnosis of Demyelinating Disorders)

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