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[show abstract]
[hide abstract]
ABSTRACT: Background: Some controversy remains about the potential applicability of cognitive potentials for evaluating the cerebral activity associated with cognitive capacity. A fundamental requirement is that these neurophysiological parameters show a high level of stability over time. Previous studies have shown that the reliability of diverse parameters of the P3 component (latency and amplitude) ranges between moderate and high. However, few studies have paid attention to the retest reliability of the P3 topography in groups or individuals. Considering that changes in P3 topography have been related to different pathologies and healthy aging, the main objective of this article was to evaluate in a longitudinal study (two sessions) the reliability of P3 topography in a group and at the individual level.
Results: The correlation between sessions for P3 topography in the grand average of groups was high (r = 0.977, p,0.001). The within-subject correlation values ranged from 0.626 to 0.981 (mean: 0.888). In the between-subjects topography comparisons, the correlation was always lower for comparisons between different subjects than for within-subjects correlations in the first session but not in the second session.
Conclusions: The present study shows that P3 topography is highly reliable for group analysis (comprising the same subjects) in different sessions. The results also confirmed that retest reliability for individual P3 maps is suitable for follow-up studies for a particular subject. Moreover, P3 topography appears to be a specific marker considering that the betweensubjects correlations were lower than the within-subject correlations. However, P3 topography appears more similar
between subjects in the second session, demonstrating that is modulated by experience. Possible clinical applications of all these results are discussed
PLoS ONE 05/2013; 8(5):e62523. · 4.09 Impact Factor
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Manuel Comabella,
Ana B Caminero,
Sunny Malhotra,
Luis Agulló,
Oscar Fernández,
Ferran Reverter,
Koen Vandenbroeck,
Alfredo Rodríguez-Antigüedad,
Fuencisla Matesanz, Guillermo Izquierdo,
Elena Urcelay,
Arturo López-Larios,
Alex Sánchez,
Susana Otero,
Mar Tintoré,
Xavier Montalban
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution-R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease. METHODS: The effects of rs1800693 and rs4149584 on 2 measures of disease severity, age at disease onset and Multiple Sclerosis Severity Score, were analyzed in 2,032 patients with MS. In a subgroup of patients, serum levels of the soluble form of TNF-R1 (sTNF-R1) were measured by ELISA; mRNA expression levels of the full-length TNF-R1 and 6-TNF-R1 isoform were investigated in peripheral blood mononuclear cells (PBMC) by real-time PCR; cell surface expression of the TNF-R1 was determined in T cells by flow cytometry. RESULTS: For rs4149584, R92Q carriers were younger at disease onset and progressed slower compared to noncarriers. However, no association with disease severity was observed for rs1800693. Serum levels of sTNF-R1 and mRNA expression levels of the full-length receptor were significantly increased in patients with MS carrying the R92Q mutation (p = 0.003 and p = 0.011, respectively), but similarly distributed among rs1800693 genotypes; cell surface TNF-R1 expression in T cells did not differ between rs4149584 and rs1800693 genotypes. The truncated soluble 6-TNF-R1 isoform was identified in PBMC from patients carrying the risk allele for rs1800693. CONCLUSIONS: These findings suggest that both rs1800693 and rs4149584 TNFRSF1A polymorphisms have functional consequences in the TNF-R1.
Neurology 04/2013; · 8.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Some controversy remains about the potential applicability of cognitive potentials for evaluating the cerebral activity associated with cognitive capacity. A fundamental requirement is that these neurophysiological parameters show a high level of stability over time. Previous studies have shown that the reliability of diverse parameters of the P3 component (latency and amplitude) ranges between moderate and high. However, few studies have paid attention to the retest reliability of the P3 topography in groups or individuals. Considering that changes in P3 topography have been related to different pathologies and healthy aging, the main objective of this article was to evaluate in a longitudinal study (two sessions) the reliability of P3 topography in a group and at the individual level.
The correlation between sessions for P3 topography in the grand average of groups was high (r = 0.977, p<0.001). The within-subject correlation values ranged from 0.626 to 0.981 (mean: 0.888). In the between-subjects topography comparisons, the correlation was always lower for comparisons between different subjects than for within-subjects correlations in the first session but not in the second session.
The present study shows that P3 topography is highly reliable for group analysis (comprising the same subjects) in different sessions. The results also confirmed that retest reliability for individual P3 maps is suitable for follow-up studies for a particular subject. Moreover, P3 topography appears to be a specific marker considering that the between-subjects correlations were lower than the within-subject correlations. However, P3 topography appears more similar between subjects in the second session, demonstrating that is modulated by experience. Possible clinical applications of all these results are discussed.
PLoS ONE 01/2013; 8(5):e62523. · 4.09 Impact Factor
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Antonio Alcina,
Maria Fedetz,
Oscar Fernández,
Albert Saiz, Guillermo Izquierdo,
Miguel Lucas,
Laura Leyva,
Juan-Antonio García-León,
María Del Mar Abad-Grau,
Iraide Alloza, [......],
Rafael Arroyo,
Manuel Comabella,
Xavier Montalban,
Natalia Petit-Marty,
Arcadi Navarro,
David Otaegui,
Javier Olascoaga,
Yolanda Blanco,
Elena Urcelay,
Fuencisla Matesanz
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND AND AIM: Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS. METHODS: Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses. RESULTS: rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously. CONCLUSIONS: This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.
Journal of Medical Genetics 11/2012; · 6.36 Impact Factor
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Lucía Ortiz,
Alzenira F. Costa,
María L. Bellido,
Francisca Solano,
Jose M. García-Moreno,
Miguel A. Gamero, Guillermo Izquierdo,
Amal Chadli,
Filipa Falcao,
Jose Ferro,
Javier Salas,
Jose C. Álvarez-Cermeño,
Mariano Montori,
María A. Ramos-Arroyo,
Alfredo Palomino,
Elizabeth Pintado,
Miguel Lucas
[show abstract]
[hide abstract]
ABSTRACT: ObjectiveWe aimed to study clinical, radiological and molecular genetic features of patients with cerebral cavernous malformations
(CCMs) from the Iberian Peninsula.
MethodsWe screened Krit1(CCM1), MGC4607(CCM2), and PDCD10(CCM3) by systematic SSCP and direct sequencing of coding exons in 48 nuclear families and 30 sporadic cases of CCM from Spain and
Portugal.
ResultsScreening of CCM patients detected nine different mutations in 19 families. We found four new mutations in Krit1. Three of them were caused by either a small insertion or deletion, which lead to frameshift and premature termination codons.
We also found a missense L308H mutation located in a highly conserved sequence within the ankyrin domain of Krit1. In CCM2, we found a redundant 14 bp deletion in exon 5 of MGC4607 which predicts a truncated protein at residue 230. We did not find mutations in CCM3.
ConclusionsFinding that the 14 bp deletion was present in eleven families from the Iberian Peninsula indicates a high prevalence of this
mutation. This redundant CCM2 mutation is worth considering in molecular diagnosis and genetic counselling of cerebral cavernous
malformations.
Journal of Neurology 04/2012; 254(3):322-326. · 3.47 Impact Factor
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Fuencisla Matesanz,
Antonio González-Pérez,
Miguel Lucas,
Serena Sanna,
Javier Gayán,
Elena Urcelay,
Ilenia Zara,
Maristella Pitzalis,
María L Cavanillas,
Rafael Arroyo, [......],
Laura Leyva,
Antonio Alcina,
Maria Fedetz,
Concha Moreno-Rey,
Juan Velasco,
Luis M Real,
Juan Luis Ruiz-Peña,
Francesco Cucca,
Agustín Ruiz, Guillermo Izquierdo
[show abstract]
[hide abstract]
ABSTRACT: Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.
PLoS ONE 01/2012; 7(5):e36140. · 4.09 Impact Factor
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Antonio Alcina,
María Del Mar Abad-Grau,
María Fedetz, Guillermo Izquierdo,
Miguel Lucas,
Oscar Fernández,
Dorothy Ndagire,
Antonio Catalá-Rabasa,
Agustín Ruiz,
Javier Gayán,
Concepción Delgado,
Carmen Arnal,
Fuencisla Matesanz
[show abstract]
[hide abstract]
ABSTRACT: The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.
PLoS ONE 01/2012; 7(1):e29819. · 4.09 Impact Factor
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Jezabel Varadé,
Manuel Comabella,
Miguel A Ortiz,
Rafael Arroyo,
Oscar Fernández,
M Jesús Pinto-Medel,
María Fedetz, Guillermo Izquierdo,
Miguel Lucas,
Carlos López Gómez, [......],
Iraide Alloza,
Alfredo Antigüedad,
María García-Barcina,
David Otaegui,
Javier Olascoaga,
Albert Saiz,
Yolanda Blanco,
Xavier Montalbán,
Koen Vandenbroeck,
Elena Urcelay
[show abstract]
[hide abstract]
ABSTRACT: Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate.
Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls.
Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353).
Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p(M-H)=0.001; OR(M-H) (95% CI)= 0.84 (0.75-0.93)], IL12B [rs6887695: p(M-H)=0.03; OR(M-H) (95% CI)= 1.09 (1.01-1.17)] and CBLB [rs9657904: p(M-H)=0.01; OR(M-H) (95% CI)= 0.89 (0.81-0.97)].
Multiple Sclerosis 12/2011; 18(7):959-65. · 4.26 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Event-related potentials (ERPs) may be used as a highly sensitive way of detecting subtle degrees of cognitive dysfunction. On the other hand, impairment of cognitive skills is increasingly recognised as a hallmark of patients suffering from multiple sclerosis (MS). We sought to determine the psychophysiological pattern of information processing among MS patients with the relapsing-remitting form of the disease and low physical disability considered as two subtypes: 'typical relapsing-remitting' (RRMS) and 'benign MS' (BMS). Furthermore, we subjected our data to a cluster analysis to determine whether MS patients and healthy controls could be differentiated in terms of their psychophysiological profile.
We investigated MS patients with RRMS and BMS subtypes using event-related potentials (ERPs) acquired in the context of a Posner visual-spatial cueing paradigm. Specifically, our study aimed to assess ERP brain activity in response preparation (contingent negative variation -CNV) and stimuli processing in MS patients. Latency and amplitude of different ERP components (P1, eN1, N1, P2, N2, P3 and late negativity -LN) as well as behavioural responses (reaction time -RT; correct responses -CRs; and number of errors) were analyzed and then subjected to cluster analysis.
Both MS groups showed delayed behavioural responses and enhanced latency for long-latency ERP components (P2, N2, P3) as well as relatively preserved ERP amplitude, but BMS patients obtained more important performance deficits (lower CRs and higher RTs) and abnormalities related to the latency (N1, P3) and amplitude of ERPs (eCNV, eN1, LN). However, RRMS patients also demonstrated abnormally high amplitudes related to the preparation performance period of CNV (cCNV) and post-processing phase (LN). Cluster analyses revealed that RRMS patients appear to make up a relatively homogeneous group with moderate deficits mainly related to ERP latencies, whereas BMS patients appear to make up a rather more heterogeneous group with more severe information processing and attentional deficits.
Our findings are suggestive of a slowing of information processing for MS patients that may be a consequence of demyelination and axonal degeneration, which also seems to occur in MS patients that show little or no progression in the physical severity of the disease over time.
BMC Neurology 06/2011; 11:64. · 2.17 Impact Factor
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Antonio Alcina,
Oscar Fernández,
Juan Ramón Gonzalez,
Antonio Catalá-Rabasa,
María Fedetz,
Dorothy Ndagire,
Laura Leyva,
Miguel Guerrero,
Carmen Arnal,
Concepción Delgado,
Miguel Lucas, Guillermo Izquierdo,
Fuencisla Matesanz
[show abstract]
[hide abstract]
ABSTRACT: A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the GFI-EVI5-RPL5-FAM69A locus. In this study, we performed an analysis and fine mapping of this locus, genotyping eight Tag-SNPs in 732 MS patients and 974 controls from Spain. We observed an association with MS in three of eight Tag-SNPs: rs11804321 (P=0.008, OR=1.29; 95% CI=1.08-1.54), rs11808092 (P=0.048, OR=1.19; 95% CI=1.03-1.39) and rs6680578 (P=0.0082, OR=1.23; 95% CI=1.07-1.41). After correcting for multiple comparisons and using logistic regression analysis to test the addition of each SNP to the most associated SNPs, we observed that rs11804321 alone was sufficient to model the association. This Tag-SNP captures two SNPs in complete linkage disequilibrium (r(2)=1), both located within the 17th intron of the EVI5 gene. Our findings agree with the corresponding data of the recent IMSGC study and present new genetic evidence that points to EVI5 as a factor of susceptibility to MS.
European journal of human genetics: EJHG 07/2010; 18(7):827-31. · 3.56 Impact Factor
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Nature Immunology 01/2010; 11(1):97. · 26.01 Impact Factor
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Antonio Alcina,
Sreeram V Ramagopalan,
Oscar Fernández,
Antonio Catalá-Rabasa,
María Fedetz,
Dorothy Ndagire,
Laura Leyva,
Carmen Arnal,
Concepción Delgado,
Miguel Lucas, Guillermo Izquierdo,
George C Ebers,
Fuencisla Matesanz
[show abstract]
[hide abstract]
ABSTRACT: A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case-Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values < or =0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648-0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716-0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS.
European journal of human genetics: EJHG 11/2009; 18(5):618-20. · 3.56 Impact Factor
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Antonio Alcina,
María Fedetz,
Dorothy Ndagire,
Oscar Fernández,
Laura Leyva,
Miguel Guerrero,
María M Abad-Grau,
Carmen Arnal,
Concepción Delgado,
Miguel Lucas, Guillermo Izquierdo,
Fuencisla Matesanz
[show abstract]
[hide abstract]
ABSTRACT: IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity.
Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3'- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS.
These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.
PLoS ONE 02/2009; 4(1):e4137. · 4.09 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A possible method of finding physiological markers of multiple sclerosis (MS) is the application of EEG quantification (QEEG) of brain activity when the subject is stressed by the demands of a cognitive task. In particular, modulations of the spectral content that take place in the EEG of patients with multiple sclerosis remitting-relapsing (RRMS) and benign multiple sclerosis (BMS) during a visuo-spatial task need to be observed.
The sample consisted of 19 patients with RRMS, 10 with BMS, and 21 control subjects. All patients were free of medication and had not relapsed within the last month. The power spectral density (PSD) of different EEG bands was calculated by Fast-Fourier-Transformation (FFT), those analysed being delta, theta, alpha, beta and gamma. Z-transformation was performed to observe individual profiles in each experimental group for spectral modulations. Lastly, correlation analyses was performed between QEEG values and other variables from participants in the study (age, EDSS, years of evolution and cognitive performance).
Nearly half (42%) the RRMS patients showed a statistically significant increase of two or more standard deviations (SD) compared to the control mean value for the beta-2 and gamma bands (F = 2.074, p = 0.004). These alterations were localized to the anterior regions of the right hemisphere, and bilaterally to the posterior areas of the scalp. None of the BMS patients or control subjects had values outside the range of +/- 2 SD. There were no significant correlations between these values and the other variables analysed (age, EDSS, years of evolution or behavioural performance).
During the attentional processing, changes in the high EEG spectrum (beta-2 and gamma) in MS patients exhibit physiological alterations that are not normally detected by spontaneous EEG analysis. The different spectral pattern between pathological and controls groups could represent specific changes for the RRMS patients, indicative of compensatory mechanisms or cortical excitatory states representative of some phases during the RRMS course that are not present in the BMS group.
BMC Neurology 12/2008; 8:44. · 2.17 Impact Factor
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Francisco J Quintana,
Mauricio F Farez,
Vissia Viglietta,
Antonio H Iglesias,
Yifat Merbl, Guillermo Izquierdo,
Miguel Lucas,
Alexandre S Basso,
Samia J Khoury,
Claudia F Lucchinetti,
Irun R Cohen,
Howard L Weiner
[show abstract]
[hide abstract]
ABSTRACT: Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.
Proceedings of the National Academy of Sciences 12/2008; 105(48):18889-94. · 9.68 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Some polymorphisms in the FCRL3 gene, a member of the Fc-receptor like family, have been associated with several autoimmune diseases and recently with multiple sclerosis (MS). We performed a case-control study of three SNPs in FCRL3 gene in 645 MS patients and 786 controls, all Caucasians from the South of Spain. Genotype and allele frequencies of two SNPs (rs7528684/FCRL3_3 and rs7522061/N28D), which were in high linkage disequilibrium (r(2) = 0.87), differed between MS cases and controls. The C allele of FCRL3_3 was found to be protective for MS (per allele OR = 0.81, 95% C.I. = 0.70-0.94; P-value = 0.007) as was the G variant of N28D, but no association was found for rs11264799/FCRL3_4. Haplotype analysis confirmed these associations with highly consistent effect sizes for haplotypes carrying the C allele of FCRL3_3.
Journal of Neuroimmunology 04/2008; 195(1-2):146-50. · 2.96 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation.
Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN beta1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years.
We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m - last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m - last visit; CH: 0.29, NCH: 0.13).
Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.
BMC Neurology 01/2008; 8:3. · 2.17 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation.
Methods
Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN β1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years.
Results
We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m – last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m – last visit; CH: 0.29, NCH: 0.13).
Conclusion
Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.
BMC Neurology. 01/2008;
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Lucía Ortiz,
Alzenira F Costa,
María L Bellido,
Francisca Solano,
Jose M García-Moreno,
Miguel A Gamero, Guillermo Izquierdo,
Amal Chadli,
Filipa Falcao,
Jose Ferro,
Javier Salas,
Jose C Alvarez-Cermeño,
Mariano Montori,
María A Ramos-Arroyo,
Alfredo Palomino,
Elizabeth Pintado,
Miguel Lucas
[show abstract]
[hide abstract]
ABSTRACT: We aimed to study clinical, radiological and molecular genetic features of patients with cerebral cavernous malformations (CCMs) from the Iberian Peninsula.
We screened Krit1(CCM1), MGC4607(CCM2), and PDCD10(CCM3) by systematic SSCP and direct sequencing of coding exons in 48 nuclear families and 30 sporadic cases of CCM from Spain and Portugal.
Screening of CCM patients detected nine different mutations in 19 families. We found four new mutations in Krit1. Three of them were caused by either a small insertion or deletion, which lead to frameshift and premature termination codons. We also found a missense L308H mutation located in a highly conserved sequence within the ankyrin domain of Krit1. In CCM2, we found a redundant 14 bp deletion in exon 5 of MGC4607 which predicts a truncated protein at residue 230. We did not find mutations in CCM3.
Finding that the 14 bp deletion was present in eleven families from the Iberian Peninsula indicates a high prevalence of this mutation. This redundant CCM2 mutation is worth considering in molecular diagnosis and genetic counselling of cerebral cavernous malformations.
Journal of Neurology 04/2007; 254(3):322-6. · 3.47 Impact Factor
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ABSTRACT: Cognitive impairment is a common feature in multiple sclerosis (MS) patients and occurs in 60% of all cases. Unfortunately, neurological examination does not always agree with the neuropsychological evaluation in determining the cognitive profile of the patient. On the other hand, psychophysiological techniques such as event-related potentials (ERPs) can help in evaluating cognitive impairment in different pathologies. Behavioural responses and EEG signals were recorded during the experiment in three experimental groups: 1) a relapsing-remitting group (RRMS), 2) a benign multiple sclerosis group (BMS) and 3) a Control group. The paradigm employed was a spatial attention task with central cues (Posner experiment). The main aim was to observe the differences in the performance (behavioural variables) and in the latency and amplitude of the ERP components among these groups.
Our data indicate that both MS groups showed poorer task performance (longer reaction times and lower percentage of correct responses), a latency delay for the N1 and P300 component, and a different amplitude for the frontal N1. Moreover, the deficit in the BMS group, indexed by behavioural and pyschophysiological variables, was more pronounced compared to the RRMS group.
The present results suggest a cognitive impairment in the information processing in all of these patients. Comparing both pathological groups, cognitive impairment was more accentuated in the BMS group compared to the RMSS group. This suggests a silent deterioration of cognitive skills for the BMS that is not usually treated with pharmacological or neuropsychological therapy.
BMC Neuroscience 02/2006; 7:39. · 3.04 Impact Factor
