Stephen L Hauser

University of California, San Francisco, San Francisco, California, United States

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Publications (335)3481.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine – i.e. the application of information technology to medicine—has the potential to radically transform medical practice. We introduce three key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real-time use of the data to assist decision-making). Together these form the stepping-stones that are expected to accelerate standardization of data across platforms, promote evidence-based medicine, support shared decision-making, and ultimately lead to improved outcomes. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 09/2014; · 11.19 Impact Factor
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    ABSTRACT: In multiple sclerosis (MS), lymphocyte-in particular B cell-transit between the central nervous system (CNS) and periphery may contribute to the maintenance of active disease. Clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MS patients; however, it remains unclear which subpopulations of the highly diverse peripheral B cell compartment share antigen specificity with intrathecal B cell repertoires and whether their antigen stimulation occurs on both sides of the blood-brain barrier. To address these questions, we combined flow cytometric sorting of PB B cell subsets with deep immune repertoire sequencing of CSF and PB B cells. Immunoglobulin (IgM and IgG) heavy chain variable (VH) region repertoires of five PB B cell subsets from MS patients were compared with their CSF Ig-VH transcriptomes. In six of eight patients, we identified peripheral CD27(+)IgD(-) memory B cells, CD27(hi)CD38(hi) plasma cells/plasmablasts, or CD27(-)IgD(-) B cells that had an immune connection to the CNS compartment. Pinpointing Ig class-switched B cells as key component of the immune axis thought to contribute to ongoing MS disease activity strengthens the rationale of current B cell-targeting therapeutic strategies and may lead to more targeted approaches.
    Science translational medicine 08/2014; 6(248):248ra106. · 10.76 Impact Factor
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    ABSTRACT: Objective: In multiple sclerosis (MS) cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SCGM atrophy. Using phase sensitive inversion recovery (PSIR) MRI, we determined the association of the SCGM and SCWM areas with MS disability and disease type.Methods: 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disc level. Two independent, clinically-masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates.Results: Relapsing (R) MS patients showed smaller SCGM areas than age and sex matched controls (p=0.008) without significant differences in SCWM areas. Progressive MS patients showed smaller SCGM and SCWM areas compared to RMS patients (all p≤0.004). SCGM, SCWM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p≤0.001). SCGM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, FLAIR lesion load, T1-lesion load, SCWM area, number of spinal cord T2 lesions, age, sex, disease duration. Brain and spinal GM independently contributed to EDSS.Interpretation: SCGM atrophy is detectable in-vivo in absence of WM atrophy in RMS. It is more pronounced in progressive than RMS and contributes more to patient disability than spinal cord WM or brain GM atrophy. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 08/2014; · 11.19 Impact Factor
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    ABSTRACT: Objective: In multiple sclerosis (MS) cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SCGM atrophy. Using phase sensitive inversion recovery (PSIR) MRI, we determined the association of the SCGM and SCWM areas with MS disability and disease type. Methods: 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disc level. Two independent, clinically-masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Results: Relapsing (R) MS patients showed smaller SCGM areas than age and sex matched controls (p=0.008) without significant differences in SCWM areas. Progressive MS patients showed smaller SCGM and SCWM areas compared to RMS patients (all p≤0.004). SCGM, SCWM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p≤0.001). SCGM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, FLAIR lesion load, T1-lesion load, SCWM area, number of spinal cord T2 lesions, age, sex, disease duration. Brain and spinal GM independently contributed to EDSS. Interpretation: SCGM atrophy is detectable in-vivo in absence of WM atrophy in RMS. It is more pronounced in progressive than RMS and contributes more to patient disability than spinal cord WM or brain GM atrophy.
    Annals of Neurology 08/2014; · 11.19 Impact Factor
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    ABSTRACT: Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.
    Nature medicine. 07/2014;
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    ABSTRACT: Objective There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N-acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects.Methods We used multivoxel spectroscopy at 3T to longitudinally estimate Glu and NAA concentrations from large areas of normal-appearing white and gray matter (NAWM and GM) in MS patients (n = 343) with a mean follow-up time of 5 years. Using linear mixed-effects models, Glu was examined as a predictor of NAA decline, annualized percentage brain volume change, and evolution of clinical outcomes (Multiple Sclerosis Functional Composite [MSFC], Paced Auditory Serial Addition Test-3 [PASAT], and Expanded Disability Status Scale). Glu/NAA ratio was tested as a predictor of brain volume loss and clinical outcomes.ResultsBaseline Glu[NAWM] was predictive of accelerated longitudinal decline in NAA[GM] (−0.06mM change in NAA[GM]/yr for each unit increase in Glu; p = 0.004). The sustained elevation of Glu[NAWM] was predictive of a loss of 0.28mM/yr in NAA[NAWM] (p < 0.001) and 0.15mM/yr in NAA[GM] (p = 0.056). Each 10% increase in Glu/NAA[NAWM] was associated with a loss of 0.33% brain volume/yr (p = 0.001), 0.009 standard deviations/yr in MSFC z-score (p < 0.001), and 0.17 points/yr on the PASAT (p < 0.001).InterpretationThese results indicate that higher Glu concentrations increase the rate of NAA decline, and higher Glu/NAA[NAWM] ratio increases the rate of decline of brain volume, MSFC, and PASAT. This provides evidence of a relationship between brain Glu and markers of disease progression in MS. Ann Neurol 2014
    Annals of Neurology 07/2014; · 11.19 Impact Factor
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    ABSTRACT: In multiple sclerosis (MS), B cell-depleting therapy using monoclonal anti-CD20 Abs, including rituximab (RTX) and ocrelizumab, effectively reduces disease activity. Based on indirect evidence, it is generally believed that elimination of the Ag-presenting capabilities and Ag nonspecific immune functions of B cells underlie the therapeutic efficacy. However, a small subset of T lymphocytes (T cells) was shown to also express CD20, but controversy prevails surrounding the true existence of this T cell subpopulation. Using single-cell imaging flow cytometry and expression profiling of sorted lymphocyte subsets, we unequivocally demonstrate the existence of CD3(+)CD20(dim) T cells. We show that in MS patients, increased levels of CD3(+)CD20(dim) T cells are effectively depleted by RTX. The pathological relevance of this T cell subset in MS remains to be determined. However, given their potential proinflammatory functionality, depletion of CD20-expressing T cells may also contribute to the therapeutic effect of RTX and other mAbs targeting CD20.
    Journal of immunology (Baltimore, Md. : 1950). 06/2014;
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    ABSTRACT: IMPORTANCE Predicting disease evolution is becoming essential for optimizing treatment decision making in multiple sclerosis (MS). Multiple sclerosis pathologic damage typically includes demyelination, neuro-axonal loss, and astrogliosis. OBJECTIVE To evaluate the potential of magnetic resonance markers of central nervous system injury to predict brain-volume loss and clinical disability in multiple sclerosis. DESIGN, SETTING, AND PARTICIPANTS Participants were selected from the Multiple Sclerosis Center at the University of California-San Francisco. The preliminary data set included 59 patients with MS and 43 healthy control individuals. The confirmatory data set included 220 patients from an independent, large genotype-phenotype research project. MAIN OUTCOMES AND MEASURES Baseline N-acetylaspartate (NAA) level, myo-inositol (mI) in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination were evaluated as predictors in a preliminary data set. Potential predictors were subsequently tested for replication in a confirmatory data set. Clinical scores and percentage of brain-volume change were obtained annually over 4 years as outcomes. Predictors of outcomes were assessed using linear models, linear mixed-effects models, and logistic regression. RESULTS N-acetylaspartate and mI both had statistically significant effects on brain volume, prompting the use of the mI:NAA ratio in normal-appearing white matter as a predictor. The ratio was a predictor of brain-volume change in both cohorts (annual slope in the percentage of brain-volume change/unit of increase in the ratio: -1.68; 95% CI, -3.05 to -0.30; P = .02 in the preliminary study cohort and -1.08; 95% CI, -1.95 to -0.20; P = .02 in the confirmatory study cohort). Furthermore, the mI:NAA ratio predicted clinical disability (Multiple Sclerosis Functional Composite evolution: -0.52 points annually, P < .001; Multiple Sclerosis Functional Composite sustained progression: odds ratio, 2.76/SD increase in the ratio; 95% CI, 1.32 to 6.47; P = .01) in the preliminary data set and predicted Multiple Sclerosis Functional Composite evolution (-0.23 points annually; P = .01), Expanded Disability Status Scale evolution (0.57 points annually; P = .04), and Expanded Disability Status Scale sustained progression (odds ratio, 1.46; 95% CI, 1.10 to 1.94; P = .009) in the confirmatory data set. Myelin water fraction did not show predictive value. CONCLUSIONS AND RELEVANCE The mI:NAA ratio in normal-appearing white matter has consistent predictive power on brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter has cardinal importance in disease severity.
    JAMA Neurology 05/2014; · 7.58 Impact Factor
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.Genes and Immunity advance online publication, 6 March 2014; doi:10.1038/gene.2014.6.
    Genes and immunity 03/2014; · 4.22 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.Genes and Immunity advance online publication, 16 January 2014; doi:10.1038/gene.2013.70.
    Genes and immunity 01/2014; · 4.22 Impact Factor
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    ABSTRACT: The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC), only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD) decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies.
    PLoS ONE 01/2014; 9(7):e97282. · 3.53 Impact Factor
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    ABSTRACT: Objective: To determine to what extent oligoclonal band (OCB) specificities are clonally interrelated and to what degree they are associated with corresponding B-cell responses in the peripheral blood of multiple sclerosis (MS) patients. Methods: Mass-spectrometric proteomic analysis of isoelectric focused (IEF) CSF IgG was used in combination with next-generation deep-immune repertoire sequencing of peripheral blood (PB) and CSF IgG heavy chain variable regions (IgG-VH) from MS patients. Results: We find evidence for ongoing stimulation and maturation to antibody expressing B cells to occur primarily inside the CNS compartment. B cells participating in OCB production can also be identified in peripheral blood; these cells appear to migrate across the blood-brain barrier (BBB) and may also undergo further antigen-stimulation in the periphery. In individual patients different bands comprising OCB are clonally related. Interpretation: Our data provide a high-resolution molecular analysis of OCB and strongly support the concept that OCB are not merely the terminal result of a targeted immune response in MS but represent a component of active B cell immunity that is dynamically supported on both sides of the blood-brain barrier. ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 12/2013; · 11.19 Impact Factor
  • Annals of Neurology 12/2013; 74(6):A5-7. · 11.19 Impact Factor
  • Annals of Neurology 11/2013; 74(5):A7-9. · 11.19 Impact Factor
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    ABSTRACT: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. Norwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708). The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P < 10(-22)). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.
    Multiple Sclerosis 10/2013; · 4.47 Impact Factor
  • Annals of Neurology 10/2013; 74(4):A5-A25. · 11.19 Impact Factor
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    ABSTRACT: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
    Nature Genetics 09/2013; · 35.21 Impact Factor
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    Annals of Neurology 09/2013; 74(3):A7-A8. · 11.19 Impact Factor
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    Stephen L Hauser, Jonah R Chan, Jorge R Oksenberg
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    ABSTRACT: In MS, we've advanced from a state in which essentially nothing could be done for our patients to a new challenge: how to select the best medication for an individual patient from among nine FDA-approved choices, with more expected soon to launch. Clinical progress has occurred in part because MS is a more tractable problem than, for example, a classical neurodegenerative disease. In MS progress was achieved almost exclusively by developing immunotherapies that kill, attenuate, or disable overactive autoreactive lymphocytes. An unsolved challenge in MS is how to protect against late neurodegeneration, the major cause of chronic disability in this disease. One noteworthy feature of the MS success story is that, despite progress, we still do not have a coherent model of pathogenesis. We do not know the primary trigger or triggers, the specificity of the culprit pathogenic immune cells, or the mechanism underlying progressive disability in longstanding disease. MS also remains one of the most compelling mysteries in modern medicine. Why has it increased in frequency over the past century and why may have this increase occurred mostly in women? What is the cause of progression? And why in 15% of patients does the disease manifest only as gradual, primary progression [primary progressive MS (PPMS)], with focal areas of inflammation and gliosis visible on MRI presenting as a gradual accumulation of disability rather than as clinical relapses? This selective overview will highlight recent progress, and outline a few areas that are particularly ripe for meaningful advances in the near future. ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 08/2013; · 11.19 Impact Factor

Publication Stats

14k Citations
3,481.75 Total Impact Points

Institutions

  • 1993–2014
    • University of California, San Francisco
      • • Department of Neurology
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2004–2012
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, ENG, United Kingdom
  • 1997–2012
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2010
    • McGill University
      • Neuroimmunology Unit
      Montréal, Quebec, Canada
  • 2006–2010
    • University of California, Berkeley
      • Division of Epidemiology
      Berkeley, MO, United States
    • University of Zurich
      • Division of Neuropsychology
      Zürich, ZH, Switzerland
  • 2002–2010
    • Vanderbilt University
      • Center for Human Genetics Research (CHGR)
      Nashville, MI, United States
    • University Hospital Vall d'Hebron
      • Department of Neurology
      Barcino, Catalonia, Spain
  • 2009
    • The Ohio State University
      • Department of Neurology
      Columbus, OH, United States
    • Montreal Heart Institute
      • Research Centre
      Montréal, Quebec, Canada
  • 1995–2009
    • Harvard Medical School
      • • Department of Genetics
      • • Department of Neurology
      Boston, Massachusetts, United States
  • 1983–2009
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Center for Neurologic Diseases
      • • Department of Neurology
      Boston, MA, United States
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2007–2008
    • Multiple Sclerosis Research Center of New York
      New York City, New York, United States
  • 2002–2007
    • Duke University Medical Center
      • Center for Human Genetics
      Durham, NC, United States
  • 2001
    • Università degli Studi di Genova
      • Dipartimento di Medicina sperimentale (DIMES)
      Genova, Liguria, Italy
  • 1999
    • Albert Einstein College of Medicine
      New York City, New York, United States
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 1988–1998
    • Massachusetts General Hospital
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1994
    • CSU Mentor
      Long Beach, California, United States
  • 1982
    • Boston Children's Hospital
      • Children's Hospital Primary Care Center
      Boston, Massachusetts, United States