CAP Profiles

Bio

Bio

28 years of experience practicing general and geriatric psychiatry, and addiction medicine - inpatient, outpatient, emergency room, residential, partial hospitalization, and telemedicine.

Board Certified in Psychiatry, Geriatric Psychiatry, and in the new medical specialty of Addiction Medicine

Trained hundreds of resident physicians and medical students in inpatient and emergency room psychiatry and addiction medicine

23 years of experience as director of NIH-funded laboratory performing molecular biology and genetics

Extensive publication record in the neurobiology of Alzheimer’s disease, and in pharmacogenetics.

Licensed to practice Medicine in California, Maryland, District of Columbia, and Virginia

Academic Appointments

Honors & Awards

  • Mrazek Award for Psychiatric Pharmacogenomics, American Psychiatric Association (2019)
  • Board Certified, Addiction Medicine, ABPM (ABMS) (2018)
  • Board Certified, Psychiatry, ABPN
  • Board Certified, Geriatric Psychiatry, ABPN
  • Fellow, American Psychiatric Association
  • Best Doctors in America, Best Doctors, Inc.
  • Knight Fellow Favorite Professor, Stanford University
  • Alpha Omega Alpha, University of California, Davis, School of Medicine
  • G. Milton Shy Award, American Academy of Neurology
  • Phi Beta Kappa, The George Washington University

Professional Education

  • M.D., University of California, Davis (1986)
  • Ph.D., University of California, Berkeley (1984)
  • B.A., The George Washington University (1974)

Contact

Links

Research & Scholarship

Current Research and Scholarly Interests

Over the years my laboratory addressed scientific problems related to neuroscience, genetics, psychiatry, neurology and addiction medicine. Initially, we investigated expression of beta amyloid and related markers in Alzheimer’s disease brain. Simultaneously we developed cell culture models using astrocytes and microglia to investigate production of cytokines by glia, thus defining the inflammatory repertoire of these cells. Next, we began human genetics studies to assess the effect of the APOE epsilon 4 allele on clinical phenotypes in Alzheimer’s disease and other conditions. We then employed organotypic hippocampal explant cultures to study glial-neuronal interactions. This involved utilizing confocal microscopy to image cells in the 3-dimentional hippocampal cultures, as well as implementing PCR techniques for quantifying gene expression in minute volumes of tissue. Ultimately, we developed a microglia-hippocampal co-culture model with genetically engineered exogenous microglia to study cell-cell inflammatory processes. With this model we discovered novel effects of inflammatory cytokines on neurons. We also engineered endogenous microglia in the organotypic cultures using biolistics, to confirm results obtained in the co-cultures. We were early adopters of microarray technology for studying gene expression as well as for genotyping and DNA sequencing. We applied microarray approaches to gene expression in transgenic mouse models for Alzheimer’s disease, identifying a variety of markers induced by brain amyloid beta. Simultaneously, we were among the first to apply microarray technology to genotyping for markers for clinical medication response, adverse reactions, and metabolism. Finally, we performed large scale genotyping studies to identify markers for antidepressant response and response to medications for smoking cessation.

Clinical Trials

  • Genetics of Symptomatology and Treatment Response in Psychotic Major Depression Not Recruiting

    We hope to learn more about the biology of psychiatric illness with the hope of improving the diagnosis and treatment of such psychiatric conditions as major depression.

    Stanford is currently not accepting patients for this trial. For more information, please contact Gregory H Cohen, MSW, 650-723-3305.

    View full details

Teaching

2019-20 Courses

Publications

All Publications

  • Corticotropin-releasing factor 1 receptor haplotype and cognitive features of major depression. Translational psychiatry Davis, E. G., Keller, J., Hallmayer, J., Pankow, H. R., Murphy, G. M., Gotlib, I. H., Schatzberg, A. F. 2018; 8 (1): 5

    Abstract

    Corticotropin-releasing factor signaling through CRF receptor type 1 (CRF1) has been shown to contribute to learning and memory function. A haplotype of alleles T-A-T in a set of common polymorphisms in the gene encoding for CRF1(CRHR1) has been associated with both depression vulnerability and alterations in cognitive functioning. The present study investigated the relations between the TAT haplotype and specific symptoms of depression, self-reported ruminative behaviors, and neuropsychological performance on a learning and memory task. Participants were adults with major depression with and without psychotic features (N = 406). Associations were examined between TAT haplotype and endorsement of depression symptoms from diagnostic interviews, scores on the rumination response scale (RRS), and verbal memory performance on the California Verbal Learning Test-II (CVLT-II). All analyses included depression subtype, age, and sex as covariates; CVLT-II analyses also included evening cortisol levels. Across the entire sample, carriers of more copies of the TAT haplotype reported greater endorsement of the symptom describing difficulty concentrating and making decisions. In separate subsamples, TAT homozygotes had higher rumination scores on the RRS, both brooding and reflection subscales, and more TAT copies were associated with poorer CVLT-II performance in both total learning and free recall trials. These data demonstrate that the CRHR1 TAT haplotype is associated with cognitive features of depression including difficulty with decision-making, higher rumination, and poorer learning and memory. It will be important in future research to identify the specific molecular mechanisms for CRF1signaling that contribute to depression-related cognitive dysfunction.

    View details for PubMedID 29317606

    View details for PubMedCentralID PMC5802461

  • HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition Molecular Psychiatry Keller, J., Gomez, R., Williams, G., Lembke, A., Lazzeroni, L., Murphy, Jr., G. M., Schatzberg, A. 2017; 22 (4): 527-536
  • Response to Transdermal Selegiline Smoking Cessation Therapy and Markers in the 15q24 Chromosomal Region. Nicotine & tobacco research Sarginson, J. E., Killen, J. D., Lazzeroni, L. C., Fortmann, S. P., Ryan, H. S., Ameli, N., Schatzberg, A. F., Murphy, G. M. 2015; 17 (9): 1126-1133

    Abstract

    Current treatments for smoking cessation have limited efficacy. A potential pharmaceutical treatment for smoking cessation is selegiline, a selective and irreversible monoamine oxidase B inhibitor. A few clinical trials have been carried out using selegiline but the results have been mixed. We sought to determine if genetic markers in cholinergic loci in the 15q24 chromosomal region predict response to smoking cessation therapy with selegiline.We performed an 8-week double-blind, placebo-controlled clinical trial of the selegiline transdermal system (STS) in heavy smokers, with follow-up at weeks 25 and 52. Eight single nucleotide polymorphisms (SNPs) in the 15q24 region, which contains the genes for the nicotinic acetylcholine receptor subunits CHRNA5, CHRNA3, and CHRNB4, were investigated for association with treatment response.The CHRNB4 promoter SNP rs3813567 was associated with both point prevalence abstinence (PPA) and post-quit craving. Carriers of the minor C allele treated with selegiline showed lower rates of abstinence and higher levels of craving than selegiline-treated non-carriers, indicating that the rs3813567 C allele adversely affects abstinence in selegiline-treated smokers. This effect was not present among placebo-treated smokers. Selegiline-treated smokers with the CHRNA5 rs680244 GG genotype had lower post-quit craving, and unlike placebo-treated GG-carrying smokers, did not experience a post-quit increase in depressive symptoms.Variants in genes encoding cholinergic receptors affect abstinence, craving and mood in selegiline-treated smokers. Selegiline primarily affects dopamine levels in the brain, but cholinergic input affects nicotine-induced dopaminergic activity. These markers may have value in identifying those likely to respond to selegiline for smoking cessation.

    View details for DOI 10.1093/ntr/ntu273

    View details for PubMedID 25572450

  • ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression PHARMACOGENOMICS JOURNAL Ray, A., Tennakoon, L., Keller, J., Sarginson, J. E., Ryan, H. S., Murphy, G. M., Lazzeroni, L. C., Trivedi, M. H., Kocsis, J. H., Debattista, C., Schatzberg, A. F. 2015; 15 (4): 332-339

    Abstract

    The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.

    View details for DOI 10.1038/tpj.2014.72

    View details for Web of Science ID 000358448500007

  • ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial American Journal of Psychiatry Schatzberg, A. F., DeBattista, C., Lazzeroni, L., Rekshan, W., Etkin, A., Murphy, G., Williams, L. 2015; In press
  • HPA axis genetic variation, cortisol and psychosis in major depression. Molecular psychiatry Schatzberg, A. F., Keller, J., Tennakoon, L., Lembke, A., Williams, G., Kraemer, F. B., Sarginson, J. E., Lazzeroni, L. C., Murphy, G. M. 2014; 19 (2): 220-227

    Abstract

    Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r(2)=0.288) and from 0100 to 0900 h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.Molecular Psychiatry advance online publication, 29 October 2013; doi:10.1038/mp.2013.129.

    View details for DOI 10.1038/mp.2013.129

    View details for PubMedID 24166410

  • BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenet Genomics Murphy GM, Sarginson JE, Ryan HS, O'Hara R, Schatzberg AF, Lazzeroni LC 2013; 23 (6): 301-13
  • Pharmacogenetics of Late-Life Depression In: Late-Life Mood Disorders, H. Lavretsky, M. Sajatovic, C. Reynolds, eds. Murphy, G. 2013; Oxford
  • Markers in the 15q24 Nicotinic Receptor Subunit Gene Cluster (CHRNA5-A3-B4) Predict Severity of Nicotine Addiction and Response to Smoking Cessation Therapy AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Sarginson, J. E., Killen, J. D., Lazzeroni, L. C., Fortmann, S. P., Ryan, H. S., Schatzberg, A. F., Murphy, G. M. 2011; 156B (3): 275-284

    Abstract

    Stopping smoking is difficult even with treatment. Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy. We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine (TN), two treatments for smoking cessation. Samples were drawn from two studies. In the first study (Maintenance 1, MT1), 301 smokers received bupropion plus TN for 11 weeks, followed by 14 weeks of placebo or bupropion. In the second study (MT2), 276 smokers received bupropion and TN for 8 weeks. We focused on eight SNPs in the 15q24 region, which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5, CHRNA3, and CHRNB4, and has previously been implicated in nicotine addiction and smoking cessation. Analyses of baseline smoking quantity (SQ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 (D398N) and the CHRNA3 SNP rs1051730 (Y215Y) in a combined cohort containing MT1 and MT2. An association between SQ and ethnicity was also identified in the combined cohort. Pharmacogenetic analysis showed a significant association between rs8192475 (R37H) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2. Two markers for point prevalence abstinence, CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008, were also identified in MT2, with the strongest findings at week 52. These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy.

    View details for DOI 10.1002/ajmg.b.31155

    View details for Web of Science ID 000288332600003

    View details for PubMedID 21268243

  • FKBP5 Polymorphisms and Antidepressant Response in Geriatric Depression AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Schatzberg, A. F., Murphy, G. M. 2010; 153B (2): 554-560

    Abstract

    Genetic variation at the FKBP5 locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. FKBP5 may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two FKBP5 single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these FKBP5 genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by FKBP5 genetic variation. These results suggest that FKBP5 is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.

    View details for DOI 10.1002/ajmg.b.31019

    View details for Web of Science ID 000275377900023

    View details for PubMedID 19676097

    View details for PubMedCentralID PMC2897151

  • ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial AMERICAN JOURNAL OF PSYCHIATRY Schatzberg, A. F., DeBattista, C., Lazzeroni, L. C., Etkin, A., Murphy, G. M., Williams, L. M. 2015; 172 (8): 751-759

    Abstract

    The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

    View details for DOI 10.1176/appi.ajp.2015.14050680

    View details for Web of Science ID 000359274700015

    View details for PubMedID 25815420

  • APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years NEUROBIOLOGY OF AGING Taylor, J. L., Scanlon, B. K., Farrell, M., Hernandez, B., Adamson, M. M., Ashford, J. W., Noda, A., Murphy, G. M., Weiner, M. W. 2014; 35 (11): 2479-2485

    View details for DOI 10.1016/j.neurobiolaging.2014.05.011

    View details for Web of Science ID 000343419800009

  • The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability BEHAVIOR GENETICS Kennedy, Q., Taylor, J. L., Noda, A., Adamson, M., Murphy, G. M., Zeitzer, J. M., Yesavage, J. A. 2011; 41 (5): 700-708

    Abstract

    The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.

    View details for DOI 10.1007/s10519-010-9436-z

    View details for Web of Science ID 000294297200008

    View details for PubMedID 21193954

    View details for PubMedCentralID PMC3163820

  • Initial Cognitive Performance Predicts Longitudinal Aviator Performance JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES Yesavage, J. A., Jo, B., Adamson, M. M., Kennedy, Q., Noda, A., Hernandez, B., Zeitzer, J. M., Friedman, L. F., Fairchild, K., Scanlon, B. K., Murphy, G. M., Taylor, J. L. 2011; 66 (4): 444-453

    Abstract

    The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age.We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (± 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise.Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age.These data suggest that longitudinal performance on an important real-world activity can be predicted by initial assessment of relevant cognitive abilities.

    View details for DOI 10.1093/geronb/gbr031

    View details for Web of Science ID 000293251900007

    View details for PubMedID 21586627

    View details for PubMedCentralID PMC3132267

  • Influences of APOE epsilon 4 and Expertise on Performance of Older Pilots PSYCHOLOGY AND AGING Taylor, J. L., Kennedy, Q., Adamson, M. M., Lazzeroni, L. C., Noda, A., Murphy, G. M., Yesavage, J. A. 2011; 26 (2): 480-487

    Abstract

    Little is known about how APOE ε4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE ε4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42-69 years were tested annually. APOE ε4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for ε4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE ε4 carriers.

    View details for DOI 10.1037/a0021697

    View details for Web of Science ID 000291668800026

    View details for PubMedID 21668123

    View details for PubMedCentralID PMC3117441

  • Failure to improve cigarette smoking abstinence with transdermal selegiline plus cognitive behavior therapy ADDICTION Killen, J. D., Fortmann, S. P., Murphy, G. M., Hayward, C., Fong, D., Lowenthal, K., Bryson, S. W., Killen, D. T., Schatzberg, A. F. 2010; 105 (9): 1660-1668

    Abstract

    To examine the effectiveness of transdermal selegiline for producing cigarette smoking abstinence.Adult smokers were randomly assigned to receive selegiline transdermal system (STS) or placebo given for 8 weeks. All participants received cognitive behavior therapy (CBT). Follow-ups were conducted at 25 and 52 weeks.Community smoking cessation clinic.243 adult smokers (> or =18 years of age; > or =10 cigarettes/day).Expired-air carbon monoxide confirmed 7-day point prevalence abstinence.STS was not superior to placebo. More women than men were abstinent at 52 week follow-up (28% vs 16%, P < 0.05). Behavioral activation (BAS) moderated treatment response (P = 0.01). The survival rate through week 52 for those with high 'drive' scores on the BAS was 47% if assigned to selegiline and 34% if assigned to placebo. The survival rate for those with low 'drive scores' on the BAS was 35% if assigned to selegiline compared to 53% if assigned to placebo.Transdermal selegiline does not appear generally effective in aiding smoking cessation though there may be a selective effect in those smokers with low 'behavioral activation'.

    View details for DOI 10.1111/j.1360-0443.2010.03020.x

    View details for Web of Science ID 000280668200027

    View details for PubMedID 20707784

  • ABCB1 ( MDR1) polymorphisms and antidepressant response in geriatric depression PHARMACOGENETICS AND GENOMICS Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Ershoff, B. D., Schatzberg, A. F., Murphy, G. M. 2010; 20 (8): 467-475

    Abstract

    Variation in the ATP-binding cassette, subfamily B, member 1 transporter (ABCB1) (multidrug-resistance gene 1) gene has been investigated as a predictor of response to treatment with a variety of medications such as antiarrhythmics, chemotherapeutic agents, anti-HIV medications, and some psychotropics. The ABCB1 gene product, P-glycoprotein, affects the transport of drugs out of many cell types, including endothelial cells at the blood-brain barrier. We sought to determine if ABCB1 polymorphisms predict response to antidepressant treatment in geriatric patients.We compared the effects of ABCB1 genetic variation on the therapeutic response to paroxetine, a P-glycoprotein substrate, and to mirtazapine, which is not thought to be transported by ABCB1, in a sample of 246 elderly patients with major depression treated in a clinical trial setting. A total of 15 single nucleotide polymorphisms in the ABCB1 gene were assessed in each patient. Two of these ABCB1 single nucleotide polymorphisms were earlier reported to predict treatment response in patients prescribed with P-glycoprotein substrate antidepressants.The two earlier identified ABCB1 markers for antidepressant response predicted time to remission in our paroxetine-treated patients, but not in the mirtazapine-treated patients. These results replicate the published findings of others. If a Bonferroni correction for type I error is made, our results do not reach the criteria for statistical significance. However, the Bonferroni correction may be too conservative given the strong linkage disequilibrium among some of the markers and our aim to replicate the earlier published findings.Our study provides confirmation that certain ABCB1 polymorphisms predict response to substrate medications in geriatric patients.

    View details for DOI 10.1097/FPC.0b013e32833b593a

    View details for Web of Science ID 000279865400001

    View details for PubMedID 20555295

  • Apolipoprotein E epsilon 4 influences on episodic recall and brain structures in aging pilots NEUROBIOLOGY OF AGING Adamson, M. M., Landy, K. M., Duong, S., Fox-Bosetti, S., Ashford, J. W., Murphy, G. M., Weiner, M., Taylor, J. L. 2010; 31 (6): 1059-1063

    Abstract

    The apolipoprotein (APOE) epsilon4 allele is associated with cognitive deficits and hippocampal atrophy in nondemented middle-aged and older adults. It is not known to what extent this genetic risk factor for Alzheimer's disease (AD) impacts performance in late middle-aged and older workers in cognitively demanding occupations. This cross-sectional analysis examines brain-cognitive-genetic relationships in actively flying general aviation pilots, half of whom are APOE epsilon4 carriers. Fifty pilots were studied with structural MRI and memory tasks. Average visual paired associate memory recall performance was lower in APOE epsilon4 carriers than non-carriers. Memory performance correlated positively with hippocampal volume, but no structural differences were found in hippocampal or frontal volumes with respect to APOE epsilon4 allele. These results were evident in healthy professionals without any presenting memory problems and without selection for a family history of AD. These findings point to basic memory testing as a sensitive tool for detecting APOE epsilon4-related influences on memory in aging workers.

    View details for DOI 10.1016/j.neurobiolaging.2008.07.017

    View details for Web of Science ID 000277246400018

    View details for PubMedID 18760504

    View details for PubMedCentralID PMC2858239

  • A beta peptide conformation determines uptake and interleukin-1 alpha expression by primary microglial cells NEUROBIOLOGY OF AGING Parvathy, S., Rajadas, J., Ryan, H., Vaziri, S., Anderson, L., Murphy, G. M. 2009; 30 (11): 1792-1804

    Abstract

    Microglia clear amyloid beta (Abeta) after immunization. The interaction of Abeta with the microglial cell surface also results in cytokine expression. Soluble oligomers and protofibrils of Abeta may be more neurotoxic than Abeta fibrils. We investigated the effects of oligomeric, protofibrillar and fibrillar Abeta40 and Abeta42 peptides on uptake and IL-1alpha expression by primary microglia. Abeta peptide assemblies were extensively characterized. Primary microglial cells were exposed to different Abeta40 and Abeta42 assemblies and IL-1alpha expression was quantified. To study uptake, microglial cells were exposed to different assemblies of Cy3-labeled Abeta. We found that Abeta42 and Abeta40 oligomers and fibrils induced IL-1alpha expression, but protofibrils did not. We also observed that all forms of Abeta42 (oligomer, protofibril and fibril) and Abeta40 fibrils were taken up by the microglial cells. These results demonstrate that microglial cells can take up non-fibrillar Abeta and that oligomeric peptide induces an inflammatory response. The uptake of oligomeric and protofibrillar Abeta by microglia merits further investigation as a potential means for removing these neurotoxic species from the brain.

    View details for DOI 10.1016/j.neurobiolaging.2008.01.011

    View details for PubMedID 18339452

  • Gene expression profile of the PDAPP mouse model for Alzheimer's disease with and without Apolipoprotein E NEUROBIOLOGY OF AGING Selwood, S. P., Parvathy, S., Cordell, B., Ryan, H. S., Oshidari, F., Vincent, V., Yesavage, J., Lazzeroni, L. C., Murphy, G. M. 2009; 30 (4): 574-590

    Abstract

    The APOE epsilon 4 allele is a strong risk factor for Alzheimer's disease (AD). However, the molecular basis for this effect remains unclear. We examined expression of approximately 12,000 genes and expressed sequence tags in the hippocampus and cortex of PDAPP (APP(V717)) mice modeling AD that show extensive amyloid beta (A beta) deposition, and in PDAPP mice lacking murine APOE expression, which show marked attenuation of A beta deposition in the brain. Wild type and APOE knockout animals were also examined. Expression levels were determined at the initial stage of A beta deposition, as well as in older animals showing extensive neuropathological changes. Fifty-four transcripts were identified using our statistical analysis as differentially regulated between the PDAPP and PDAPP/APOE ko mice, whereas 31 transcripts were classified as differentially regulated among PDAPP mice and WT animals, and seven transcripts were identified as regulated between the PDAPP/APOE ko animals and the APOE ko animals. Interestingly, many of the differentially regulated genes we detected can be related to biological processes previously shown to be important in AD pathophysiology, including inflammation, calcium homeostasis, cholesterol transport and uptake, kinases and phosphatases involved in tau phosphorylation and dephosphorylation, mitochondrial energy metabolism, protein degradation, neuronal growth, endoplasmic reticulum (ER) stress related proteins, antioxidant activity, cytoskeletal organization, and presenilin binding proteins. Regulated genes also included some not directly associated with AD in the past but likely to be involved in known AD pathophysiologic mechanisms, and others that may represent completely novel factors in the pathogenesis of AD. These results provide a global molecular profile of hippocampal and cortical gene expression during the initial and intermediate stages Abeta deposition, and the effects of APOE deletion on this process.

    View details for DOI 10.1016/j.neurobiolaging.2007.08.006

    View details for PubMedID 17904698

  • Extended cognitive behavior therapy for cigarette smoking cessation ADDICTION Killen, J. D., Fortmann, S. P., Schatzberg, A. F., Arredondo, C., Murphy, G., Hayward, C., Celio, M., Cromp, D., Fong, D., Pandurangi, M. 2008; 103 (8): 1381-1390

    Abstract

    PRIMARY AIM: Examine the effectiveness of extended cognitive behavior therapy (CBT) in promoting longer-term smoking abstinence.Open-label treatment phase followed by extended treatment phase. Randomization conducted prior to entry into open-label treatment phase; analysis based on intention-to-treat to avoid threat of selection bias.Community smoking cessation clinic.A total of 304 adult smokers (> or = 18 years of age; > or = 10 cigarettes/day).Open-label (8 weeks): all participants received bupropion SR, nicotine patch, CBT. Extended treatment (12 weeks): participants received either CBT + voicemail monitoring and telephone counseling or telephone-based general support.Seven-day point prevalence abstinence, expired-air carbon monoxide.At week 20 follow-up, CBT produced a higher 7-day point prevalence abstinence rate: 45% versus 29%, P = 0.006; at 52 weeks the difference in abstinence rates (31% versus 27%) was not significant. History of depression was a moderator of treatment. Those with a positive history had a better treatment response at 20 weeks when assigned to the less intensive telephone support therapy (P < 0.05).The superiority of CBT to 20 weeks suggests that continued emphasis on the development of cognitive and behavioral strategies for maintaining non-smoking during an extended treatment phase may help smokers to maintain abstinence in the longer term. At present, the minimum duration of therapy is unknown.

    View details for DOI 10.1111/j.1360-0443.2008.02273.x

    View details for Web of Science ID 000257692800021

    View details for PubMedID 18855829

  • Slower speed-of-processing of cognitive tasks is associated with presence of the apolipoprotein epsilon 4 allele JOURNAL OF PSYCHIATRIC RESEARCH O'Hara, R., Sommer, B., Way, N., Kraemer, H. C., Taylor, J., Murphy, G. 2008; 42 (3): 199-204

    Abstract

    Detection of preclinical cognitive deficits is important for identifying those at greatest risk for such disorders as Alzheimer's disease. However, available neuropsychological measures may not be sufficiently sensitive to preclinical cognitive impairment, particularly in high functioning or younger older adults. This study utilizes a battery of computerized cognitive tests (Cognometer) designed to provide a more sensitive measure of age-related cognitive performance by incorporating speed-of-processing components. Fifty-one community-dwelling older adults were administered the Cognometer battery, which incorporates speed-of-processing components into measures of verbal, spatial and working memory, attention, and visuo-spatial ability. Performance of 18 subjects with the epsilon4 allele was compared to that of 33 subjects without the epsilon4 allele. A brief battery of standard neuropsychological measures was also administered. No significant differences were observed between the two groups with respect to performance on any of the neuropsychological measures. However, with respect to the Cognometer battery, individuals with the epsilon4 allele were significantly slower in performing all the cognitive tasks, with the exception of the visuo-spatial task. With respect to performance, the two genotype groups did not differ significantly except on immediate memory, with the epsilon4 group exhibiting increased errors. Overall, the epsilon4 group was significantly slower in performing all of the Cognometer memory tasks. These findings provide continued support for the negative impact of the epsilon4 allele on cognition and further suggest that speed-of-processing during memory tasks may have the potential to detect subtle cognitive deficits.

    View details for DOI 10.1016/j.jpsychires.2006.12.001

    View details for PubMedID 17250852

  • A novel quantitative trait locus on mouse chromosome 18, "era1," modifies the entrainment of circadian rhythms SLEEP Wisor, J. P., Striz, M., DeVoss, J., Murphy, G. M., Edgar, D. M., O'Hara, B. F. 2007; 30 (10): 1255-1263

    Abstract

    The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-h rhythmicity to sleep-wake cycles, locomotor activity, and other behavioral and physiological processes. The timing of rhythms relative to the light/dark (LD12:12) cycle is influenced in part by the endogenous circadian period and the time of day specific sensitivity of the clock to light. We now describe a novel circadian rhythm phenotype, and a locus influencing that phenotype, in a segregating population of mice.By crossbreeding 2 genetically distinct nocturnal strains of mice (Cast/Ei and C57BL/6J) and backcrossing the resulting progeny to Cast/Ei, we have produced a novel circadian phenotype, called early runner mice.Early runner mice entrain to a light/dark cycle at an advanced phase, up to 9 hours before dark onset. This phenotype is not significantly correlated with circadian period in constant darkness and is not associated with disruption of molecular circadian rhythms in the SCN, as assessed by analysis of period gene expression. We have identified a genomic region that regulates this phenotype-a major quantitative trait locus on chromosome 18 (near D18Mit184) that we have named era1 for Early Runner Activity locus one. Phase delays caused by light exposure early in the subjective night were of smaller magnitude in backcross offspring that were homozygous Cast/Ei at D18Mit184 than in those that were heterozygous at this locus.Genetic variability in the circadian response to light may, in part, explain the variance in phase angle of entrainment in this segregating mouse population.

    View details for Web of Science ID 000250019300003

    View details for PubMedID 17969459

  • Potential ethnic modifiers in the assessment and treatment of Alzheimer's disease: challenges for the future INTERNATIONAL PSYCHOGERIATRICS Faison, W. E., Schultz, S. K., Aerssens, J., Alvidrez, J., Anand, R., Farrer, L. A., Jarvik, L., Manly, J., McRae, T., Murphy, G. M., Olin, J. T., Regier, D., Son, M., Mintzer, J. E. 2007; 19 (3): 539-558

    Abstract

    Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups?Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants.The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed.Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

    View details for DOI 10.1017/S104161020700511X

    View details for Web of Science ID 000246984800016

    View details for PubMedID 17451614

  • A Novel Quantitative Trait Locus on Mouse Chromosome 18, ?era1,? Modifies the Entrainment of Circadian Rhythm Sleep Wisor JP, Striz M, DeVoss J, Murphy GM, Edgar DM, O'Hara B 2007; 30 (10): 1255-1263
  • Cerebral Inflammation and Alzheimer's Dementia In: Research Progress in Alzheimer's Disease and Dementia, vol. 2, edited by Miao-Kun Sun Saravanapavan, P., Murphy, GM. 2007: 57-96
  • Application of microarray technology in psychotropic drug trials. Journal of psychopharmacology Murphy, G. M. 2006; 20 (4): 72-78

    Abstract

    Microarrays can be manufactured to detect hundreds of thousands of polymorphisms in DNA from patients in psychotropic drug trials. Some of these polymorphisms may be useful as pharmacogenetic predictors of treatment outcomes. We tested a microarray designed to detect common polymorphisms in the CYP2D6 gene that encodes debrisoquine hydroxylase (DH). DH is involved in the hepatic metabolism of many psychotropics. CYP2D6 genotypes predicted plasma steady state concentrations of nortriptyline, a classic DH substrate, in a sample of geriatric patients with major depression. However, in a sample of 246 geriatric patients treated with paroxetine or mirtazapine, both of which are metabolized in part by DH, CYP2D6 genotypes determined with microarrays did not predict discontinuations due to adverse events or severity of adverse events. For modern antidepressants such as paroxetine and mirtazapine, pharmacokinetic factors that are regulated by CYP2D6 such as plasma drug concentrations may be less important than pharmacodynamic factors in determining outcomes. Studies of single candidate genes such as CYP2D6 have only begun to utilize the potential of microarrays for pharmacogenetic prediction. Yet, there is controversy as to whether genome-wide studies designed to detect millions of genotypes with microarrays will lead to new pharmacogenetic discoveries, or whether a more focused, hypothesis-driven approach is better.

    View details for PubMedID 16785274

  • Extended treatment with bupropion SR for cigarette smoking cessation JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY Killen, J. D., Fortmann, S. P., Murphy, G. M., Hayward, C., Arredondo, C., Cromp, D., Celio, M., Abe, L., Wang, Y., Schatzberg, A. F. 2006; 74 (2): 286-294

    Abstract

    The authors present results of a randomized clinical trial of the efficacy of extended treatment with bupropion SR in producing longer term cigarette smoking cessation. Adult smokers (N = 362) received open-label treatment (11 weeks) that combined relapse prevention training, bupropion SR, and nicotine patch followed by extended treatment (14 weeks) with bupropion SR or matching placebo. Abstinence percentages were relatively high (week 11: 52%; week 25: bupropion, 42%; placebo, 38%; week 52: bupropion, 33%; placebo, 34%), but bupropion SR did not surpass placebo. Gender and baseline craving level were identified as significant, independent moderators of treatment response. Men were more likely to abstain than women (week 11: 59% vs. 43%, p = .001; week 25: 48% vs. 31%, p = .001; week 52: 39% vs. 27%, p = .01). Because most smokers suffer relapse with any current cessation treatment, the comparatively high abstinence percentages achieved in this trial are of interest.

    View details for DOI 10.1037/0022-006X.74.2.286

    View details for Web of Science ID 000237667500009

    View details for PubMedID 16649873

  • The brain-derived neurotrophic factor Val66Met polymorphism and rate of decline in Alzheimer's disease JOURNAL OF ALZHEIMERS DISEASE Chuu, J. Y., Taylor, J. L., Tinklenberg, J., Noda, A., Yesavage, J., Murphy, G. M. 2006; 9 (1): 43-49

    Abstract

    It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD.

    View details for Web of Science ID 000237795900004

    View details for PubMedID 16627933

  • Spatial test for agricultural pesticide "blow-In" effect on prevalence of Parkinson's disease JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY Yesavage, J. A., Sheikh, J., Noda, A., Murphy, G., O'Hara, R., Hierholzer, R., Battista, M., Ashford, J. W., Schneider, B., Hoblyn, J., Kraemer, H. C., Tinklenberg, J. 2006; 19 (1): 32-35

    Abstract

    The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.

    View details for DOI 10.1177/0891988705284707

    View details for Web of Science ID 000235366800006

    View details for PubMedID 16449758

  • Nocturnal sleep apnea/hypopnea is associated with lower memory performance in APOE epsilon 4 carriers NEUROLOGY O'Hara, R., Schroder, C. M., Kraemer, H. C., Kryla, N., Cao, C., Miller, E., Schatzberg, A. F., Yesavage, J. A., Murphy, G. M. 2005; 65 (4): 642-644

    Abstract

    The authors investigated the relationship between obstructive sleep apnea/hypopnea (OSAH) and cognition in 36 older adults, 18 APOE epsilon4 carriers, and 18 non-carriers. Greater numbers of respiratory events negatively impacted memory function in epsilon4 carriers only. This is the first study to provide preliminary evidence for a negative interaction of APOE epsilon4 and OSAH on memory in older adults, which may have important implications for treating cognitive decline and delaying dementia onset.

    View details for Web of Science ID 000231371600035

    View details for PubMedID 16116137

  • Microglia overexpressing the macrophage colony-stimulating factor receptor are neuroprotective in a microglial-hippocampal organotypic coculture system JOURNAL OF NEUROSCIENCE Mitrasinovic, O. M., Grattan, A., Robinson, C. C., Lapustea, N. B., Poon, C., Ryan, H., Phong, C., Murphy, G. M. 2005; 25 (17): 4442-4451

    Abstract

    Microglia with increased expression of the macrophage colony-stimulating factor receptor (M-CSFR; c-fms) are found surrounding plaques in Alzheimer's disease (AD) and in mouse models for AD and after ischemic or traumatic brain injury. Increased expression of M-CSFR causes microglia to adopt an activated state that results in proliferation, release of cytokines, and enhanced phagocytosis. To determine whether M-CSFR-induced microglial activation affects neuronal survival, we assembled a coculture system consisting of BV-2 microglia transfected to overexpress the M-CSFR and hippocampal organotypic slices treated with NMDA. Twenty-four hours after assembly of the coculture, microglia overexpressing M-CSFR proliferated at a higher rate than nontransfected control cells and exhibited enhanced migration toward NMDA-injured hippocampal cultures. Surprisingly, coculture with c-fms-transfected microglia resulted in a dramatic reduction in NMDA-induced neurotoxicity. Similar results were observed when cocultures were treated with the teratogen cyclophosphamide. Biolistic overexpression of M-CSFR on microglia endogenous to the organotypic culture also rescued neurons from excitotoxicity. Furthermore, c-fms-transfected microglia increased neuronal expression of macrophage colony-stimulating factor (M-CSF), the M-CSFR, and neurotrophin receptors in the NMDA-treated slices, as determined with laser capture microdissection. In the coculture system, direct contact between the exogenous microglia and the slice was necessary for neuroprotection. Finally, blocking expression of the M-CSF ligand by exogenous c-fms-transfected microglia with a hammerhead ribozyme compromised their neuroprotective properties. These results demonstrate a protective role for microglia overexpressing M-CSFR in our coculture system and suggest under certain circumstances, activated microglia can help rather than harm neurons subjected to excitotoxic and teratogen-induced injury.

    View details for DOI 10.1523/JNEUROSCI.0514-05.2005

    View details for Web of Science ID 000228702900025

    View details for PubMedID 15858070

  • Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer's disease: A role for cholinergic transmission NEUROSCIENCE Wisor, J. P., Edgar, D. M., Yesavage, J., Ryan, H. S., McCormick, C. M., Lapustea, N., Murphy, G. M. 2005; 131 (2): 375-385

    Abstract

    The Tg2576 mouse model of Alzheimer's disease (AD) exhibits age-dependent amyloid beta (Abeta) deposition in the brain. We studied electroencephalographically defined sleep and the circadian regulation of waking activities in Tg2576 mice to determine whether these animals exhibit sleep abnormalities akin to those in AD. In Tg2576 mice at all ages studied, the circadian period of wheel running rhythms in constant darkness was significantly longer than that of wild type mice. In addition, the increase in electroencephalographic delta (1-4 Hz) power that occurs during non-rapid eye movement sleep after sleep deprivation was blunted in Tg2576 mice relative to controls at all ages studied. Electroencephalographic power during non-rapid eye movement sleep was shifted to higher frequencies in plaque-bearing mice relative to controls. The wake-promoting efficacy of the acetylcholinesterase inhibitor donepezil was lower in plaque-bearing Tg2576 mice than in controls. Sleep abnormalities in Tg2576 mice may be due in part to a cholinergic deficit in these mice. At 22 months of age, two additional deficits emerged in female Tg2576 mice: time of day-dependent modulation of sleep was blunted relative to controls and rapid eye movement sleep as a percentage of time was lower in Tg2576 than in wild type controls. The rapid eye movement sleep deficit in 22 month-old female Tg2576 mice was abolished by brief passive immunization with an N-terminal antibody to Abeta. The Tg2576 model provides a uniquely powerful tool for studies on the pathophysiology of and treatments for sleep deficits and associated cholinergic abnormalities in AD.

    View details for DOI 10.1016/j.neuroscience.2004.11.018

    View details for Web of Science ID 000227258400011

    View details for PubMedID 15708480

  • Sleep apnea/hypopnea is associated with lower memory performance in APOE epsilon 4 allele carriers only 19th Annual Meeting of the Associated-Professional-Sleep-Societies O'Hara, R. M., Schroder, C. M., Kraemer, H. C., Kryla, N. R., Cao, C., Miller, E. H., Schatzberg, A. F., Yesavage, J. A., Murphy, G. M. AMER ACAD SLEEP MEDICINE. 2005: A109–A109

    View details for Web of Science ID 000228906100322

  • Cytokines and Neurodegeneration Cytokines and the CNS Murphy, G., Saravanapavan, P 2005: 163-191
  • Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression ARCHIVES OF GENERAL PSYCHIATRY Murphy, G. M., Hollander, S. B., Rodrigues, H. E., Kremer, C., Schatzberg, A. F. 2004; 61 (11): 1163-1169

    Abstract

    The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors.To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression.Double-blind, randomized 8-week study.Eighteen academic and private outpatient clinics.We evaluated 246 cognitively intact patients 65 years or older with major depression.Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122).The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes.Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses.These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.

    View details for Web of Science ID 000224898700011

    View details for PubMedID 15520364

  • Biolistic expression of the macrophage colony stimulating factor receptor in organotypic cultures induces an inflammatory response JOURNAL OF NEUROSCIENCE RESEARCH Mitrasinovic, O. M., Robinson, C. C., Tenen, D. G., Lee, Y. L., Poon, C., Murphy, G. M. 2004; 77 (3): 420-429

    Abstract

    The receptor for macrophage colony-stimulating factor (M-CSFR; c-fms) is expressed at increased levels by microglia in Alzheimer's disease (AD) and in mouse models for AD. Increased expression of M-CSFR on cultured microglia results in a strong proinflammatory response, but the relevance of this cell culture finding to intact brain is unknown. To determine the effects of increased microglial expression of M-CSFR in a complex organotypic environment, we developed a system for biolistic transfection of microglia in hippocampal slice cultures. The promoter for the Mac-1 integrin alpha subunit CD11b is active in cells of myeloid origin. In the brain, CD11b expression is restricted to microglia. Constructs consisting of the promoter for CD11b and a c-fms cDNA or an enhanced green fluorescent protein (EGFP) cDNA were introduced into monotypic cultures of microglia, neurons, and astrocytes. Strong CD11b promoter activity was observed in microglia, whereas little activity was observed in other cell types. Biolistic transfection of organotypic hippocampal cultures with the CD11b/c-fms construct resulted in expression of the c-fms mRNA and protein that was localized to microglia. Furthermore, biolistic overexpression of M-CSFR on microglia resulted in significantly increased production by the hippocampal cultures of the proinflammatory cytokines interleukin (IL)-1alpha macrophage inflammatory protein (MIP-1alpha), and trends toward increased production of IL-6 and M-CSF. These findings demonstrate that microglial overexpression of M-CSFR in an organotypic environment induces an inflammatory response, and suggest that increased microglial expression of M-CSFR could contribute to the inflammatory response observed in AD brain.

    View details for DOI 10.1002/jnr.20168

    View details for Web of Science ID 000222881300012

    View details for PubMedID 15248298

  • Microarray comparison of gene expression in the hippocampus of aged apoE E3 and E4 transgenic mice 9th International Conference on Alzheimers Disease and Related Disorders Murphy, G. M., Mitrasinovic, O. M., Sullivan, P. M. ELSEVIER SCIENCE INC. 2004: S316–S316

    View details for Web of Science ID 000223058701036

  • Use of a VA pharmacy database to screen for areas at high risk for disease: Parkinson's disease and exposure to pesticides JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY Yesavage, J. A., Sheikh, J., Noda, A., Murphy, G., O'Hara, R., Hierholzer, R., Battista, M., Ashford, J. W., Kraemer, H. C., Tinklenberg, J. 2004; 17 (1): 36-38

    Abstract

    The purpose of this study was to assess whether pharmacy database information from US Department of Veterans Affairs (VA) medical centers could be used to screen for areas of higher Parkinson's disease prevalence in patients exposed to pesticides. The authors used pharmacy data sets and compared the use of antiparkinsonian medications at 2 VA medical centers in California: one in Palo Alto, near the ocean, and one in Fresno, downwind from extensively farmed parts of the Central Valley. They found that patients at Fresno had higher odds ratios (1.5-1.8) for the use of Parkinson's disease medications than patients at Palo Alto. These data are consistent with the observations of prior epidemiologic studies and suggest that VA pharmacy databases can prioritize locations for further epidemiologic research. However, a thorough exploration of alternative explanations is needed to reach definitive conclusions regarding the findings suggested by this method.

    View details for DOI 10.1117/0891988703258672

    View details for Web of Science ID 000223474900007

    View details for PubMedID 15018696

  • Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal course JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY Yesavage, J. A., Friedman, L., Kraemer, H., Tinklenberg, J. R., Salehi, A., Noda, A., Taylor, J. L., O'Hara, R., Murphy, G. 2004; 17 (1): 20-24

    Abstract

    Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele.

    View details for DOI 10.1117/0891988703261994

    View details for Web of Science ID 000223474900004

    View details for PubMedID 15018693

  • Microglial overexpression of the M-CSF receptor augments phagocytosis of opsonized A beta NEUROBIOLOGY OF AGING Mitrasinovic, O. M., Murphy, G. M. 2003; 24 (6): 807-815

    Abstract

    The role of microglia in Alzheimer's disease (AD) has come under intense scrutiny recently because microglia may clear amyloid beta (Abeta) by phagocytosis after immunization of transgenic mice. Increased expression of the macrophage colony-stimulating factor receptor (M-CSFR) is an important feature of microglia in AD and transgenic mouse models for AD. Increased expression of M-CSFR on mouse and human microglia accelerates phagocytosis of aggregated Abeta in part through macrophage scavenger receptors. We now show that Abeta phagocytosis by microglia overexpressing M-CSFR is further enhanced by antibody opsonization of Abeta. M-CSFR overexpression increased microglial phagocytosis of opsonized aggregated Abeta in culture medium, and accelerated ingestion of native Abeta from AD brain sections. M-CSFR overexpression also increased microglial expression of Fcgamma receptors, and blocking Fcgamma receptors attenuated the enhanced Abeta uptake observed after M-CSFR overexpression and antibody opsonization. Microglia in AD and in AD mouse models with increased expression of M-CSFR are likely to rapidly ingest opsonized Abeta after immunization, making high intracerebral antibody titers unnecessary.

    View details for DOI 10.1016/S0197-4580(02)00237-3

    View details for Web of Science ID 000185453200006

    View details for PubMedID 12927763

  • The apolipoprotein E epsilon 4 allele and antidepressant efficacy in cognitively intact elderly depressed patients BIOLOGICAL PSYCHIATRY Murphy, G. M., Kremer, C., Rodrigues, H., Schatzberg, A. F. 2003; 54 (7): 665-673

    Abstract

    Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE epsilon4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that epsilon4 carriers would show impaired antidepressant response.The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15-45 mg (n = 124) or paroxetine 20-40 mg (n = 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping.Patients carrying the epsilon4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the epsilon4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age.The APOE epsilon4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications.

    View details for DOI 10.1016/S0006-3223(03)00174-4

    View details for Web of Science ID 000185500500001

    View details for PubMedID 14512205

  • Pharmacogenetics of antidepressant medication intolerance 40th Annual Meeting of the American-College-of-Neuropsychopharmacology Murphy, G. M., Kremer, C., Rodrigues, H. E., Schatzberg, A. F. AMER PSYCHIATRIC PUBLISHING, INC. 2003: 1830–35

    Abstract

    The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect).An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood.Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication.Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.

    View details for Web of Science ID 000185880300020

    View details for PubMedID 14514498

  • Macrophage colony stimulating factor promotes phagocytosis by murine microglia NEUROSCIENCE LETTERS Mitrasinovic, O. M., Vincent, V. A., Simsek, D., Murphy, G. M. 2003; 344 (3): 185-188

    Abstract

    Macrophage colony stimulating factor (M-CSF) and its receptor are upregulated in the brain in Alzheimer's disease. M-CSF induces activation and proliferation of microglial cells and expression of proinflammatory cytokines. Amyloid beta (Abeta) immunization experiments suggest that microglia have the capacity to aggressively clear Abeta from the brain under certain circumstances. We examined the role of M-CSF in phagocytosis of fluorescent microspheres and Abeta by cultured microglia. M-CSF treatment increased microglial cell phagocytosis of both microspheres and of Abeta. Antibody neutralization of M-CSF inhibited Abeta uptake induced by overexpression of the M-CSF receptor on microglia. These results suggest that M-CSF could be important in promoting microglial clearance of abnormal protein aggregates such as Abeta.

    View details for DOI 10.1016/S0304-3940(03)00474-9

    View details for Web of Science ID 000183621000011

    View details for PubMedID 12812836

  • Sleep/wake cycle disturbance in Alzheimer's disease: Longitudinal change in relation to APOE status Yesavage, J., Friedman, L., Kraemer, H., Murphy, G., Salehi, A., O'Hara, R., Noda, A., Taylor, J., Tinklenberg, J. CAMBRIDGE UNIV PRESS. 2003: 241–241

    View details for Web of Science ID 000222209400569

  • Developing novel treatments for mood disorders: Accelerating discovery BIOLOGICAL PSYCHIATRY Tamminga, C. A., Nemeroff, C. B., Blakely, R. D., Brady, L., Carter, C. S., Davis, K. L., Dingledine, R., Gorman, J. M., Grigoriadis, D. E., Henderson, D. C., Innis, R. B., Killen, J., Laughren, T. P., McDonald, W. M., Murphy, G. M., Paul, S. M., Rudorfer, M. V., Sausville, E., Schatzberg, A. F., SCOLNICK, E. M., Suppes, T. 2002; 52 (6): 589-609

    Abstract

    This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

    View details for Web of Science ID 000178297000008

    View details for PubMedID 12361670

  • Analysis of neuronal gene expression with laser capture microdissection JOURNAL OF NEUROSCIENCE RESEARCH Vincent, V. A., DeVoss, J. J., Ryan, H. S., Murphy, G. M. 2002; 69 (5): 578-586

    Abstract

    The brain is a heterogeneous tissue in which the numbers of neurons, glia, and other cell types vary among anatomic regions. Gene expression studies performed on brain homogenates yield results reflecting mRNA abundance in a mixture of cell types. Therefore, a method for quantifying gene expression in individual cell populations would be useful. Laser capture microdissection (LCM) is a new technique for obtaining pure populations of cells from heterogeneous tissues. Most studies thus far have used LCM to detect DNA sequences. We developed a method to quantify gene expression in hippocampal neurons from mouse brain using LCM and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). This method was optimized to permit histochemical or immunocytochemical visualization of nerve cells during LCM while minimizing RNA degradation. As an example, gene expression was quantified in hippocampal neurons from the Tg2576 mouse model for Alzheimer's disease.

    View details for DOI 10.1002/jnr.10329

    View details for Web of Science ID 000177745500002

    View details for PubMedID 12210823

  • Macrophage colony stimulating factor prevents NMDA-induced neuronal death in hippocampal organotypic cultures JOURNAL OF NEUROCHEMISTRY Vincent, V. A., Robinson, C. C., Simsek, D., Murphy, G. M. 2002; 82 (6): 1388-1397

    Abstract

    Macrophage colony stimulating factor (M-CSF) and its receptor are up-regulated in the brain in Alzheimer's disease (AD), in transgenic mouse models for AD, and experimental models for traumatic and ischemic brain injury. M-CSF induces activation and proliferation of microglial cells and expression of proinflammatory cytokines. We examined the role of M-CSF in excitotoxic neuronal cell death in organotypic hippocampal cultures. NMDA treatment induced neuronal apoptosis and caspase-3 activation in organotypic hippocampal cultures, whereas treatment with M-CSF protected hippocampal neurons from NMDA-induced apoptosis. Caspase-3 activation was inhibited by M-CSF treatment to the same degree as with the caspase inhibitor Z-VAD-FMK. These results suggest that M-CSF has neuroprotective properties through inhibition of caspase-3 that could promote neuronal survival after excitotoxic insult. The role of M-CSF in neurological disease should be reevaluated as a microglial activator with potentially neuroprotective effects.

    View details for Web of Science ID 000177790000008

    View details for PubMedID 12354286

  • Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Schatzberg, A. F., Kremer, C., Rodrigues, H. E., Murphy, G. M. 2002; 10 (5): 541-550

    Abstract

    Authors studied the efficacy and tolerability of mirtazapine and paroxetine in elderly patients with major depression during an acute phase (8 weeks) and an extension phase (16 weeks).Patients with major depression and without dementia, at least 65 years old, were eligible; they were randomized to mirtazapine or paroxetine once daily, with doses increasing over 42 days. Efficacy was assessed with the Ham-D and Clinical Global Impressions Scale, and tolerability was assessed from adverse events.Of 255 patients randomized, 126 on mirtazapine and 120 on paroxetine were included in the efficacy analysis. Differences favoring mirtazapine were observed for the mean change from baseline in Ham-D-17 score. Other significant differences were in the proportion of patients classified as responders (50% decrease from baseline Ham-D-17 scores) at Day 14 and in remission (Ham-D-17 score of 7 or less) at Day 42. The median time to response was 26 days in the mirtazapine group and 40 days in the paroxetine group. The mirtazapine group also showed more reduction in Ham-D Factor I (Anxiety/Somatization) and Factor VI (Sleep Disturbance) scores. Efficacy of both drugs was maintained during the extension phase. Patients on paroxetine were more likely to discontinue therapy in the acute phase because of adverse events.During the first weeks of treatment, antidepressant effects were more pronounced in the mirtazapine group, suggesting that mirtazapine has an earlier onset of action. Mirtazapine also demonstrated a better tolerability profile and represents a valuable option for the treatment of depression in elderly patients.

    View details for Web of Science ID 000177864500007

    View details for PubMedID 12213688

  • Accelerated phagocytosis of amyloid-beta by mouse and human microglia overexpressing the macrophage colony-stimulating factor receptor JOURNAL OF BIOLOGICAL CHEMISTRY Mitrasinovic, O. M., Murphy, G. M. 2002; 277 (33): 29889-29896

    Abstract

    Microglia surrounding A beta plaques in Alzheimer's disease and in the APPV717F transgenic mouse model of Alzheimer's disease have enhanced immunoreactivity for the macrophage colony-stimulating factor receptor (M-CSFR), encoded by the proto-oncogene c-fms. Increased expression of M-CSFR on cultured microglia results in proliferation and release of pro-inflammatory cytokines and expression of inducible nitric-oxide synthase. We transfected mouse BV-2 and human SV-A3 microglia to overexpress M-CSFR and examined microglial phagocytosis of fluorescein-conjugated A beta. Flow cytometry and laser confocal microscopy showed accelerated phagocytosis of A beta in mouse and human microglia because of M-CSFR overexpression that was time- and concentration-dependent. In contrast, microglial uptake of 1-microm diameter polystyrene microspheres was not enhanced by M-CSFR overexpression. Microglial uptake of A beta was blocked by cytochalasin D, which inhibits phagocytosis. M-CSFR overexpression increased the mRNA for macrophage scavenger receptor A, and fucoidan blocking of macrophage scavenger receptors inhibited uptake of A beta. M-CSFR antibody blocking experiments demonstrated that increased A beta uptake depended on the interaction of the M-CSFR with its ligand. These results suggest that overexpression of M-CSFR in APPV717F mice may prime microglia for phagocytosis of A beta after immunization.

    View details for DOI 10.1074/jbc.M200868200

    View details for Web of Science ID 000177509300069

    View details for PubMedID 12032144

  • Cardiac gene expression profile and lipid accumulation in response to starvation AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Suzuki, J., Shen, W. J., Nelson, B. D., Selwood, S. P., Murphy, G. M., Kanefara, H., Takahashi, S., Oida, K., Miyamori, I., Kraemer, F. B. 2002; 283 (1): E94-E102

    Abstract

    Starvation induces many biochemical and histological changes in the heart; however, the molecular events underlying these changes have not been fully elucidated. To explore the molecular response of the heart to starvation, microarray analysis was performed together with biochemical and histological investigations. Serum free fatty acids increased twofold in both 16- and 48-h-fasted mice, and cardiac triglyceride content increased threefold and sixfold in 16- and 48-h-fasted mice, respectively. Electron microscopy showed numerous lipid droplets in hearts of 48-h-fasted mice, whereas fewer numbers of droplets were seen in hearts from 16-h-fasted mice. Expression of 11,000 cardiac genes was screened by microarrays. More than 50 and 150 known genes were detected by differential expression analysis after 16- and 48-h-fasts, respectively. Genes for fatty acid oxidation and gluconeogenesis were increased, and genes for glycolysis were decreased. Many other genes for metabolism, signaling/cell cycle, cytoskeleton, and tissue antigens were affected by fasting. These data provide a broad perspective of the molecular events occurring physiologically in the heart in response to starvation.

    View details for DOI 10.1152/ajpendo.00017.2002

    View details for Web of Science ID 000176191000013

    View details for PubMedID 12067848

  • Proinflammatory effects of M-CSF and A beta in hippocampal organotypic cultures NEUROBIOLOGY OF AGING Vincent, V. A., Selwood, S. P., Murphy, G. M. 2002; 23 (3): 349-362

    Abstract

    Macrophage colony stimulating factor (M-CSF) is a microglial activator expressed at increased levels in the brain in Alzheimer's disease. In monotypic microglial cultures, M-CSF strongly augments amyloid beta (Abeta) induced microglial production of proinflammatory cytokines and nitric oxide. However, this augmentation could be due to strong autocrine and paracrine effects in monotypic cultures. We used hippocampal organotypic cultures to test M-CSF/Abeta augmentation in a system modeling intact brain. Combined M-CSF/Abeta treatment increased interleukin-1 (IL-1) and macrophage inflammatory protein 1-alpha expression by microglia, whereas inducible nitric oxide synthase (iNOS) expression was localized primarily to astroglia. Induction of cytokines and iNOS was also observed after lipopolysaccharide treatment of organotypic hippocampal cultures, but iNOS expression was localized mainly to microglia rather than astrocytes. Treatment with M-CSF/Abeta did not result in neuronal death. These results demonstrate that combined M-CSF/Abeta treatment results in a strong inflammatory response in the organotypic environment without inducing neurotoxicity.

    View details for Web of Science ID 000175175600003

    View details for PubMedID 11959396

  • Accelerated Phagocytosis of Amyloid-beta by Mouse and Human Microglia Overexpressing the M-CSF Receptor. Journal of Biological Chemistry Murphy, GM., Mitrasinovic, O. 2002: 29889-29896
  • Single base pair polymorphisms and their characterization with oligonucleotide microarrays. Psychiatric Genetics Murphy, GM., Dalma, D 2002: 97-107
  • Rapid detection of the C-1496G polymorphism in the CYP2D6*2 allele CLINICAL CHEMISTRY Claassen, J. D., Pascoe, N., Schatzberg, A. F., Murphy, G. M. 2001; 47 (12): 2153-2155

    View details for Web of Science ID 000172325000012

    View details for PubMedID 11719482

  • CYP2D6 genotyping with oligonucleotide microarrays and nortriptyline concentrations in geriatric depression NEUROPSYCHOPHARMACOLOGY Murphy, G. M., Pollock, B. G., Kirshner, M. A., Pascoe, N., Cheuk, W., Mulsant, B. H., Reynolds, C. F. 2001; 25 (5): 737-743

    Abstract

    Recent advances in oligonucleotide microarray technology ("gene chips") permit rapid screening for DNA sequence variation. The CYP2D6 gene encodes debrisoquine hydroxylase, which metabolizes the antidepressant nortriptyline and other psychotropic medications. Nortriptyline plasma concentrations were obtained after at least three weeks of treatment in 36 geriatric patients with major depression who were taking a mean of 8.6 other medications besides nortriptyline. Oligonucleotide microarrays were used to detect 16 CYP2D6 alleles that affect debrisoquine hydroxylase activity. Subjects carrying alleles encoding impaired debrisoquine hydroxylase activity had significantly greater nortriptyline concentrations and lower nortriptyline doses than did other subjects. Significant correlations were found between the numbers of alleles encoding decreased metabolism and nortriptyline plasma concentration, nortriptyline dose, and nortriptyline plasma concentration standardized for dose, indicating a gene dosage effect. These results demonstrate that CYP2D6 genotyping on a microarray platform can be used to predict plasma antidepressant concentrations despite advanced patient age and numerous concurrent medications.

    View details for Web of Science ID 000171952200014

    View details for PubMedID 11682257

  • Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Suzuki, J., Shen, W. J., Nelson, B. D., Patel, S., Veerkamp, J. H., Selwood, S. P., Murphy, G. M., Reaven, E., Kraemer, F. B. 2001; 281 (4): E857-E866

    Abstract

    Hormone-sensitive lipase (HSL) hydrolyzes triglyceride (TG) in adipose tissue. HSL is also expressed in heart. To explore the actions of cardiac HSL, heart-specific, tetracycline (Tc)-controlled HSL-overexpressing mice were generated. Tc-responsive element-HSL transgenic (Tg) mice were generated and crossed with myosin heavy chain (MHC)alpha-tTA Tg mice, which express the Tc-responsive transactivator (tTA) in the heart. The double-Tg mice (MHC-HSL) were maintained with doxycycline (Dox) to suppress Tg HSL. Upon removal of Dox, cardiac HSL activity and protein increased 12- and 8-fold, respectively, and the expression was heart specific. Although cardiac TG content increased twofold in control mice after an overnight fast, it did not increase in HSL-induced mice. Electron microscopy showed numerous lipid droplets in the myocardium of fasted control mice, whereas fasted HSL-induced mice showed virtually no droplets. Microarray analysis showed altered expression of cardiac genes for fatty acid oxidation, transcription factors, signaling molecules, cytoskeletal proteins, and histocompatibility antigens in HSL-induced mice. Thus cardiac HSL plays a role in controlling accumulation of triglyceride droplets and can affect the expression of a number of cardiac genes.

    View details for Web of Science ID 000171583200026

    View details for PubMedID 11551864

  • Apolipoprotein E epsilon 4 allele affects the relationship between stress and depression in caregivers of patients with Alzheimer's disease JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY Gallagher-Thompson, D., O'Hara, R., Simmons, A., Kraemer, H. C., Murphy, G. M. 2001; 14 (3): 115-119

    Abstract

    We examined the effect of the apolipoprotein E (apo E) epsilon4 allele on the relationship between self-reported stress and mood in caregivers of patients with Alzheimer's disease. Eighty-six female subjects between the ages of 28 and 82 years who were community-dwelling AD patient caregivers participated in the study. A cross-sectional analysis of stress and mood was performed using the Revised Memory and Behavior Problem Checklist and the Geriatric Depression Scale. All subjects were evaluated for normal cognitive function (Mini-Mental Status Examination) and apo E genotype. The results indicated that increased levels of stress were associated with increased levels of depressive symptoms in nondemented caregivers with the epsilon4 allele. This relationship was not observed in caregivers without the epsilon4 allele. These results suggest that carriers of the epsilon4 allele may respond differently to psychological stress than do individuals without the epsilon4 allele.

    View details for Web of Science ID 000170894200002

    View details for PubMedID 11563433

  • Overexpression of macrophage colony-stimulating factor receptor on microglial cells induces an inflammatory response JOURNAL OF BIOLOGICAL CHEMISTRY Mitrasinovic, O. M., Perez, G. V., Zhao, F. F., Lee, Y. L., Poon, C., Murphy, G. M. 2001; 276 (32): 30142-30149

    Abstract

    Microglia are important in the inflammatory response in Alzheimer's disease (AD). We showed previously that macrophage colony-stimulating factor receptor (M-CSFR), encoded by the c-fms protooncogene, is overexpressed on microglia surrounding amyloid beta (Abeta) deposits in the APP(V717F) mouse model for AD. The M-CSFR is also increased on microglia after experimental brain injury and in AD. To determine the relevance of these findings, we transiently expressed M-CSFR on murine BV-2 and human SV-A3 microglial cell lines using an SV40-promoted c-fms construct. M-CSFR overexpression resulted in microglial proliferation and increased expression of inducible nitric-oxide synthase, the proinflammatory cytokines interleukin-1alpha, macrophage inflammatory protein 1-alpha, and interleukin-6 and of macrophage colony-stimulating factor (M-CSF) itself. Antibody neutralization of M-CSF showed that the M-CSFR-induced proinflammatory response was dependent on M-CSF in the culture media. By using a co-culture of c-fms-transfected murine microglia and rat organotypic hippocampal slices and a species-specific real time reverse transcriptase-polymerase chain reaction assay and enzyme-linked immunosorbent assay, we showed that M-CSFR overexpression on exogenous microglia induced expression of interleukin-1alpha by the organotypic culture. These results show that increased M-CSFR expression induces microglial proliferation, cytokine expression, and a paracrine inflammatory response, suggesting that in APP(V717F) mice increased M-CSFR on microglia could be an important factor in Abeta-induced inflammatory response.

    View details for Web of Science ID 000170558000073

    View details for PubMedID 11387343

  • Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro GLIA Lue, L. F., Rydel, R., Brigham, E. F., Yang, L. B., Hampel, H., Murphy, G. M., Brachova, L., Yan, S. D., Walker, D. G., Shen, Y., Rogers, J. 2001; 35 (1): 72-79

    Abstract

    We have previously developed and characterized isolated microglia and astrocyte cultures from rapid (<4 h) brain autopsies of Alzheimer's disease (AD) and nondemented elderly control (ND) patients. In the present study, we evaluate the inflammatory repertoire of AD and ND microglia cultured from white matter (corpus callosum) and gray matter (superior frontal gyrus) with respect to three major proinflammatory cytokines, three chemokines, a classical pathway complement component, a scavenger cell growth factor, and a reactive nitrogen intermediate. Significant, dose-dependent increases in the production of pro-interleukin-1beta (pro-IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide-1alpha (MIP-1alpha), IL-8, and macrophage colony-stimulating factor (M-CSF) were observed after exposure to pre-aggregated amyloid beta peptide (1-42) (Abeta1-42). Across constitutive and Abeta-stimulated conditions, secretion of complement component C1q, a reactive nitrogen intermediate, and M-CSF was significantly higher in AD compared with ND microglia. Taken together with previous in situ hybridization findings, these results demonstrate unequivocally that elderly human microglia provide a brain endogenous source for a wide range of inflammatory mediators.

    View details for Web of Science ID 000169671000008

    View details for PubMedID 11424194

  • Association between apolipoprotein E epsilon 4 and sleep-disordered breathing in adults JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION KADOTANI, H., Kadotani, T., Young, T., Peppard, P. E., Finn, L., Colrain, I. M., Murphy, G. M., Mignot, E. 2001; 285 (22): 2888-2890

    Abstract

    Apolipoprotein E epsilon4(ApoE epsilon4) is a well-known risk factor for Alzheimer disease and cardiovascular disease. Sleep-disordered breathing occurs in Alzheimer disease patients and increases risks for cardiovascular disease. Complex interactions among sleep, brain pathology, and cardiovascular disease may occur in ApoE epsilon4 carriers.To study whether genetic variation at the level of ApoE is associated with sleep-disordered breathing or sleep abnormalities in the general population.Ongoing longitudinal cohort study of sleep disorders at a US university beginning in 1989, providing a population-based probability sample of 791 middle-aged adults (mean [SD] age, 49 [8] years; range, 32-68 years).Nocturnal polysomnography to evaluate apnea-hypopnea index.The probability of moderate-to-severe sleep-disordered breathing (apnea-hypopnea index >/=15%) was significantly higher in participants with epsilon4, independent of age, sex, body mass index, and ethnicity (12.0% vs 7.0%; P =.003). Mean (SEM) apnea-hypopnea index was also significantly higher in participants with ApoE epsilon4 (6.5 [0.6] vs 4.8 [0.3]; P =.01). These effects increased with the number of ApoE epsilon4 alleles carried.A significant portion of sleep-disordered breathing is associated with ApoE epsilon4 in the general population.

    View details for Web of Science ID 000169156300028

    View details for PubMedID 11401610

  • Rate of cognitive decline in AD is accelerated by the interleukin-1 alpha-889*1 allele NEUROLOGY Murphy, G. M., Claassen, J. D., DeVoss, J. J., Pascoe, N., Taylor, J., Tinklenberg, J. R., Yesavage, J. A. 2001; 56 (11): 1595-1597

    Abstract

    The reason for differences in rate of cognitive decline in AD is unknown. The interleukin-1 alpha (IL-1 alpha) -889 *2 allele is associated with increased risk for AD. Surprisingly, in a sample of 114 patients followed for an average of 3.8 years, individuals homozygous for the IL-1 alpha -889 *1 allele declined significantly more rapidly on the Mini-Mental State Examination than did others. There was no difference in rate of decline between patients with and without the APOE epsilon 4 allele. These results support the hypothesis that inflammation is important in the clinical course of AD.

    View details for Web of Science ID 000169187100033

    View details for PubMedID 11402127

  • Expression of macrophage colony-stimulating factor receptor is increased in the A beta PPV717F transgenic mouse model of Alzheimer's disease AMERICAN JOURNAL OF PATHOLOGY Murphy, G. M., Zhao, F. F., Yang, L., Cordell, B. 2000; 157 (3): 895-904

    Abstract

    Inflammation is an important neuropathological change in Alzheimer's disease (AD). However, the pathophysiological factors that initiate and maintain the inflammatory response in AD are unknown. We examined AbetaPP(V717F) transgenic mice, which show numerous brain amyloid-beta (Abeta) deposits, for expression of the macrophage colony-stimulating factor (M-CSF) and its receptor (M-CSFR). M-CSF is increased in the brain in AD and dramatically augments the effects of Abeta on cultured microglia. AbetaPP(V717F) animals 12 months of age showed large numbers of microglia strongly labeled with an M-CSFR antibody near Abeta deposits. M-CSFR mRNA and protein levels were also increased in brain homogenates from AbetaPP(V717F) animals. Dystrophic neurites and astroglia showed no M-CSFR labeling in the transgenic animals. A M-CSF antibody decorated neuritic structures near hippocampal Abeta deposits in transgenic animals. M-CSF mRNA was also increased in AbetaPP(V717F) animals in comparison with wild-type controls. Simultaneous overexpression of M-CSFR and its ligand in AbetaPP(V717F) animals could result in augmentation of Abeta-induced activation of microglia. Because chronic activation of microglia is thought to result in neuronal injury, the M-CSF system may be a potential target for therapeutic intervention in AD.

    View details for Web of Science ID 000089207200023

    View details for PubMedID 10980129

  • A longitudinal study of Apolipoprotein-E genotype and depressive symptoms in community-dwelling older adults AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Mauricio, M., O'Hara, R., Yesavage, J. A., FRIEDMAN, E., Kraemer, H. C., Van de Water, M., Murphy, G. M. 2000; 8 (3): 196-200

    Abstract

    The Apolipoprotein-E (APOE) epsilon 4 allele is a risk factor for Alzheimer's disease (AD) and cognitive decline in older adults. Depression may also be a risk factor for dementia, and depression is important in the differential diagnosis of dementia. The authors performed a 5-year longitudinal study of APOE genotype and change in Geriatric Depression Scale scores in 113 community-dwelling older adults. No association was observed between APOE genotype and change in depressive symptoms. These results do not support the hypothesis that the APOE epsilon 4 allele is associated with depression. Important objections have been raised to APOE genotyping in the diagnosis of AD. However, the specificity of APOE genotyping in AD diagnosis would not appear to be compromised by an association with depression.

    View details for Web of Science ID 000088230700003

    View details for PubMedID 10910416

  • Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF NEUROLOGY Kahle, P. J., Jakowec, M., Teipel, S. J., Hampel, H., Petzinger, G. M., Di Monte, D. A., Silverberg, G. D., Moller, H. J., Yesavage, J. A., Tinklenberg, J. R., Shooter, E. M., Murphy, G. M. 2000; 54 (7): 1498-1504

    Abstract

    Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects.AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration.Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed.Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients.CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

    View details for Web of Science ID 000086460900021

    View details for PubMedID 10751266

  • alpha 2 macroglobulin and the risk of Alzheimer's disease NEUROLOGY Dodel, R. C., Du, Y., Bales, K. R., Gao, F., Eastwood, B., Glazier, B., Zimmer, R., Cordell, B., Hake, A., Evans, R., Gallagher-Thompson, D., Thompson, L. W., Tinklenberg, J. R., Pfefferbaum, A., SULLIVAN, E. V., Yesavage, J., Altstiel, L., Gasser, T., Farlow, M. R., Murphy, G. M., Paul, S. M. 2000; 54 (2): 438-442

    Abstract

    alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56).We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism.We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors.Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

    View details for Web of Science ID 000085043800030

    View details for PubMedID 10668709

  • The APOE epsilon 4 allele is associated with decline on delayed recall performance in community-dwelling older adults JOURNAL OF THE AMERICAN GERIATRICS SOCIETY O'Hara, R., Yesavage, J. A., Kraemer, H. C., Mauricio, M., Friedman, L. F., Murphy, G. M. 1998; 46 (12): 1493-1498

    Abstract

    This study investigated whether the Apolipoprotein (APOE) epsilon4 allele was associated with cognitive decline in community-dwelling older adults.Longitudinal cognitive performance of older adults with the epsilon3/epsilon4 genotype was compared with that of older adults with the epsilon3/epsilon3 genotype.Aging Clinical Research Center, Stanford University.One hundred community-dwelling older adults were recruited from a pool of 531 individuals who had participated in a memory training study 4 to 5 years earlier. These individuals were concerned about their memory functioning and were recruited through newspaper advertisements and contacts with local senior centers. The 100 individuals who agreed to participate in the follow-up investigation were between 59 and 95 years of age.At both baseline and follow-up, subjects were administered a battery of seven cognitive tests that examined verbal and spatial memory, attention, speed-of-processing, and language abilities. APOE genotype was determined at follow-up.Individuals with the epsilon3/epsilon4 APOE genotype were significantly younger than individuals with the APOE epsilon3/epsilon3 genotype. No significant differences were observed between the two groups on measures of attention, speed-of-processing, vocabulary, immediate verbal memory, and immediate spatial memory. However, those older adults with the epsilon3/epsilon4 genotype exhibited significantly greater decline in performance on delayed recall of verbal material than did those with the epsilon3/epsilon3 APOE genotype.These findings are consistent with previous studies, which suggest that the APOE epsilon4 allele predicts decline on measures of delayed recall.

    View details for Web of Science ID 000077358700001

    View details for PubMedID 9848808

  • Macrophage colony-stimulating factor augments beta-amyloid-induced interleukin-1, interleukin-6, and nitric oxide production by microglial cells JOURNAL OF BIOLOGICAL CHEMISTRY Murphy, G. M., Yang, L., Cordell, B. 1998; 273 (33): 20967-20971

    Abstract

    In Alzheimer's disease (AD), a chronic cerebral inflammatory state is thought to lead to neuronal injury. Microglia, intrinsic cerebral immune effector cells, are likely to be key in the pathophysiology of this inflammatory state. We showed that macrophage colony-stimulating factor, a microglial activator found at increased levels in the central nervous system in AD, dramatically augments beta-amyloid peptide (betaAP)-induced microglial production of interleukin-1, interleukin-6, and nitric oxide. In contrast, granulocyte macrophage colony-stimulating factor, another hematopoietic cytokine found in the AD brain, did not augment betaAP-induced microglial secretory activity. These results indicate that increased macrophage colony-stimulating factor levels in AD could magnify betaAP-induced microglial inflammatory cytokine and nitric oxide production, which in turn could intensify the cerebral inflammatory state by activating astrocytes and additional microglia, as well as directly injuring neurons.

    View details for Web of Science ID 000075386100039

    View details for PubMedID 9694846

  • No neuropathologic evidence for an increased frequency of Alzheimer's disease among elderly schizophrenics BIOLOGICAL PSYCHIATRY Murphy, G. M., Lim, K. O., Wieneke, M., Ellis, W. G., Forno, L. S., Hoff, A. L., Nordahl, T. 1998; 43 (3): 205-209

    Abstract

    There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology.We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease.Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56-95 years). Of these 51, only I met neuropathologic criteria for AD, a frequency of 2%.The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.

    View details for Web of Science ID 000072174800007

    View details for PubMedID 9494702

  • Mouse microglial cell line-BV-2 lack functional electrogenic glutamate uptake transporters Eng, D. L., Murphy, G. M., Shih, C., Wu, J., Eng, L. F. WILEY-BLACKWELL PUBLISHING, INC. 1998: S70–S70

    View details for Web of Science ID 000072167200278

  • No association between the alpha 1-antichymotrypsin A allele and Alzheimer's disease NEUROLOGY Murphy, G. M., SULLIVAN, E. V., GALLAGHERTHOMPSON, D., Thompson, L. W., vanDuijn, C. M., Forno, L. S., Ellis, W. G., Jagust, W. J., Yesavage, J., Tinklenberg, J. R. 1997; 48 (5): 1313-1316

    Abstract

    The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.

    View details for Web of Science ID A1997WZ77800030

    View details for PubMedID 9153464

  • No association between apolipoprotein E epsilon 4 allele and rate of decline in Alzheimer's disease AMERICAN JOURNAL OF PSYCHIATRY Murphy, G. M., Taylor, J., Kraemer, H. C., Yesavage, J., Tinklenberg, J. R. 1997; 154 (5): 603-608

    Abstract

    The relationship between number of apolipoprotein E epsilon 4 (APOE epsilon 4) alleles and the rate of cognitive decline in patients with Alzheimer's disease was examined.Rate of decline in score on the Mini-Mental State was measured during the active phase of the decline curve between Mini-Mental State scores of 23 and 0. To characterize onset, the authors also estimated for each subject the age at which the Mini-Mental State score fell below 23 and obtained a retrospective report of age at onset from the caregiver. The number of APOE epsilon 4 alleles carried by each subject was determined from genomic DNA samples. The study included 86 subjects with probable Alzheimer's disease who had had at least two cognitive evaluations (a mean of 5.6 evaluations per subject over an average period of 3.6 years).The results did not support an association between APOE epsilon 4 dosage and rate of cognitive decline. Age at onset and age at which the Mini-Mental State score fell below 23 were also not related to APOE epsilon 4 dosage. The APOE allele frequencies were similar to those in other studies of subjects with Alzheimer's disease, showing an enrichment of the epsilon 4 allele.Although the APOE epsilon 4 allele is a risk factor for Alzheimer's disease, there is no support of a strong association between APOE epsilon 4 dosage and rate of cognitive decline. The epsilon 4 allele did not predict age at onset. Methodological inconsistencies may account for discrepancies between these results and previous findings.

    View details for Web of Science ID A1997WX13000004

    View details for PubMedID 9137113

  • Inhibition of beta-amyloid formation by haloperidol: A possible mechanism for reduced frequency of Alzheimer's disease pathology in schizophrenia JOURNAL OF NEUROCHEMISTRY Higaki, J., Murphy, G. M., Cordell, B. 1997; 68 (1): 333-336

    Abstract

    Several reports have suggested that the frequency of Alzheimer's disease (AD) neuropathology is significantly reduced in elderly individuals with schizophrenia (SZ), and it has been proposed that medications used for treatment of SZ may be responsible. A central event in AD pathology is the formation of beta-amyloid (A beta) peptide, which is derived by enzymatic processing of its precursor protein. Haloperidol, an antipsychotic medication commonly used in the treatment of SZ, can act as an inhibitor of select proteinases; hence, we examined the ability of this compound to inhibit A beta formation by cultured cells. Haloperidol and, to a lesser extent, droperidol inhibited A beta in a dose-dependent manner. These results may explain the apparent reduction of AD neuropathological changes in elderly patients with SZ as well as provide a possible mechanism for this difference.

    View details for Web of Science ID A1997VY89300041

    View details for PubMedID 8978743

  • Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease AMERICAN JOURNAL OF PATHOLOGY Murphy, G. M., Forno, L. S., Ellis, W. G., Nochlin, D., LEVYLAHAD, E., Poorkaj, P., Bird, T. D., Jiang, Z. L., Cordell, B. 1996; 149 (6): 1839-1846

    Abstract

    Mutations in the presenilin (PS)-1 and PS-2 genes have been shown to be linked with the development of Alzheimer's disease (AD). We examined Alzheimer's brain tissue by immunohistochemistry using a set of antibodies raised to sequences shared between PS-1 and PS-2 proteins. These antibodies reacted exclusively with a subset of neurofibrillary tangles and not with neuropil threads or dystrophic neurites. Detection of the presenilin epitope in neurofibrillary tangles was observed in sporadic Alzheimer's disease brain samples and in samples from individuals carrying PS-1 and PS-2 mutations with no qualitative difference. These data indicate that both wild-type and mutant PS proteins are involved in a common pathogenic pathway in AD.

    View details for Web of Science ID A1996VW78700007

    View details for PubMedID 8952521

    View details for PubMedCentralID PMC1865361

  • Rate of cognitive decline in Alzheimer's disease is not affected by the alpha-1-antichymotrypsin A allele or the CYP2D6 B mutant NEUROSCIENCE LETTERS Murphy, G. M., Yang, L., Yesavage, J., Tinklenberg, J. R. 1996; 217 (2-3): 200-202

    Abstract

    Patients with Alzheimer's disease (AD) show considerable heterogeneity in the rate at which they decline cognitively. The biological basis for this heterogeneity is unknown. We genotyped 86 subjects with diagnoses of probable AD to determine if they carried the alpha-1-antichymotrypsin (ACT) A allele, which has been associated with AD, or the CYP2D6 B mutant, found at increased frequency in the Lewy body variant (LBV) of AD. We then examined longitudinally-collected cognitive data to determine if these genetic markers were associated with rate of cognitive decline. Our results indicate that neither the ACT A allele nor the CYP2D6 B allele have a significant association with rate of decline on the Folstein Mini Mental State examination. Further, subjects with both the ACT A allele and the apolipoprotein epsilon 4 allele showed no evidence of accelerated decline. These findings suggest that any increased risk of developing AD or LBV conferred by these markers is not necessarily accompanied by a more rapid rate of decline.

    View details for Web of Science ID A1996VQ39800033

    View details for PubMedID 8916107

  • p3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain AMERICAN JOURNAL OF PATHOLOGY Higgins, L. S., Murphy, G. M., Forno, L. S., Catalano, R., Cordell, B. 1996; 149 (2): 585-596

    Abstract

    The presence of beta-amyloid in brain tissue is characteristic of Alzheimer's disease (AD). A naturally occurring derivative of the beta-amyloid peptide, p3, possesses all of the structural determinants required for fibril assembly and neurotoxicity. p3-specific antibodies were used to examine the distribution of this peptide in brain. p3 reactivity was absent or sparse in aged non-AD brains but was prevalent in selected areas of AD brain in diffuse deposits and in a subset of dystrophic neurites. p3-reactive dystrophic neurites were found both independent in the neuropil and associated with plaques. Little or no reactivity was observed to amyloid cores in classical plaques or to amyloid in the cerebral vasculature. The exclusive appearance of p3 reactivity in AD brain plus the selective localization of p3 reactivity to abnormal structures in the temporal lobe limbic system suggests that p3 may be a contributing factor to AD pathology.

    View details for Web of Science ID A1996UZ76300023

    View details for PubMedID 8701997

    View details for PubMedCentralID PMC1865300

  • beta-amyloid peptide secretion by a microglial cell line is induced by beta-amyloid-(25-35) and lipopolysaccharide JOURNAL OF BIOLOGICAL CHEMISTRY Bitting, L., Naidu, A., Cordell, B., Murphy, G. M. 1996; 271 (27): 16084-16089

    Abstract

    beta-Amyloid protein (betaAP) deposition is a neuropathologic hallmark of Alzheimer's disease (AD). Yet, the source of cerebral betaAP in AD is controversial. We examined the production of betaAP by the BV-2 immortalized microglial cell line using a sensitive enzyme immunoassay. Constitutive production of betaAP was detected in conditioned media from unstimulated BV-2 cells. Further, production of betaAP was induced by treatment of cultures by lipopolysaccharide (LPS) or betaAP-(25-35) and was inhibited by the calpain protease inhibitor MDL 28170. Treatment of BV-2 cells with LPS or betaAP-(25-35) did not affect cell-associated beta-amyloid precursor protein levels. These findings suggest that microglia may be an important source of betaAP in AD, and that microglial production of betaAP may be augmented by proinflammatory stimuli or by betaAP itself.

    View details for Web of Science ID A1996UW35200036

    View details for PubMedID 8663228

  • TUMOR-NECROSIS-FACTOR-ALPHA AND BASIC FIBROBLAST GROWTH-FACTOR DECREASE GLIAL FIBRILLARY ACIDIC PROTEIN AND ITS ENCODING MESSENGER-RNA IN ASTROCYTE CULTURES AND GLIOBLASTOMA CELLS JOURNAL OF NEUROCHEMISTRY Murphy, G. M., Lee, Y. L., Jia, X. C., Yu, A. C., Majewska, A., Song, Y. L., Schmidt, K., Eng, L. F. 1995; 65 (6): 2716-2724

    Abstract

    Tumor necrosis factor-alpha is a pluripotent cytokine that is reportedly mitogenic to astrocytes. We examined expression of the astrocyte intermediate filament component glial fibrillary acidic protein in astrocyte cultures and the U373 glioblastoma cell line after treatment with tumor necrosis factor-alpha. Treatment with tumor necrosis factor-alpha for 72 h resulted in a decrease in content of glial fibrillary acidic protein and its encoding mRNA. At the same time, tumor necrosis factor-alpha treatment increased the expression of the cytokine interleukin-6 by astrocytes. The decrease in glial fibrillary acidic protein expression was greater when cells were subconfluent than when they were confluent. Thymidine uptake studies demonstrated that U373 cells proliferated in response to tumor necrosis factor-alpha, but primary neonatal astrocytes did not. However, in both U373 cells and primary astrocytes tumor necrosis factor-alpha induced an increase in total cellular protein content. Treatment of astrocytes and U373 cells for 72 h with the mitogenic cytokine basic fibroblast growth factor also induced a decrease in glial fibrillary acidic protein content and an increase in total protein level, demonstrating that this effect is not specific for tumor necrosis factor-alpha. The decrease in content of glial fibrillary acidic protein detected after tumor necrosis factor-alpha treatment is most likely due to dilution by other proteins that are synthesized rapidly in response to cytokine stimulation.

    View details for PubMedID 7595570

  • EXPRESSION OF INTERLEUKIN-11 AND ITS ENCODING MESSENGER-RNA BY GLIOBLASTOMA CELLS NEUROSCIENCE LETTERS Murphy, G. M., Bitting, L., Majewska, A., Schmidt, K., Song, Y. L., Wood, C. R. 1995; 196 (3): 153-156

    Abstract

    Interleukin-11 (IL-11) is a pleiotropic cytokine with important effects on hematopoietic and other cells. IL-11 was originally described as a product of stromal cell lines and fibroblasts. Using RT-PCR, Northern blotting, and ELISA we demonstrated that the human U373 and U87 glioblastoma cell lines expressed IL-11 and its encoding mRNA when stimulated with IL-1 beta, phorbol ester, and calcium ionophore. The neuroblastoma cell line SH-SY5Y did not express IL-11 mRNA in response to these agents. Cerebral expression of IL-11 by glial cells is important because IL-11 has been shown to have effects on neuronal electrophysiology, has overlapping functions with the neuroactive cytokine interleukin-6, and is part of the gp130-associated neuropoietic family of cytokines.

    View details for Web of Science ID A1995RU16500003

    View details for PubMedID 7501271

  • MACROPHAGE INFLAMMATORY PROTEIN 1-ALPHA MESSENGER-RNA EXPRESSION IN AN IMMORTALIZED MICROGLIAL CELL-LINE AND CORTICAL ASTROCYTE CULTURES JOURNAL OF NEUROSCIENCE RESEARCH Murphy, G. M., Jia, X. C., Song, Y., Ong, E., Shrivastava, R., Bocchini, V., Lee, Y. L., Eng, L. F. 1995; 40 (6): 755-763

    Abstract

    Macrophage inflammatory protein 1 (MIP-1) is a recently characterized inflammatory and chemokinetic cytokine. Proinflammatory stimuli have been shown to induce expression of MIP-1 by macrophages. We hypothesized that microglia and astrocytes express MIP-1 alpha because of their many immunologic similarities to macrophages. MIP-1 alpha mRNA was examined with quantitative reverse transcription and polymerase chain reaction in an immortalized mouse microglial cell line (BV-2) and in mouse cortical astrocyte cultures. We found that in both the BV-2 microglial cell line and in astrocyte cultures, MIP-1 alpha mRNA was strongly induced by lipopolysaccharide and the phorbol ester PMA. MIP-1 alpha mRNA was reduced by dBcAMP, interferon-gamma, and PGE1. Dexamethasone decreased MIP-1 alpha mRNA levels in astrocyte cultures, but not in BV-2 microglial cells. Interleukin-1 beta, tumor necrosis factor alpha, and MIP-1 alpha had no effect on MIP-1 alpha mRNA expression. These findings demonstrate that MIP-1 alpha mRNA is expressed by cultured glial cells and is regulated by proinflammatory and anti-inflammatory stimuli. MIP-1 alpha may be expressed by microglia and astrocytes in vivo, and may help modulate cerebral inflammation.

    View details for PubMedID 7629889

  • LEUKEMIA INHIBITORY FACTOR MESSENGER-RNA IS EXPRESSED IN CORTICAL ASTROCYTE CULTURES BUT NOT IN AN IMMORTALIZED MICROGLIAL CELL-LINE NEUROSCIENCE LETTERS Murphy, G. M., Song, Y. L., Ong, E., Lee, Y. L., Schmidt, K. G., Bocchini, V., Eng, L. F. 1995; 184 (1): 48-51

    Abstract

    Leukemia inhibitory factor (LIF) is a multifunctional cytokine synthesized by a variety of cell types. In the nervous system LIF affects neuronal differentiation, and may be important during cerebral infection and inflammation. To clarify the cellular source of LIF in the brain, we examined the expression of LIF mRNA by primary cortical astrocyte cultures and an immortalized microglial cell line. The microglial cell line did not express LIF mRNA in response to pro-inflammatory agents such as lipopolysaccharide (LPS) that induced expression of other cytokine mRNAs. In contrast, primary astrocyte cultures grown in serum-containing medium expressed LIF mRNA constitutively, and this expression was regulated by pro-inflammatory and anti-inflammatory stimuli. Agents which activate the cAMP and protein kinase C second messenger systems also increased LIF mRNA in astrocyte cultures. These results suggest that astrocytes, but not microglia, may be an important source of LIF during cerebral inflammation and infection.

    View details for Web of Science ID A1995QD59100013

    View details for PubMedID 7739804

  • A RT-PCR study of gene expression in a mechanical injury model 2nd Stanford International Neuroscience Symposium Eng, L. F., Lee, Y. L., Murphy, G. M., Yu, A. C. ELSEVIER SCIENCE BV. 1995: 219–229

    View details for Web of Science ID A1995BE39G00020

    View details for PubMedID 7568880

  • AGING AND THE NIGROSTRIATAL DOPAMINE SYSTEM - A NONHUMAN PRIMATE STUDY NEURODEGENERATION Irwin, I., DeLanney, L. E., McNeill, T., Chan, P., Forno, L. S., Murphy, G. M., DIMONTE, D. A., Sandy, M. S., Langston, J. W. 1994; 3 (4): 251-265

    Abstract

    The present study examined neurochemical, morphological and functional markers of the nigrostriatal dopamine system in young, intermediate-aged and old squirrel monkeys. Striking reductions in motoric activity were observed with advancing age. significant age-related loss of dopamine occurred in the substantia nigra (70%) and the putamen (30%) but not in the caudate. There was a strong correlation between the reductions in motoric activity and the loss of putamen dopamine. However, nigrostriatal dopamine loss did not appear to be the consequence of age-related loss of dopaminergic nigral neurons since the number of tyrosine immunoreactive cells was not significantly different among the three age groups. These results suggest that the aging squirrel monkey demonstrates the age-related loss of nigrostriatal dopamine thought to occur in humans and identify this non-human primate as a useful model to further investigate the underlying mechanism(s) and functional consequences of age-related decline of the nigrostriatal dopamine system. In addition, the selective loss of dopamine in the putamen but not the caudate parallels the regional vulnerability observed in Parkinson's disease, an age-related neurodegenerative disorder, raising the possibility of a relationship between normal aging and the development of this disease. Finally, because the number of tyrosine hydroxylase (TH) positive cells remains constant with age, these results raise the possibility that therapeutic strategies aimed at increasing dopamine concentrations may benefit elderly individuals.

    View details for Web of Science ID A1994PY42600001

    View details for PubMedID 7531106

  • TGF-BETA(1) CAUSES INCREASED ENDOTHELIAL ICAM-1 EXPRESSION AND LUNG INJURY JOURNAL OF APPLIED PHYSIOLOGY Suzuki, Y., Tanigaki, T., Heimer, D., Wang, W. Z., Ross, W. G., Murphy, G. A., Sakai, A., Sussman, H. H., Vu, T. H., Raffin, T. A. 1994; 77 (3): 1281-1287

    Abstract

    Neutrophil adherence to vascular endothelium is partially mediated by adhesion molecules, including intracellular adhesion molecule 1 (ICAM-1), on endothelial cells. We examined the effect of transforming growth factor-beta 1 (TGF-beta 1) on the expression of ICAM-1 in human umbilical vein endothelial cells (HUVEC). TGF-beta 1 (1 ng/ml) increased ICAM-1 and ICAM-1 mRNA expression in HUVEC, as assessed by flow cytometry and Northern blot analysis, respectively. In addition, we investigated whether exogenous recombinant TGF-beta 1 can cause neutrophil-mediated lung injury in guinea pigs. The plasma half-life of 125I-labeled TGF-beta 1 in guinea pigs was 4.6 +/- 0.1 min, and the 125I activity was 2.8 +/- 0.2% 8 h after injection. The ratio of 125I-labeled albumin concentration in lung tissue and bronchoalveolar lavage (BAL) fluid to that in plasma, lung wet-to-dry weight ratio, numbers of neutrophils in BAL fluid, and numbers of neutrophils per alveolus in fixed lung sections increased in guinea pigs that received a high dose of TGF-beta 1 (25 micrograms i.v. followed by 2 micrograms/h for 8 h) compared with the control group. These results suggest that TGF-beta 1 causes neutrophil-mediated lung injury, possibly through upregulation of ICAM-1 on endothelial cells, and might be important in the pathogenesis of lung injury.

    View details for Web of Science ID A1994PG91600032

    View details for PubMedID 7836132

  • DEVELOPMENT OF A MONOCLONAL-ANTIBODY SPECIFIC FOR THE COOH-TERMINAL OF BETA-AMYLOID-1-42 AND ITS IMMUNOHISTOCHEMICAL REACTIVITY IN ALZHEIMERS-DISEASE AND RELATED DISORDERS AMERICAN JOURNAL OF PATHOLOGY Murphy, G. M., Forno, L. S., Higgins, L. 1994; 144 (5): 1082-1088

    Abstract

    The beta-amyloid peptide (beta AP) has been characterized by protein sequencing techniques as a 39-43 amino acid protein with heterogeneous COOH-termini. Controversy exists regarding the predominant form of beta AP in neuritic plaques (NP) and cerebral vasculature of Alzheimer's disease (AD) brain. A monoclonal antibody was developed that selectively recognizes the free COOH-terminal of beta AP 1-42 but not beta AP species with shorter or longer COOH-termini. Brain sections from AD and related disorders were examined using this antibody. In AD samples, the antibody stained diffuse amyloid and NP cores, many intraneuronal and extraneuronal neurofibrillary tangles (NFT), but not cerebrovascular amyloid. Pick and Lewy bodies lacked immunoreactivity. These findings suggest that beta AP 1-42 is present in early and mature amyloid deposits and NFT, but that species of beta AP other than 1-42 comprise human vascular deposits.

    View details for Web of Science ID A1994NK79500025

    View details for PubMedID 8178931

    View details for PubMedCentralID PMC1887348

  • VOLUMETRIC MRI ASSESSMENT OF TEMPORAL-LOBE STRUCTURES IN SCHIZOPHRENIA BIOLOGICAL PSYCHIATRY Zipursky, R. B., Marsh, L., Lim, K. O., DEMENT, S., Shear, P. K., SULLIVAN, E. V., Murphy, G. M., Csernansky, J. G., Pfefferbaum, A. 1994; 35 (8): 501-516

    Abstract

    This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

    View details for Web of Science ID A1994NJ34700001

    View details for PubMedID 8038294

  • REVERSE TRANSCRIPTION AND POLYMERASE CHAIN-REACTION TECHNIQUE FOR QUANTIFICATION OF MESSENGER-RNA IN PRIMARY ASTROCYTE CULTURES JOURNAL OF NEUROSCIENCE RESEARCH Murphy, G. M., Jia, X. C., Yu, A. C., Lee, Y. L., Tinklenberg, J. R., Eng, L. F. 1993; 35 (6): 643-651

    Abstract

    The reverse transcription and polymerase chain reaction technique (RT-PCR) was assessed for the quantification of changes in mRNA levels from primary astrocyte cultures. The effects of dibutyryl cyclic AMP (dBcAMP) on glial fibrillary acidic protein (GFAP) mRNA and the effects of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and lipopolysaccharide (LPS) on interleukin-6 (IL-6) mRNA were examined. Two quantitative PCR methods were used: one involved carrying out the reaction in the exponential phase and the other involved the coamplification of a competitive target sequence. Increased GFAP mRNA in response to chronic dBcAMP treatment and increased IL-6 mRNA in response to TNF-alpha/IL-1 beta were readily detected. Both RT-PCR techniques were found to be suitable for the detection of large as well as smaller (twofold) changes in mRNA levels. The advantages and limitations of RT-PCR for mRNA quantification are discussed.

    View details for PubMedID 7692077

  • ALZHEIMERS-DISEASE - BETA-AMYLOID PRECURSOR PROTEIN EXPRESSION IN THE NUCLEUS BASALIS OF MEYNERT AMERICAN JOURNAL OF PATHOLOGY Murphy, G. M., Greenberg, B. D., Ellis, W. G., Forno, L. S., Salamat, S. M., GONZALEZDEWHITT, P. A., Lowery, D. E., Tinklenberg, J. R., Eng, L. F. 1992; 141 (2): 357-361

    Abstract

    The nucleus basalis of Meynert (nbM) was examined using immunocytochemistry for beta-amyloid precursor protein (beta APP) expression in Alzheimer's disease (AD). In mild AD cases, light labeling of the cell body and proximal processes was observed, and small intracellular structures were labeled rarely. In the more severe cases, intense cytoplasmic beta APP labeling was seen, often along with small beta APP-positive structures. Double-labeling experiments demonstrated that in the more severe cases these small structures were also decorated by a neurofibrillary tangle (NFT) antiserum. Other neurons in the severe cases showed incorporation of beta APP into large inclusions, which were also labeled with the NFT antiserum. However, some large inclusions in the severe cases were labeled by the NFT antiserum but contained no beta APP. Extraneuronal NFTs did not show beta APP labeling and did not react with an antibody to the beta-amyloid peptide. These results suggest that increased expression of beta APP coincides with intracellular NFT formation in the nbM, but that the formation of extraneuronal NFTs results in a loss of beta APP immunoreactivity.

    View details for Web of Science ID A1992JH62500011

    View details for PubMedID 1386714

  • ASTROCYTIC GLIOSIS IN THE AMYGDALA IN DOWNS-SYNDROME AND ALZHEIMERS-DISEASE PROGRESS IN BRAIN RESEARCH Murphy, G. M., Ellis, W. G., Lee, Y. L., STULTZ, K. E., Shrivastava, R., Tinklenberg, J. R., Eng, L. F. 1992; 94: 475-483

    View details for Web of Science ID A1992KG21500040

    View details for PubMedID 1287731

  • ASTROCYTIC GLIOSIS IN THE AMYGDALA IN DOWNS-SYNDROME AND ALZHEIMERS-DISEASE STANFORD CENTENNIAL SYMP ON NEURONAL-ASTROCYTIC INTERACTIONS Murphy, G. M., Ellis, W. G., Lee, Y. L., STULTZ, K. E., Shrivastava, R., Tinklenberg, J. R., Eng, L. F. ELSEVIER SCIENCE PUBL B V. 1992: 475–83

    View details for Web of Science ID A1992BX24B00040

  • ALZHEIMERS-DISEASE - BETA-AMYLOID PRECURSOR PROTEIN MESSENGER-RNA EXPRESSION IN MONONUCLEAR BLOOD-CELLS NEUROSCIENCE LETTERS Allen, J. S., Murphy, G. M., Eng, L. F., STULTZ, K. E., Davies, H. D., Pickford, L. B., Tinklenberg, J. R. 1991; 132 (1): 109-112

    Abstract

    beta-Amyloid precursor protein (beta APP) mRNA was examined in peripheral mononuclear blood cells (PMBCs) in Alzheimer's disease, Down's syndrome and control subjects. Total RNA from PMBCs was reverse transcribed and then amplified using the polymerase chain reaction (PCR). The 3 major beta APP transcripts were expressed in PMBCs from all subjects. These results suggest that PMBCs could be a circulating source for abnormal amyloid deposition in the brain and in peripheral tissues.

    View details for Web of Science ID A1991GN66500029

    View details for PubMedID 1838578

  • ALZHEIMERS-DISEASE - BETA-AMYLOID PRECURSOR PROTEIN EXPRESSION IN PLAQUES VARIES AMONG CYTOARCHITECTONIC AREAS OF THE MEDIAL TEMPORAL-LOBE NEUROSCIENCE LETTERS Murphy, G. M., Murphy, E., Greenberg, B. D., Cordell, B., Eng, L. F., Ellis, W. G., Forno, L. S., Salamat, S. M., GONZALEZDEWHITT, P. A., Lowery, D. E., Tinklenberg, J. R. 1991; 131 (1): 100-104

    Abstract

    The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.

    View details for Web of Science ID A1991GK15300024

    View details for PubMedID 1791966

  • THE AMYGDALA IN DOWNS-SYNDROME AND FAMILIAL ALZHEIMERS-DISEASE - 4 CLINICOPATHOLOGICAL CASE-REPORTS BIOLOGICAL PSYCHIATRY Murphy, G. M., Ellis, W. G. 1991; 30 (1): 92-106

    Abstract

    Senile plaques and neurofibrillary tangles were quantified in 14 subnuclei of the amygdala in the brains of 3 patients with Down's syndrome (DS), aged 19, 56, and 64 years, and in 1 patient with familial Alzheimer's disease (AD), aged 54 years. The amygdala of the 19-year-old Down's case contained numerous senile plaques (SPs) but no neurofibrillary tangles (NFTs). The distribution of neuropathological change in the amygdala was similar among the Down's and the Alzheimer's cases. Medical and ventral regions contained more SPs and NFTs than did lateral regions, and the SPs in ventromedial subnuclei generally were the "mature" type with a prominent amyloid core. In general, the numbers of SPs and NFTs were parallel in a given subnucleus with the striking exceptions of the deep medial basal, deep cortical, and lateral central nuclei that contained far more SPs than NFTs, and the medial and lateral superficial cortical nuclei that contained numerous NFTs but few SPs. Several subnuclei strongly interconnected with hippocampus and entorhinal cortex were more heavily involved than subnuclei related to the nucleus basalis of Meynert. The patterns of SP and NFT deposition are consistent with amygdaloid abnormalities found by others in sporadic AD. These findings demonstrate the similarity in amygdaloid pathology among Down's syndrome, familial Alzheimer's disease, and sporadic AD. The presence of senile plaques in the amygdala of the 19-year-old patient with DS suggests that the amygdala is a focus of early pathological change in DS and possibly AD.

    View details for Web of Science ID A1991FX21600012

    View details for PubMedID 1832566

  • IMMUNOCYTOCHEMISTRY OF LEWY BODIES IN SYMPATHETIC-GANGLIA Forno, L. S., Murphy, G., Eng, L. F. LIPPINCOTT WILLIAMS & WILKINS. 1991: 318–18

    View details for Web of Science ID A1991FK14000095

  • ANTIGENIC PROFILE OF PLAQUES AND NEUROFIBRILLARY TANGLES IN THE AMYGDALA IN DOWNS-SYNDROME - A COMPARISON WITH ALZHEIMERS-DISEASE BRAIN RESEARCH Murphy, G. M., Eng, L. F., Ellis, W. G., Perry, G., MEISSNER, L. C., Tinklenberg, J. R. 1990; 537 (1-2): 102-108

    Abstract

    Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990EP96100013

    View details for PubMedID 1707726

  • INVIVO QUANTIFICATION OF THE LIMBIC SYSTEM USING MRI - EFFECTS OF NORMAL AGING PSYCHIATRY RESEARCH-NEUROIMAGING Lim, K. O., Zipursky, R. B., Murphy, G. M., Pfefferbaum, A. 1990; 35 (1): 15-26

    Abstract

    Limbic system structures are of central interest in many neuropsychiatric disorders. Magnetic resonance imaging (MRI) has a unique potential for imaging limbic system structures in vivo, but methodological constraints can limit the usefulness and interpretation of the collected image data. In this article, we present approaches for the acquisition and quantification of high resolution MR images of the limbic system. We used a long TR, cardiac gated, flow compensated, spin echo sequence to collect 22, 3-mm thick contiguous sections encompassing the limbic system. The sections were oriented relative to standard internal neuroanatomical landmarks. The sequence provided good gray matter/white matter/cerebrospinal fluid (CSF) and CSF/bone contrast; the latter is necessary for quantifying intracranial size and total CSF volume. Using operationalized criteria, we achieved high interrater reliability in volumetric measurement of temporal horn and hippocampus. This technique was then used to examine the effect of normal aging by comparing eight young (mean = 24 years) and seven old (mean = 73 years) healthy community members. We were able to demonstrate a significant age-related increase in temporal horn volume and a trend toward an age-related decrease in hippocampal volume.

    View details for Web of Science ID A1990DT48100002

    View details for PubMedID 2367609

  • BETA-AMYLOID PRECURSOR DETECTED IN HUMAN CEREBRAL-CORTEX PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Murphy, G. M., Eng, L. F., Cordell, B., Wang, Y., Ellis, W. G., MEISSNER, L., Tinklenberg, J. R. 1990; 14 (3): 309-317

    Abstract

    1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.

    View details for Web of Science ID A1990DC78100004

    View details for PubMedID 2113696

  • ON THE BRAIN OF A SCIENTIST - EINSTEIN,ALBERT EXPERIMENTAL NEUROLOGY Diamond, M. C., Scheibel, A. B., Murphy, G. M., Harvey, T. 1985; 88 (1): 198-204

    Abstract

    Neuron:glial ratios were determined in specific regions of Albert Einstein's cerebral cortex to compare with samples from 11 human male cortices. Cell counts were made on either 6- or 20-micron sections from areas 9 and 39 from each hemisphere. All sections were stained with the Klüver-Barrera stain to differentiate neurons from glia, both astrocytes and oligodendrocytes. Cell counts were made under oil immersion from the crown of the gyrus to the white matter by following a red line drawn on the coverslip. The average number of neurons and glial cells was determined per microscopic field. The results of the analysis suggest that in left area 39, the neuronal: glial ratio for the Einstein brain is significantly smaller than the mean for the control population (t = 2.62, df 9, p less than 0.05, two-tailed). Einstein's brain did not differ significantly in the neuronal:glial ratio from the controls in any of the other three areas studied.

    View details for Web of Science ID A1985AFJ1300015

    View details for PubMedID 3979509

  • LANGUR MONKEY MOTHER LOSS - PROFILE ANALYSIS WITH MULTIVARIATE-ANALYSIS OF VARIANCE FOR SEPARATION SUBJECTS AND CONTROLS FOLIA PRIMATOLOGICA DOLHINOW, P., Murphy, G. 1983; 40 (3): 181-196

    Abstract

    We present an analysis of observational data on the behavior profiles for two groups of infant langur monkeys (Presbytis entellus): one that had experienced mother loss, and the other, a control group, that had not undergone mother loss. Observations were analyzed in three 2-week time periods: 2 preseparation, 2 separation, and 2 postseparation periods for both groups. The profile analysis application of the multivariate analysis of variance (MANOVA) was employed to test the hypothesis that the two groups had similar patterns of change across time. For each group a vector of 5 difference scores was computed; then MANOVA was used to test the similarity of the mean vectors of difference scores for the two groups. Profiles for the separation and control infants were significantly different for some behaviors, and changes between some time periods were also significant.

    View details for Web of Science ID A1983RA81400003

    View details for PubMedID 6884906

  • A MORPHOLOGICAL-STUDY OF MALE-RAT CEREBRAL CORTICAL ASYMMETRY EXPERIMENTAL NEUROLOGY Dowling, G. A., Diamond, M. C., Murphy, G. M., Johnson, R. E. 1982; 75 (1): 51-67

    View details for Web of Science ID A1982MX42100005

    View details for PubMedID 7060681

  • INCREASED BRANCHING OF BASAL DENDRITES ON PYRAMIDAL NEURONS IN THE OCCIPITAL CORTEX OF HOMOZYGOUS BRATTLEBORO RATS IN STANDARD AND ENRICHED ENVIRONMENTAL-CONDITIONS - A GOLGI-STUDY EXPERIMENTAL NEUROLOGY GREER, E. R., Diamond, M. C., Murphy, G. M. 1982; 76 (2): 254-262

    View details for Web of Science ID A1982NN60700003

    View details for PubMedID 7095053

  • MORPHOLOGIC HIPPOCAMPAL ASYMMETRY IN MALE AND FEMALE RATS EXPERIMENTAL NEUROLOGY Diamond, M. C., Murphy, G. M., Akiyama, K., Johnson, R. E. 1982; 76 (3): 553-565

    View details for Web of Science ID A1982NS59600010

    View details for PubMedID 7084374

  • CORRELATION BETWEEN WATER-INTAKE AND DENDRITIC BRANCHING IN HOMOZYGOUS BRATTLEBORO RATS - A GOLGI-STUDY EXPERIMENTAL NEUROLOGY GREER, E. R., Diamond, M. C., Murphy, G. M. 1982; 78 (1): 15-25

    View details for Web of Science ID A1982PJ65300003

    View details for PubMedID 7117476

  • LANGUR MONKEY (PRESBYTIS-ENTELLUS) DEVELOPMENT - THE 1ST 3 MONTHS OF LIFE FOLIA PRIMATOLOGICA DOLHINOW, P., Murphy, G. 1982; 39 (3-4): 305-331

    Abstract

    Observation for the first 3 months of life of 19 Indian langur monkey infants (Presbytis entellus) living in well-established colony social groups revealed complex and related patterns of social development. This is a period of rapidly increasing infant motor ability and increasing infant-initiated independence. Infant transfer, a behavior initiated by others towards the infant and a characteristic of the species, occurs most frequently in weeks 1 and 2, then steadily declines to low frequency in weeks 11 and 12. Infants are not punished or rejected, and to the extent the mother allows, the infant leaves her. She leaves her infant infrequently. The infant widens its radius of activity and increases the kinds and frequency of active interactions it has with others in the group. Patterns of behavior appear to develop in tandem during key periods of early life. Week 1 is the time of greatest dependence with 100% contact at first. During weeks 3 and 4, the infant efficiently expresses itself and can actively prevent transfers. Week 4 sees a constellation of major changes and a rising infant drive for independence. Play increases as do interactions with other immatures. Carrying decreases as the infant is able to follow. Some restraints are observed because of a new set of infant management problems presented to the mother. Throughout the first 3 months of life the mother is the focus of her infant's attention and activities--she is crucial to its survival. The 3-month-old infant is an active strategist with many options of action and choices of behavior and social partners.

    View details for Web of Science ID A1982QA58500008

    View details for PubMedID 7166290

  • EFFECT OF CONTACT INHIBITION ON THE REGULATION OF CHOLESTEROL-METABOLISM IN CULTURED VASCULAR ENDOTHELIAL-CELLS JOURNAL OF BIOLOGICAL CHEMISTRY Fielding, P. E., Vlodavsky, I., GOSPODAROWICZ, D., Fielding, C. J. 1979; 254 (3): 749-755

    Abstract

    Cholesterol synthesis in actively growing bovine vascular endothelial cells is regulated by low density lipoprotein (LDL) at a step prior to mevalonate formation, in a manner comparable to that found in aortic smooth muscle cells. LDL uptake by these cells is associated with induction of cholesterol esterification, an increase in total cell cholesterol, and an inhibition of endogenous sterol synthesis. In contrast, cholesterol metabolism in confluent contact-inhibited endothelial cultures was not significantly affected by LDL even though the cells bind the lipoprotein at high affinity receptor sites. Lysosomal degradation and subsequent regulatory effects on cellular cholesterol metabolism, however, were observed in contact-inhibited endothelial cells incubated with cationized rather than native LDL. Cationized LDL enter the cells independently of the high affinity sites. Therefore, the primary regulation of cholesterol metabolism in these cells is neither through the appropriate intracellular enzymes nor through the high affinity surface receptors, but via an inhibition of LDL internalization. It is suggested that this inhibition is due to a strict contact-inhibited morphology which enables the endothelium of the larger arteries to function as a selective barrier to the high circulating levels of plasma LDL.

    View details for Web of Science ID A1979GL96600031

    View details for PubMedID 216681

  • COMPARISON OF BEHAVIORAL-EFFECTS OF SYSTEMIC L-DOPA AND INTRACRANIAL DOPAMINE IN MESOLIMBIC FOREBRAIN OF NONHUMAN-PRIMATES PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR DILL, R. E., Jones, D. L., Gillin, J. C., Murphy, G. 1979; 10 (5): 711-716

    Abstract

    The systemic administration of L-DOPA and carbidopa to six rhesus and four squirrel monkeys produced an initial period of depressed activity followed by increased locomotion, hypervigilance, involuntary oral-facial movements and a gnawing syndrome. The squirrel monkey exhibited a depressed phase, locomotor stimulation, searching behavior, stereotypic grooming and gnawing syndrome. Most of these activities were prevented by pretreatment with 0.1 mg/kg haloperidol. Bilateral injection of 100 microgram dopamine into the mesolimbic forebrain of four squirrel monkeys also produced an initial depression followed by hyperactivity similar to that produced by L-DOPA, but without gnawing. A stereotyped submissive or juvenile posturing occurred in three animals. These DA-induced activities were blocked by 0.1 mg/kg haloperidol. Similar injection of 100 microgram L-norepinephrine produced a profound depression followed by moderate activity coupled with loss of extensor muscle strength in the legs. Bilateral injection of 300 microgram dopamine into the nucleus accumbens of a rhesus monkey produced stereotypic pacing. These data confirm in primates the importance of dopaminergic mechanisms of the mesolimbic forebrain in locomotor activity and behavior.

    View details for Web of Science ID A1979HA51500012

    View details for PubMedID 115011

  • PHENYLETHYLAMINE IN RHESUS-MONKEYS - INTERACTIONS WITH ALPHA-METHYL-PARA-TYROSINE AND L-DOPA AMERICAN JOURNAL OF PSYCHIATRY Tinklenberg, J. R., Gillin, J. C., Murphy, G. M., Staub, R., WYATT, R. J. 1979; 136 (3): 311-313

    Abstract

    Rhesus monkeys, pretreated with alpha-methyl-para-tryosine (AMPT) and subsequently injected with phenylethylamine (PEA), did not demonstrate the characteristic amphetamine-like PEA effects. However, when AMPT pretreatment was followed with l-dopa and then PEA injection, PEA effects were restored. These results are compatible with a dopamine theory of schizophrenia.

    View details for Web of Science ID A1979GL37400009

    View details for PubMedID 105644

  • EFFECTS OF PHENYLETHYLAMINE IN RHESUS-MONKEYS AMERICAN JOURNAL OF PSYCHIATRY Tinklenberg, J. R., Gillin, J. C., Murphy, G. M., Staub, R., WYATT, R. J. 1978; 135 (5): 576-578

    Abstract

    In controlled experiments rhesus monkeys that had received phenylethylamine (PEA) demonstrated behavior similar to that reported after the administration of amphetamines, except that tolerance to PEA did not develop. These findings are of psychiatric interest because PEA is found in the human body and is a specific substrate for type B MAO, which is found in decreased quantities in certain schizophrenic patients.

    View details for Web of Science ID A1978EX57300012

    View details for PubMedID 417638