The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) is characterized by an increasing neurodegenerative component. Identifying biomarkers that distinguish these disease stages is crucial for early diagnosis and treatment optimization. This study aimed to compare serum levels of progranulin, interleukin-6 (IL-6), semaphorin 3A (SEMA3A), and neurofilaments between RRMS and SPMS patients and to investigate their correlation with clinical characteristics, including disability measured by the Expanded Disability Status Scale (EDSS). This observational study included 118 MS patients (63 RRMS and 55 SPMS). Serum biomarker levels were measured using an enzyme-linked immunosorbent assay (ELISA). Statistical analyses included group comparisons using non-parametric tests and correlation analyses using Pearson's correlation coefficient with multiple testing corrections. While demographic and clinical parameters significantly differed between groups (p < 0.001), biomarker levels showed no statistically significant differences (p > 0.05). However, in SPMS patients, SEMA3A correlated positively with neurofilaments (r = 0.359, p = 0.007), and progranulin correlated with IL-6 (r = 0.354, p = 0.008). No significant biomarker correlations with EDSS were found. Although absolute biomarker levels did not distinguish RRMS from SPMS, specific biomarker correlations may reflect processes relevant to disease progression and warrant further longitudinal validation.

• Klíčová slova
• functional capacity, immunity, multiple sclerosis, neuroimmunology,
• MeSH
• biologické markery krev   MeSH
• chronicko-progresivní roztroušená skleróza * krev   diagnóza   MeSH
• dospělí MeSH
• interleukin-6 krev   MeSH
• intermediární filamenta * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neurofilamentové proteiny * krev   MeSH
• prognóza MeSH
• progranuliny krev   MeSH
• progrese nemoci MeSH
• relabující-remitující roztroušená skleróza * krev   diagnóza   MeSH
• semaforin-3a * krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Názvy látek
• biologické markery MeSH
• interleukin-6 MeSH
• neurofilamentové proteiny * MeSH
• progranuliny MeSH
• SEMA3A protein, human MeSH Prohlížeč
• semaforin-3a * MeSH

PURPOSE: To estimate the timepoint of onset of the lower urinary tract symptoms (LUTS) over the course of multiple sclerosis (MS), determine which of the LUTS typically appears first, and identify risk factors for early development of LUTS in patients with MS (PwMS). METHODS: This observational study included 1167 PwMS. The participants were predominantly women (72%), median age was 45 (IQR 36;53) years, and median disease duration was 11 (IQR 6;16) years. Inclusion criteria were age over 18 years, proven MS diagnosis according to McDonald´s criteria (2017), and complete medical records since establishment of MS diagnosis. A structured in-person interview addressing the study objectives was performed during routine follow-up visit. The data were cross-checked with the medical records. RESULTS: Median LUTS-free survival time after MS diagnosis has been made, was 8 (IQR 7;10) years. Storage, voiding and postmicturition symptoms were identified as a first LUTS in 549/709 (77%), 130/709 (18%), and 30/709 (4.2%) PwMS, respectively. Most frequently reported first LUTS was urgency 360 (51%). Using multivariate analysis, higher age, higher degree of disability, and presence of cerebellar and/or pyramidal symptoms at the time of MS diagnosis were significantly associated with shorter LUTS-free survival. No significant relationship between LUTS-free survival and sex or type of MS was found. CONCLUSIONS: Our data show, that LUTS occur after median time of 8 years after MS diagnosis, with urgency being the most frequently reported first LUTS.

• Klíčová slova
• Incontinence, Lower urinary tract symptoms, Multiple sclerosis, Urgency,
• MeSH
• časové faktory MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• rizikové faktory MeSH
• roztroušená skleróza * komplikace   MeSH
• symptomy dolních močových cest * etiologie   epidemiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

Multiple sclerosis (MS) is characterized by a progressive worsening of disability over time. As many regulatory-cleared disease-modifying treatments aiming to slow down this progression are now available, a clear need has arisen for a personalized and data-driven approach to treatment optimization in order to more efficiently slow down disease progression and eventually, progressive disability worsening. This strongly depends on the availability of biomarkers that can detect and differentiate between the different forms of disease worsening, and on predictive models to estimate the disease trajectory for each patient under certain treatment conditions. To this end, we here describe a multicenter, retrospective, observational study, aimed at setting up a harmonized database to allow the development, training, optimization, and validation of such novel biomarkers and AI-based decision models. Additionally, the data will be used to develop the tools required to better monitor this progression and to generate further insights on disease worsening and progression, patient prognosis, treatment decisions and responses, and patient profiles of patients with MS.

• Klíčová slova
• AI model, biomarker, clinical trial, data, disease worsening, multiple sclerosis, observational study, real-world data,
• Publikační typ
• časopisecké články MeSH

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical. This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

• Klíčová slova
• ageing, de-escalation, discontinuation, disease-modifying therapy, multiple sclerosis, pregnancy,
• MeSH
• imunologické faktory * aplikace a dávkování   MeSH
• imunosupresiva aplikace a dávkování   MeSH
• lidé MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• imunologické faktory * MeSH
• imunosupresiva MeSH

BACKGROUND AND OBJECTIVES: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS. METHODS: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS). RESULTS: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes (B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (ΔR2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change (r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (ΔR2 = 0.064, p < 0.001). DISCUSSION: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

• MeSH
• deep learning * MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• magnetická rezonanční tomografie * MeSH
• mozek * diagnostické zobrazování   patologie   MeSH
• neurodegenerativní nemoci diagnostické zobrazování   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• roztroušená skleróza * diagnostické zobrazování   patologie   MeSH
• stárnutí * patologie   fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies.

• MeSH
• biologické markery krev   MeSH
• chronicko-progresivní roztroušená skleróza * terapie   diagnostické zobrazování   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• progrese nemoci * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH

Multiple sclerosis is a chronic, inflammatory, and neurodegenerative disease of the central nervous system and a major cause of neurological disability in young adults. Its prevalence and incidence are increasing, and it has been estimated at over 2.8 million cases worldwide, in addition to recent trends towards a shift in MS prevalence to older ages, with peak prevalence estimates in the sixth decade of life. Although historically the relapsing and progressive phases of the disease have been considered separate clinical entities, recent evidence of progression independent of relapse activity (PIRA) has led to a reconsideration of multiple sclerosis as a continuum, in which relapsing and progressive features variably coexist from the earliest stages of the disease, challenging the traditional view of the disease course. In this Series article, we provide an overview of how the traditional description of the clinical course of MS and epidemiological trends in Europe have evolved. For this purpose, we focus on the concept of PIRA, discussing its potential as the main mechanism by which patients acquire disability, how its definition varies between studies, and ongoing research in this field. We emphasise the importance of incorporating the assessment of hidden clinical manifestations into patient management to help uncover and quantify the PIRA phenomenon and the possible implications for future changes in the clinical classification of the disease. At the same time, we provide insights into overcoming the challenges of identifying and defining PIRA and adopting a new understanding of the clinical course of MS.

• Klíčová slova
• Clinical classification, Epidemiology, Multiple sclerosis, Progression idependent of relapse activity,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• optická koherentní tomografie * MeSH
• prognóza MeSH
• progrese nemoci * MeSH
• retina diagnostické zobrazování   patologie   patofyziologie   MeSH
• roztroušená skleróza * patofyziologie   diagnostické zobrazování   MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system resulting in progressive disability accumulation. As there is no cure available yet for MS, the primary therapeutic objective is to reduce relapses and to slow down disability progression as early as possible during the disease to maintain and/or improve health-related quality of life. However, optimizing treatment for people with MS (pwMS) is complex and challenging due to the many factors involved and in particular, the high degree of clinical and sub-clinical heterogeneity in disease progression among pwMS. In this paper, we discuss these many different challenges complicating treatment optimization for pwMS as well as how a shift towards a more pro-active, data-driven and personalized medicine approach could potentially improve patient outcomes for pwMS. We describe how the 'Clinical Impact through AI-assisted MS Care' (CLAIMS) project serves as a recent example of how to realize such a shift towards personalized treatment optimization for pwMS through the development of a platform that offers a holistic view of all relevant patient data and biomarkers, and then using this data to enable AI-supported prognostic modelling.

• Klíčová slova
• AI, data, diagnosis, disease progression, multiple sclerosis, personalized medicine, prognosis,
• MeSH
• biologické markery MeSH
• individualizovaná medicína * metody   trendy   MeSH
• kvalita života MeSH
• lidé MeSH
• prognóza MeSH
• progrese nemoci MeSH
• roztroušená skleróza * terapie   imunologie   MeSH
• umělá inteligence * trendy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH

BACKGROUND: Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system leading to demyelination and axonal loss. Relapsing-remitting multiple sclerosis (RRMS) is commonly treated by anti-inflammatory drugs, where one of the most effective drugs to date is the monoclonal antibody natalizumab. METHODS: The cerebrospinal fluid (CSF) proteome was analyzed in 56 patients with RRMS before and after natalizumab treatment, using label-free mass spectrometry and a subset of the changed proteins were verified by parallel reaction monitoring in a new cohort of 20 patients, confirming the majority of observed changes. RESULTS: A total of 287 differentially abundant proteins were detected including (i) the decrease of proteins with roles in immunity, such as immunoglobulin heavy constant mu, chitinase-3-like protein 1 and chitotriosidase, (ii) an increase of proteins involved in metabolism, such as lactate dehydrogenase A and B and malate-dehydrogenase cytoplasmic, and (iii) an increase of proteins associated with the central nervous system, including lactadherin and amyloid precursor protein. Comparison with the CSF-PR database provided evidence that natalizumab counters protein changes commonly observed in RRMS. Furthermore, vitamin-D binding protein and apolipoprotein 1 and 2 were unchanged during treatment with natalizumab, implying that these may be involved in disease activity unaffected by natalizumab. CONCLUSIONS: Our study revealed that some of the previously suggested biomarkers for MS were affected by the natalizumab treatment while others were not. Proteins not previously suggested as biomarkers were also found affected by the treatment. In sum, the results provide new information on how the natalizumab treatment impacts the CSF proteome of MS patients, and points towards processes affected by the treatment. These findings ought to be explored further to disclose potential novel disease mechanisms and predict treatment responses.

• MeSH
• antiflogistika terapeutické užití   MeSH
• biologické markery metabolismus   MeSH
• imunologické faktory terapeutické užití   MeSH
• lidé MeSH
• natalizumab terapeutické užití   MeSH
• proteom MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   mozkomíšní mok   MeSH
• roztroušená skleróza * farmakoterapie   mozkomíšní mok   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika MeSH
• biologické markery MeSH
• imunologické faktory MeSH
• natalizumab MeSH
• proteom MeSH