Xavier Montalban

VHIR Vall d’Hebron Research Institute, Barcino, Catalonia, Spain

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Publications (419)2495.62 Total impact

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    ABSTRACT: We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.
    Multiple sclerosis (Houndmills, Basingstoke, England). 11/2014;
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    ABSTRACT: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months.
    Multiple sclerosis (Houndmills, Basingstoke, England). 11/2014;
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    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;
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    Multiple sclerosis (Houndmills, Basingstoke, England). 09/2014; 20(10):1417-1419.
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    ABSTRACT: The presence of oligoclonal IgM bands (OCMB) in cerebrospinal fluid (CSF) is an unfavourable prognostic marker in multiple sclerosis. There is no commercial test to investigate OCMB status. However, a sensitive and specific isoelectrofocusing (IEF) and western blot method was described. We aimed to study the inter-centre reproducibility of this technique, a necessary condition for a reliable test to be incorporated into clinical practice.
    Clinica Chimica Acta. 08/2014; 438.
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    ABSTRACT: Objective Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.Methods This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.
    Annals of Clinical and Translational Neurology. 08/2014;
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    ABSTRACT: To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy.
    Annals of Neurology 08/2014; 76(2). · 11.19 Impact Factor
  • Nicolás Fissolo, Xavier Montalban, Manuel Comabella
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    ABSTRACT: Multiple sclerosis (MS) is the most common inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS) in humans. Although the etiology of MS remains unknown, several lines of evidence support the notion that autoimmunity against components of the myelin sheath plays a major role in susceptibility to and development of the disease. At present, there are no approved MS therapies aimed specifically toward downregulating antigen-specific autoreactive immune cells. One antigen-specific approach that appears promising for the treatment of MS is DNA vaccination. This technique has demonstrated efficacy in clinical trials while maintaining safety.Here, we describe the generation of DNA vaccines containing immunologically relevant antigens of MS. Moreover, we present a detailed protocol for the prophylactic and therapeutic administration of DNA vaccines via intramuscular injection targeting on the development of experimental autoimmune encephalomyelitis (EAE), an animal model resembling MS.
    Methods in molecular biology (Clifton, N.J.) 06/2014; · 1.29 Impact Factor
  • Carmen Tur, Xavier Montalban
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    ABSTRACT: At present, three risk factors for the development of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients have been identified: the presence of antibodies against JC virus (JCV); the duration of natalizumab treatment, especially if longer than 2 years; and the use of immunosuppressants prior to receiving natalizumab. The most commonly used strategy to assess the individual PML risk includes serum anti-JCV antibody testing. Based on the knowledge on all known risk factors, an algorithm for PML risk stratification has been proposed, where patients with the highest PML risk are those with positive anti-JCV antibodies, treatment duration longer than 2 years, with or without prior history of immunosuppression. These patients would have an approximate incidence of PML of 11.1 (with prior immunosuppression) or 4.6 (without prior immunosuppression) cases per 1,000 patients treated with natalizumab (and treatment duration longer than 2 years). In this review, new data on PML risk factors and possible new strategies for PML risk stratification are discussed.
    CNS Drugs 06/2014; · 4.38 Impact Factor
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    ABSTRACT: Multiple sclerosis is a chronic, demyelinating and inflammatory disease of the central nervous system that mainly affects young adults. It is characterised by processes involving inflammation, demyelination and axonal destruction, and as a result the pathogenic aspects and response to treatment of the disease vary widely. It is therefore difficult to establish a prognosis for these patients or to determine the effectiveness of the different drugs that are employed. Current clinical research into the development of new biomarkers has advanced a great deal in recent years, especially in the early stages of the disease. Yet, it is essential to further our knowledge about novel markers of the disease, and not only in the more advanced stages, so as to be able to stop disability from progressing and to establish new therapy regimens in these patients. This review presents an update on the information available about the biomarkers that are currently validated and used in multiple sclerosis, together with the possible candidates for utilisation in routine clinical practice.
    Revista de neurologia. 06/2014; 58(12):553-570.
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    ABSTRACT: Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. Open access full paper at //www.neurology.org/content/83/3/278.abstract
    Neurology 05/2014; · 8.30 Impact Factor
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    ABSTRACT: Impairment of nerve conduction is common in neurodegenerative and neuroinflammatory diseases such as multiple sclerosis (MS), and measurement of evoked potentials (visual, motor, or sensory) has been widely used for diagnosis and recently also as a prognostic marker for MS. We used a classical genetic approach to identify novel genes controlling nerve conduction. First, we used quantitative trait mapping in F2 progeny of B10/SJL mice to identify EAE31, a locus controlling latency of motor evoked potentials (MEPs) and clinical onset of experimental autoimmune encephalomyelitis. Then, by combining congenic mapping, in silico haplotype analyses, and comparative genomics we identified inositol polyphosphate-4- phosphatase, type II (Inpp4b) as the quantitative trait gene for EAE31. Sequence variants of Inpp4b (C/A, exon 13; A/C, exon 14) were identified as differing among multiple mouse strains and correlated with individual cortical MEP latency differences. To evaluate the functional relevance of the amino acid ex- changes at positions S474R and H548P, we generated transgenic mice carrying the longer-latency allele (Inpp4b474R/548P) in the C57BL/6J background. Inpp4b474R/548P mice exhibited significantly longer cortical MEP latencies (4.5 ` 0.22 ms versus 3.7 ` 0.13 ms; P Z 1.04 10�9), indicating that INPP4B regulates nerve conduction velocity. An association of an INPP4B polymorphism (rs13102150) with MS was observed in German and Spanish MS cohorts (3676 controls and 911 cases) (P Z 8.8 10�3).
    American Journal Of Pathology 05/2014; · 4.60 Impact Factor
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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.
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    ABSTRACT: Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe. Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives. The combined presence of DRB1*07/DQA1*02 with A*26 or B*14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB1*04:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A*11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB1*03/DQA1*05/DQB1*02 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB1*13/DQA1*01:03/DQB1*06:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)). 50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.
    Journal of Medical Genetics 04/2014; · 5.70 Impact Factor
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    ABSTRACT: The levels of soluble tumor necrosis factor receptor II (sTNF-RII) were determined in serum of 161 untreated multiple sclerosis (MS) patients with different clinical forms and 46 healthy controls (HC) by ELISA. Our results show that serum sTNF-RII levels were significantly increased in patients with primary progressive MS (PPMS) compared with other MS forms and HC. Although sTNF-RII levels significantly increased over a 2-year follow-up period in a subgroup of PPMS patients, they could not discriminate between patients with and without disability progression. Additional studies are needed to further implicate sTNF-RII in patients with PPMS.
    Journal of neuroimmunology 04/2014; · 2.84 Impact Factor
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    Neurology 04/2014; 82(10):P2.245. · 8.30 Impact Factor
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    ABSTRACT: Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks. Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity. MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies. This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.
    Neurology 03/2014; · 8.30 Impact Factor
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    ABSTRACT: AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intra-species diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch specific-selection at the catarrhini lineage for IFI16. Application of a population-genetics phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA binding interface in both IFI16 and AIM2. In IFI16 several sites positively selected in primates and in the human lineage were located in the PYD domain, which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.
    Genome Biology and Evolution 03/2014; · 4.76 Impact Factor
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    ABSTRACT: In the SELECT trial, disease activity was reduced in patients with multiple sclerosis who received daclizumab high-yield process (HYP) for 52 weeks. The primary aim of the SELECTION extension study was to assess the safety and immunogenicity of extended treatment with daclizumab HYP. A multicentre, randomised, double-blind, 52-week extension trial was done in 74 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, and the UK between Feb 13, 2009, and Oct 3, 2012. Eligible patients were aged 18-55 years, had relapsing-remitting multiple sclerosis, and had completed the SELECT study. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 mg or 300 mg subcutaneous daclizumab HYP every 4 weeks for 52 weeks (treatment initiation group); those who had received daclizumab HYP were randomly assigned (1:1) to continue their present dose with (washout and re-initiation group) or without (continuous treatment group) a washout period of 20 weeks. All randomisation was done with a centralised, interactive voice-response system. Patients and personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug but had no interaction with patients. The primary endpoints were the safety and immunogenicity of daclizumab HYP. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00870740. 517 (91%) of 567 patients who completed the SELECT trial entered SELECTION, of whom 170 were in the treatment initiation group, 173 in the continuous treatment group, and 174 in the washout and re-initiation group. 11 patients in the treatment initiation group (6%), 13 in the continuous treatment group (8%), and ten in the washout and re-initiation group (6%) had any serious adverse event other than relapse of multiple sclerosis. One patient in the washout and re-initiation group (300 mg daclizumab HYP) died because of autoimmune hepatitis; a contributory role of daclizumab HYP could not be excluded. Seven patients tested positive for neutralising antidrug antibodies: one (1%) of 128 for whom data were available in the continuous treatment group (this patient also tested positive at SELECTION baseline), four (2%) in the treatment initiation group, and two (2%) of 129 in the washout and re-initiation group. Adverse events and immunogenicity were not increased in the second year of continuous treatment with daclizumab HYP or during treatment washout and re-initiation. These results support further assessment of daclizumab HYP for relapsing-remitting multiple sclerosis. Biogen Idec and AbbVie Biotherapeutics.
    The Lancet Neurology 03/2014; · 23.92 Impact Factor

Publication Stats

9k Citations
2,495.62 Total Impact Points

Institutions

  • 2012–2014
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
    • Universität Basel
      Bâle, Basel-City, Switzerland
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1995–2014
    • University Hospital Vall d'Hebron
      • • Department of Neurology
      • • Department of Radiology
      Barcino, Catalonia, Spain
  • 2013
    • Hospital Universitario Puerta de Hierro-Majadahonda
      • Servicio de Neurofisiología
      Madrid, Spain
    • Universidad de Las Palmas de Gran Canaria
      Las Palmas, Canary Islands, Spain
  • 2000–2013
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
    • Polytechnic University of Catalonia
      Barcino, Catalonia, Spain
    • Hospital de Barcelona. SCIAS
      Barcino, Catalonia, Spain
  • 2011–2012
    • Hospital Virgen del Camino
      Cádiz, Andalusia, Spain
    • IMIM Hospital del Mar Medical Research Institute
      Barcino, Catalonia, Spain
  • 2009–2012
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
    • Fondazione Don Carlo Gnocchi
      • Multiple Sclerosis Centre
      Milano, Lombardy, Italy
    • University of Zurich
      • Institut für Experimentelle Immunologie
      Zürich, ZH, Switzerland
  • 2006–2012
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, England, United Kingdom
    • Hospital Clinica Benidorm
      Benidorm, Valencia, Spain
  • 2005–2012
    • University College London
      • • Department of Neuroinflammation
      • • Institute of Neurology
      London, ENG, United Kingdom
    • Hospital Universitari de Bellvitge
      l'Hospitalet de Llobregat, Catalonia, Spain
  • 1995–2012
    • Hospital Regional Universitario Carlos Haya Málaga
      • Departamento de Neurología
      Málaga, Andalusia, Spain
  • 2007–2011
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
  • 2010
    • Catalan Institution for Research and Advanced Studies
      Barcino, Catalonia, Spain
    • University of Barcelona
      • Departament de Medicina
      Barcelona, Catalonia, Spain
    • Università degli Studi di Siena
      Siena, Tuscany, Italy
  • 2006–2010
    • VU University Medical Center
      • • Department of Neurology
      • • Department of Radiology
      Amsterdam, North Holland, Netherlands
  • 2004–2009
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2008
    • University of Oxford
      Oxford, England, United Kingdom
    • Università degli Studi di Genova
      • Dipartimento di Scienze della salute (DISSAL)
      Genova, Liguria, Italy
  • 2007–2008
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2005–2008
    • University of California, San Francisco
      • • Department of Neurology
      • • Division of Hospital Medicine
      San Francisco, CA, United States
  • 2003
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2001
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden