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Objective: To evaluate the safety of COVID-19 vaccines in patients with multiple sclerosis (MS) by assessing their impact on serum neurofilament light chain (sNfL) levels as a marker of neuroaxonal damage. Methods: Single-center observational longitudinal study including patients with MS who consecutively received their initial vaccination against SARS-CoV-2 at Hospital Universitario Ramón y Cajal, following the first national immunization program in Spain. Serum samples were collected at baseline and after receiving the second dose of the vaccine. sNfL levels were quantified using the single molecule array (SIMOA) technique. Adverse events, including clinical or radiological reactivation of the disease, were recorded. Results: Fifty-two patients were included (median age, 39.7 years [range, 22.5-63.3]; 71.2% female). After SARS-CoV-2 vaccination, no increased inflammatory activity, either determined by the presence of relapses and/or new MRI lesions and/or high sNfL levels, was detected. Accordingly, there was no difference between median sNfL levels before and after vaccination (5.39 vs. 5.76 pg/ml, p=0.6). Despite this, when looking at baseline patient characteristics before vaccination, younger age associated with disease activity after vaccination (OR 0.87, 95% CI: 0.77-0.98, p=0.022). Larger studies are needed to validate these results. Conclusion: COVID-19 vaccines did not cause reactivation of disease at a clinical, radiological or molecular level, thus suggesting that they are safe in MS patients.
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Vacunas contra la COVID-19 , COVID-19 , Esclerosis Múltiple , Proteínas de Neurofilamentos , SARS-CoV-2 , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/sangre , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Proteínas de Neurofilamentos/sangre , SARS-CoV-2/inmunología , Adulto Joven , Estudios Longitudinales , Biomarcadores/sangre , Axones/patología , España/epidemiología , Vacunación/efectos adversosRESUMEN
Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS). Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years. Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison. Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values. Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values.
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Alemtuzumab , Proteína Ácida Fibrilar de la Glía , Esclerosis Múltiple Recurrente-Remitente , Proteínas de Neurofilamentos , Humanos , Alemtuzumab/uso terapéutico , Femenino , Masculino , Adulto , Proteínas de Neurofilamentos/sangre , Estudios Prospectivos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Proteína Ácida Fibrilar de la Glía/sangre , Biomarcadores/sangre , Resultado del Tratamiento , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/sangreRESUMEN
BACKGROUND AND OBJECTIVES: There is an urgent need to discover blood-based biomarkers of multiple sclerosis (MS) to better define the underlying biology of relapses and monitor disease progression. The main goal of this study is to search for candidate biomarkers of MS relapses associated with circulating extracellular vesicles (EVs), an emerging tool for biomarker discovery. METHODS: EVs, purified from unpaired plasma and CSF samples of RRMS patients by size-exclusion chromatography (SEC), underwent proteomic analysis to discover novel biomarkers associated with MS relapses. The candidate biomarkers of disease activity were detected by comparison approach between plasma- and CSF-EV proteomes associated with relapses. Among them, a selected potential biomarker was evaluated in a cohort of MS patients, using a novel and highly reproducible flow cytometry-based approach in order to detect low abundant EV subsets in a complex body fluid such as plasma. RESULTS: The proteomic profiles of both SEC-purified plasma EVs (from 6 patients in relapse and 5 patients in remission) and SEC-purified CSF EVs (from 4 patients in relapse and 3 patients in remission) revealed a set of proteins associated with MS relapses significant enriched in the synaptic transmission pathway. Among common proteins, excitatory amino-acid transporter 2, EAAT2, responsible for the majority of the glutamate uptake in CNS, was worthy of further investigation. By screening plasma samples from 110 MS patients, we found a significant association of plasma EV-carried EAAT2 protein (EV-EAAT2) with MS relapses, regardless of disease-modifying therapies. This finding was confirmed by investigating the presence of EV-EAAT2 in plasma samples collected longitudinally from 10 RRMS patients, during relapse and remission. Moreover, plasma EV-EAAT2 levels correlated positively with Expanded Disability Status Scale (EDSS) score in remitting MS patients but showed a negative correlation with age in patients with secondary progressive (SPMS). CONCLUSION: Our results emphaticize the usefulness of plasma EVs as a source of accessible biomarkers to remotely analyse the CNS status. Plasma EV-EAAT2 showed to be a promising biomarker for MS relapses. Further studies are required to assess the clinical relevance of this biomarker also for disability progression independent of relapse activity and transition from RRMS towards SPMS.
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Transportador 2 de Aminoácidos Excitadores , Vesículas Extracelulares , Esclerosis Múltiple , Proteómica , Humanos , Vesículas Extracelulares/metabolismo , Masculino , Femenino , Adulto , Proteómica/métodos , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/sangre , Estudios de CohortesRESUMEN
Several studies have suggested a correlation between serum vitamin D (VitD) level and multiple sclerosis (MS). MS has a known latitudinal distribution pattern, with greater incidence, prevalence, and mortality rates at higher latitudes. This study aims to assess levels of VitD and serum potassium in subjects with MS and the impact of gender and age as disease risk factors. A cross-sectional case-control study was conducted in a high-altitude region of Saudi Arabia. VitD deficiency was defined as serum 25 (OH)D level of ≤20 ng/mL and insufficiency as a serum level between >20 ng/mL and <30 ng/mL. Two hundred patients with MS volunteered for the study, and 160 healthy participants served as controls. VitD and serum potassium were measured in patients and controls. Student t test and regression analysis were used to analyze the data. The average MS patient age was 37.37â ±â 10.8 years. Most (73.02%) MS patients suffered from deficient vitamin D, while insufficiency (20-29 ng/mL) was found in 12.17%. Only 6.35% had sufficient vitamin D (30-40 ng/mL). VitD was significantly decreased in MS patients compared to the healthy controls (17.036 vs 25.01 ng/mL, Pâ <â .001), while serum potassium was also decreased (4.278 vs 4.329 mmol/L, Pâ =â .269). Risk factors found to have a statistically significant association with MS included female gender (odd ratio [OR]â =â 1.72, 95% confidence interval: 1.016-2.915; Pâ =â .044) and patient ageâ <â 40 years (ORâ =â 1.04, 95% confidence interval: 1.023-1.054; Pâ =â .044). VitD was significantly lower in MS patients. The prevalence of MS was higher among women and younger individuals in a high-altitude population in Saudi Arabia.
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Altitud , Esclerosis Múltiple , Deficiencia de Vitamina D , Vitamina D , Humanos , Femenino , Masculino , Adulto , Esclerosis Múltiple/sangre , Esclerosis Múltiple/epidemiología , Estudios de Casos y Controles , Factores de Riesgo , Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Estudios Transversales , Arabia Saudita/epidemiología , Persona de Mediana Edad , Potasio/sangre , Factores Sexuales , Factores de EdadRESUMEN
Our study aimed to investigate the associations between CXCL12 rs1029153, rs1801157, and rs2297630 single-nucleotide polymorphisms (SNPs), CXCL12 protein levels, MS prevalence, and clinical parameters. This study included 250 individuals diagnosed with MS and 250 sex- and age-matched healthy control individuals from Lithuania. The SNPs were genotyped with real-time PCR-based assays. The CXCL12 protein concentration was evaluated in serum using the ELISA method. Of the studied CXCL12 SNPs, we found that the rs1801157 CT genotype in the males was associated with 2.3 times reduced MS odds when compared with the CC genotype according to the overdominant and codominant models (p = 0.011 and p = 0.012, respectively). There was a tendency, which did not reach adjusted statistical significance, for a lower CXCL12 protein concentration in the healthy individuals with the rs1801157 CT genotype (p = 0.028). Sensory symptoms were rarer in the women with the rs1801157 TT genotype (p = 0.004); however, this genotype was also associated with a shorter MS disease duration (p = 0.007). CXCL12 rs1801157 was associated with reduced odds of MS occurrence in the male individuals. In women, rs1801157 was associated with a sensory symptom prevalence.
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Quimiocina CXCL12 , Predisposición Genética a la Enfermedad , Esclerosis Múltiple , Polimorfismo de Nucleótido Simple , Humanos , Quimiocina CXCL12/genética , Quimiocina CXCL12/sangre , Masculino , Femenino , Lituania/epidemiología , Adulto , Esclerosis Múltiple/genética , Esclerosis Múltiple/sangre , Esclerosis Múltiple/epidemiología , Prevalencia , Persona de Mediana Edad , Estudios de Casos y Controles , Genotipo , Frecuencia de los Genes , Estudios de Asociación GenéticaRESUMEN
PURPOSE: Metabolic vulnerabilities can exacerbate inflammatory injury and inhibit repair in multiple sclerosis (MS). The purpose was to evaluate whether blood biomarkers of inflammatory and metabolic vulnerability are associated with MS disability and neurodegeneration. METHODS: Proton nuclear magnetic resonance spectra were obtained from serum samples from 153 healthy controls, 187 relapsing-remitting, and 91 progressive MS patients. The spectra were analyzed to obtain concentrations of lipoprotein sub-classes, glycated acute-phase proteins, and small-molecule metabolites, including leucine, valine, isoleucine, alanine, and citrate. Composite indices for inflammatory vulnerability, metabolic malnutrition, and metabolic vulnerability were computed. MS disability was measured on the Expanded Disability Status Scale. MRI measures of lesions and whole-brain and tissue-specific volumes were acquired. RESULTS: Valine, leucine, isoleucine, alanine, the Inflammatory Vulnerability Index, the Metabolic Malnutrition Index, and the Metabolic Vulnerability Index differed between healthy control and MS groups in regression analyses adjusted for age, sex, and body mass index. The Expanded Disability Status Scale was associated with small HDL particle levels, inflammatory vulnerability, and metabolic vulnerability. Timed ambulation was associated with inflammatory vulnerability and metabolic vulnerability. Greater metabolic vulnerability and inflammatory vulnerability were associated with lower gray matter, deep gray matter volumes, and greater lateral ventricle volume. CONCLUSIONS: Serum-biomarker-derived indices of inflammatory and metabolic vulnerability are associated with disability and neurodegeneration in MS.
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Biomarcadores , Humanos , Femenino , Masculino , Biomarcadores/sangre , Persona de Mediana Edad , Adulto , Imagen por Resonancia Magnética , Esclerosis Múltiple/sangre , Esclerosis Múltiple Recurrente-Remitente/sangre , Estudios de Casos y Controles , Espectroscopía de Resonancia Magnética , Inflamación/sangre , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Esclerosis Múltiple Crónica Progresiva/sangre , Evaluación de la Discapacidad , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely utilized to investigate plasticity mechanisms and functional reorganization in multiple sclerosis (MS). Among many resting state (RS) networks, a significant role is played by the salience network (SN, ventral attention network). Previous reports have demonstrated the involvement of osteopontin (OPN) in the pathogenesis of MS, which acts as a proinflammatory cytokine ultimately leading to neurodegeneration. Concentration of serum OPN was related to MRI findings 10.22±2.84 years later in 44 patients with MS. Local and interhemispheric correlations (LCOR, IHC), ROI-to-ROI and seed-based connectivity analyses were performed using serum OPN levels as independent variable along with age and gender as nuisance variables. We found significant associations between OPN levels and local correlation in right and left clusters encompassing the central opercular- and insular cortices (p-FDR = 0.0018 and p-FDR = 0.0205, respectively). Moreover, a significant association was identified between OPN concentration and interhemispheric correlation between central opercular- and insular cortices (p-FDR = 0.00015). Significant positive associations were found between OPN concentration and functional connectivity (FC) within the SN (FC strength between the anterior insula ventral division and 3 other insular regions, F(2,13) = 7.84, p-FDR = 0.0117). Seed-based connectivity analysis using the seven nodes of the SN resulted in several positive and inverse associations with OPN level. Serum OPN level may predict FC alterations within the SN in 10 years.
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Imagen por Resonancia Magnética , Esclerosis Múltiple , Osteopontina , Humanos , Osteopontina/sangre , Femenino , Masculino , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/sangre , Adulto , Persona de Mediana Edad , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatologíaRESUMEN
Immunohistochemical studies have identified complement component C1q in MS lesions. We aimed to compare serum (sC1q) and CSF (csfC1q) levels in a large cohort of MS patients (pwMS) (n = 222) with those of healthy controls (HC, n = 52), individuals with other immune (IND, n = 14), and non-immune neurological disorders (nIND, n = 15), and to analyze their correlation with other biomarkers. pwMS were divided into three series based on their origin. CSF samples were unavailable for HC. All three pwMS cohorts had lower sC1q levels compared to HC and IND. csfC1q was higher in one pwMS cohort, with a trend in another, and correlated with IgG, Free Kappa Light Chains, GFAP, and Chitinase-3 Like Protein-1 in CSF. Our findings suggest a significant role for C1q in MS pathophysiology, potentially serving as a biomarker for disease identification.
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Biomarcadores , Complemento C1q , Esclerosis Múltiple , Humanos , Complemento C1q/líquido cefalorraquídeo , Complemento C1q/análisis , Femenino , Masculino , Adulto , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/sangre , Estudios de Cohortes , Anciano , Adulto Joven , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Proteína Ácida Fibrilar de la Glía/sangreRESUMEN
Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic-pituitary-adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients' peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers' PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making.
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Leucocitos Mononucleares , Esclerosis Múltiple , Receptores de Mineralocorticoides , Transducción de Señal , Humanos , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/genética , Esclerosis Múltiple/sangre , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Femenino , Masculino , Adulto , Leucocitos Mononucleares/metabolismo , Persona de Mediana EdadRESUMEN
Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.
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Aprendizaje Automático , Esclerosis Múltiple , Transcriptoma , Humanos , Esclerosis Múltiple/sangre , Esclerosis Múltiple/genética , Esclerosis Múltiple/diagnóstico , Transcriptoma/genética , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/sangre , Enfermedades Desmielinizantes/diagnóstico , Algoritmos , Perfilación de la Expresión Génica/métodosRESUMEN
BACKGROUND: Although there is evidence of a link between vitamin D status and risk of multiple sclerosis (MS), there has been no systematic review where the exposure measure was vitamin D deficiency rather than 25 hydroxy vitamin D (25(OH)D) concentration. We conducted an updated systematic review and meta-analysis to estimate the association between vitamin D deficiency, defined in most studies as a serum 25(OH)D concentration of < 50 nmol L-1, and MS. METHODS: We searched the MEDLINE, EMBASE, and CINAHL databases to identify relevant publications. We estimated the pooled odds ratio (OR) using a random effects model for the association between vitamin D deficiency and MS, overall and stratified by several factors, including whether or not studies included participants who were taking vitamin D supplements. We also analysed the association between mean 25(OH)D concentration and MS, and used meta-regression to assess the effects of vitamin D supplementation, latitude, age, ethnicity, vitamin D definition and seasonality on the OR estimates. The Newcastle-Ottawa Scale was used to assess study quality. RESULTS: Results were pooled across 14 case-control studies published between 2007 and 2021 (n = 4130 cases, n = 4604 controls). Persons with vitamin D deficiency had a 54 % higher risk of multiple sclerosis than those with sufficient vitamin D status (OR 1.54; 95 % CI 1.05, 2.24). In studies that excluded participants taking vitamin D supplements (N = 7), the OR was 2.19 (95 % CI: 1.44, 3.35), whereas, in studies that did not exclude participants taking supplements, there was no increase in risk (OR 0.82; 95 % CI: 0.43, 1.58). Mean age (R2 = 27.4 %) and inclusion/exclusion of participants taking supplements (R2 = 33.4 %) contributed most to variability in the OR of vitamin D deficiency and MS. CONCLUSION: Vitamin D deficiency is associated with an increased likelihood of multiple sclerosis. Maintaining sufficient vitamin D may be an important modifiable risk factor for MS.
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Esclerosis Múltiple , Deficiencia de Vitamina D , Vitamina D , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/sangre , Humanos , Esclerosis Múltiple/sangre , Esclerosis Múltiple/epidemiología , Vitamina D/sangre , Vitamina D/análogos & derivados , Suplementos DietéticosRESUMEN
Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.
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Interferón beta , Esclerosis Múltiple Recurrente-Remitente , Proteómica , Transcriptoma , Humanos , Interferón beta/uso terapéutico , Interferón beta/inmunología , Femenino , Masculino , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/sangre , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Biomarcadores/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangreRESUMEN
BACKGROUND: The assessment of serum neurofilament light chain (sNfL) concentration in multiple sclerosis (MS) is a useful tool for predicting clinical outcomes and assessing treatment response. However, its use in clinical practice is still limited. We aimed to assess how measurement of sNfL influences neurologists' treatment decisions in MS. METHODS: We conducted a cross-sectional, web-based study in collaboration with the Spanish Society of Neurology. Neurologists involved in MS care were presented with different simulated case scenarios of patients experiencing either their first demyelinating MS event or a relapsing-remitting MS. The primary outcome was therapeutic inertia (TI), defined as the absence of treatment initiation or intensification despite elevated sNfL levels. Nine cases were included to estimate the TI score (range 0-9, where higher values represented a higher degree of TI). RESULTS: A total of 116 participants were studied. Mean age (standard deviation-SD) was 41.9 (10.1) years, 53.4 % male. Seventy-eight (67.2 %) were neurologists fully dedicated to the care of demyelinating disorders. Mean (SD) TI score was 3.65 (1.01). Overall, 92.2 % of participants (n = 107) presented TI in at least 2/9 case scenarios. The lack of full dedication to MS care (p = 0.014), preference for taking risks (p = 0.008), and low willingness to adopt evidence-based innovations (p = 0.009) were associated with higher TI scores in the multivariate analysis after adjustment for confounders. CONCLUSION: TI was a common phenomenon among neurologists managing MS patients when faced with the decision to initiate or escalate treatment based on elevated sNfL levels. Identifying factors associated with this phenomenon may help optimize treatment decisions in MS care.
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Toma de Decisiones Clínicas , Esclerosis Múltiple , Proteínas de Neurofilamentos , Neurólogos , Humanos , Femenino , Masculino , Proteínas de Neurofilamentos/sangre , Estudios Transversales , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/terapia , Esclerosis Múltiple/diagnóstico , Biomarcadores/sangre , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/terapia , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
BACKGROUND: Several studies reported lower drug concentrations with subcutaneous natalizumab compared to intravenous natalizumab. With the emergence of extended interval dosing, gaining more insight into lower concentrations after subcutaneous administration is essential. METHODS: We compared serum trough concentrations between subcutaneous and intravenous administration within a matched cohort (n = 50). RESULTS: Subcutaneous administration (n = 25) was associated with lower concentrations compared to intravenous administration (n = 25) (log-B=-0.28, p = 0.01). In an exploratory group of 11 patients receiving extended interval dosing of subcutaneous natalizumab, the median trough concentration was even lower. CONCLUSION: Subcutaneous natalizumab can lead to lower drug concentrations, potentially limiting extended interval dosing.
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Administración Intravenosa , Factores Inmunológicos , Natalizumab , Humanos , Natalizumab/administración & dosificación , Natalizumab/sangre , Femenino , Masculino , Inyecciones Subcutáneas , Adulto , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacocinética , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/sangreRESUMEN
INTRODUCTION: The gold standard for serum neurofilament light chain (sNfL) determination is the single molecule array (SIMOA), the use of which is limited by availability and cost. The VEUS method is a fully automated, user-friendly diagnostic system requiring no sample preparation, with high reported sensitivity, multiplexing capability, and rapid diagnostics. The aim of this study was to compare the SIMOA and VEUS methods for determining sNfL levels in patients with multiple sclerosis (MS). METHODOLOGY: A single-centre cross-sectional study was conducted at the MS Centre of University Hospital Ostrava. Patients were enrolled in the study from January 18 to January 31, 2024. Inclusion criteria were: 1) diagnosis of MS according to the revised 2017 McDonald criteria, 2) age ≥18 years, and 3) signed informed consent. The NF-light V2 diagnostic kit (SIMOA, Quanterix) and the Singleplex Neurology assay kit (VEUDx, EZDiatech) were used to determine sNfL concentrations. The two methods were compared by use of Spearman correlation, Passing-Bablok regression, and Bland-Altman analysis. RESULTS: A total of 49 patients were included in the study, of whom 39 (79.6 %) were female. The median sNfL concentration was 7.73 (IQR 5.80-9.93) ng/L determined by SIMOA and 1.31 (IQR 1.18-1.65) ng/L by VEUS. We did not find a correlation between SIMOA and VEUS (rs = 0.025, p = 0.866). Passing-Bablok regression demonstrated a systematic and proportional difference between the two methods. A significant disagreement between them was also confirmed by the Bland-Altman plots. On average, sNfL values measured by SIMOA were 3.56 ng/L (95 % CI 0.78 to 6.34) higher than those measured by VEUS. CONCLUSION: Our investigation uncovered noteworthy disparities between the SIMOA and VEUS techniques in determining sNfL levels. Specifically, the VEUS technique systematically produces lower estimates of sNFL levels. This substantial variance emphasizes the importance of carefully evaluating assay methods when quantifying sNfL.
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Esclerosis Múltiple , Proteínas de Neurofilamentos , Humanos , Femenino , Masculino , Proteínas de Neurofilamentos/sangre , Estudios Transversales , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico , Biomarcadores/sangreRESUMEN
BACKGROUND: Exercise in patients with multiple sclerosis (pwMS) found to improve symptom management and regain function. Whether exercise lowers neurofilament light chain (NfL), neuroaxonal injury biomarker, in MS remains unknown with conflicting findings. In this study, we aimed to assess the interaction between exercise and NfL levels in pwMS. METHODS: Systematic search of Medline, CENTRAL, Embase, and Web of Science was conducted until March 2024 to identify relevant reports. We included studies that investigated the mean change in NfL levels pre- and post-training programs and compared them to different exercise programs or no exercise activity control groups. A standardized mean difference (SMD) with a 95 % confidence interval were applied using a random-effects model. RESULTS: Of 222 articles, 7 studies met the inclusion criteria. Patients who underwent structured exercise programs had a significant decrease in blood NfL levels post-training (SMD -0.55; 95 % CI -1.00, -0.09). Specifically, outdoor Pilates and home-based trainings were significantly associated with blood NfL reduction (SMD -2.08; 95 % CI -2.99, -1.17) and (SMD -1.46; 95 % CI -2.28, -0.64), respectively. Patients in the control group did not show significant differences in blood NfL levels between the baseline and at the end of the study (SMD 0.04; 95 % CI -0.17, 0.24). Subgroup analysis based on duration revealed that 8 weeks of exercise significantly reduced blood NfL levels (SMD -0.73; 95 % CI -1.35, -0.11). CONCLUSION: Our study provides preliminary evidence for the potential role of training in reducing blood NfL levels in pwMS. However, more rigorous, and well-designed studies are warranted to confirm these findings.
Asunto(s)
Terapia por Ejercicio , Esclerosis Múltiple , Proteínas de Neurofilamentos , Humanos , Proteínas de Neurofilamentos/sangre , Esclerosis Múltiple/sangre , Esclerosis Múltiple/terapia , Esclerosis Múltiple/fisiopatología , Terapia por Ejercicio/métodos , Ejercicio Físico/fisiología , Biomarcadores/sangreRESUMEN
OBJECTIVE: To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). MATERIAL AND METHODS: Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. RESULTS: Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). CONCLUSION: The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.
Asunto(s)
Biomarcadores , Encéfalo , Progresión de la Enfermedad , Imagen por Resonancia Magnética , Esclerosis Múltiple , Proteínas de Neurofilamentos , Humanos , Femenino , Masculino , Biomarcadores/sangre , Adulto , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Proteína Ácida Fibrilar de la Glía/sangreRESUMEN
Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8+ T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8+ MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.
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Esclerosis Amiotrófica Lateral , Células T Invariantes Asociadas a Mucosa , Humanos , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/sangre , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Biomarcadores , Citometría de FlujoRESUMEN
The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453-459.
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Péptidos beta-Amiloides , Esclerosis Múltiple , Humanos , Femenino , Masculino , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/sangre , Esclerosis Múltiple/patología , Esclerosis Múltiple/sangre , Persona de Mediana Edad , Adulto , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , AncianoRESUMEN
BACKGROUND: The clinical spectrum and diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has evolved in the setting of an optimized anti-MOG-IgG cell-based assay and expert consensus. The McDonald criteria for MS have been revised multiple times to improve the accuracy and specificity of diagnosis on a framework based on clinical presentation, MRI findings, and CSF results. While the uses of MS and MOGAD diagnostic criteria are helpful for typical cases, such utility for patients with overlapping clinical, laboratorial, and imaging features is unknown, posing diagnostic and management uncertainties. OBJECTIVES: To report a multicenter cohort of patients with overlapping phenotypic features of MOGAD and MS and evaluate the application of new MOGAD diagnostic criteria. METHODS: A collaborative retrospective cohort study was performed to identify patients with both positive serum anti-MOG-IgG and fulfillment of the MS revised 2017 McDonald criteria. Clinical and radiographic features of patients fulfilling inclusion criteria were reviewed longitudinally, including relapses, repeated MRI, and MOG-IgG testing in detail to allow the panel of expert opinion to assign to each case. The International MOGAD Panel proposed criteria were applied at onset and last follow-up to each case and compared to the expert author diagnosis assignment based on presentation, clinical and imaging features, and response to treatment. RESULTS: Ten of 225 (4%) MOG-IgG seropositive cases met study inclusion criteria [seven of 10 were female; age at initial event: eight adults (mean age 26.8 years), two adolescents (mean age 14.5 years)]. AQP4-IgG was negative for all. Apart from serum titers of MOG-IgG, distinguishing clinical and radiographic features [i.e., clinical severity of the initial demyelinating event, radiographic features (optic nerve/spine/brain), and presence/absence of lesion normalization on serial scans] led to consensus of three separate classifications differing by degrees of shared features of MOGAD and MS. Patients were classified by expert panel into (1) Classic MOGAD even with MS-like, well-defined brain lesions, when severe events and most T2 lesions normalized (n = 5; MOG-IgG titers 1:100, 1:20, 1:160, 1:40, 1:200); (2) Classic RRMS included cases thought to have likely false positive or clinically irrelevant MOG-IgG, due to mild clinical events and no radiographic normalization of well-defined MS-like lesions (n = 3; MOG titers 1:20, 1:100, 1:40); (3) MOGAD and MS overlapping phenotype was defined by those with a combination of mild and severe clinical events, partial T2 lesion normalization, both well- and ill-defined lesions (n = 2; MOG titers 1:20, 1:100). The application of the International MOGAD Panel criteria categorized five patients (50%) in agreement with expert assignment. One additional patient was classified in agreement to assignment when MOGAD criteria were applied after serial MOG-IgG titers testing. DISCUSSION: While the International MOGAD Panel diagnostic criteria have helped with accuracy for the diagnosis of this condition, in a group of patients seropositive for MOG-IgG with overlapping clinical and imaging features of RRMS criteria review may lead to increased accuracy. Serial serologies, repeated imaging, close attention to clinical course, and response to therapy are possible variables to consider for further refinement of MOGAD diagnostic criteria.