Association of Serum Neurofilament Light Chain Levels at Disease Onset With Disability Worsening in Patients With a First Demyelinating Multiple Sclerosis Event Not Treated With High-Efficacy Drugs.

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial.

Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event.

Design, Setting, And Participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022).

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis.

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB.

Predicting Aggressive Multiple Sclerosis With Intrathecal IgM Synthesis Among Patients With a Clinically Isolated Syndrome.

Objective: To determine the best method to measure intrathecal immunoglobulin (Ig) M synthesis (ITMS), a biomarker of worse prognosis in multiple sclerosis (MS). We compared the ability for predicting a poor evolution of 4 methods assessing ITMS (IgM oligoclonal bands [OCMBs], lipid-specific OCMBs [LS-OCMBs], Reibergram, and IgM index) in patients with a clinically isolated syndrome (CIS).

Methods: Prospective study with consecutive patients performed at a referral MS center.

Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab.

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years.

Focused ultrasound thalamotomy for multiple sclerosis-associated tremor.

Multiple sclerosis (MS)-related tremor is frequent and can often be refractory to medical treatment, which makes it a potential source of major disability. Functional neurosurgery approaches such as thalamic deep brain stimulation (DBS) or radiofrequency thalamotomy are proven to be effective, but the application of invasive techniques in MS tremor has so far been limited. Magnetic resonance (MR)-guided focused ultrasound thalamotomy, which has already been approved for treating essential and parkinsonian tremor, provides a minimally invasive approach that could be useful in the management of MS tremor.

Manipulation of Gut Microbiota Influences Immune Responses, Axon Preservation, and Motor Disability in a Model of Progressive Multiple Sclerosis.

Gut microbiota dysbiosis has been implicated in MS and other immune diseases, although it remains unclear how manipulating the gut microbiota may affect the disease course. Using a well-established model of progressive MS triggered by intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), we sought to determine whether dysbiosis induced by oral antibiotics (ABX) administered on pre-symptomatic and symptomatic phases of the disease influences its course. We also addressed the effects of microbiota recolonization after ABX withdrawn in the presence or absence of probiotics.

A pharmacogenetic study implicates in the response to Interferon-β in multiple sclerosis.

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients.

Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role.

Quantification of the Light Subunit of Neurofilament Protein in Cerebrospinal Fluid of Huntington's Disease Patients.

 Neurofilament light proteins (NFL) are a structural element of the neuronal cytoskeleton and are released with neuronal damage. Its levels are increased in cerebrospinal fluid (CSF) in the setting of neurodegenerative diseases. We investigated the CSF-NFL levels of Huntington´s disease (HD) patients (participating in a clinical trial SAT-HD) as well as of premanifest carriers and compared their results with a sample of healthy controls and correlated CSF-NFL levels with demographic and clinical variables (baseline demographic characteristics and HD measures of disease severity).

Cerebrospinal fluid mitochondrial DNA levels in patients with multiple sclerosis.

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction.

Different clinical response to interferon beta and glatiramer acetate related to the presence of oligoclonal IgM bands in CSF in multiple sclerosis patients.

Objective: To study the efficacy of interferon beta (IFNβ) and glatiramer acetate (GA) related to the presence of oligoclonal M bands (OCMB) in the cerebrospinal fluid in relapsing-remitting multiple sclerosis (RRMS).

Method: This is an observational, multicenter and retrospective study with prospectively collected data of patients that started treatment with IFNβ or GA. Treatment decision was made blinded to the OCMB status.

Multimarker risk stratification approach at multiple sclerosis onset.

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.

Metabolomic signatures associated with disease severity in multiple sclerosis.

Objective: To identify differences in the metabolomic profile in the serum of patients with multiple sclerosis (MS) compared to controls and to identify biomarkers of disease severity.

Methods: We studied 2 cohorts of patients with MS: a retrospective longitudinal cohort of 238 patients and 74 controls and a prospective cohort of 61 patients and 41 controls with serial serum samples. Patients were stratified into active or stable disease based on 2 years of prospective assessment accounting for presence of clinical relapses or changes in disability measured with the Expanded Disability Status Scale (EDSS).

miRNAs in cerebrospinal fluid identify patients with MS and specifically those with lipid-specific oligoclonal IgM bands.

Background: MicroRNAs (miRNAs) are non-coding RNAs that regulate cellular processes by controlling protein translation and mRNA degradation.

Objective: We aimed to explore the miRNA signature of multiple sclerosis (MS) patients versus controls and the possibility that patients with lipid-specific oligolconal IgM bands (LS_OCMB), a predictor of a more severe disease course, may have a distinct profile.

Methods: An extensive profile of 754 miRNAs was evaluated in the cerebrospinal fluid (CSF) of 14 women using TaqMan low-density arrays.

Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS.

Protein-Based Classifier to Predict Conversion from Clinically Isolated Syndrome to Multiple Sclerosis.

Multiple sclerosis is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. In most patients, the disease initiates with an episode of neurological disturbance referred to as clinically isolated syndrome, but not all patients with this syndrome develop multiple sclerosis over time, and currently, there is no clinical test that can conclusively establish whether a patient with a clinically isolated syndrome will eventually develop clinically defined multiple sclerosis. Here, we took advantage of the capabilities of targeted mass spectrometry to establish a diagnostic molecular classifier with high sensitivity and specificity able to differentiate between clinically isolated syndrome patients with a high and a low risk of developing multiple sclerosis.

Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β.

Objectives: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS).

Methods: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-β response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-β responders and 274 nonresponders).

A functional variant that affects exon-skipping and protein expression of SP140 as genetic mechanism predisposing to multiple sclerosis.

Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7.

Validation of semaphorin 7A and ala-β-his-dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis.

Background: In a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-β-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Here, we aimed to validate these results in individual CSF samples using alternative techniques.

Methods: In a first replication study, levels of apolipoproteins AI and AIV, vitronectin, and plasminogen were measured by ELISA in CSF and serum of 56 CIS patients (29 patients who converted to CDMS (MS converters) and 27 patients who remained with CIS during follow-up (MS non-converters)) and 26 controls with other neurological disorders.

A new risk variant for multiple sclerosis at the immunoglobulin heavy chain locus associates with intrathecal IgG, IgM index and oligoclonal bands.

Background: Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS).

Objectives: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters.

Methods: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls.

Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis.

In most patients with multiple sclerosis, the disease initiates with a first attack or clinically isolated syndrome. At this phase, magnetic resonance imaging is an important predictor of conversion to multiple sclerosis. With the exception of oligoclonal bands, the role of other biomarkers in patients with clinically isolated syndrome is controversial.