M Tintoré

Vall d’Hebron Institute of Oncology, Barcino, Catalonia, Spain

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Publications (170)747.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) over a long period of follow-up [median (interquartile range) 9 (5.5-12.5) years] in 19 PPMS and 4 SPMS patients, and to T2 lesion load, T1 lesion load, and brain parenchymal fraction at the time of lumbar puncture. Nf light was higher in PPMS (p < 0.005) and Nf heavy was increased in both SPMS and PPMS (p < 0.05 and p < 0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability measured by MSSS (R (2) = 0.17, β = 0.413; p < 0.05). Conversely, Nf light was the only predictor of the EDSS annual increase (R (2) = 0.195, β = 0.441; p < 0.05). The frequency of abnormal biomarkers did not differ between the two MS progressive subtypes. Our data suggest that PP and SPMS likely share similar mechanisms of axonal damage. Moreover, Nf heavy can be a biomarker of ongoing axonal damage. Conversely, Nf light can be used as a prognostic marker for accumulating disability suggesting it as a good tool for possible treatment monitoring in the progressive MS forms.
    Journal of neurology. 09/2014;
  • Multiple sclerosis (Houndmills, Basingstoke, England). 08/2014;
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    ABSTRACT: The 2010 McDonald criteria allow diagnosing multiple sclerosis (MS) with one magnetic resonance imaging (MRI) scan. Nevertheless, not all patients at risk fulfil criteria at baseline. Other predictive factors (PFs) are: age ≤40 years, positive oligoclonal bands (OBs), and ≥3 periventricular lesions.
    Multiple sclerosis (Houndmills, Basingstoke, England). 05/2014;
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    ABSTRACT: Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system. Its presentation is variable and its course and prognosis are unpredictable. Approximately 85% of individuals present a relapsing-remitting form of the disease, but some patients may evolve into a progressive course, accumulating irreversible neurological disability, defining its secondary progressive phase. Despite all the advances that had been reached in terms of diagnosis, many decisions are still taken based only on pure clinical skills. We present the case of a patient that, after being diagnosed with a clinically isolated syndrome many years ago, seemed to be entering in a secondary progressive course, developing a clinical picture dominated by a progressive gait disturbance. Nevertheless, multiple sclerosis heterogeneity asks for some clinical expertise, in order to exclude all other possible causes for patients' complaints. Here we present an important red flag in the differential diagnosis of secondary progressive multiple sclerosis.
    Acta médica portuguesa. 05/2014; 27(3):393-6.
  • Mar Tintore, Carmen Tur
    Multiple Sclerosis 04/2014; 20(5):518-9. · 4.47 Impact Factor
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    ABSTRACT: In patients with relapsing-remitting multiple sclerosis (RRMS), a scoring system based on new magnetic resonance imaging (MRI) active lesions, relapses and sustained disability progression after a 1-year treatment with IFNβ predicted patient disability progression over time; however, this score had not been tested in patients receiving glatiramer acetate (GA). The objective of this study was to evaluate whether this previous scoring system can also be applied to patients treated with GA. This was a prospective, longitudinal study of 151 RRMS patients treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables. The total possible score range was 0-3. Patients with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively). In RRMS patients treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.
    Multiple Sclerosis 03/2014; · 4.47 Impact Factor
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    ABSTRACT: Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes. Our aim was to analyse the added value of neBHs in patients with clinically isolated syndromes (CISs) for predicting conversion to clinically definite MS (CDMS). Patients were classified based on the presence or absence of neBHs and on the number of Barkhof-Tintoré (B-T) criteria fulfilled. Dissemination in space (DIS) was defined as the presence of at least three of the four B-T criteria. Dissemination in time (DIT)1 was defined by simultaneous presence of enhancing and non-enhancing lesions. DIT2 was defined by simultaneous presence of neBHs and T2 lesions not apparent on T1-weighted images. Focal T2-hyperintense brain lesions were identified in 87.7% of the 520 CIS patients, and 41.4% of them presented at least one neBH. Patients meeting DIS, DIT1, and DIT2 had a significantly higher rate of conversion to CDMS. After adjusting for DIS, only patients who fulfilled DIT1 preserved a significant increase in CDMS conversion. Non-enhancing black holes in CIS patients are associated with a higher risk of conversion to CDMS. However, the predictive value of this finding is lost when added to the DIS criteria.
    Multiple Sclerosis 02/2014; · 4.47 Impact Factor
  • Xavier Montalban, Mar Tintoré
    Nature Reviews Neurology 01/2014; · 15.52 Impact Factor
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    ABSTRACT: To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria. Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model. Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11-74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01-21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96-0.99); p = 0.03], sex (male) [HR: 1.93 (1.24-2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06-4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event. These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.
    PLoS ONE 01/2014; 9(3):e90509. · 3.53 Impact Factor
  • Multiple Sclerosis 12/2013; · 4.47 Impact Factor
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    ABSTRACT: Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain. The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse. Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks' post-treatment initiation. Secondary outcomes were safety and tolerability. The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0-1) vs 0 (0-0.5), p = 0.630), volume of Gd+ lesions (0 (0-88.0) vs 0 (0-32.9) mm(3), p = 0.735), or new or enlarged T2 lesions (0 (0-194) vs 0 (0-123), p = 0.769). MP was well tolerated, and no serious adverse events were reported. This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe. clinicaltrials.gov identifier: NCT00753792.
    Multiple Sclerosis 10/2013; · 4.47 Impact Factor
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    ABSTRACT: The most significant data presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in France in October 2012, have been summarised in the fifth edition of the Post-ECTRIMS Experts Meeting, held in Madrid in October 2012. This led to the drafting of this review, which has been published in three parts. This third part of the Post-ECTRIMS review presents the findings from the latest studies conducted with disease-modifying treatments, more specifically with glatiramer acetate, laquinimod, ponesimod, BG-12, teriflunomide, daclizumab, natalizumab and secukinumab (AIN457). Likewise, we also address the reasons that justify the search for innovative treatments for multiple sclerosis, with antigen-specific therapy, cell therapy and therapy aimed at promoting remyelination being highlighted among other future therapeutic strategies. Access to new pharmacological agents and the complexity of the therapy of multiple sclerosis in the future will require new design strategies and directions in clinical trials, including the use of surrogate markers, new statistical applications, superiority, inferiority or equivalence clinical trials and adaptable designs.
    Revista de neurologia 10/2013; 57(7):317-329. · 1.18 Impact Factor
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    ABSTRACT: The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in October 2012 in France have been summarised in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. This review is the result of the meeting, which is being published in three parts. This second part of the Post-ECTRIMS review discusses the biology of recovery and remyelination in multiple sclerosis (MS) as well as the different repair and endogenous and exogenous remyelination strategies currently being evaluated based on the fact that resident microglia and oligodendroglial progenitor cells have been implicated in the remyelination process. This review also discusses the current state and future use of biomarkers in MS and proposes as markers of neurodegeneration the following: T2 lesion volume and brain atrophy using MRI and the loss of the ganglion cell layer as assessed by optical coherence tomography. A greater future utility for double inversion recovery (DIR) sequences is proposed to correlate cognitive impairment with MS impairment, given its higher diagnostic yield in locating and defining cortical lesions. The availability of novel biomarkers in the future requires strict validation. In this context, this paper proposes possible areas of action to improve the current situation and also presents the latest research results in identifying potential candidates with useful diagnostic characteristics, prognostic characteristics, treatment responses, and safety procedures.
    Revista de neurologia 09/2013; 57(6):269-281. · 1.18 Impact Factor
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    ABSTRACT: The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in October 2012 in France, have been summarized in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. The present review summarizes the views and results of the meeting and is being published in three parts. This first part of the Post-ECTRIMS review addresses the incidence and prevalence of multiple sclerosis (MS), which has increased at the global level, largely due to the increased incidence in women because the risk of developing the disease is increased in females, with minimal concurrent effect on the progression of MS. Sexual dimorphism is evident in MS, and all evidence points to an interaction between hormonal, genetic, and environmental factors. The paediatric population represents an ideal group to study susceptibility factors to the disease, which is why collaborative studies designed to increase the patient samples are being considered, given its low prevalence. In this review, inflammatory and neurodegenerative phenomena involved in the pathogenesis of the disease and that have a cause-and-effect or shared relationship with the disease are being discussed. Current hypotheses suggest a phenomenon of compartmentalization, presumably inaccessible to current immunomodulatory therapy. Among the possible mechanisms involved in these processes of inflammation and demyelination, the role of Th17 cells, mitochondrial dysfunction, early disruption of astrocytic processes, and chronic hypoxia are discussed.
    Revista de neurologia 09/2013; 57(5):217-229. · 1.18 Impact Factor
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    ABSTRACT: Background Neutralising antibodies (NABs)against interferon beta have been describedin one third of patients with multiple sclerosistreated with interferon beta. We haveanalysed the frequency of NABs and theirclinical consequences. Patients and methods We have studied 68patients. NABs were determined by proteinA Myxovirus assay. Results Positive NABs were detected in 13%of the patients after 2 years of treatment. Conclusions It does not seem to exist a relationshipbetween presence of NABs and apoor evolution of the disease in our patientswith multiple sclerosis treated with beta interferon.
    Medicina Clínica. 08/2013; 114(5):169–170.
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    ABSTRACT: Several innovative disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis have been licensed recently or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least 1 of 4 properties, namely (1) trafficking, (2) survival, (3) function, or (4) proliferation. In contrast to β-interferons and glatiramer acetate, the first-generation DMTs, several newer therapies are imbued with safety issues, which may be attributed to their structure or metabolism. In addition to efficacy, understanding the relationship between the mechanism of action of the DMTs and their safety profile is pertinent for decision making and patient care. In this article, we focus primarily on the safety of DMTs in the context of understanding their pharmacological characteristics, including molecular targets, mechanism of action, chemical structure, and metabolism. While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients and to ensure future therapies have the most advantageous benefit-risk profiles. Recognizing the individual classes of DMTs described here may be valuable when considering use of such agents sequentially or possibly in combination.
    JAMA Neurology 08/2013; · 7.58 Impact Factor
  • Hanne F Harbo, Ralf Gold, Mar Tintoré
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    ABSTRACT: Multiple sclerosis (MS) is universally found to be more prevalent in women than men. This has led to extensive studies of differences in the immune system or nervous system between women and men, which might be caused by the effects of gonadal hormones, genetic differences, and different environmental exposures and modern lifestyle in men and women. We review the effects of sex and gender from a genetic, immunological and clinical point of view. We discuss the effects of sex on the clinical expression of MS and responses to therapy, as well as issues concerning pregnancy.
    Therapeutic Advances in Neurological Disorders 07/2013; 6(4):237-48.
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    ABSTRACT: BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. METHODS: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. RESULTS: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (- 0.65% versus + 0.059%; p < 0.001). PBVC decreases below - 0.817% independently predicted shorter times to a second attack. CONCLUSIONS: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.
    Multiple Sclerosis 05/2013; · 4.47 Impact Factor
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    ABSTRACT: Although neuromyelitis optica (NMO) is known to be a more severe disease than relapsing-remitting multiple sclerosis (RRMS), few studies comparing both conditions in a single center have been done. Methods: Comparison of our previously published cohort of 41 NMO patients with 177 RRMS patients followed in the same center, from 1994 to 2007. Results: Mean age of onset was 32.6 for NMO and 30.2 for RRMS (p=0.2062) with mean disease duration of 7.4 years for NMO and 10.3 years for RRMS. Patients with NMO had a higher annualized relapse rate (1.0 versus 0.8, p=0.0013) and progression index (0.9 versus 0.6, p≪0.0001), with more patients reaching expanded disability status scale (EDSS) 6.0 (39 versus 17%, p=0.0036). The odds ratio for reaching EDSS 6.0 and being deceased due to NMO in comparison to RRMS were, respectively, 3.14 and 12.15. Conclusion: Patients with NMO have a more severe disease than patients with RRMS, including higher risk of dying of a demyelinating disease.
    Arquivos de neuro-psiquiatria 05/2013; 71(5):275-279. · 0.55 Impact Factor
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    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; · 8.25 Impact Factor

Publication Stats

2k Citations
747.48 Total Impact Points

Institutions

  • 2000–2014
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
    • Hospital de Barcelona. SCIAS
      Barcino, Catalonia, Spain
  • 1991–2014
    • University Hospital Vall d'Hebron
      • Department of Neurology
      Barcino, Catalonia, Spain
  • 2013
    • Universidad de Las Palmas de Gran Canaria
      Las Palmas, Canary Islands, Spain
    • Oslo University Hospital
      • Department of Neurology
      Oslo, Oslo, Norway
  • 2011–2013
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2012
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
  • 2011–2012
    • Junta De Andalucía
      Cádiz, Andalusia, Spain
  • 2008–2010
    • VU University Medical Center
      • Department of Neurology
      Amsterdam, North Holland, Netherlands
    • Università degli Studi di Genova
      • Dipartimento di Scienze della salute (DISSAL)
      Genova, Liguria, Italy
  • 2007
    • Hospital Clínico San Carlos
      • Servicio de Neurología
      Madrid, Madrid, Spain
  • 2006
    • Hospital Clinica Benidorm
      Benidorm, Valencia, Spain
  • 2001
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden