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Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an...
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Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an Accurate Prognosis

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 20074

Special Issue Editor

Prof. Dr. Massimiliano Calabrese

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Guest Editor
Multiple Sclerosis Center of Neurology Clinic, Department of Neurosciences, Biomedicine and Movement, University Hospital of Verona, (Policlinico GB Rossi, Borgo Roma), Piazzale L.A. Scuro 10, 37134 Verona, Italy
Interests: multiple sclerosis; MRI; cerebro-spinal fluid; biomarkers; artificial intelligence

Special Issue Information

Dear Colleagues,

Although the early diagnosis and treatment of multiple sclerosis is associated with better patient outcomes, many people remain undiagnosed or are initially misdiagnosed. Furthermore, the identification of patients at high risk of disease activity and disability progression is still a major unmet therapeutic aim.

The aim of this Special Issue is to shed light on the new biomarkers which can help physicians in making the diagnostic work-up more accurate while also improving the accuracy in predicting disease activity, disability progression, and treatment efficacy. Clinical (both physical and cognitive), radiological, and biological diagnostic or prognostic markers will be welcome.

Original papers and reviews will be accepted.

Prof. Dr. Massimiliano Calabrese
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multiple sclerosis
  • biomarkers
  • diagnosis and prognosis
  • MRI
  • precision medicine

Published Papers (5 papers)

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Research

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22 pages, 2367 KiB  
Article
Cognitive Fatigue Is Associated with Altered Functional Connectivity in Interoceptive and Reward Pathways in Multiple Sclerosis
by Michelle H. Chen, John DeLuca, Helen M. Genova, Bing Yao and Glenn R. Wylie
Diagnostics 2020, 10(11), 930; https://doi.org/10.3390/diagnostics10110930 - 10 Nov 2020
Cited by 21 | Viewed by 2915
Abstract
Cognitive fatigue is common and debilitating among persons with multiple sclerosis (pwMS). Neural mechanisms underlying fatigue are not well understood, which results in lack of adequate treatment. The current study examined cognitive fatigue-related functional connectivity among 26 pwMS and 14 demographically matched healthy [...] Read more.
Cognitive fatigue is common and debilitating among persons with multiple sclerosis (pwMS). Neural mechanisms underlying fatigue are not well understood, which results in lack of adequate treatment. The current study examined cognitive fatigue-related functional connectivity among 26 pwMS and 14 demographically matched healthy controls (HCs). Participants underwent functional magnetic resonance imaging (fMRI) scanning while performing a working memory task (n-back), with two conditions: one with higher cognitive load (2-back) to induce fatigue and one with lower cognitive load (0-back) as a control condition. Task-independent residual functional connectivity was assessed, with seeds in brain regions previously implicated in cognitive fatigue (dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), insula, and striatum). Cognitive fatigue was measured using the Visual Analogue Scale of Fatigue (VAS-F). Results indicated that as VAS-F scores increased, HCs showed increased residual functional connectivity between the striatum and the vmPFC (crucial in reward processing) during the 2-back condition compared to the 0-back condition. In contrast, pwMS displayed increased residual functional connectivity from interoceptive hubs—the insula and the dACC—to the striatum. In conclusion, pwMS showed a hyperconnectivity within the interoceptive network and disconnection within the reward circuitry when experiencing cognitive fatigue. Full article
(This article belongs to the Special Issue Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an Accurate Prognosis)
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11 pages, 1593 KiB  
Article
Kappa Index versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders
by Diana Ferraro, Roberta Bedin, Patrizia Natali, Diego Franciotta, Krzysztof Smolik, Mario Santangelo, Paolo Immovilli, Valentina Camera, Francesca Vitetta, Matteo Gastaldi, Tommaso Trenti, Stefano Meletti and Patrizia Sola
Diagnostics 2020, 10(10), 856; https://doi.org/10.3390/diagnostics10100856 - 21 Oct 2020
Cited by 20 | Viewed by 3825
Abstract
Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin [...] Read more.
Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID). Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer. Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis. Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information. Full article
(This article belongs to the Special Issue Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an Accurate Prognosis)
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Review

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11 pages, 1442 KiB  
Review
Gait Pattern in People with Multiple Sclerosis: A Systematic Review
by María Coca-Tapia, Alicia Cuesta-Gómez, Francisco Molina-Rueda and María Carratalá-Tejada
Diagnostics 2021, 11(4), 584; https://doi.org/10.3390/diagnostics11040584 - 24 Mar 2021
Cited by 20 | Viewed by 4265
Abstract
The aim of the present systematic review was to describe the gait pattern in people with multiple sclerosis (MS) by compiling the main findings obtained from studies using three-dimensional capture systems of human movement. The search was carried out in PubMed, Web of [...] Read more.
The aim of the present systematic review was to describe the gait pattern in people with multiple sclerosis (MS) by compiling the main findings obtained from studies using three-dimensional capture systems of human movement. The search was carried out in PubMed, Web of Science, Physiotherapy Evidence Database (PEDro), and the Cumulative Index to Nursing and Allied Health (CINAHL) databases. Studies that used three-dimensional gait analysis systems and that analyzed spatiotemporal, kinematic, kinetic, or electromyographic parameters, were included. The quality of the studies was assessed using the Critical Review Form–Quantitative Studies scale. 12 articles were included with 523 (342 women and 181 men) people with a diagnosis of MS. The present work suggests that people with MS have a decrease in speed and stride length, as well as an increase in double-stance intervals during gait. Likewise, it is common to observe a decrease in hip extension during the stance period, a decrease in knee flexion in the swing period, a decrease in ankle dorsiflexion in the initial contact and a decrease in ankle plantar flexion during the pre-swing phase. The subjects with MS decrease the hip extensor moment and the ankle power during the stance period of walking. Full article
(This article belongs to the Special Issue Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an Accurate Prognosis)
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15 pages, 2972 KiB  
Review
The Use of the Central Vein Sign in the Diagnosis of Multiple Sclerosis: A Systematic Review and Meta-analysis
by Marco Castellaro, Agnese Tamanti, Anna Isabella Pisani, Francesca Benedetta Pizzini, Francesco Crescenzo and Massimiliano Calabrese
Diagnostics 2020, 10(12), 1025; https://doi.org/10.3390/diagnostics10121025 - 29 Nov 2020
Cited by 35 | Viewed by 4176
Abstract
Background: The central vein sign (CVS) is a radiological feature proposed as a multiple sclerosis (MS) imaging biomarker able to accurately differentiate MS from other white matter diseases of the central nervous system. In this work, we evaluated the pooled proportion of [...] Read more.
Background: The central vein sign (CVS) is a radiological feature proposed as a multiple sclerosis (MS) imaging biomarker able to accurately differentiate MS from other white matter diseases of the central nervous system. In this work, we evaluated the pooled proportion of the CVS in brain MS lesions and to estimate the diagnostic performance of CVS to perform a diagnosis of MS and propose an optimal cut-off value. Methods: A systematic search was performed on publicly available databases (PUBMED/MEDLINE and Web of Science) up to 24 August 2020. Analysis of the proportion of white matter MS lesions with a central vein was performed using bivariate random-effect models. A meta-regression analysis was performed and the impact of using particular sequences (such as 3D echo-planar imaging) and post-processing techniques (such as FLAIR*) was investigated. Pooled sensibility and specificity were estimated using bivariate models and meta-regression was performed to address heterogeneity. Inclusion and publication bias were assessed using asymmetry tests and a funnel plot. A hierarchical summary receiver operating curve (HSROC) was used to estimate the summary accuracy in diagnostic performance. The Youden index was employed to estimate the optimal cut-off value using individual patient data. Results: The pooled proportion of lesions showing a CVS in the MS population was 73%. The use of the CVS showed a remarkable diagnostic performance in MS cases, providing a pooled specificity of 92% and a sensitivity of 95%. The optimal cut-off value obtained from the individual patient data pooled together was 40% with excellent accuracy calculated by the area under the ROC (0.946). The 3D-EPI sequences showed both a higher pooled proportion compared to other sequences and explained heterogeneity in the meta-regression analysis of diagnostic performances. The 1.5 Tesla (T) scanners showed a lower (58%) proportion of MS lesions with a CVS compared to both 3T (74%) and 7T (82%). Conclusions: The meta-analysis we have performed shows that the use of the CVS in differentiating MS from other mimicking diseases is encouraged; moreover, the use of dedicated sequences such as 3D-EPI and the high MRI field is beneficial. Full article
(This article belongs to the Special Issue Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an Accurate Prognosis)
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16 pages, 3054 KiB  
Review
Iron Rims as an Imaging Biomarker in MS: A Systematic Mapping Review
by Amjad I. AlTokhis, Abdulmajeed M. AlOtaibi, Ghadah A. Felmban, Cris S. Constantinescu and Nikos Evangelou
Diagnostics 2020, 10(11), 968; https://doi.org/10.3390/diagnostics10110968 - 18 Nov 2020
Cited by 16 | Viewed by 3744
Abstract
Background: Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating and degenerative disease of the central nervous system (CNS). To date, there is no definitive imaging biomarker for diagnosing MS. The current diagnostic criteria are mainly based on clinical relapses supported by the presence [...] Read more.
Background: Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating and degenerative disease of the central nervous system (CNS). To date, there is no definitive imaging biomarker for diagnosing MS. The current diagnostic criteria are mainly based on clinical relapses supported by the presence of white matter lesions (WMLs) on MRI. However, misdiagnosis of MS is still a significant clinical problem. The paramagnetic, iron rims (IRs) around white matter lesions have been proposed to be an imaging biomarker in MS. This study aimed to carry out a systematic mapping review to explore the detection of iron rim lesions (IRLs), on clinical MR scans, and describe the characteristics of IRLs presence in MS versus other MS-mimic disorders. Methods: Publications from 2001 on IRs lesions were reviewed in three databases: PubMed, Web of Science and Embase. From the initial result set 718 publications, a final total of 38 papers were selected. Results: The study revealed an increasing interest in iron/paramagnetic rims lesions studies. IRs were more frequently found in periventricular regions and appear to be absent in MS-mimics. Conclusions IR is proposed as a promising imaging biomarker for MS. Full article
(This article belongs to the Special Issue Biomarkers in Multiple Sclerosis: From an Early Diagnosis to an Accurate Prognosis)
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