P Murali Doraiswamy

Duke University Medical Center, Durham, North Carolina, United States

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Publications (264)1546.79 Total impact

  • James A Blumenthal, P Murali Doraiswamy
    JAMA The Journal of the American Medical Association 11/2014; 312(20):2166-7. · 30.39 Impact Factor
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    ABSTRACT: A positive family history (FH) raises the risk for late-onset Alzheimer's disease though, other than the known risk conferred by apolipoprotein ε4 (ApoE4), much of the genetic variance remains unexplained. We examined the effect of family history on longitudinal regional brain atrophy rates in 184 subjects (42% FH+, mean age 79.9) with mild cognitive impairment (MCI) enrolled in a national biomarker study. An automated image analysis method was applied to T1-weighted MR images to measure atrophy rates for 20 cortical and subcortical regions. Mixed-effects linear regression models incorporating repeated-measures to control for within-subject variation over multiple time points tested the effect of FH over a follow-up of up to 48 months. Most of the 20 regions showed significant atrophy over time. Adjusting for age and gender, subjects with a positive FH had greater atrophy of the amygdala (p < 0.01), entorhinal cortex (p < 0.01), hippocampus (p < 0.053) and cortical gray matter (p < 0.009). However, when E4 genotype was added as a covariate, none of the FH effects remained significant. Analyses by ApoE genotype showed that the effect of FH on amygdala atrophy rates was numerically greater in ε3 homozygotes than in E4 carriers, but this difference was not significant. FH+ subjects had numerically greater 4-year cognitive decline and conversion rates than FH− subjects but the difference was not statistically significant after adjusting for ApoE and other variables. We conclude that a positive family history of AD may influence cortical and temporal lobe atrophy in subjects with mild cognitive impairment, but it does not have a significant additional effect beyond the known effect of the E4 genotype.
    NeuroImage: Clinical. 09/2014; 6.
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    Ilan Tur-Kaspa, Roohi Jeelani, P Murali Doraiswamy
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    ABSTRACT: Preimplantation genetic diagnosis (PGD) is an option for couples at risk of having offspring with an inherited debilitating or fatal neurological disorder who wish to conceive a healthy child. PGD has been carried out for conditions with various modes of inheritance, including spinal muscular atrophy, Huntington disease, fragile X syndrome, and chromosomal or mitochondrial disorders, and for susceptibility genes for cancers with nervous system involvement. Most couples at risk of transmitting a genetic mutation would opt for PGD over prenatal testing and possible termination of a pregnancy. The aim of this Perspectives article is to assist neurologists in counselling and treating patients who wish to explore the option of PGD to enable conception of an unaffected child. PGD can be accomplished for most disorders in which the genetic basis is known, and we argue that it is time for clinicians and neurological societies to consider the evidence and to formulate guidelines for the responsible integration of PGD into modern preventative neurology.
    Nature Reviews Neurology 05/2014; · 14.10 Impact Factor
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    ABSTRACT: This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66±1.47 vs -0.71±1.09, P=0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P<0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P<0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.Molecular Psychiatry advance online publication, 11 March 2014; doi:10.1038/mp.2014.9.
    Molecular Psychiatry 03/2014; · 15.15 Impact Factor
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    ABSTRACT: IMPORTANCE To describe the first case of preimplantation genetic diagnosis (PGD) and in vitro fertilization (IVF) performed for the prevention of genetic prion disease in the children of a 27-year-old asymptomatic woman with a family history of Gerstmann-Sträussler-Sheinker syndrome (GSS). OBSERVATIONS PGD and fertilization cycles resulted in detection of 6 F198S mutation-free embryos. Of these, 2 were selected for embryo transfer to the patient's uterus, yielding a clinical twin pregnancy and birth of healthy but slightly premature offspring with normal development at age 27 months. CONCLUSION AND RELEVANCE IVF with PGD is a viable option for couples who wish to avoid passing the disease to their offspring. Neurologists should be aware of PGD to be able to better consult at-risk families on their reproductive choices.
    JAMA neurology. 02/2014; 71(4).
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    ABSTRACT: Subjects with higher cognitive reserve (CR) may be at a lower risk for Alzheimer's disease (AD), but the neural mechanisms underlying this are not known. Hippocampal volume loss is an early event in AD that triggers cognitive decline. Regression analyses of the effects of education on MRI-measured baseline HV in 675 subjects (201 normal, 329 with mild cognitive impairment (MCI), and 146 subjects with mild AD), adjusting for age, gender, APOE ɛ4 status and intracranial volume (ICV). Subjects were derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large US national biomarker study. The association between higher education and larger HV was significant in AD (P=0.014) but not in cognitively normal or MCI subjects. In AD, HV was about 8% larger in a person with 20 years of education relative to someone with 6 years of education. There was also a trend for the interaction between education and APOE ɛ4 to be significant in AD (P=0.056). A potential protective association between higher education and lower hippocampal atrophy in patients with AD appears consistent with prior epidemiologic data linking higher education levels with lower rates of incident dementia. Longitudinal studies are warranted to confirm these findings.
    Journal of Neuroradiology 01/2014; · 1.13 Impact Factor
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    Frontiers in Neurology 01/2014; 4:216.
  • Radiology 12/2013; · 6.21 Impact Factor
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    Pablo Billeke, Samantha Boardman, P Murali Doraiswamy
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    ABSTRACT: Social cognition refers to the brain mechanisms by which we process social information about other humans and ourselves. Alterations in interpersonal and social functioning are common in major depressive disorder, though only poorly addressed by current pharmacotherapies. Further standardized tests, such as depression ratings or neuropsychologic tests, used in routine practice provide very little information on social skills, schemas, attributions, stereotypes and judgments related to social interactions. In this article, we review recent literature on how healthy human brains process social decisions and how these processes are altered in major depressive disorder. We especially focus on interactive paradigms (e.g., game theory based tasks) that can reproduce daily life situations in laboratory settings. The evidences we review, together with the rich literature on the protective role of social networks in handling stress, have implications for developing more ecologically-valid biomarkers and interventions in order to optimize functional recovery in depressive disorders
    Translational Neuroscience. 12/2013; 4(4):437-447.
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    ABSTRACT: Purpose To determine the effect of the apolipoprotein E (APOE) genotype on atrophy rates of specific brain gray matter regions hypothesized to be key components of cognitive networks disrupted in Alzheimer disease. Materials and Methods The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All subjects and their legal representatives gave written informed consent prior to data collection. The authors analyzed data from 237 subjects (mean age, 79.9 years; 40% female) with mild cognitive impairment (MCI) in the ADNI database and assessed the effect of the APOE ε4 and ε2 alleles on regional brain atrophy rates over a 12-48-month period. Brain regions were selected a priori: 15 experimental and five control regions were included. Regional atrophy rates were derived by using a fully automated algorithm applied to T1-weighted magnetic resonance (MR) imaging data. Analysis consisted of mixed-effects linear regression with repeated measures; results were adjusted for multiple testing with Bonferroni correction. Results Thirteen of 15 experimental regions showed a significant effect of ε4 for higher atrophy rates (P < .001 for all). Cohen d values ranged from 0.26 to 0.42, with the largest effects seen in the amygdalae and hippocampi. The transverse temporal cortex showed a trend (P = .02, but did not survive Bonferroni correction) for a protective effect (Cohen d value = 0.15) of ε2. No control region showed an APOE effect. Conclusion The APOE ε4 allele is associated with accelerated rates of atrophy in 13 distinct brain regions in limbic and neocortical areas. This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially contribute to cognitive decline. © RSNA, 2014 Online supplemental material is available for this article.
    Radiology 12/2013; · 6.21 Impact Factor
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    ABSTRACT: Neuropathologic heterogeneity is often present among Alzheimer disease (AD) patients. We sought to determine whether amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinically and pathologically defined AD and 17 nondemented patients with quantitative florbetapir F-18 (F-AV-45) positron emission tomography (PET) imaging during life and postmortem histological β-amyloid quantification and neuropathologic examination were assessed. AD patients were divided on the basis of concurrent pathologies, including those with Lewy bodies (LBs) (n = 21), white matter rarefaction (n = 27), severe cerebral amyloid angiopathy (n = 11), argyrophilic grains (n = 5), and TAR DNA binding protein-43 inclusions (n = 18). Many patients exhibited more than 1 type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in 6 cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p < 0.001). All AD subgroups had significantly greater amyloid measures versus nondemented patients, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with LBs had significantly lower SUVr measures versus AD cases without LBs (p = 0.002); there were no other paired comparison differences. These findings indicate that florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
    Journal of neuropathology and experimental neurology. 12/2013;
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    ABSTRACT: Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78weeks (18months). Eighty DEP-CI outpatients (age 55 to 95years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.
    Contemporary clinical trials 12/2013; · 1.51 Impact Factor
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    ABSTRACT: PURPOSE The hypothesis of the current study is that relationships between the structural connectome and cortical amyloid burden may provide complementary information about pathologic changes in Alzheimer's Disease (AD). METHOD AND MATERIALS Subjects were those newly enrolled in the ADNI2 study. Baseline data was used. T1 anatomical images were parcellated using FreeSurfer. DTI scans were registered to the T1 images using FSL. Structural connectomes were created using the Connectome Mapper Toolkit. Node degree, local efficiency, and clustering coefficient were calculated for the precuneus, posterior cingulate, inferior temporal, superior parietal, and superior frontal connectome nodes. The FreeSurfer parcellations were registered to the florbetapir PET scans. The global SUVR and four local SUVRs (frontal, cingulate, parietal, and temporal) were calculated. Clinical cognitive assessments included MMSE, ADAS-Cog, and Rey AVLT. Statistical analyses were performed between structural connection metrics, amyloid status, and clinical cognitive scores. RESULTS There were 102 ADNI2 subjects (64 males, 38 females) available at the time of the analysis. There were 37 normal control, 19 early mild cognitive impairment (MCI), 25 late MCI, and 21 AD subjects. All global and local AV45 amyloid burden measures were significantly associated with RAVLT, MMSE, and ADAS-Cog (p < 0.05). The strongest associations between amyloid burden and structural connection metrics were in the posterior cingulate and precuneus (node degree; p < 0.05). The strongest associations between structural connection metrics and clinical dementia scores were in the precuneus, superior parietal, and superior temporal regions (node degree vs. MMSE and ADAS-cog; p < 0.05). CONCLUSION Brain amyloid burden has significant associations with clinical cognitive status in all regions analyzed, consistent with globally increased amyloid burden as an important condition for AD. The strongest associations between amyloid burden and structural connection metrics were in the posterior cingulate and precuneus (node degree; p < 0.05), suggesting that these regions are most likely to have structural changes related to amyloid deposition in AD. CLINICAL RELEVANCE/APPLICATION The combination of quantitative amyloid PET and DTI tractography can provide information about global and local structural changes in AD, aiding in diagnosis and disease tracking.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
  • Anthony S Zannas, Yasushi Okuno, P Murali Doraiswamy
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    ABSTRACT: Case reports suggest a relationship between cholinesterase inhibitors (ChEIs) and Pisa syndrome (PS), also known as pleurothotonus, a form of dystonia, but this relationship has not been systematically examined. Our objective was to estimate the adjusted reporting ratios of PS with donepezil, rivastigmine, and galantamine in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Retrospective analysis of adverse event reports in the FAERS database. Patients with drug-related adverse events in the FAERS database. The Gamma Poisson Shrinker algorithm was used to estimate the empirical Bayes geometric mean (EBGM) along with the lower and upper 90% confidence interval (CI) limits (EB05 and EB95, respectively), as measures of the adjusted reporting ratio of PS in patients taking ChEIs. EB05 > 2.0 was used as the cutoff for significance for the signals. The EBGM (EB05) was 37.9 (30) for all ChEIs, 25.6 (17.6) for donepezil, 76.4 (50.3) for galantamine, and 33.7 (21.2) for rivastigmine. All adverse event signals were strongly significant based on the a priori set EB05 cutoff. The female:male ratio in the reported cases was 2:1. No significant signals were found between ChEIs and other dystonias. About half of the ChEI users were also taking concomitant antipsychotics. Although FAERS data cannot establish causality due to reporting biases, our findings support a potential dopaminergic-cholinergic imbalance as an underlying mechanism for PS and may help increase clinician awareness, early identification, and treatment of ChEI-related dystonias.
    Pharmacotherapy 10/2013; · 2.31 Impact Factor
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    ABSTRACT: Neurological and neurocognitive dysfunction occurs frequently in the large number of increasingly elderly patients undergoing cardiac surgery every year. Perioperative cognitive deficits have been shown to persist after discharge and up to several years after surgery. More importantly, perioperative cognitive decline is predictive of long-term cognitive dysfunction, reduced quality of life and increased mortality. The proposed mechanisms to explain the cognitive decline associated with cardiac surgery include the neurotoxic accumulation of β-amyloid. This study will be the first to provide molecular imaging to assess the relationship between neocortical β-amyloid deposition and postoperative cognitive dysfunction. 40 patients providing informed consent for participation in this Institutional Review Board-approved study and undergoing cardiac (coronary artery bypass graft (CABG), valve or CABG+valve) surgery with cardiopulmonary bypass will be enrolled based on defined inclusion and exclusion criteria. At 6 weeks after surgery, participants will undergo (18)F-florbetapir positron emission tomography imaging to assess neocortical β-amyloid burden along with a standard neurocognitive battery and blood testing for apolipoprotein E ε-4 genotype. The results will be compared to those of 40 elderly controls and 40 elderly patients with mild cognitive impairment who have previously completed (18)F-florbetapir imaging. This study has been approved by the Duke University Institutional Review Board. The results will provide novel mechanistic insights into postoperative cognitive dysfunction that will inform future studies into potential treatments or preventative therapies of long-term cognitive decline after cardiac surgery.
    BMJ Open 09/2013; 3(9):e003669. · 2.06 Impact Factor
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    ABSTRACT: All antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents. To estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community. A retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone. Risperidone, olanzapine and haloperidol showed a dose-response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06-1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73-0.89) and olanzapine (HR = 0.82, 95% CI 0.74-0.90). Significant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community.
    The British journal of psychiatry: the journal of mental science 08/2013; · 6.62 Impact Factor
  • Alzheimer's and Dementia 07/2013; 9(4):P571. · 17.47 Impact Factor
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    ABSTRACT: Background A critical and as-yet unmet need in Alzheimer disease (AD) research is the development of novel markers that can identify individuals at risk for cognitive decline due to AD. This would aid intervention trials designed to slow the progression of AD by increasing diagnostic certainty, and provide new pathophysiologic clues and potential drug targets. Results We used two metabolomics platforms (gas chromatography-time of flight mass spectrometry [GC-TOF] and liquid chromatography LC-ECA array [LC-ECA]) to measure a number of metabolites in cerebrospinal fluid (CSF) from patients with AD dementia and from cognitively normal controls. We used stepwise logistic regression models with cross-validation to assess the ability of metabolite markers to discriminate between clinically diagnosed AD participants and cognitively normal controls and we compared these data with traditional CSF Luminex immunoassay amyloid-β and tau biomarkers. Aβ and tau biomarkers had high accuracy to discriminate cases and controls (testing area under the curve: 0.92). The accuracy of GC-TOF metabolites and LC-ECA metabolites by themselves to discriminate clinical AD participants from controls was high (testing area under the curve: 0.70 and 0.96, respectively). Conclusions Our study identified several CSF small-molecule metabolites that discriminated especially well between clinically diagnosed AD and control groups. They appear to be suitable for further confirmatory and validation studies, and show the potential to provide predictive performance for AD.
    Acta Neuropathologica Communications. 06/2013; 1(1):28.
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    ABSTRACT: OBJECTIVE: To compare differences in gray matter volumes, white matter and subcortical gray matter hyperintensities, neuropsychological factors, and treatment outcome between early- and late-onset late-life depressed (LLD) subjects. METHODS: We conducted a prospective, nonrandomized, controlled trial at the outpatient clinics at Washington University and Duke University on 126 subjects, aged 60 years or older, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received neuropsychological testing and magnetic resonance imaging. Subjects were excluded for cognitive impairment or severe medical disorders. After 12 weeks of sertraline treatment, subjects' MADRS scores over time and neuropsychological factors were studied. RESULTS: Left anterior cingulate thickness was significantly smaller in the late-onset depressed group than in the early-onset LLD subjects. The late-onset group also had more hyperintensities than the early-onset LLD subjects. No differences were found in neuropsychological factor scores or treatment outcome between early-onset and late-onset LLD subjects. CONCLUSION: Age at onset of depressive symptoms in LLD subjects are associated with differences in cortical thickness and white matter and subcortical gray matter hyperintensities, but age at onset did not affect neuropsychological factors or treatment outcome.
    The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 06/2013; · 3.35 Impact Factor
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    ABSTRACT: (18)F-florbetapir positron emission tomography (PET) imaging of the brain is now approved by the Food and Drug Administration (FDA) approved for estimation of β-amyloid neuritic plaque density when evaluating patients with cognitive impairment. However, its impact on clinical decision-making is not known. We present 11 cases (age range 67-84) of cognitively impaired subjects in whom clinician surveys were done before and after PET scanning to document the theoretical impact of amyloid imaging on the diagnosis and treatment plan of cognitively impaired subjects. Subjects have been clinically followed for about 5 months after the PET scan. Negative scans occurred in five cases, leading to a change in diagnosis for four patients and a change in treatment plan for two of these cases. Positive scans occurred in six cases, leading to a change in diagnosis for four patients and a change in treatment plan for three of these cases. Following the scan, only one case had indeterminate diagnosis. Our series suggests that both positive and negative florbetapir PET scans may enhance diagnostic certainty and impact clinical decision-making. Controlled longitudinal studies are needed to confirm our data and determine best practices.
    Neurocase 05/2013; · 1.38 Impact Factor

Publication Stats

8k Citations
1,546.79 Total Impact Points

Institutions

  • 1990–2014
    • Duke University Medical Center
      • • Duke Institute for Brain Sciences (DIBS)
      • • Department of Psychiatry
      • • Department of Psychiatry and Behavioral Science
      • • Department of Radiology
      Durham, North Carolina, United States
  • 2013
    • University of Pennsylvania
      • Center for Neurodegenerative Disease Research
      Philadelphia, Pennsylvania, United States
    • St. Bonaventure University
      Saint Bonaventure, New York, United States
  • 1993–2013
    • Duke University
      • • Department of Psychology and Neuroscience
      • • Department of Economics
      Durham, North Carolina, United States
  • 1990–2013
    • Washington University in St. Louis
      • Department of Psychiatry
      Saint Louis, MO, United States
  • 2011–2012
    • Avid Radiopharmaceuticals
      Philadelphia, Pennsylvania, United States
    • University of California, Riverside
      • Department of Psychology
      Riverside, CA, United States
  • 2009
    • Bristol-Myers Squibb
      New York City, New York, United States
  • 2007
    • University of New South Wales
      • School of Psychiatry
      Kensington, New South Wales, Australia
  • 2006
    • Tohoku University
      • Division of Cognitive Neuroscience
      Sendai, Kagoshima-ken, Japan
  • 2002–2006
    • U.S. Food and Drug Administration
      • • Center for Drug Evaluation and Research
      • • Division of Metabolism and Endocrinology Products (DMEP)
      Washington, D. C., DC, United States
  • 2004
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2003
    • Nathan Kline Institute
      Orangeburg, New York, United States
  • 2000
    • University of Vermont
      • Department of Psychiatry
      Burlington, VT, United States
  • 1992
    • Hackensack University Medical Center
      Hackensack, New Jersey, United States