Bruno Dubois

Université Paris-Sorbonne - Paris IV, Lutetia Parisorum, Île-de-France, France

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Publications (539)3008.84 Total impact

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    Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0099-0 · 3.50 Impact Factor
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    ABSTRACT: We investigated the utility of sulcal width measures in the diagnosis of Alzheimer’s disease (AD). Sixty-six biologically confirmed AD patients (positive amyloid Positron Emission Tomography – PET and/or AD Cerebro-Spinal Fluid profile) were contrasted to 35 controls with negative amyloid PET. Patients were classified into prodromal or dementia stages as well as into late onset (LOAD, n=31) or ealy onset (EOAD, n=35) subgroups according to their age of onset. An automated method was used to calculate sulcal widths and hippocampal volumes (HV). In EOAD, the greatest ability to differentiate patients from age-matched controls, regardless of severity, was displayed by the temporo-parietal cortex. Diagnosis accuracy was better in this region than the HV, especially at prodromal stage. In LOAD, HV provided the best discrimination power from age-matched controls. In conclusion, sulcal width measures are better markers than the HV for identifying prodromal AD in patients younger than 65 years of age. In contrast, in older patients, the risk of over-diagnosis from using only sulcal enlargement is important.
    Neurobiology of Aging 04/2015; in press. · 4.85 Impact Factor
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    ABSTRACT: The clinical differential diagnosis of Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) can no longer rely only on episodic memory impairment or executive dysfunctions, as highlighted by recent findings showing that both diseases could present with similar impairments. Objective cognitive tests assessing specific symptoms, such as impulsivity in bvFTD, are thus crucially needed. The aim of this study was to evaluate the differences in impulsivity between bvFTD and AD using a delay-discounting paradigm. An ecological delay-discounting test was administrated to 70 participants including 30 ADs, 20 bvFTD and 20 controls. AD patients were divided according to the severity of the disease into mild or moderate group. The delay-discounting score, reflecting the total percentage of impulsive choice across the entire task, was analyzed for each group. This score showed that bvFTD patients were significantly more impulsive than controls and AD patients at mild or moderate stage. AD patients, regardless of disease stage, did not differ from controls. ROC analyses revealed high and significant area under the curve (AUC, 95% confidence interval) for this score to differentiate bvFTD from AD (0.704) or controls (0.904), or both group (AD + controls; AUC = 0.791). The total delay-discounting score provided by our task showed that it could accurately differentiate bvFTD patients from AD and controls. These results support the relevancy of using tests inspired by experimental psychoeconomics and taping into reward processing to increase the distinction between both diseases. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
    Neuropsychology 04/2015; DOI:10.1037/neu0000197 · 3.43 Impact Factor
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    ABSTRACT: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aβ1-42), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia. A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases. CSF Aβ1-42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32-62) to 77% (for FTD, 95% CI = 62-90). CSF Aβ1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2015; DOI:10.1016/j.jalz.2014.12.006 · 17.47 Impact Factor
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    ABSTRACT: Hippocampus volumetry based on magnetic resonance imaging (MRI) has not yet been translated into everyday clinical diagnostic patient care, at least in part due to limited availability of appropriate software tools. In the present study, we evaluate a fully-automated and computationally efficient processing pipeline for atlas based hippocampal volumetry using freely available Statistical Parametric Mapping (SPM) software in 198 amnestic mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). Subjects were grouped into MCI stable and MCI to probable Alzheimer's disease (AD) converters according to follow-up diagnoses at 12, 24, and 36 months. Hippocampal grey matter volume (HGMV) was obtained from baseline T1-weighted MRI and then corrected for total intracranial volume and age. Average processing time per subject was less than 4 minutes on a standard PC. The area under the receiver operator characteristic curve of the corrected HGMV for identification of MCI to probable AD converters within 12, 24, and 36 months was 0.78, 0.72, and 0.71, respectively. Thus, hippocampal volume computed with the fully-automated processing pipeline provides similar power for prediction of MCI to probable AD conversion as computationally more expensive methods. The whole processing pipeline has been made freely available as an SPM8 toolbox. It is easily set up and integrated into everyday clinical patient care.
    Journal of Alzheimer's disease: JAD 02/2015; DOI:10.3233/JAD-142280 · 3.61 Impact Factor
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    ABSTRACT: To study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2015; DOI:10.1016/j.jalz.2014.10.003 · 17.47 Impact Factor
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    Simone Lista, B Dubois, H Hampel
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    ABSTRACT: Alzheimer's disease (AD) represents an increasing worldwide healthcare epidemic. Secondary preventive disease-modifying treatments under clinical development are considered most effective when initiated as early as possible in the pathophysiological course and progression of the disease. Major targets are to enhance clearance and to reduce cerebral accumulation of amyloid, decrease hyperphosphorylation of tau and the generation of neurofibrillary tangles, reduce inflammation, and finally progressive neurodegeneration. Comprehensive sets of biological markers are needed to characterize the pathophysiological mechanisms, indicate effects of treatment and to facilitate early characterisation and detection of AD during the prodromal or even at asymptomatic stages. No primary or secondary preventive treatments for AD have been approved. Epidemiological research, however, has provided evidence of specifically modifiable risk and protective factors. Among them are vascular, lifestyle and psychological risk factors that may act both independently and by potentiating each other. These factors may be substantially impacted by single or multi-domain strategies to prevent or postpone the onset of AD-related pathophysiology. Researchers have recently started the European Dementia Prevention Initiative (EDPI), an international consortium to improve strategies for preventing dementia. EDPI, in particular, includes the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) which aims at optimizing the early identification of subjects at increased risk of late-life cognitive deterioration, and at the evaluation of multi-domain intervention strategies. The ongoing discussion on new diagnostic criteria provided by the International Working Group (IWG), as well as by the recommendations summoned by the National Institute on Aging and Alzheimer's Association (NIA-AA) initiative, has inspired the creation of novel study designs and the definition of earlier target populations for trials in pre- and asymptomatic at-risk and prodromal stages of AD. As a result, a number of promising international prevention trials are currently ongoing. In this review, we critically discuss the main paths to AD prevention through control of modifiable risk factors and lifestyle changes. We will also review the role of biomarkers to identify subgroups of patients who would most likely benefit from secondary prevention strategies, and to evaluate the benefit of treatment in such patients.
    The Journal of Nutrition Health and Aging 01/2015; 19(2):154-63. DOI:10.1007/s12603-014-0515-3 · 2.66 Impact Factor
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    ABSTRACT: Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described. We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient. This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present.
    JAMA Neurology 12/2014; 72(2). DOI:10.1001/jamaneurol.2014.3308 · 7.01 Impact Factor
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    ABSTRACT: Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
    Expert Review of Neurotherapeutics 12/2014; 15(1):1-23. DOI:10.1586/14737175.2015.995637 · 2.83 Impact Factor
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    ABSTRACT: Concept formation is the ability to create an abstract link between dissimilar objects or thoughts and is crucial for abstract and creative thinking. This process is related to the integrity of the prefrontal cortex, given the altered performances reported in patients with frontal damage, particularly those suffering from the behavioural variant of frontotemporal dementia. However, the cognitive mechanisms and neural bases of verbal concept formation are not clearly understood. The present study was aimed at addressing the following unresolved issues regarding concept formation in the field of neurology and cognitive neuroscience: (i) Are alterations in concept formation specific to frontotemporal dementia or are they also present in other cortical neurodegenerative disorders such as Alzheimer's disease? (ii) Is impaired performance in concept formation due to cortical lesions specific to frontotemporal dementia or to a cortico-subcortical frontal syndrome? and (iii) What are the cognitive mechanisms and neural bases underlying concept formation? To address these questions, we designed the Verbal Concept Formation Task, an experimental paradigm based on the similarities test. Patients presenting with severe frontal dysfunction (frontotemporal dementia, n = 18, and the Richardson form of progressive supranuclear palsy, n = 21) or with medial temporal pathology (amnestic mild cognitive impairment or Alzheimer's disease, n = 14) and healthy participants (n = 18) were given the Verbal Concept Formation Task and a large battery of neuropsychological tests. In addition, all participants underwent 3D T1-weighted MRI to analyse grey matter volume using voxel-based morphometry. Frontal patients were significantly impaired on the Verbal Concept Formation Task as compared to non-frontal participants (P = 0.00001). Global performance score was positively correlated with scores in cognitive tasks assessing executive functions and with grey matter volume in several areas, mostly in the frontal-basal-ganglion network. Two types of errors were observed in frontal patients. The most frequent was discriminating instead of grouping items ('linking deficit'). Patients also linked items on a concrete instead of an abstract basis ('abstraction deficit'). Linking and abstraction deficits were related to partially different areas: the linking deficit to the dorsal anterior cingulate cortex, right middle frontal gyrus and both inferior parietal lobules and the abstraction deficit to the head of the caudate nuclei and the left superior frontal gyrus. These data suggest that verbal concept formation requires the integrity of the prefrontal-basal-ganglion functional network. In addition, it can be divided into two distinct cognitive processes, which are underlain by two partially different neural networks. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 12/2014; DOI:10.1093/brain/awu359 · 10.23 Impact Factor
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    ABSTRACT: The extent to which social cognitive changes reflect a discrete constellation of symptoms dissociable from general cognitive changes in Alzheimer's disease (AD) is unclear. Moreover, whether social cognitive symptoms contribute to disease severity and progression is unknown. The current multicenter study investigated cross-sectional and longitudinal associations between social cognition measured with six items from the Blessed Dementia Rating Scale, general cognition, and dependence in 517 participants with probable AD. Participants were monitored every 6 months for 5.5 years. Results from multivariate latent growth curve models adjusted for sex, age, education, depression, and recruitment site revealed that social cognition and general cognition were unrelated cross-sectionally and throughout time. However, baseline levels of each were related independently to dependence, and change values of each were related independently to change in dependence. These findings highlight the separability of social and general cognition in AD. Results underscore the relevance of considering social cognition when modeling disease and estimating clinical outcomes related to patient disability.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2014; 10(6). DOI:10.1016/j.jalz.2013.12.021 · 17.47 Impact Factor
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    ABSTRACT: Abstract Objective: To define a practice guideline for biological treatment of dementias for general practitioners in primary care. Methods: This paper is a short and practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines for the Biological treatment of Alzheimer's disease and other dementias for treatment in primary care. The recommendations were developed by a task force of international experts in the field and are based on randomized controlled studies. Results: Anti-dementia medications neither cure, nor arrest, or alter the course of the disease. The type of dementia, the individual symptom constellation and the tolerability and evidence for efficacy should determine what medications should be used. In treating neuropsychiatric symptoms, psychosocial intervention should be the treatment of first choice. For neuropsychiatric symptoms, medications should only be considered when psychosocial interventions are not adequate and after cautious risk-benefit analysis. Conclusions: Depending on the diagnostic entity and clinical presentation different anti-dementia drugs can be recommended. These guidelines provide a practical approach for general practitioners managing dementias.
    International Journal of Psychiatry in Clinical Practice 09/2014; DOI:10.3109/13651501.2014.961931 · 1.31 Impact Factor
  • Bruno Dubois
    La Presse Médicale 09/2014; DOI:10.1016/j.lpm.2014.06.002 · 1.17 Impact Factor
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    ABSTRACT: The Allais Paradox represents one of the earliest empirical challenges to normative models of decision-making, and suggests that choices in one part of a gamble may depend on the possible outcome in another, independent, part of the gamble—a violation of the so-called "independence axiom." To account for Allaisian behavior, one well-known class of models propose that individuals' choices are influenced not only by possible outcomes resulting from one's choices, but also the anticipation of regret for foregone options. Here we test the regret hypothesis using a population of patients with behavioral variant frontotemporal dementia (bvFTD), a clinical population known to present ventromedial prefrontal cortex dysfunctions and associated with impaired regret processing in previous studies of decision-making. Compared to matched controls and Alzheimer's disease (AD) patients, we found a striking diminution of Allaisian behavior among bvFTD patients. These results are consistent with the regret hypothesis and furthermore suggest a crucial role for prefrontal regions in choices that typically stands in contradiction with a basic axiom of rational decision-making.
    Frontiers in Neuroscience 09/2014; 8. DOI:10.3389/fnins.2014.00287
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    ABSTRACT: The objective of our study was to compare Movement Disorder Society Task Force criteria for diagnosis of Parkinson's disease dementia (PDD) with the gold standard of traditional neuropsychological testing. A short checklist (Level I) and a protocol of neuropsychological tests (Level II) have been proposed by a Movement Disorder Society Task Force but not fully validated in clinical practice. Ninety-one Parkinson's disease (PD) subjects were categorized as having dementia or no dementia based on a battery of neuropsychological test results and clinical judgment. The isolated components needed for Level I and Level II diagnoses were then culled from the neuropsychological evaluations and independently used to designate PDD. Compared with traditional neuropsychological testing, the sensitivity and specificity of Level I criteria for PDD was 66.7% and 98.8%, and for Level II criteria 100% and 92.7%, respectively. Using Level II criteria, 6 additional subjects were diagnosed with PDD that were classified as having no dementia when full neuropsychological data were used for the diagnosis. These 6 subjects had more education years and were less impaired on cognitive tests. The Movement Disorder Society's Level II criteria more frequently classify subjects with PDD than does traditional neuropsychological testing. Whereas Level II criteria may overclassify subjects as having PDD, they are very accurate in ruling out dementia. Movement Disorder Society's criteria are practical and timesaving, although full neuropsychological testing may still be needed. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 09/2014; 29(10). DOI:10.1002/mds.25902 · 5.63 Impact Factor
  • Bruno Dubois
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    ABSTRACT: To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-β42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.
    Translational Psychiatry 08/2014; 4(8):e425. DOI:10.1038/tp.2014.61 · 4.36 Impact Factor
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    ABSTRACT: Hippocampal atrophy as assessed by magnetic resonance Imaging (MRI) is a supportive feature for the diagnosis of AD and is assumed to be a marker of neuronal injury. This study aims to test the diagnostic value of HV decrease with one-year interval in biological confirmed AD.
    Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Vol. 10, Issue 4, P834; 07/2014
  • Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Vol. 10, Issue 4, P706; 07/2014

Publication Stats

26k Citations
3,008.84 Total Impact Points


  • 2015
    • Université Paris-Sorbonne - Paris IV
      Lutetia Parisorum, Île-de-France, France
  • 2007–2015
    • Pierre and Marie Curie University - Paris 6
      • Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière
      Lutetia Parisorum, Île-de-France, France
  • 2010–2014
    • UPMC
      Pittsburgh, Pennsylvania, United States
    • L'Institut du Cerveau et de la Moelle Épinière
      Lutetia Parisorum, Île-de-France, France
  • 2005–2014
    • Assistance Publique – Hôpitaux de Paris
      • Department of Neurology
      Lutetia Parisorum, Île-de-France, France
    • University of Louisville
      • Division of Movement Disorders
      Louisville, Kentucky, United States
    • University of Thessaly
      • Κλινική Νευρολογίας
      Iolcus, Thessaly, Greece
    • Centre Hospitalier Universitaire de Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1995–2014
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Médecine Nucléaire
      Lutetia Parisorum, Île-de-France, France
  • 1988–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1985–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2009–2013
    • Columbia University
      • • Taub Institute for Research on Alzheimer's Disease and the Aging Brain
      • • Department of Neuroscience
      New York City, New York, United States
    • Catholic University of Louvain
      Лувен-ла-Нев, Walloon, Belgium
    • Icahn School of Medicine at Mount Sinai
      Borough of Manhattan, New York, United States
  • 2005–2013
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2009–2012
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2007–2012
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • University of Toronto
      • Division of Neurology
      Toronto, Ontario, Canada
    • Banner Sun Health Research Institute
      Sun City, Arizona, United States
    • Universitair Ziekenhuis Leuven
      • Department of Neurology
      Leuven, VLG, Belgium
  • 1998–2011
    • University of Leuven
      • • Laboratory of Experimental Transplantation
      • • Department of Microbiology and Immunology
      Louvain, Flanders, Belgium
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      Créteil, Île-de-France, France
    • Duke University
      Durham, North Carolina, United States
  • 2008
    • Université Paris 13 Nord
      Île-de-France, France
    • Brookhaven National Laboratory
      New York, New York, United States
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • University of Santiago, Chile
      CiudadSantiago, Santiago Metropolitan, Chile
  • 2002
    • University of Strasbourg
      Strasburg, Alsace, France
  • 2001
    • Centre Hospitalier Universitaire de Limoges
      Limages, Limousin, France
  • 1989–2000
    • Atomic Energy and Alternative Energies Commission
      Fontenay, Île-de-France, France
  • 1996
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
  • 1990
    • Institute of Geophysics, China Earthquake Administration
      Peping, Beijing, China