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Background: Early diagnosis and treatment of patients with multiple sclerosis (MS) are associated with better outcomes; however, diagnostic delays remain a major problem. Objective: Describe the prevalence, determinants and consequences of delayed diagnoses. Methods: This single-centre ambispective study analysed 146 adult relapsing-remitting MS patients (2016–2021) for frequency and determinants of diagnostic delays and their associations with clinical, cognitive, imaging and biochemical measures. Results: Diagnostic delays were identified in 77 patients (52.7%), including 42 (28.7%) physician-dependent cases and 35 (24.0%) patient-dependent cases. Diagnosis was delayed in 22 (15.1%) patients because of misdiagnosis by a neurologist. A longer diagnostic delay was associated with trends towards greater Expanded Disability Status Scale (EDSS) scores (B = 0.03; p = 0.034) and greater z -score of the blood neurofilament light chain (B = 0.35; p = 0.031) at the time of diagnosis. Compared with patients diagnosed at their first clinical relapse, patients with a history of >1 relapse at diagnosis (n = 63; 43.2%) had a trend towards greater EDSS scores (B = 0.06; p = 0.006) and number of total (B = 0.13; p = 0.040) and periventricular (B = 0.06; p = 0.039) brain lesions. Conclusion: Diagnostic delays in MS are common, often determined by early misdiagnosis and associated with greater disease burden. [ABSTRACT FROM AUTHOR]

Background and purpose: The effect of pregnancy on brain changes and radiological disease activity in women with multiple sclerosis (MS) is not well understood. This study was undertaken to describe the dynamics of lesion activity and brain volume changes during the pregnancy and postpartum periods. Methods: This observational study of 62 women with relapsing–remitting MS included magnetic resonance imaging (221 scans) as well as clinical visits at baseline (<24 and >6 months before pregnancy), prepregnancy (<6 months before pregnancy), postpartum (<3 months after delivery), and follow‐up (>12 and <24 months after delivery) periods. Results: The majority of women had a mild disability and a short disease duration (median = 5.5 years). Eighteen (29.0%) women had a relapse during the year preceding pregnancy onset, nine (14.5%) during pregnancy, and 20 (32.3%) in the year following delivery. Disability status remained unchanged during follow‐up. Women in the postpartum period (n = 62) had higher T2 lesion volume (median = 1.18 ml vs. 0.94 ml), greater annualized T2 lesion volume increase (0.23 ml vs. 0.0 ml), lower brain parenchymal fraction (85.6% vs. 86.4%), and greater annualized brain volume loss (‐1.74% vs. ‐0.16%) compared with the prepregnancy period (all p < 0.001). At 12–24 months after delivery, women (n = 41) had higher T2 lesion volume (1.16 ml vs. 1.0 ml) and lower brain parenchymal fraction (86.0% vs. 86.5%) compared to the prepregnancy period (both p < 0.001). Conclusions: The postpartum period was associated with an increase in T2 lesion volume and accelerated brain volume loss in a considerable proportion of women. This should be considered in treatment decision‐making and designing clinical trials. [ABSTRACT FROM AUTHOR]

Background: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. Objective: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. Methods: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). Results: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36%; 95% CI = [−0.60, −0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). Conclusion: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information. [ABSTRACT FROM AUTHOR]

Background and Purpose: A high variability of brain MRI volume change measurement renders challenging its interpretation in multiple sclerosis (MS). Occurrence and clinical relevance of observed apparent brain volume increase (BVI) in MS patients have not been investigated yet. The objective was to quantify the prevalence and factors associated with BVI.Methods: We examined 366 MS patients (2,317 scans) and 44 controls (132 scans). Volumetric analysis of brain volume changes was performed by SIENA and ScanView. BVI was defined as brain volume change >0%. We compared characteristics of patients with and without BVI.Results: BVI was found in 26.3% (from 1,951) longitudinal scans (SIENA). If BVI occurred, a probability that BVI will be repeated consecutively more than or equal to two times was 15.9%. The repeated BVI was associated with clinical disease activity in 50% of cases. BVI was associated with shorter time and lower T2 lesion volume increase between two MRI scans, and higher normalized brain volume (all P < .0001). A proportion of scans with BVI was higher when analyzed by ScanView (35.3%) and in controls (36.4% by SIENA).Conclusions: BVI occurs in a great proportion of MR scans over short-term follow-up and is not associated with disease stabilization. Although BVI can be caused by several factors, the results indicate that measurement error may contribute to BVI in the majority of cases. Clinicians should be aware of the frequent occurrence of apparent BVI, interpret brain volume changes in MS patients with great caution, and use methods with precise quantification of brain volume changes. [ABSTRACT FROM AUTHOR]

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene (HLA DRB1)*1501, anti-Epstein–Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient (p < 0.001), CSF CD80+ (p = 0.012), and CD80+ CD19+ (p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels (p = 0.0026). Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI. [ABSTRACT FROM AUTHOR]

Background: Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury. There is a lack of studies investigating the dynamics of relationships between sNfL levels and radiological disease activity over long-term follow-up in multiple sclerosis (MS). Objectives: To investigate the relationship among repeated measures of sNfL, lesion burden accumulation, brain volume loss and clinical measures. Methods: We investigated 172 patients in the early stages of MS (McDonald 2017 criteria). Clinical exams were performed every 3 months and brain magnetic resonance imaging (MRI) scans were collected annually over 48 months. sNfL levels were measured in serum by Simoa assay at the time of treatment initiation and then annually over 36 months. Results: In repeated-measures analysis, considering all time points, we found a strong relationship between percentage changes of sNfL and lesion burden accumulation assessed by T1 lesion volume (p < 0.001) and T2 lesion number (p < 0.001). There was no relationship between percentage changes of sNfL and brain volume loss over 36 months (p > 0.1). Early sNfL levels were associated with delayed brain volume loss after 48 months (p < 0.001). Patients with No Evidence of Disease Activity (NEDA-3) status showed lower sNfL levels compared with active MS patients. Conclusions: sNfL is associated with ongoing neuroinflammation and predictive of future neurodegeneration in early MS. [ABSTRACT FROM AUTHOR]

Background: Volumetric MRI surrogate markers of disease progression are lacking. Objective: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients. Methods: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients. Results: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (−0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%−49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability. Conclusion: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients. [ABSTRACT FROM AUTHOR]

Introduction: Fabry disease (FD) can be undiagnosed in the context of multiple sclerosis (MS) due to similar clinical and paraclinical features. Our study aimed to determine the prevalence (and the necessity of screening) of FD among patients with possible or definite MS. Methods: In this prospective monocentric observational study, we included consecutive patients enrolled between May 2017 and May 2019 after the first clinical event suggestive of MS. All patients underwent FD screening using dried blood spots in a stepwise manner combining genetic and enzyme testing. Patients were followed until May 2022. Results: We included 160 patients (73.1% female, mean age 33.9 years). The 2017 revised McDonald's criteria for definite MS were fulfilled by 74 (46.3%) patients at the time of study recruitment and 89 (55.6%) patients after 3–5 years of follow-up. None of the patients had a pathogenic GLA variant, and four (2.5%) had a variant of unknown significance (p.A143T, p.S126G, 2 × p.D313Y). In two of these patients, the intrathecal synthesis of oligoclonal bands was absent, and none had hyperproteinorachia or pleocytosis in cerebrospinal fluid. Detailed examination of FD organ manifestations revealed only discrete ocular and kidney involvement in two patients. Conclusion: The prevalence of FD in the population of suspected or definite MS patients does not appear to be high. Our results do not support routine FD screening in all patients with a possible diagnosis of MS, but there is an urgent need to search for red flags and include FD in the differential diagnosis of MS. [ABSTRACT FROM AUTHOR]

Background and Purpose: A relatively high intraindividual variability of longitudinal magnetic resonance imaging (MRI) of brain volume loss (BVL) measurements over time renders challenging its application to individual multiple sclerosis (MS) patients. Objective of this study was to investigate if high-frequency brain MRI monitoring affects identification of pathological BVL in an individual patient.Methods: One hundred fifty-seven relapsing-remitting MS patients had seven MRI scans over 12 months follow-up. All 1,585 MRI scans were performed on the same 1.5T scanner using an identical scanning protocol. Volumetric analysis was performed by ScanView and SIENA software. Linear regression analysis was used for estimation of annualized BVL, with a cutoff greater than .4% defined as pathological. We compared proportions of patients with pathological BVL obtained by analysis of different number of MRI time-points.Results: An analysis of seven MRI scans (months 0, 2, 4, 6, 8, 10, and 12) showed pathological BVL in 105 (65%) of patients. When three MRI scans were included (months 0, 6, and 12), we found 10 (6.4%) false negative and 9 (5.7%) false positive results compared with the analysis of seven MRI scans, used as a reference for assessment of pathological BVL. Analysis of two MRI time-points (months 0 and 12) showed 10 (6.4%) false negative and 13 (8.3%) false positive results compared with analysis of seven MRI time-points. Change in the accuracy of pathological BVL between results obtained by analysis of seven and two time-points was 14.7%.Conclusions: High-frequency MRI monitoring may have a considerable effect on improving the precision of precisely identifying pathological BVL in individual patients. However, limitations in translation to clinical practice remain. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate whether the strength of the association between magnetic resonance imaging (MRI) metrics and cognitive outcomes differs between various multiple sclerosis subpopulations. Methods: A total of 1052 patients were included in this large cross‐sectional study. Brain MRI (T1 and T2 lesion volume and brain parenchymal fraction) and neuropsychological assessment (Brief International Cognitive Assessment for Multiple Sclerosis and Paced Auditory Serial Addition Test) were performed. Results: Weak correlations between cognitive domains and MRI measures were observed in younger patients (age≤30 years; absolute Spearman's rho = 0.05–0.21), with short disease duration (<2 years; rho = 0.01–0.21), low Expanded Disability Status Scale [EDSS] (≤1.5; rho = 0.08–0.18), low T2 lesion volume (lowest quartile; <0.59 mL; rho = 0.01–0.20), and high brain parenchymal fraction (highest quartile; >86.66; rho = 0.01–0.16). Stronger correlations between cognitive domains and MRI measures were observed in older patients (age>50 years; rho = 0.24–0.50), with longer disease duration (>15 years; rho = 0.26–0.53), higher EDSS (≥5.0; rho = 0.23–0.39), greater T2 lesion volume (highest quartile; >5.33 mL; rho = 0.16–0.32), and lower brain parenchymal fraction (lowest quartile; <83.71; rho = 0.13–0.46). The majority of these observed results were confirmed by significant interactions (P ≤ 0.01) using continuous variables. Interpretation: The association between structural brain damage and functional cognitive impairment is substantially weaker in multiple sclerosis patients with a low disease burden. Therefore, disease stage should be taken into consideration when interpreting associations between structural and cognitive measures in clinical trials, research studies, and clinical practice. [ABSTRACT FROM AUTHOR]

Background and Purpose: Lesion burden and brain volume changes are frequent end points in research but nowadays are becoming important in the clinical practice of multiple sclerosis (MS). The objective of this study was to investigate the correlation between magnetic resonance imaging (MRI) measures obtained by in-house developed ScanView software and commonly used volumetric techniques for assessment of T2 lesion and whole brain volumes and their changes.Methods: Together 3,340 MRI scans from 209 patients after first demyelinating event suggestive of MS, 181 relapsing-remitting MS patients and 43 controls were analyzed. The average number of MRI scans and follow-up duration was 8.2 and 6.5 years, respectively. All MRI scans were performed in a single center but independently analyzed in two neuroimaging centers. Volumetric analysis by ScanView software was applied in Prague. Commonly used techniques, such as SIENA, SIENAX, and Jim software, were applied in Buffalo. Correlations between MRI measures were evaluated using correlation coefficients. Intraindividual variability of longitudinal MRI data was estimated by mean squared error.Results: The associations of the cross-sectional and longitudinal MRI measures between commonly used techniques and ScanView were significant (r/rho = .83-.95). The associations of cross-sectional MRI measures were stronger (r/rho = .90-.95) compared with longitudinal ones (r = .83). Standardized intraindividual variability of whole brain % volume change was greater in ScanView compared with SIENA (mean squared error .32 vs. .21; P < .001).Conclusions: We found relatively strong correlations of cross-sectional and longitudinal data obtained by both techniques. However, SIENA showed lower intraindividual variability than the ScanView method in measuring whole brain volume loss over time. [ABSTRACT FROM AUTHOR]

Background: No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity. Objectives: To investigate the persistence of NEDA status over long-term follow-up in MS patients treated with weekly intramuscular interferon beta-1a. Methods: We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients. Results: NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR) = 2.3–4.0; p = 0.005–0.03) over 6 years. Conclusions: Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow-up; however, specificity for individual patient was low. [ABSTRACT FROM AUTHOR]

Background: Disease progression and treatment efficacy vary among individuals with multiple sclerosis. Reliable predictors of individual disease outcomes are lacking. Objective: To examine the accuracy of the early prediction of 12-year disability outcomes using clinical and magnetic resonance imaging (MRI) parameters. Methods: A total of 177 patients from the original Avonex-Steroids-Azathioprine study were included. Participants underwent 3-month clinical follow-ups. Cox models were used to model the associations between clinical and MRI markers at baseline or after 12 months with sustained disability progression (SDP) over the 12-year observation period. Results: At baseline, T2 lesion number, T1 and T2 lesion volumes, corpus callosum (CC), and thalamic fraction were the best predictors of SDP (hazard ratio (HR) = 1.7–4.6; p ⩽ 0.001–0.012). At 12 months, Expanded Disability Status Scale (EDSS) and its change, number of new or enlarging T2 lesions, and CC volume % change were the best predictors of SDP over the follow-up (HR = 1.7–3.5; p ⩽ 0.001–0.017). A composite score was generated from a subset of the best predictors of SDP. Scores of ⩾4 had greater specificity (90%–100%) and were associated with greater cumulative risk of SDP (HR = 3.2–21.6; p < 0.001) compared to the individual predictors. Conclusion: The combination of established MRI and clinical indices with MRI volumetric predictors improves the prediction of SDP over long-term follow-up and may provide valuable information for therapeutic decisions. [ABSTRACT FROM AUTHOR]

Background: We explored the evolution of brain atrophy in relation to development of confirmed disability progression (CDP) on serial 1.5T magnetic resonance imaging (MRI) scans over a 10-year period in 181 patients with early relapsing–remitting multiple sclerosis (RRMS). Methods: At 10-year follow-up, they were divided into those with (100) or without (76) CDP (confirmed after 48 weeks). Changes in whole brain (WB), cortical, gray matter (GM), white matter, and ventricular cerebrospinal fluid (vCSF) volumes were calculated on three-dimensional T1-weighted (3D-T1) scans between all available time points. Results: In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, −7.5% vs −5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, −7.7% vs −6.2%, p = 0.001), and GM (d = 0.40, −7.1% vs −5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes. Conclusions: WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years. [ABSTRACT FROM AUTHOR]

Background: The utility of blood--brain barrier (BBB) biomarkers for clinical and magnetic resonance imaging progression in multiple sclerosis (MS) has not been extensively investigated. Objectives: To determine whether cerebrospinal fluid (CSF) measures of BBB at clinical onset predict radiological and clinical deterioration over 48 months. Methods: This longitudinal study included 182 patients after first clinical event suggestive of MS treated with weekly intramuscular interferon beta-1a. CSF and serum samples were analyzed for leukocytes, total protein, albumin, immunoglobulins, and oligoclonal bands. Optimal thresholds for the albumin quotient (QAlb) were determined. Mixed-effect model analyses, adjusted for age, gender, and treatment escalation, were used to analyze relationship between CSF measures and disease activity outcomes over 48 months of follow-up. Results: Increased QAlb at clinical onset was associated with enlargement of lateral ventricles (p = .001) and greater whole brain (p = .003), white matter (p < .001), corpus callosum (p < .001), and thalamus (p = .003) volume loss over 48 months. Higher QAlb was associated with higher Expanded Disability Status Scale score over 48 months (p = .002). Conclusions: Increased QAlb at clinical onset is associated with increased brain atrophy and greater disability in patients after first clinical event suggestive of MS. [ABSTRACT FROM AUTHOR]

In this prospective longitudinal study, we quantified regional brain volume and susceptibility changes during the first two years after the diagnosis of multiple sclerosis (MS) and identified their association with cerebrospinal fluid (CSF) markers at baseline. Seventy patients underwent MRI (T1 and susceptibility weighted images processed to quantitative susceptibility maps, QSM) with neurological examination at the diagnosis and after two years. In CSF obtained at baseline, the levels of oxidative stress, products of lipid peroxidation, and neurofilaments light chain (NfL) were determined. Brain volumetry and QSM were compared with a group of 58 healthy controls. In MS patients, regional atrophy was identified in the striatum, thalamus, and substantia nigra. Magnetic susceptibility increased in the striatum, globus pallidus, and dentate and decreased in the thalamus. Compared to controls, MS patients developed greater atrophy of the thalamus, and a greater increase in susceptibility in the caudate, putamen, globus pallidus and a decrease in the thalamus. Of the multiple calculated correlations, only the decrease in brain parenchymal fraction, total white matter, and thalamic volume in MS patients negatively correlated with increased NfL in CSF. Additionally, negative correlation was found between QSM value in the substantia nigra and peroxiredoxin-2, and QSM value in the dentate and lipid peroxidation levels. [ABSTRACT FROM AUTHOR]

Background Repeated administration of Paced Auditory Serial Addition Test (PASAT) results in a considerable learning effect in short- or long-term follow-up studies. However, the relationship between PASAT learning and changes in magnetic resonance imaging (MRI) parameters is yet to be investigated. Objectives The aim of this study is to determine if change in brain MRI metrics predicts evolution of PASAT in high functioning clinically isolated syndrome (CIS) patients on disease-modifying treatment (DMT). Methods This prospective 48-month observational study examined 128 CIS patients treated with 30 μg of intramuscular interferon beta-1a once a week. The correlation between PASAT and MRI measures was assessed at baseline, at 6 months and then annually over the 48-month follow up. Linear mixed model analysis adjusted for age, gender, education and DMT was used to model the temporal association between MRI measures and PASAT performance. Results MRI revealed 2.5% gray matter (GM) volume loss and 4.3 point increase in PASAT score over 48 months. MS patients evidenced significantly greater PASAT score absolute change, had lower loss of GM volume ( p = .008) but not significant change in cortical ( p = .061), white matter ( p = .086) or whole brain volumes ( p = .879). Conclusions The present study reveals a significant relationship between higher PASAT learning effect and less GM atrophy in CIS patients on DMT. These findings suggest that change in PASAT associated more with GM than WM pathology, and that treatment strategies oriented toward GM volume preservation may play an important role in prevention of cognitive deterioration in CIS patients. [ABSTRACT FROM AUTHOR]

Cognitive impairment (CI) may occur in clinically isolated syndrome (CIS) patients. While the relationship between CI and magnetic resonance imaging (MRI) has been investigated extensively in multiple sclerosis (MS), MRI correlates of CI in CIS patients are unknown. To investigate the evolution of CI and to determine brain MRI structural correlates associated with CI in CIS patients. This prospective 24-month observational study examined 81 CIS patients treated with 30 µg of intramuscular interferon beta 1a once a week. MRI acquisition and neuropsychological (NP) assessment were performed at baseline, 6, 12 and 24 months. Participants were tested with Czech-validated version of Minimal Assessment of Cognitive Function in MS battery and MRI measures of lesion activity and burden, and global, tissue-specific and regional brain atrophy were performed. Over 24 months, 36 CIS patients developed clinically definite MS (CDMS). CI was observed in 10 (12.3 %) CIS patients at baseline and at the 24 months follow-up. Eight CIS patients changed their CI status over the follow-up (four improved and four worsened). No significant difference in development of CI was detected between stable CIS patients and those who developed CDMS. In multivariate regression and mixed-effect model analyses, no significant relationship was found between NP and MRI parameters. The lack of significant relationship between MRI metrics and cognition in this group of CIS patients could be attributed to several factors including the cognitive reserve, effect of disease-modifying therapy and relatively short follow-up period. [ABSTRACT FROM AUTHOR]

There is evidence that neuropathic pain component in low back pain (LBP) patients is associated with higher ratings of comorbidities such as depression and anxiety disorders. In line with current findings, the purpose of this clinical study is to examine a hypothesis regarding a relationship of neuropathic pain component, depression, and other psychopathological symptoms in a specific group of LBP patients with sciatica pain. With respect to findings that depression is related to inflammatory changes, and inflammatory mediators may play a role in neuropathic pain generation, we have assessed also serum C-reactive protein (CRP). Results of the present study show that increased neuropathic pain component in sciatica patients is associated with elevated levels of depression, anxiety, alexithymia, and serum CRP levels. In conclusion, results of this study indicate that CRP levels in sciatica patients are closely associated with neuropathic pain. [ABSTRACT FROM AUTHOR]

Abstract: Recent findings document numerous interactions between neuronal and glial systems that likely play a role in the pathophysiology of depression. These findings suggest that glia-derived neurotrophic protein S100B may play a significant role in developing depression. To test the relationship between S100B and depressive symptoms we designed cross-sectional clinical study including S100B serum and CSF levels in neurological patients with non-inflammatory disorders (NIND), who undergone cerebrospinal fluid assessment for diagnostic purposes. The present study was focused on psychometric testing of depression (BDI-II), anxiety (SAS) and alexithymia (TAS-20), and neurochemical measure of cerebrospinal fluid (CSF) and serum levels of S100B in 40 NIND inpatients [mean age 41.67]. The main result shows that S100B in CSF is significantly negatively correlated with BDI-II (Spearman R =−0.51, p <0.0009) but not with SAS and TAS-20. The finding indicates that decreased level of S100B in CSF is related to increased symptoms of depression in the NIND patients. [Copyright &y& Elsevier]

Summary: Several recent findings indicate that various interactions between nervous and immune system are important in the pathophysiology of alexithymia. These findings show that a significant role in developing alexithymia may play proinflammatory cytokines. Recent data also indicate that negative emotions related to depressive symptoms and anxiety are related to disturbed levels of interleukin-8 (IL-8). These findings suggest that IL-8 could present also useful immunological marker related to emotional dysregulation in alexithymia. In the present study we have performed psychometric measurement of alexithymia (TAS-20), depression (BDI-II) and anxiety (SAS), and immunochemical measure of cerebrospinal fluid (CSF) and serum levels of IL-8 in 33 inpatients with non-inflammatory neurological disorders (NIND) (mean age 38.8±12.5). The results show that IL-8 in CSF is significantly correlated with TAS-20 (Spearman R =0.46, p =0.007) and SAS (Spearman R =0.44, p =0.009) but not to BDI-II. The findings of the present study indicate that increased level of IL-8 (in CSF) may be related to symptoms of alexithymia and anxiety in patients with NIND. [ABSTRACT FROM AUTHOR]

Oxidative stress has been implied in cellular injury even in the early phases of multiple sclerosis (MS). In this study, we quantified levels of biomarkers of oxidative stress and antioxidant capacity in cerebrospinal fluid (CSF) in newly diagnosed MS patients and their associations with brain atrophy and iron deposits in the brain tissue. Consecutive treatment-naive adult MS patients (n = 103) underwent brain MRI and CSF sampling. Healthy controls (HC, n = 99) had brain MRI. CSF controls (n = 45) consisted of patients with non-neuroinflammatory conditions. 3T MR included isotropic T1 weighted (MPRAGE) and gradient echo (GRE) images that were processed to quantitative susceptibility maps. The volume and magnetic susceptibility of deep gray matter (DGM) structures were calculated. The levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-iso prostaglandin F2α (8-isoPG), neutrophil gelatinase-associated lipocalin (NGAL), peroxiredoxin-2 (PRDX2), and malondialdehyde and hydroxyalkenals (MDA + HAE) were measured in CSF. Compared to controls, MS patients had lower volumes of thalamus, pulvinar, and putamen, higher susceptibility in caudate nucleus and globus pallidus, and higher levels of 8-OHdG, PRDX2, and MDA + HAE. In MS patients, the level of NGAL correlated negatively with volume and susceptibility in the dentate nucleus. The level of 8-OHdG correlated negatively with susceptibility in the caudate, putamen, and the red nucleus. The level of PRDX2 correlated negatively with the volume of the thalamus and both with volume and susceptibility of the dentate nucleus. From MRI parameters with significant differences between MS and HC groups, only caudate susceptibility and thalamic volume were significantly associated with CSF parameters. Our study shows that increased oxidative stress in CSF detected in newly diagnosed MS patients suggests its role in the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Objectives: Microstructural characterization of patients with multiple sclerosis (MS) has been shown to correlate better with disability compared to conventional radiological biomarkers. Quantitative MRI provides effective means to characterize microstructural brain tissue changes both in lesions and normal-appearing brain tissue. However, the impact of the location of microstructural alterations in terms of neuronal pathways has not been thoroughly explored so far. Here, we study the extent and the location of tissue changes probed using quantitative MRI along white matter (WM) tracts extracted from a connectivity atlas. Methods: We quantified voxel-wise T1 tissue alterations compared to normative values in a cohort of 99 MS patients. For each WM tract, we extracted metrics reflecting tissue alterations both in lesions and normal-appearing WM and correlated these with cross-sectional disability and disability evolution after 2 years. Results: In early MS patients, T1 alterations in normal-appearing WM correlated better with disability evolution compared to cross-sectional disability. Further, the presence of lesions in supratentorial tracts was more strongly associated with cross-sectional disability, while microstructural alterations in infratentorial pathways yielded higher correlations with disability evolution. In progressive patients, all major WM pathways contributed similarly to explaining disability, and correlations with disability evolution were generally poor. Conclusions: We showed that microstructural changes evaluated in specific WM pathways contribute to explaining future disability in early MS, hence highlighting the potential of tract-wise analyses in monitoring disease progression. Further, the proposed technique allows to estimate WM tract-specific microstructural characteristics in clinically compatible acquisition times, without the need for advanced diffusion imaging. [ABSTRACT FROM AUTHOR]

Background:Research in telerehabilitation (TR) in neurology tends to focus on patients with low to moderate disability. For neurology patients with severe mobility limitations, TR can help to enable rehabilitation for people whose mobility limitations make it difficult for them to access rehabilitation facilities. The aim of this study is to evaluate the interest of people with neurological disability caused by multiple sclerosis (MS) in TR services. Methods:This electronic survey targeted individuals with MS, specifically those with a higher level of disability. Results:A total of 355 patients with MS (155 with severe disabilities) participated in this study. There was no difference in interest in rehabilitation between people with mild-to-moderate and severe disabilities (p = 0.1258, confidence interval [CI] = 95%). However, we found a higher interest in upper limb exercises (p = 0.0006, CI = 95%) and balance training (p = 0.0000, CI = 95%) among people with higher disability. Conclusion:The results of this study may help to improve the planning and targeting of TR interventions, where a different focus of intervention is appropriate for patients with different levels of disability. This may enable TR to be maximally tailored to patient capabilities and current greatest limitations. For example, for people with severe disabilities, it is appropriate to focus on training the upper limb function to maintain self-sufficiency and implement interventions to prevent falls. [ABSTRACT FROM AUTHOR]

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P -values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of this study was to investigate bleeding risk in patients treated with VKAs after ground-level falls, considering the type and severity of bleeding. METHODS: The study was designed as a retrospective cohort study and included a total of 204 elderly patients aged > 65 years treated for AF continuously with warfarin for more than 3 years. Data were obtained from hospital registries in Bratislava, Slovakia. A 5-year assessment of death/survival was performed to determine mortality. RESULTS: There was no statistically significant difference in severe bleeding (2.13 % with falls vs 2.55 % without, p=1) and 5-year mortality (45 % and 38 % respectively, p=0.3987) based on the presence of falls. Multivariate analysis, after adjustment for age, CHA2DS2VASc, HASBLED, stroke history, labile INR and number of falls showed that only HASBLED score was a statistically significant contributor (CI: 1.0245 - 1.0919, p=0.0007) to severe bleeding. There was statistically significant difference in severe bleeding (18 % vs 0 %, p=0.0132) between patients suffering from spontaneous and bleeding after falls and also when comparing individual bleeding episodes (12 % vs 1 %, p < 0.0001). There was no statistically significant difference in 5-year mortality between the two groups (43 % vs 42 % respectively, p=0.3931). CONCLUSIONS: Our results show that occurrence of falls in AF patients treated with VKAs have no significant impact on the incidence of severe bleeding and 5-year mortality and that spontaneous bleeding was associated with a significantly higher risk of severe bleeding compared to bleeding after falling (Tab. 4, Ref. 30). [ABSTRACT FROM AUTHOR]

Background and Purpose: White matter (WM) tract disruption impacts volume loss in connected deep gray matter (DGM) over 5 years in people with multiple sclerosis (PwMS). However, the timeline of this phenomenon remains poorly characterized. Materials and Methods: Annual serial MRI for 181 PwMS was retrospectively analyzed from a 10-year clinical trial database. Annualized thalamic atrophy, DGM atrophy, and disruption of connected WM tracts were measured. For time series analysis, ~700 epochs were collated using a sliding 5-year window, and regression models predicting 1-year atrophy were applied to characterize the influence of new tract disruption from preceding years, while controlling for whole brain atrophy and other relevant factors. Results: Disruptions of WM tracts connected to the thalamus were significantly associated with thalamic atrophy 1 year later (β: 0.048–0.103). This effect was not observed for thalamic tract disruption concurrent with the time of atrophy nor for thalamic tract disruption preceding the atrophy by 2–4 years. Similarly, disruptions of white matter tracts connected to the DGM were significantly associated with DGM atrophy 1 year later (β: 0.078–0.111), but not for tract disruption concurrent with, nor preceding the atrophy by 2–4 years. Conclusion: Increased rates of thalamic and DGM atrophy were restricted to 1 year following newly developed disruption in connected WM tracts. In research and clinical settings, additional gray matter atrophy may be expected 1 year following new lesion growth in connected white matter. [ABSTRACT FROM AUTHOR]

Background: Early infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume.Methods: We investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions.Results: We found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9-321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002).Conclusions: Diffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions. [ABSTRACT FROM AUTHOR]

Purpose: To identify the clinical and paraclinical markers of employment status in multiple sclerosis (MS). Methods: This was a cross-sectional sub-study investigating 1226 MS patients. To minimalized confounding effect, two groups of patients, matched by sex, age, and education, were selected: 307 patients with full time employment and 153 unemployed patients receiving disability pension. We explored associations between employment status and Expanded Disability Status Scale (EDSS), 25 Foot Walk Test (25FWT), Nine Hole Peg Test (9HPT), Brief International Cognitive Assessment for MS (BICAMS), Paced Auditory Serial Addition Test (PASAT), Beck Depression Inventory (BDI), SLOAN charts (SLOAN), and brain volumetric MRI measures. Results: Both groups differed significantly on all variables of interest (p < 0.001). In the univariate analyses, EDSS, SDMT (Symbol Digit Modalities Test) adjusted for BDI, 25FWT, and 9HPT best explained variability in vocational status. In multivariate analyses, the combination of EDSS, 25FWT, SDMT, BDI, and corpus callosum fraction (CCF) explained the greatest variability. As a next step, after patients were matched by EDSS, differences in SDMT, 25FWT (both p < 0.001), 9HPT, CCF, and T2 lesion volume were still present (all p < 0.005) between both groups. The best multivariate model consisted of SDMT, BDI, and T2 lesion volume. Conclusions: EDSS, walking ability, cognitive performance, and MRI volumetric parameters are independently associated with employment status. [ABSTRACT FROM AUTHOR]

Although dysarthria is a common pattern in multiple sclerosis (MS), the contribution of specific brain areas to key factors of dysarthria remains unknown. Speech data were acquired from 123 MS patients with Expanded Disability Status Scale (EDSS) ranging from 1 to 6.5 and 60 matched healthy controls. Results of computerized acoustic analyses of subtests on spastic and ataxic aspects of dysarthria were correlated with MRI-based brain volume measurements. Slow articulation rate during reading was associated with bilateral white and grey matter loss whereas reduced maximum speed during oral diadochokinesis was related to greater cerebellar involvement. Articulation rate showed similar correlation to whole brain atrophy (r = 0.46, p < 0.001) as the standard clinical scales such as EDSS (r = -0.45, p < 0.001). Our results support the critical role of the pyramidal tract and cerebellum in the modification of motor speech timing in MS. [ABSTRACT FROM AUTHOR]

Background Multiple sclerosis (MS) is frequently diagnosed in the most productive years of adulthood and is often associated with worsening employment status. However, reliable predictors of employment status change are lacking. Objective To identify early clinical and brain magnetic resonance imaging (MRI) markers of employment status worsening in MS patients at 12-year follow-up. Methods A total of 145 patients with early relapsing-remitting MS from the original Avonex-Steroids-Azathioprine (ASA) study were included in this prospective, longitudinal, observational cohort study. Cox models were conducted to identify MRI and clinical predictors (at baseline and during the first 12 months) of worsening employment status (patients either (1) working full-time or part-time with no limitations due to MS and retaining this status during the course of the study, or (2) patients working full-time or part-time with no limitations due to MS and switching to being unemployed or working part-time due to MS). Results In univariate analysis, brain parenchymal fraction, T1 and T2 lesion volume were the best MRI predictors of worsening employment status over the 12-year follow-up period. MS duration at baseline (hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.03–1.18; p  = 0.040) was the only significant clinical predictor. Having one extra milliliter of T1 lesion volume was associated with a 53% greater risk of worsening employment status (HR = 1.53, 95% CI 1.16–2.02; p  = 0.018). A brain parenchymal fraction decrease of 1% increased the risk of worsening employment status by 22% (HR = 0.78, 95% CI 0.65–0.95; p  = 0.034). Conclusion Brain atrophy and lesion load were significant predictors of worsening employment status in MS patients. Using a combination of clinical and MRI markers may improve the early prediction of an employment status change over long-term follow-up. [ABSTRACT FROM AUTHOR]

Introduction As neurodegeneration is recognized as a major contributor to disability in multiple sclerosis ( MS), brain atrophy quantification could have a high added value in clinical practice to assess treatment efficacy and disease progression, provided that it has a sufficiently low measurement error to draw meaningful conclusions for an individual patient. Method In this paper, we present an automated longitudinal method based on Jacobian integration for measuring whole-brain and gray matter atrophy based on anatomical magnetic resonance images ( MRI), named MS metrix. MS metrix is specifically designed to measure atrophy in patients with MS, by including iterative lesion segmentation and lesion filling based on FLAIR and T1-weighted MRI scans. Results MS metrix is compared with SIENA with respect to test-retest error and consistency, resulting in an average test-retest error on an MS data set of 0.13% ( MS metrix) and 0.17% ( SIENA) and a consistency error of 0.07% ( MS metrix) and 0.05% ( SIENA). On a healthy subject data set including physiological variability the test-retest is 0.19% ( MS metrix) and 0.31% ( SIENA). Conclusion Therefore, we can conclude that MS metrix could be of added value in clinical practice for the follow-up of treatment and disease progression in MS patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS leading to demyelination and axonal degeneration. An increasing body of evidence suggests that lipid metabolism is associated with adverse clinical and MRI outcomes in MS. In this review we summarize the findings of association between low-density lipoproteins (LDL), high-density lipoproteins (HDL), their apolipoproteins and oxysterols with clinical and radiological disease activity in MS. Although the causality between disease activity in MS and abnormalities in lipid metabolism has not yet been elucidated, we suggest that advances in this field of research have the potential to improve understanding of MS pathophysiology and the identification of new treatment targets and strategies. • There is a link between lipid metabolism and multiple sclerosis disease activity. • Higher HDL-C levels are associated with decreased disease activity. • Higher LDL-C levels are associated with increase disease activity. • Immunomodulatory treatment has positive effect on lipid profile in multiple sclerosis. • Causality between lipid metabolism multiple sclerosis is yet to be elucidated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

(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. [ABSTRACT FROM AUTHOR]