Bradley T Hyman

Harvard Medical School, Boston, Massachusetts, United States

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Publications (764)5031.79 Total impact

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    ABSTRACT: Introduction: AV-1451 is a PET tracer tailored to allow in vivo detection of paired helical filament-(PHF)-tau- containing lesions. There is great need to better understand the regional and substrate specific binding patterns of this tracer not only in AD brains but also in non-AD tauopathies. Objective: To carefully examine the correlation of in vivo and postmortem AV-1451 binding patterns in the first two cases of autopsy-confirmed non-AD tauopathy studied at MGH. Methods: Detailed neuropathologic examination, phosphor-screen and nuclear emulsion autoradiography, [H-3]-AV- 1451 binding assays and SDD-AGE tau measurements on postmortem samples containing multiple brain regions from two subjects with a clinical diagnosis of bvFTD (MAPT P301L mutation carrier) and PSP, respectively, who had [F- 18]-AV-1451 PET imaging within 8 months of death. Results: In both subjects, we observed elevated [F-18]-AV-1451 signal on in vivo PET imaging predominantly in striatum, midbrain and inferior temporal region, and some weaker scattered signal in grey/white matter junction. At autopsy, the P301L mutation carrier showed multiple tau grains in several brain regions both in cortex and white matter, and predominant basal ganglia involvement with glial tauopathy. A neuropathological diagnosis of PSP was confirmed in the second subject. In both cases, autoradiography failed to show any detectable [F-18]-AV-1451 binding in any of the regions examined with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangle pathology) and neuromelanin-containing neurons in the substantia nigra (reflecting off-target binding). Correlation analyses of regional patterns of in vivo uptake, in vitro binding assays and detailed biochemical quantification of soluble and insoluble tau pools at postmortem are currently ongoing. Conclusion: Our results suggest that AV-1451 does not bind to non-PHF tau lesions primarily made of straight tau filaments with an affinity that could explain the in vivo signal in these two non-AD tauopathy cases. This emphasizes the need for further clinico-pathological correlation studies.
    No preview · Conference Paper · Jan 2016
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    ABSTRACT: Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312+ dystrophic neurites, GFAP+ reactive astrocytes, and IBA1+ and CD68+ activated microglia in randomly selected dense-core (Thioflavin-S+) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall τ = 0.34, P = 0.001), reactive astrocytes (Kendall τ = 0.30, P = 0.003), and CD68+ (Kendall τ = 0.48, P < 0.0001), but not IBA1 microglia (Kendall τ = 0.045, P = 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68+ microglia and symptom duration remained significant (Kendall τ = 0.39, P = 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline.
    Full-text · Article · Dec 2015 · American Journal Of Pathology
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    ABSTRACT: Although the clustering of GFAP immunopositive astrocytes around amyloid-β plaques in Alzheimer's disease has led to the widespread assumption that plaques attract astrocytes, recent studies suggest that astrocytes stay put in injury. Here we reexamine astrocyte migration to plaques, using quantitative spatial analysis and computer modeling to investigate the topology of astrocytes in 3D images obtained by two-photon microscopy of living APP/PS1 mice and WT littermates. In WT mice, cortical astrocyte topology fits a model in which a liquid of hard spheres exclude each other in a confined space. Plaques do not disturb this arrangement except at very large plaque loads, but, locally, cause subtle outward shifts of the astrocytes located in three tiers around plaques. These data suggest that astrocytes respond to plaque-induced neuropil injury primarily by changing phenotype, and hence function, rather than location.
    Full-text · Article · Dec 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: In early stages of Alzheimer's disease (AD), neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex. This observation from human neuropathological studies led us to pose two alternative hypotheses: that amyloid in the cortex is permissive for the spread of tangles from the medial temporal lobe, or that these are co-occurring but not causally related events simply reflecting progression of AD pathology. We now directly test the hypothesis that cortical amyloid acts as an accelerant for spreading of tangles beyond the medial temporal lobe. We crossed rTgTauEC transgenic mice that demonstrate spread of tau from entorhinal cortex to other brain structures at advanced age with APP/PS1 mice, and examined mice with either NFTs, amyloid pathology, or both. We show that concurrent amyloid deposition in the cortex 1) leads to a dramatic increase in the speed of tau propagation and an extraordinary increase in the spread of tau to distal brain regions, and 2) significantly increases tau-induced neuronal loss. These data strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD.
    Full-text · Article · Dec 2015
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    ABSTRACT: Amyloid β-protein oligomers play a key role in Alzheimer's disease (AD), but well-validated assays that routinely detect them in cerebrospinal fluid (CSF) are just emerging. We sought to confirm and extend a recent study using the Singulex Erenna platform that reported increased mean CSF oligomer levels in AD. We tested four antibody pairs and chose one pair that was particularly sensitive, using 1C22, our new oligomer-selective monoclonal antibody, for capture. We applied this new assay to extracts of human brain and CSF. A combination of 1C22 for capture and 3D6 for detection yielded an Erenna immunoassay with a lower limit of quantification of approximately 0.15 pg/ml that was highly selective for oligomers over monomers and detected a wide size-range of oligomers. Most CSFs we tested had detectable oligomer levels but with a large overlap between AD and controls and a trend for higher mean levels in mild cognitive impairment (MCI) than controls. Aβ oligomers are detectable in most human CSFs, but AD and controls overlap. MCI CSFs may have a modest elevation in mean value by this assay.
    Full-text · Article · Dec 2015 · Alzheimer's Research and Therapy
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    ABSTRACT: Alzheimer's disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death.
    Full-text · Article · Nov 2015 · Scientific Reports
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    Alberto Serrano-Pozo · Bradley T Hyman
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    ABSTRACT: In a new study, one-quarter of individuals with a clinical diagnosis of mild to moderate Alzheimer dementia had no or only sparse neuritic amyloid plaques in their brains, and most were also at a low or an intermediate neurofibrillary tangle stage. The findings have enormous implications for clinical trials of anti-amyloid-beta and anti-tau therapies.
    Full-text · Article · Nov 2015 · Nature Reviews Neurology
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    ABSTRACT: In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion-like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans-synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau-overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau-null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein.
    No preview · Article · Nov 2015 · The EMBO Journal
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    ABSTRACT: IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3%of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22%of cases with ROHs >3Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
    Full-text · Article · Nov 2015
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    ABSTRACT: Objective: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer's disease (AD), staging and monitoring of disease progression, and development of disease modifying therapies. Methods: We acquired tau positron emission tomography (PET) using (18) F T807 (AV1451), and amyloid-β PET using (11) C Pittsburgh Compound B (PIB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. Results: We found abnormally high cortical (18) F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18) F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18) F T807 than with mean cortical (11) C PIB. Regional (18) F T807 was correlated with mean cortical (11) C PiB among both impaired and control subjects. Interpretation: These findings suggest that (18) F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment. This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2015 · Annals of Neurology
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    ABSTRACT: Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.
    Full-text · Article · Oct 2015 · Nature Communications
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    ABSTRACT: Objective To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins. Methods We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography, and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-transactive response DNA binding protein 43 (TDP-43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology. ResultsOur data suggest that [F-18]-AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to lesions containing -amyloid, -synuclein, or TDP-43. [F-18]-AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified. InterpretationOur data suggest that [F-18]-AV-1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some [F-18]-AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679-696
    No preview · Article · Sep 2015 · Annals of Neurology

  • No preview · Article · Aug 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    ABSTRACT: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    ABSTRACT: There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Jul 2015 · Brain
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    ABSTRACT: In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Jul 2015 · Brain
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    ABSTRACT: Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ-, and amyloid (A) β42-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE ε4/ε4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level versus those in APOE ε3/ε3 or APOE ε3/ε4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. Cerebrospinal fluid apoE-positive and β-amyloid (Aβ42)-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients versus age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring.
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    Full-text · Conference Paper · Jul 2015

Publication Stats

65k Citations
5,031.79 Total Impact Points

Institutions

  • 1991-2015
    • Harvard Medical School
      • • Department of Neurology
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 1990-2015
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      • • Department of Neurology
      • • Alzheimer Research Unit
      Boston, Massachusetts, United States
  • 2004-2013
    • Institute for Neurodegenerative Disorders
      New Haven, Connecticut, United States
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 2006-2011
    • McLaughlin Research Institute
      Great Falls, Montana, United States
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2010
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2007
    • University of Pittsburgh
      • Department of Psychiatry
      Pittsburgh, Pennsylvania, United States
  • 2005
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 1997-2004
    • Massachusetts Institute of Technology
      • Department of Brain and Cognitive Sciences
      Cambridge, Massachusetts, United States
    • The Rockefeller University
      New York City, New York, United States
  • 2000
    • Nathan Kline Institute
      Orangeburg, New York, United States
    • Washington University in St. Louis
      • Department of Psychiatry
      San Luis, Missouri, United States
  • 1999-2000
    • George Washington University
      Washington, Washington, D.C., United States
    • Cardiff University
      • School of Psychology
      Cardiff, Wales, United Kingdom
  • 1998-1999
    • Cornell University
      Итак, New York, United States
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 1996
    • Mass General Hospital
      Charlestown, Rhode Island, United States
  • 1995
    • Boston University
      • Center for Polymer Studies
      Boston, Massachusetts, United States
  • 1993
    • University of Santiago, Chile
      CiudadSantiago, Santiago Metropolitan, Chile
  • 1992
    • University of Toronto
      • Department of Psychiatry
      Toronto, Ontario, Canada
  • 1987-1991
    • University of Iowa
      • Department of Neurology
      Iowa City, Iowa, United States
  • 1985
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States