Frank R Sharp

University of California, Davis, Davis, California, United States

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Publications (345)1588.73 Total impact

  • Glen C Jickling, Frank R Sharp
    Stroke 02/2015; · 6.02 Impact Factor
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    ABSTRACT: The goal of this study was to show that myelin and axons in cortical gray matter are damaged in Alzheimer's disease (AD) brain. Superior temporal gyrus gray matter of AD patients (9 male, 14 female) was compared to cognitively normal controls (8 male, 7 female). Myelin basic protein (MBP) and a degraded myelin basic protein complex (dMBP) were quantified by Western blot. Brain sections were immunostained for MBP, dMBP, axonal neurofilament protein (NF), autophagy marker microtubule-associated proteins 1A/B light chain 3B precursor (LC3B), amyloid-β protein precursor (AβPP), and amyloid markers amyloid β1-42 (Aβ1-42) and FSB. Co-immunoprecipitation and mass spectroscopy evaluated interaction of AβPP/Aβ1-42 with MBP/dMBP. Evidence of axonal injury in AD cortex included appearance of AβPP in NF stained axons, and NF at margins of amyloid plaques. Evidence of myelin injury in AD cortex included (1) increased dMBP in AD gray matter compared to control (p < 0.001); (2) dMBP in AD neurons; and (3) increased LC3B that co-localized with MBP. Evidence of interaction of AβPP/Aβ1-42 with myelin or axonal components included (1) greater binding of dMBP with AβPP in AD brain; (2) MBP at the margins of amyloid plaques; (3) dMBP co-localized with Aβ1-42 in the core of amyloid plaques in AD brains; and (4) interactions between Aβ1-42 and MBP/dMBP by co-immunoprecipitation and mass spectrometry. We conclude that damaged axons may be a source of AβPP. dMBP, MBP, and NF associate with amyloid plaques and dMBP associates with AβPP and Aβ1-42. These molecules could be involved in formation of amyloid plaques.
    Journal of Alzheimer's disease: JAD 01/2015; 44(4):1213-29. · 3.61 Impact Factor
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    ABSTRACT: Deletion of the 1.5-3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70-80%), hypocalcemia (20-60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.
    PLoS ONE 08/2014; 9(8):e103884. · 3.53 Impact Factor
  • Frank R Sharp, Glen C Jickling
    Stroke 07/2014; 45(9). · 6.02 Impact Factor
  • Frank R Sharp, Glen C Jickling
    Stroke 07/2014; 45(9). · 6.02 Impact Factor
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    ABSTRACT: Epidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells.
    PLoS ONE 07/2014; 9(7):e102550. · 3.53 Impact Factor
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    ABSTRACT: Background: The superior temporal sulcus (STS) plays a critical role in social behavior, a core impairment in autism, yet the molecular mechanisms that underlie abnormal STS function remain largely unexplored. Small non-coding RNAs (sncRNA), including microRNA (miRNA) and small nucleolar RNA (snoRNA), show increased importance as key regulators of translation during development and throughout life. Aberrant expression of sncRNA could lead to widespread changes in protein and cellular function related to autism. This study evaluated differences is sncRNA expression in the STS in the autism brain. In addition, this study sought to determine if differences were localized to association cortices, such as STS, or may also include neural regions involved in more basic perceptual processing, such as the primary auditory cortex (PAC), that are not typically associated with the core impairments of autism. Objectives: Examine the changes in expression of small non-coding RNAs expressed in association (STS) and primary (PAC) cortex of autism and typically developing brains. Methods: Brain tissue from subjects diagnosed with autism (n=10) and typically developing controls (n=8) was obtained from the Harvard Brain Tissue Resource Center. The STS and PAC were dissected from each fresh-frozen brain. Total RNA was isolated from each region and assessed for concentration and quality. Two hundred nanograms of total RNA were processed on Affymetrix GeneChip miRNA 3.0 Arrays. Arrays were scanned and resulting CEL files analyzed with Partek Genomics Suite. Only small non-coding RNAs (mature miRNA, precursor miRNA and snoRNA) with human annotation (5663 targets) were included in the analysis. Functional significance of altered miRNA was determined through analysis of over-representation of their computationally derived mRNA targets in KEGG pathways using DIANA miRPath and Exploratory Gene Association Networks (EGAN) software. Results: In STS, the expression of 3 miRNA significantly differed (P<0.005, FC>|1.2|) between autism and typically developing control brains (miR-1, miR-4753-5p, and miR-513a-5p). These miRNA regulate pathways relating to synapse, brain maturation function and processes, and immune function. An additional 11 stem-loop precursor miRNA and 6 snoRNA were also different in STS. In PAC, 3 miRNA were significantly different in autism compared to typical control (miR-297, miR-664, and miR-4709-3p). These were unique to PAC and may represent affected function of other cell signaling pathways and developmental cues. There were also 7 stem-loop precursor miRNA and 4 snoRNA differentially expressed in PAC. Commonly affected elements/functions of miRNA in both regions, include Akt and glutamate signalling. The presence of significantly altered snoRNA in autism brain may implicate alterations in splicing mechanisms and patterns as important contributors to autism. Conclusions: Regional differences in miRNA and other sncRNA expression were observed between autism and control brains in the STS and PAC. These changes in small regulatory non-coding RNA may have important regulatory effects on mRNA transcript splicing and translation to proteins. These findings help identify molecular mechanisms underlying autism and elucidate specific targets to restore perturbations that might occur in autism.
    2014 International Meeting for Autism Research; 05/2014
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    ABSTRACT: Defining the RNA transcriptome in Alzheimer Disease (AD) will help understand the disease mechanisms and provide biomarkers. Though the AD blood transcriptome has been studied, effects of white matter hyperintensities (WMH) were not considered. This study investigated the AD blood transcriptome and accounted for WMH. RNA from whole blood was processed on whole-genome microarrays. A total of 293 probe sets were differentially expressed in AD versus controls, 5 of which were significant for WMH status. The 288 AD-specific probe sets classified subjects with 87.5% sensitivity and 90.5% specificity. They represented 188 genes of which 29 have been reported in prior AD blood and 89 in AD brain studies. Regulated blood genes included MMP9, MME (Neprilysin), TGFβ1, CA4, OCLN, ATM, TGM3, IGFR2, NOV, RNF213, BMX, LRRN1, CAMK2G, INSR, CTSD, SORCS1, SORL1, and TANC2. RNA expression is altered in AD blood irrespective of WMH status. Some genes are shared with AD brain.
    Alzheimer disease and associated disorders 04/2014; · 2.88 Impact Factor
  • Glen C Jickling, Frank R Sharp
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    ABSTRACT: Despite testing more than 1,026 therapeutic strategies in models of ischemic stroke and 114 therapies in human ischemic stroke, only one agent tissue plasminogen activator has successfully been translated to clinical practice as a treatment for acute stroke. Though disappointing, this immense body of work has led to a rethinking of animal stroke models and how to better translate therapies to patients with ischemic stroke. Several recommendations have been made, including the STAIR recommendations and statements of RIGOR from the NIH/NINDS. In this commentary we discuss additional aspects that may be important to improve the translational success of ischemic stroke therapies. These include use of tissue plasminogen activator in animal studies; modeling ischemic stroke heterogeneity in terms of infarct size and cause of human stroke; addressing the confounding effect of anesthesia; use of comparable therapeutic dosage between humans and animals based on biological effect; modeling the human immune system; and developing outcome measures in animals comparable to those used in human stroke trials. With additional study and improved animal modeling of factors involved in human ischemic stroke, we are optimistic that new stroke therapies will be developed.
    Metabolic Brain Disease 02/2014; · 2.40 Impact Factor
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    ABSTRACT: Objective: Myelin disruption is an important feature of Alzheimer's disease (AD) that contributes to impairment of neuronal circuitry and cognition. In this study we characterize myelin degradation in the brains of patients with Alzheimer's disease compared with normal aged controls. Methods: Myelin from patients with AD (n=13) was compared to matched controls (n=6). Myelin degradation was examined by immunohistochemistry in frontal white matter (WM) for intact myelin basic protein (MBP), degraded MBP, the presence of myelin lipid and for PAS staining. The relationship of myelin degradation and axonal injury was also assessed. Results: Brains from patients with AD had significant loss of intact MBP, and an increase in degraded MBP in periventricular WM adjacent to a denuded ependymal layer. In regions of myelin degradation, vesicles were identified that stained positive for degraded MBP, myelin lipid, and neurofilament but not for intact MBP. Most vesicles stained for PAS, a corpora amylacea marker. The vesicles were significantly more abundant in the periventricular WM of AD patients compared to controls (44.5±11.0 versus 1.7±1.1, p=0.02). Conclusion: In AD patients degraded MBP is associated in part with vesicles particularly in periventricular WM that is adjacent to areas of ependymal injury.
    Current Alzheimer research 01/2014; · 4.97 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) is often associated with intracerebral and intraventricular hemorrhage. Thrombin is a neurotoxin generated at bleeding sites following TBI, and can lead to cell death and subsequent cognitive dysfunction via activation of Src family kinases (SFKs). We hypothesize that inhibiting SFKs can protect hippocampal neurons and improve cognitive memory function following TBI. To test these hypotheses we show that moderate lateral fluid percussion (LFP) TBI in adult rats produces bleeding into the cerebrospinal fluid (CSF) in both lateral ventricles, which elevates oxyhemoglobin and thrombin levels in CSF, activates the SFK family member Fyn, and increases Rho-kinase 1(ROCK1) expression. Systemic administration of the SFK inhibitor, PP2, immediately following moderate TBI blocks ROCK1 expression, protects hippocampal CA2-3 neurons, and improves spatial memory function. These data suggest the possibility that inhibiting SFKs following TBI might improve clinical outcomes.
    Journal of neurotrauma 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Autophagy is responsible for the bulk degradation of cytoplasmic contents including organelles through the lysosomal machinery. Neonatal hypoxia–ischemia (HI) causes cell death in the brain by caspase-dependent and independent pathways. Ischemic insults also increase the formation of autophagosomes and activate autophagy. This study assessed the possible sex- and region-specific differences of autophagy activity in neonates subjected to HI brain injury. HI males had a modest decrease in lysosome numbers with no effect on LC3B-II protein in the cortex. In contrast, HI females had decreased lysosome numbers and their LC3B-II protein expression was significantly increased in the cortex following HI. In the hippocampus, both HI males and all females had increased numbers of autolysosomes suggesting activation of autophagy but with no effect on lysosome numbers, or Beclin-1 or LC3B protein levels. Males and females had increases in caspase 3/7 activity in their cortices and hippocampi following HI, though the increases were three to sixfold greater in females. The present data: (a) confirm greater caspase activation in the brains of females compared to males following HI; (b) suggest a partial failure to degrade LC3B-II protein in cortical but not hippocampal lysosomes of females as compared to males following neonatal HI; (c) all females have greater basal autophagy activity than males which may protect cells against injury by increasing cell turnover and (d) demonstrate that autophagy pathways are disturbed in regional- and sex-specific patterns in the rat brain following neonatal HI.
    Neuroscience 01/2014; 256:201–209. · 3.33 Impact Factor
  • Frank R Sharp, Xinhua Zhan, Da-Zhi Liu
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    ABSTRACT: Heat shock proteins (Hsps) are induced by heat shock via heat shock factor proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types but is induced mainly in neurons in the ischemic penumbra. Overexpression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In the brain, protein kinase D phosphorylates Hsp27 following ischemia which then binds apoptosis signal-regulating kinase 1 to prevent MKK4/7, c-Jun NH(2)-terminal kinase, and Jun-induced apoptosis, and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion, and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant, both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic.
    Translational Stroke Research 12/2013; 4(6):685-92.
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    ABSTRACT: Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (<18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood-brain barrier (BBB) disruption. This contrasts to delayed HT (>18 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 27 November 2013; doi:10.1038/jcbfm.2013.203.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 11/2013; · 5.46 Impact Factor
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    ABSTRACT: Autophagy is responsible for the bulk degradation of cytoplasmic contents including organelles through the lysosomal machinery. Neonatal hypoxia-ischemia (HI) causes cell death in brain by caspase-dependent and independent pathways. Ischemic insults also increase the formation of autophagosomes and activate autophagy. This study assessed the possible sex- and region-specific differences of autophagy activity in neonates subjected to HI brain injury. HI males had a modest decrease in lysosome numbers with no effect on LC3B-II protein in cortex. In contrast, HI females had decreased lysosome numbers and their LC3B-II protein expression was significantly increased in cortex following HI. In the hippocampus, both HI males and all females had increased numbers of autolysosomes suggesting activation of autophagy but with no effect on lysosome numbers, or Beclin-1 or LC3B protein levels. Males and females had increases in caspase 3/7 activity in their cortex and hippocampus following HI, though the increases were 3 to 6 fold greater in females. The present data: a) confirm greater caspase activation in brains of females compared to males following HI; b) suggest a partial failure to degrade LC3B-II protein in cortical but not hippocampal lysosomes of females as compared to males following neonatal HI; c) all females have greater basal autophagy activity than males which may protect cells against injury by increasing cell turnover and d) demonstrate that autophagy pathways are disturbed in regional- and sex-specific patterns in the rat brain following neonatal hypoxia-ischemia.
    Neuroscience 10/2013; · 3.33 Impact Factor
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    ABSTRACT: Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. RNA from blood was processed on whole genome exon arrays for 2-4--year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_NTCV versus ASD_LTCV. These differences were significant at P <0.05 after false discovery rate corrections for multiple comparisons (FDR <5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling. The only pathways significant after multiple comparison corrections (FDR <0.05) were the Nrf2-mediated reactive oxygen species (ROS) oxidative response (superoxide dismutase 2, catalase, peroxiredoxin 1, PIK3C3, DNAJC17, microsomal glutathione S-transferase 3) and superoxide radical degradation (SOD2, CAT). These data support differences in alternative splicing of mRNA in blood of ASD subjects compared to TD controls that differ related to head size. The findings are preliminary, need to be replicated in independent cohorts, and predicted alternative splicing differences need to be confirmed using direct analytical methods.
    Molecular Autism 09/2013; 4(1):30. · 5.49 Impact Factor
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    ABSTRACT: The discovery of genetic or genomic markers plays a central role in the development of personalized medicine. A notable challenge exists when dealing with the high dimensionality of the data sets, as thousands of genes or millions of genetic variants are collected on a relatively small number of subjects. Traditional gene-wise selection methods using univariate analyses face difficulty to incorporate correlational, structural, or functional structures amongst the molecular measures. For microarray gene expression data, we first summarize solutions in dealing with 'large p, small n' problems, and then propose an integrative Bayesian variable selection (iBVS) framework for simultaneously identifying causal or marker genes and regulatory pathways. A novel partial least squares (PLS) g-prior for iBVS is developed to allow the incorporation of prior knowledge on gene-gene interactions or functional relationships. From the point view of systems biology, iBVS enables user to directly target the joint effects of multiple genes and pathways in a hierarchical modeling diagram to predict disease status or phenotype. The estimated posterior selection probabilities offer probabilitic and biological interpretations. Both simulated data and a set of microarray data in predicting stroke status are used in validating the performance of iBVS in a Probit model with binary outcomes. iBVS offers a general framework for effective discovery of various molecular biomarkers by combining data-based statistics and knowledge-based priors. Guidelines on making posterior inferences, determining Bayesian significance levels, and improving computational efficiencies are also discussed.
    PLoS ONE 07/2013; 8(7):e67672. · 3.53 Impact Factor
  • 2013 International Meeting for Autism Research; 05/2013
  • 2013 International Meeting for Autism Research; 05/2013
  • Christopher Cox, Frank R Sharp
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    ABSTRACT: Stroke is a leading cause of death and disability, and considerable effort is being expended to investigation of its pathological mechanisms, as well as the identification of clinically relevant biomarkers that could assist in diagnosis. RNA-based analysis of gene expression in blood represents a new field of study addressing both paradigms. A number of recent animal and human studies using microarray technology demonstrate rapidly-induced, measurable changes in gene expression in response to ischemic trauma, and distinct expression ?profiles? specific to the injury subtype. The incorporation of newer technologies for a more detailed transcriptome analysis holds great promise for further improving our knowledge of stroke at the molecular level, and potentially enhancing standards of diagnosis.
    Neurological Research 04/2013; · 1.45 Impact Factor

Publication Stats

16k Citations
1,588.73 Total Impact Points

Institutions

  • 2005–2015
    • University of California, Davis
      • Department of Neurology
      Davis, California, United States
  • 2009–2013
    • Child Mind Institute
      New York, New York, United States
  • 2011
    • National Human Genome Research Institute
      Maryland, United States
  • 2000–2009
    • University of Cincinnati
      • Department of Neurology
      Cincinnati, OH, United States
    • University of Tampere
      • Department of Neurology and Rehabilitation
      Tampere, Western Finland, Finland
  • 2006
    • University of California, Los Angeles
      • Department of Neurology
      Los Angeles, CA, United States
  • 2002–2005
    • Cincinnati Children's Hospital Medical Center
      Cincinnati, Ohio, United States
  • 2004
    • Cyceron
      Caen, Lower Normandy, France
    • The Ohio State University
      • Department of Neurology
      Columbus, OH, United States
  • 2003
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1985–2003
    • University of California, San Francisco
      • • Department of Neurological Surgery
      • • Department of Neurology
      San Francisco, CA, United States
  • 1987–2000
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 1998
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 1995
    • Albert Einstein College of Medicine
      • Department of Neuroradiology
      New York City, NY, United States
  • 1994
    • Tohoku University
      • Department of Neurosurgery
      Sendai, Kagoshima, Japan
  • 1983–1989
    • Stanford University
      Palo Alto, California, United States
    • Naval Medical Center San Diego
      San Diego, California, United States
  • 1981–1985
    • University of California, San Diego
      • • Department of Neurosciences
      • • Department of Medicine
      • • Department of Surgery
      San Diego, California, United States
  • 1978
    • National Institute of Mental Health (NIMH)
      • Laboratory of Neuropsychology
      Maryland, United States