63 research outputs found

    Liquid Biopsy in Neurological Diseases

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    Liquid biopsy; MicroRNA; Neurological diseasesBiòpsia líquida; MicroARN; Malalties neurològiquesBiopsia líquida; MicroARN; Enfermedades neurológicasThe most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.S.M. was supported by the grant from Instituto Salud Carlos III (PI20/01697)

    Role of high mobility group box protein 1 (HMGB1) in peripheral blood from patients with multiple sclerosis

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    Altres ajuts: The authors thank the 'Red Española de Esclerosis Múltiple (REEM)' sponsored by the 'Fondo de Investigación Sanitaria' (FIS), Ministry of Science and Innovation, Spain, and the 'Ajuts per donar Suport als Grups de Recerca de Catalunya,' sponsored by the 'Agència de Gestió d'Ajuts Universitaris i de Recerca' (AGAUR), Generalitat de Catalunya, Spain.High mobility group box protein 1 (HMGB1) is a transcriptional regulator that is receiving increasing attention in autoimmune disorders including multiple sclerosis (MS). Here, we investigated the role of HMGB1 in the peripheral blood compartment from MS patients. HMGB1 mRNA expression levels were determined by PCR in peripheral blood mononuclear cells (PBMC) of 29 healthy controls and 57 untreated MS patients (26 with relapsing-remitting MS - RRMS, 13 with secondary progressive MS - SPMS, and 18 with primary progressive MS - PPMS). HMGB1 protein levels were measured by ELISA in serum samples from 18 HC and 37 untreated MS patients (13 with RRMS, 14 with SPMS, and 10 with PPMS). HMGB1 expression levels were increased in PBMC from the whole MS group compared with controls (P = 0.03). Further stratification of the MS group revealed higher expression levels in PBMC from patients with relapse-onset MS, and differences were statistically significant for RRMS patients compared with PPMS patients and controls (P = 4 × 10 −5 and P = 0.005, respectively) and also for SPMS patients compared with PPMS patients (P = 0.001). HMGB1 serum levels were increased in the whole MS group compared with controls (P = 2 × 10 −4). In MS clinical forms, the highest HMGB1 serum levels were observed in RRMS patients, and differences were statistically significant compared to PPMS patients (P = 5 × 10 −5), SPMS patients (P = 0.001), and controls (P = 0.001). These results point to a role of HMGB1 mRNA and protein levels as disease activity biomarkers to discriminate the more inflammatory relapse-onset MS forms, particularly RRMS, from the less inflammatory PPMS form of the disease. The online version of this article (doi:10.1186/s12974-015-0269-9) contains supplementary material, which is available to authorized users

    Increased NLRP3 Inflammasome Activation and Pyroptosis in Patients With Multiple Sclerosis With Fingolimod Treatment Failure

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    Inflammasome; Pyroptosis; Multiple sclerosisInflamasoma; Piroptosis; Esclerosis múltipleInflamasoma; Piroptosi; Esclerosi múltipleBackground and Objectives Inflammasomes are involved in the pathogenesis of different neuroimmune and neurodegenerative diseases, including multiple sclerosis (MS). In a previous study by our group, the nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain–containing 3 (NLRP3) inflammasome was reported to be associated with the response to interferon-beta in MS. Based on recent data showing the potential for the oral therapy fingolimod to inhibit NLRP3 inflammasome activation, here we investigated whether fingolimod could also be implicated in the response to this therapy in patients with MS. Methods NLRP3 gene expression levels were measured by real-time PCR in peripheral blood mononuclear cells at baseline and after 3, 6, and 12 months in a cohort of patients with MS treated with fingolimod (N = 23), dimethyl fumarate (N = 21), and teriflunomide (N = 21) and classified into responders and nonresponders to the treatment according to clinical and radiologic criteria. In a subgroup of fingolimod responders and nonresponders, the percentage of monocytes with an oligomer of ASC was determined by flow cytometry, and the levels of interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor (TNF)α, and galectin-3 were quantified by ELISA. Results NLPR3 expression levels were significantly increased in fingolimod nonresponders after 3 (p = 0.03) and 6 months (p = 0.008) of treatment compared with the baseline but remained similar in responders at all time points. These changes were not observed in nonresponders to the other oral therapies tested. The formation of an oligomer of ASC in monocytes after lipopolysaccharide and adenosine 5′-triphosphate stimulation was significantly decreased in responders (p = 0.006) but increased in nonresponders (p = 0.0003) after 6 months of fingolimod treatment compared with the baseline. Proinflammatory cytokine release from stimulated peripheral blood mononuclear cells was comparable between responders and nonresponders, but galectin-3 levels on cell supernatants, as a marker of cell damage, were significantly increased in fingolimod nonresponders (p = 0.02). Discussion The differential effect of fingolimod on the formation of an inflammasome-triggered ASC oligomer in monocytes between responders and nonresponders could be used as a response biomarker after 6 months of fingolimod treatment and suggests that fingolimod may exert their beneficial effects by reducing inflammasome signaling in a subset of patients with MS.MCIN/AEI/10.13039/501100011033 (grant PID2020-116709RB-I00)—Fundación Séneca (grant 20859/PI/18) and the Instituto Salud Carlos III (grant DTS21/00080). L. Hurtado-Navarro was supported by the fellowship 21214/FPI/19 (Fundación Séneca, Región de Murcia, Spain)

    Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

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    Autoimmune; Multiple sclerosisAutoinmune; Esclerosis múltipleAutoimmune; Esclerosi múltipleIntronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.This research was supported by grants to KV from MINECO (SAF2016-74891-R), Instituto de Salud Carlos III (FIS-PI20/00123), Gobierno Vasco RIS3 (Ref. 2019222043), and Red Española de Esclerosis Múltiple (REEM; RD16/0015/0005). NV and LMV were supported by ISCIII (FIS-PI18/00572) and REEM (RD16/0015/0001). RTN is a recipient of a fellowship from the Secretaría Nacional de Ciencia y Tecnología e Innovación (SENACYT; Convocatoria Doctorado de Investigación Ronda III, 2018; Ref. BIDP-III-2018-12) of the Gobierno Nacional, República de Panamá

    Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis

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    © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.Objective : There is a lack of sensitive and specific biomarkers for use in progressive multiple sclerosis (MS). The study aimed to assess the potential of serum neurofilament light chain (sNfL) levels as biomarker of disability progression in patients with progressive MS. Methods: We performed a prospective observational cohort study in 51 patients with progressive MS who participated in a 2-year phase II single-centre, randomised, double-blind, placebo-controlled trial of interferon-beta. Mean (SD) follow-up duration was 13.9 (6.2) years. Levels of sNfL were measured using a single molecule array immunoassay at baseline, 1, 2 and 6 years. Univariable and multivariable analyses were carried out to evaluate associations between sNfL levels and disability progression at short term (2 years), medium term (6 years) and long term (at the time of the last follow-up). Results: A sNfL cut-off value of 10.2¿pg/mL at baseline discriminated between long-term progressors and non-progressors with a 75% sensitivity and 67% specificity (adjusted OR 7.8; 95%¿CI 1.8 to 46.4; p=0.01). Similar performance to discriminate between long-term progressors and non-progressors was observed using age/body mass index-adjusted sNfL Z-scores derived from a normative database of healthy controls. A cut-off increase of 5.1¿pg/mL in sNfL levels between baseline and 6 years also discriminated between long-term progressors and non-progressors with a 71% sensitivity and 86% specificity (adjusted OR 49.4; 95%¿CI 4.4 to 2×103; p=0.008). Conclusions: sNfL can be considered a prognostic biomarker of future long-term disability progression in patients with progressive MS. These data expand the little knowledge existing on the role of sNfL as long-term prognostic biomarker in patients with progressive MS.Postprint (author's final draft

    Circulating EZH2-positive T cells are decreased in multiple sclerosis patients

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    BACKGROUND: Recent studies in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), suggest an involvement of the histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in important processes such as cell adhesion and migration. METHODS: Here, we aimed to expand these initial observations by investigating the role of EZH2 in MS. mRNA expression levels for EZH2 were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) from 121 MS patients (62 untreated and 59 receiving treatment) and 24 healthy controls. RESULTS: EZH2 expression levels were decreased in PBMC from untreated patients compared to that from controls, and treatment significantly upregulated EZH2 expression. Expression of miR-124 was increased in MS patients compared to controls. Blood immunophenotyping revealed EZH2 expression mostly restricted to CD4+ and CD8+ T cells, and circulating EZH2+ CD4+ and CD8+ T cells were decreased in untreated MS patients compared to controls. CD8+ T cells expressing EZH2 exhibited a predominant central memory phenotype, whereas EZH2+ CD4+ T cells were of effector memory nature, and both T cell subsets produced TNF-α. EZH2+ T cells were enriched in the cerebrospinal fluid compartment compared to blood and were found in chronic active lesions from MS patients. EZH2 inhibition and microarray analysis in PBMC was associated with significant downregulation of key T cell adhesion molecules. CONCLUSION: These findings suggest a role of EZH2 in the migration of T cells in MS patients. The observation of TNF-α expression by CD4+ and CD8+ T cells expressing EZH2 warrants additional studies to explore more in depth the pathogenic potential of EZH2+-positive cells in MS

    Influence of the LILRA3 Deletion on Multiple Sclerosis Risk : Original Data and Meta-Analysis

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    Altres ajuts: Junta de Andalucía (JA)- Fondos Europeos de Desarrollo Regional (FEDER) (grant number CTS2704 to FM).Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15 : 01 risk allele

    Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles

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    Altres ajuts: Ajuts per donar Suport als Grups de Recerca de Catalunya," sponsored by the "Agència de Gestió d'Ajuts Universitaris i de Recerca" (AGAUR), Generalitat de CatalunyaWe aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p = 3 × 10 −7 ; odds ratio [OR] = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p = 6 × 10 −4 ; OR = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%. HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration

    A Herschel/PACS Far-infrared line emission survey of local luminous infrared galaxies

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    We present an analysis of [OI]63, [OIII]88, [NII]122 and [CII]158 far-infrared (FIR) fine-structure line observations obtained with Herschel/PACS, for ~240 local luminous infrared galaxies (LIRGs) in the Great Observatories All-sky LIRG Survey (GOALS). We find pronounced declines -deficits- of line-to-FIR-continuum emission for [NII]122, [OI]63 and [CII]158 as a function of FIR color and infrared luminosity surface density, ΣIR\Sigma_{\rm IR}. The median electron density of the ionized gas in LIRGs, based on the [NII]122/[NII]205 ratio, is nen_{\rm e} = 41 cm−3^{-3}. We find that the dispersion in the [CII]158 deficit of LIRGs is attributed to a varying fractional contribution of photo-dissociation-regions (PDRs) to the observed [CII]158 emission, f([CII]PDR) = [CII]PDR/[CII], which increases from ~60% to ~95% in the warmest LIRGs. The [OI]63/[CII]158PDR ratio is tightly correlated with the PDR gas kinetic temperature in sources where [OI]63 is not optically-thick or self-absorbed. For each galaxy, we derive the average PDR hydrogen density, nHn_{\rm H}, and intensity of the interstellar radiation field, in units of G0_0, and find G0_0/nHn_{\rm H} ratios ~0.1-50 cm3^3, with ULIRGs populating the upper end of the distribution. There is a relation between G0_0/nHn_{\rm H} and ΣIR\Sigma_{\rm IR}, showing a critical break at ΣIR⋆\Sigma_{\rm IR}^{\star} ~ 5 x 1010^{10} Lsun/kpc2^2. Below ΣIR⋆\Sigma_{\rm IR}^{\star}, G0_0/nHn_{\rm H} remains constant, ~0.32 cm3^3, and variations in ΣIR\Sigma_{\rm IR} are driven by the number density of star-forming regions within a galaxy, with no change in their PDR properties. Above ΣIR⋆\Sigma_{\rm IR}^{\star}, G0_0/nHn_{\rm H} increases rapidly with ΣIR\Sigma_{\rm IR}, signaling a departure from the typical PDR conditions found in normal star-forming galaxies towards more intense/harder radiation fields and compact geometries typical of starbursting sources

    Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course

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    BACKGROUND: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients. METHODS: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies. RESULTS: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia. CONCLUSIONS: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis
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