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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 29962

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Special Issue Editors

Dr. Robert Živadinov

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Guest Editor

University at Buffalo, State University of New York, Buffalo, NY, USA
Interests: multiple sclerosis; neuroimaging; neurology; cognition; neuropsychological assessment; dementia; MRI

Dr. Dejan Jakimovski

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Guest Editor

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
Interests: multiple sclerosis; neuroimaging; MRI; neurology; non-conventional MRI measures; neurodegeneration

Special Issue Information

Dear Colleagues,

We continue to observe significant advancements in multiple biomarkers that can be utilized in the diagnosis and routine follow-up of multiple sclerosis (MS) patients. The implementation of novel approaches, such as advanced magnetic resonance imaging (MRI), optical coherence tomography (OCT), positron emission tomography (PET), and biologic biomarkers, are accelerating the understanding of MS pathophysiology and facilitating in the timely detection of the disease activity.

This Special Issue focuses on advanced modes of MS diagnostics, such as novel MRI metrics, artificial intelligence-based methodologies, and the use of para-clinical data in the early detection of disease progression and/or transition to progressive MS. We further welcome original or review manuscripts regarding the use of cognitive measures, clinical diagnostics outcomes, and determinants of disease-modifying treatment (DMT) responses.

Lastly, case reports and interesting images (please refer to https://0-www-mdpi-com.brum.beds.ac.uk/journal/diagnostics/instructions) highlighting the use and feasibility of such biomarkers are similarly welcomed.

Dr. Robert Živadinov
Dr. Dejan Jakimovski
Guest Editors

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
Magnetic resonance imaging
Non-conventional MRI metrics
Neurodegenerative measures (atrophy)
Artificial intelligence
Positron emission tomography (PET)
Clinical diagnostics
Disease progression
Transition to progressive MS
SPMS diagnostics
Serum and CSF-based biomarkers
Serum neurofilament light chain (sNfL)
Optical coherence tomography (OCT)
Cognitive measures in MS
Disease modifying treatment (DMT) response

Published Papers (11 papers)

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Editorial

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4 pages, 192 KiB

Open AccessEditorial

Editorial of Special Issue “Multiple Sclerosis: From Diagnostic Biomarkers to Imaging and Clinical Predictors”

by Dejan Jakimovski and Robert Zivadinov

Diagnostics 2022, 12(2), 482; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12020482 - 13 Feb 2022

Viewed by 1449

Abstract

Multiple sclerosis (MS) is a chronic, neuroinflammatory and neurodegenerative disease of the central nervous system (CNS) that can present with a plethora of physical and cognitive impairments [...] Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

Research

Jump to: Editorial

10 pages, 757 KiB

Open AccessArticle

Clinical Predictors of Neurogenic Lower Urinary Tract Dysfunction in Persons with Multiple Sclerosis

by Janina Beck, Anke Kirsten Jaekel, Federico Leopoldo Zeller, Michael Kowollik, Ines Kurze, Albert Kaufmann, Wolfgang Feneberg, Anna Brandt, Peter Flachenecker, Thomas Henze, Burkhard Domurath, Paul Schmidt, Will Nelson Vance, Franziska Goldschmidt, Ruth Klara Maria Kirschner-Hermanns and Stephanie C. Knüpfer

Diagnostics 2022, 12(1), 191; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12010191 - 13 Jan 2022

Cited by 6 | Viewed by 1531

Abstract

Background: Multiple sclerosis patients often develop neurogenic lower urinary tract dysfunction with a potential risk of upper urinary tract damage. Diagnostic tools are urodynamics, bladder diary, uroflowmetry, and post-void residual, but recommendations for their use are controversial. Objective: We aimed to identify clinical parameters indicative of neurogenic lower urinary tract dysfunction in multiple sclerosis patients. Methods: 207 patients were prospectively assessed independent of the presence of lower urinary tract symptoms. We analyzed Expanded Disability Status Scale scores, uroflowmetry, post-void residual, rate of urinary tract infections, standardized voiding frequency, and voided volume in correlation with urodynamic findings. Results: We found a significant correlation between post-void residual (odds ratio (OR) 4.17, confidence interval (CI) 1.20–22.46), urinary tract infection rate (OR 3.91, CI 1.13–21.0), voided volume (OR 4.53, CI 1.85–11.99), increased standardized voiding frequency (OR 7.40, CI 2.15–39.66), and urodynamic findings indicative of neurogenic lower urinary tract dysfunction. Expanded Disability Status Scale shows no correlation. Those parameters (except post-void residual) are also associated with reduced bladder compliance, as potential risk for kidney damage. Conclusion: Therefore, bladder diary and urinary tract infection rate should be routinely assessed to identify patients who require urodynamics. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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11 pages, 1409 KiB

Open AccessArticle

Information Processing Speed Assessed with Letter Digit Substitution Test in Croatian Sample of Multiple Sclerosis Patients

by Ana Jerković, Meri Matijaca, Ana Proroković, Anđela Šikić, Vana Košta, Ana Ćurković Katić, Krešimir Dolić, Klaudia Duka Glavor, Joško Šoda, Zoran Đogaš and Maja Rogić Vidaković

Diagnostics 2022, 12(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12010111 - 04 Jan 2022

Cited by 5 | Viewed by 1967

Abstract

Cognitive impairment is a common complaint in people with multiple sclerosis (pwMS). The study objective was to determine the psychometric properties of the letter digit substitution test (LDST) that measures information processing speed and to investigate the impact of relevant predictors of LDST achievement in pwMS. The design was cross-sectional. The study included 87 pwMS and 154 control subjects. The validity of LDST was examined, and a hierarchical regression model was used to explore relevant predictors of LDST success. The LDST had excellent construct validity, as expressed by differences between pwMS and control subjects. Convergent validity of the LDST was supported by a significant moderate correlation with the expanded disability status scale (EDSS) (ρ = −0.36; p < 0.05) and a significantly strong correlation with the multiple sclerosis impact scale (MSIS-29) physical subscale (r = −0.64; p < 0.01). The LDTS score well differentiated the pwMS considering age, education, EDSS, disease duration, comorbidity, and medication therapy. Using the LDST as a criterion variable in pwMS results showed consistent evidence for the age, education, and EDSS impact on LDST performance. The best cut-off score of ≤35 discriminated the control and MS group. LDST proved to be a valid test for assessing information processing speed in pwMS. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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12 pages, 2009 KiB

Open AccessArticle

Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis

by Ranjani Ganapathy Subramanian, Dana Horakova, Manuela Vaneckova, Balazs Lorincz, Jan Krasensky, Eva Kubala Havrdova and Tomas Uher

Diagnostics 2021, 11(12), 2230; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11122230 - 29 Nov 2021

Cited by 2 | Viewed by 2082

Abstract

Background: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. Aim: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Methods: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Results: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10⁻¹⁵), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10⁻¹⁵), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was −0.50% (IQR = −0.96, −0.16) and was predicted by the baseline IgM index (B = −0.37; p = 0.003). Conclusions: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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10 pages, 1760 KiB

Open AccessArticle

MRI of the Entire Spinal Cord—Worth the While or Waste of Time? A Retrospective Study of 74 Patients with Multiple Sclerosis

by Esben Nyborg Poulsen, Anna Olsson, Stefan Gustavsen, Annika Reynberg Langkilde, Annette Bang Oturai and Jonathan Frederik Carlsen

Diagnostics 2021, 11(8), 1424; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11081424 - 06 Aug 2021

Cited by 3 | Viewed by 3115

Abstract

Spinal cord lesions are included in the diagnosis of multiple sclerosis (MS), yet spinal cord MRI is not mandatory for diagnosis according to the latest revisions of the McDonald Criteria. We investigated the distribution of spinal cord lesions in MS patients and examined how it influences the fulfillment of the 2017 McDonald Criteria. Seventy-four patients with relapsing-remitting MS were examined with brain and entire spinal cord MRI. Sixty-five patients received contrast. The number and anatomical location of MS lesions were assessed along with the Expanded Disability Status Scale (EDSS). A Chi-square test, Fischer’s exact test, and one-sided McNemar’s test were used to test distributions. MS lesions were distributed throughout the spinal cord. Diagnosis of dissemination in space (DIS) was increased from 58/74 (78.4%) to 67/74 (90.5%) when adding cervical spinal cord MRI to brain MRI alone (p = 0.004). Diagnosis of dissemination in time (DIT) was not significantly increased when adding entire spinal cord MRI to brain MRI alone (p = 0.04). There was no association between the number of spinal cord lesions and the EDSS score (p = 0.71). MS lesions are present throughout the spinal cord, and spinal cord MRI may play an important role in the diagnosis and follow-up of MS patients. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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9 pages, 1797 KiB

Open AccessArticle

Kinesiophobia in Stroke Patients, Multiple Sclerosis and Parkinson’s Disesase

by Dagmara Wasiuk-Zowada, Andrzej Knapik, Justyna Szefler-Derela, Anna Brzęk and Ewa Krzystanek

Diagnostics 2021, 11(5), 796; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11050796 - 28 Apr 2021

Cited by 10 | Viewed by 2895

Abstract

Background: Stroke (S), multiple sclerosis (MS), Parkinson’s disease (PD) are chronic neurological diseases that are a challange for public health and represent a real social problem. Physical activity (PA) improves functional performance, reduces various symptoms in PD and MS, in stroke- reduced neurological impairment of patients and provides a chance for independence. One of the main obstacles in successful rehabilitation is patients’ movement passivity. The reason might be the psychological aspects, in particular fear of movement—kinesiophobia. Aim: To determine how many patients with S, MS, and PD suffer from kinsiophobia and what factors influence this process. Methods: Fifty patients after stroke, eighty one MS patients and sixty one PD patients were consecutively recruited from hospital and outpatients clinics. The sociodemographic data, self- assesment of fitness, Visual Analogue Scale (VAS) for pain, Tampa Scale of Kinesiophobia (TSK) and The Modified Baecke Questionnarie for Older Adults for physical activity were collected. A score >37 was considered to indicate a high level of kinesiophobia according to the TSK. Results: High level of kinesiophobia was shown in 66.67% of the subjects. TSK medians in particular illnesses were above the cut-off score and amounted: S—42.50 points; MS—38 points; PD—42.00 points. Regression showed 15% of fluctuation of variance (R2 = 0.1498; p < 0.0001), where regression factor showed: for mobility self-assessment: b = −0.2137 and for the age b = 0.0065. Conclusions: Kinesiophobia among the patients suffering from S, MS and PD concerns most of the subjects. Predictors of kinesiophobia are: limitations connected with functioning and age. The meaning of kinesiophobia in neurological disorders requires further research. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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14 pages, 5345 KiB

Open AccessArticle

Assessment of ¹⁸F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis

by Valerie L. Jewells, Hong Yuan, Joseph R. Merrill, Jonathan E. Frank, Akhil Patel, Stephanie M. Cohen, Ben Giglio, Nana Nikolaishvili Feinberg, Glenn K. Matsushima and Zibo Li

Diagnostics 2021, 11(5), 786; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11050786 - 27 Apr 2021

Cited by 2 | Viewed by 1957

Abstract

The study aims to assess site assessment of the performance of ¹⁸F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). ¹⁸F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of ¹⁸F-PBR-111 PET in preclinical MS research and future animal and future human applications. ¹⁸F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. ¹⁸F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant ¹⁸F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High ¹⁸F-PBR-111 uptake regions correlated with microglial/macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. ¹⁸F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that ¹⁸F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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17 pages, 26451 KiB

Open AccessArticle

Contribution of Gray Matter Atrophy and White Matter Damage to Cognitive Impairment in Mildly Disabled Relapsing-Remitting Multiple Sclerosis Patients

by Ángela Bernabéu-Sanz, Sandra Morales, Valery Naranjo and Ángel P. Sempere

Diagnostics 2021, 11(3), 578; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11030578 - 23 Mar 2021

Cited by 6 | Viewed by 2845

Abstract

Cognitive impairment (CI) is frequently present in multiple sclerosis patients. Despite ongoing research, the neurological substrates have not been fully elucidated. In this study we investigated the contribution of gray and white matter in the CI observed in mildly disabled relapsing-remitting multiple sclerosis (RRMS) patients. For that purpose, 30 patients with RRMS (median EDSS = 2), and 30 age- and sex-matched healthy controls were studied. CI was assessed using the symbol digit modalities test (SDMT) and the memory alteration test. Brain magnetic resonance imaging, diffusion tensor imaging (DTI), voxel-based morphometry (VBM), brain segmentation, thalamic vertex analysis, and connectivity-based thalamic parcellation analyses were performed. RRMS patients scored significantly lower in both cognitive tests. In the patient group, significant atrophy in the thalami was observed. Multiple regression analyses revealed associations between SDMT scores and GM volume in both hemispheres in the temporal, parietal, frontal, and occipital lobes. The DTI results pointed to white matter damage in all thalamocortical connections, the corpus callosum, and several fasciculi. Multiple regression and correlation analyses suggested that in RRMS patients with mild disease, thalamic atrophy and thalamocortical connection damage may lead to slower cognitive processing. Furthermore, white matter damage at specific fasciculi may be related to episodic memory impairment. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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13 pages, 3791 KiB

Open AccessArticle

Social Cognition in Multiple Sclerosis: A 3-Year Follow-Up MRI and Behavioral Study

by Stefano Ziccardi, Marco Pitteri, Helen M. Genova and Massimiliano Calabrese

Diagnostics 2021, 11(3), 484; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11030484 - 09 Mar 2021

Cited by 13 | Viewed by 2970

Abstract

Social cognition (SC) has become a topic of widespread interest in the last decade. SC deficits were described in multiple sclerosis (MS) patients, in association with amygdala lesions, even in those without formal cognitive impairment. In this 3-year follow-up study, we aimed at longitudinally investigating the evolution of SC deficits and amygdala damage in a group of cognitive-normal MS patients, and the association between SC and psychological well-being. After 3 years (T3) from the baseline examination (T0), 26 relapsing-remitting MS patients (RRMS) were retested with a neuropsychological battery and SC tasks (theory of mind, facial emotion recognition, empathy). A SC composite score (SCcomp) was calculated for each patient. Emotional state, fatigue, and quality of life (QoL) were also evaluated. RRMS patients at T3 underwent a 3T-MRI as performed at T0, from which were calculated both volume and cortical lesion volume (CLV) of the amygdalae. Compared to T0, at T3 all RRMS patients were still cognitive-normal and remained stable in their global SC impaired performance. At T0, SCcomp correlated with amygdala CLV (p = 0.002) while, at T3, was more associated with amygdala volume (p = 0.035) rather than amygdala CLV (p = 0.043). SCcomp change T3-T0 correlated with global emotional state (p = 0.043), depression (p = 0.046), anxiety (p = 0.034), fatigue (p = 0.025), and QoL-social functioning (p = 0.033). We showed the longitudinal stability of SC deficits in cognitive-normal RRMS patients, mirroring the amygdala structural damage and the psychological well-being. These results highlight that SC exerts a key role in MS. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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13 pages, 1620 KiB

Open AccessArticle

Isolated Cognitive Decline in Neurologically Stable Patients with Multiple Sclerosis

by Jiri Motyl, Lucie Friedova, Manuela Vaneckova, Jan Krasensky, Balazs Lorincz, Jana Blahova Dusankova, Michaela Andelova, Tom A. Fuchs, Eva Kubala Havrdova, Ralph H. B. Benedict, Dana Horakova and Tomas Uher

Diagnostics 2021, 11(3), 464; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11030464 - 07 Mar 2021

Cited by 10 | Viewed by 4914

Abstract

(1) Background: Cognitive deterioration is an important marker of disease activity in multiple sclerosis (MS). It is vital to detect cognitive decline as soon as possible. Cognitive deterioration can take the form of isolated cognitive decline (ICD) with no other clinical signs of disease progression present. (2) Methods: We investigated 1091 MS patients from the longitudinal GQ (Grant Quantitative) study, assessing their radiological, neurological, and neuropsychological data. Additionally, the confirmatory analysis was conducted. Clinical disease activity was defined as the presence of new relapse or disability worsening. MRI activity was defined as the presence of new or enlarged T2 lesions on brain MRI. (3) Results: Overall, 6.4% of patients experienced cognitive decline and 4.0% experienced ICD without corresponding clinical activity. The vast majority of cognitively worsening patients showed concomitant progression in other neurological and radiologic measures. There were no differences in disease severity between completely stable patients and cognitively worsening patients but with normal cognition at baseline. (4) Conclusions: Only a small proportion of MS patients experience ICD over short-term follow-up. Patients with severe MS are more prone to cognitive decline; however, patients with normal cognitive performance and mild MS might benefit from the early detection of cognitive decline the most. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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16 pages, 1647 KiB

Open AccessArticle

Measuring Aqueduct of Sylvius Cerebrospinal Fluid Flow in Multiple Sclerosis Using Different Software

by Maria Marcella Laganà, Dejan Jakimovski, Niels Bergsland, Michael G. Dwyer, Francesca Baglio and Robert Zivadinov

Diagnostics 2021, 11(2), 325; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11020325 - 17 Feb 2021

Cited by 1 | Viewed by 2823

Abstract

Aqueduct of Sylvius (AoS) cerebrospinal fluid flow can be quantified using phase-contrast (PC) Magnetic Resonance Imaging. The software used for AoS segmentation might affect the PC-derived measures. We analyzed AoS PC data of 30 people with multiple sclerosis and 19 normal controls using three software packages, and estimated cross-sectional area (CSA), average and highest AoS velocity (Vmean and Vmax), flow rate and volume. Our aims were to assess the repeatability and reproducibility of each PC-derived measure obtained with the various software packages, including in terms of group differentiation. All the variables had good repeatability, except the average Vmean, flow rate and volume obtained with one software package. Substantial to perfect agreement was seen when evaluating the overlap between the AoS segmentations obtained with different software packages. No variable was significantly different between software packages, with the exception of Vmean diastolic peak and CSA. Vmax diastolic peak differentiated groups, regardless of the software package. In conclusion, a clinical study should preliminarily evaluate the repeatability in order to interpret its findings. Vmax seemed to be a repeatable and reproducible measure, since the pixel with its value is usually located in the center of the AoS, and is thus unlikely be affected by ROI size. Full article

(This article belongs to the Special Issue Multiple Sclerosis Diagnostics)

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