Jerome A. Yesavage

VA Palo Alto Health Care System, Palo Alto, California, United States

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Publications (399)

  • [Show abstract] [Hide abstract] ABSTRACT: Mild cognitive impairment (MCI) is a precursor phase of Alzheimer’s disease (AD). As current treatments may be effective only at the early stages of AD, it is important to track MCI patients who will convert to AD. The aim of this study is to develop a high performance semi-mechanism based approach to predict the conversion from MCI to AD and improve our understanding of MCI-to-AD conversion mechanism. First, analysis of variance (ANOVA) test and lasso regression are employed to identify the markers related to the conversion. Then the Bayesian network based on selected markers is established to predict MCI-to-AD conversion. The structure of Bayesian network suggests that the conversion may start with fibrin clot formation, verbal memory impairment, eating pattern changing and hyperinsulinemia. The Bayesian network achieves a high 10-fold cross-validated prediction performance with 96% accuracy, 95% sensitivity, 65% specificity, area under the receiver operating characteristic curve of 0.82 on data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The semi-mechanism based approach provides not only high prediction performance but also clues of mechanism for MCI-to-AD conversion.
    Article · Jun 2016 · Scientific Reports
  • Wei Zhou · Elizabeth Hitchner · Jyoti Bhat · [...] · Jerome Yesavage
    Article · Jun 2016
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    [Show abstract] [Hide abstract] ABSTRACT: The Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer’s disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in β-amyloid (Aβ) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify the possible approach by that CLU impacts AD. Finally, four loci (rs11136000, rs1532278, rs2279590, rs7982) showed significant associations with the Aβ deposition at the baseline level while genotypes of rs9331888 (P = 0.042) increased Aβ deposition. Besides, rs9331888 was significantly associated with baseline volume of left hippocampus (P = 0.014). We then further validated the association with Aβ deposition in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. The results in sub-groups confirmed the association between CLU genotypes and Aβ deposition further. Our findings revealed that CLU genotypes could probably modulate the cerebral the Aβ loads on imaging and volume of hippocampus. These findings raise the possibility that the biological effects of CLU may be relatively confined to neuroimaging trait and hence may offer clues to AD.
    Full-text Article · May 2016 · Scientific Reports
  • T Ho · B G Pollock · B H Mulsant · [...] · R Bies
    [Show abstract] [Hide abstract] ABSTRACT: Aims: To determine the relationship between (R) and (S) - citalopram enantiomer exposure (AUC24) and therapeutic response in agitated individuals greater than 60 years old with Alzheimer's dementia (AD). Methods: Citalopram enantiomer exposures (AUC24) derived from an established population pharmacokinetic analysis were utilized to explore the relationship between (R)- and (S)-citalopram area under the curve (AUC24) and Mini-Mental State Examination (MMSE), Neurobehavioral Rating Scale-Agitation Subscale (NBRS-A), modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Neuropsychiatric Inventory agitation subscale (NPIA) scores. Time dependent changes in these scores (disease progression) were accounted for prior to exploring the exposure effect relationship for each enantiomer. These relationships were evaluated using a nonlinear-mixed effects modelling approach as implemented in NONMEM v7.3. Results: (S)-AUC24 and (R)-AUC24 each contributed to improvement in NBRS-A scores (k3(R): -0.502; k4(S): -0.712) as did time in treatment. However, increasing (R)-AUC24 decreased the probability of patient response (maxΔ: -0.182%/AUC24) based on the CGIC while (S)-AUC24 improved the probability of response (maxΔ 0.112%/AUC24). (R)-AUC24 was also associated with worsening in MMSE scores (-0.5 points). Conclusions: Our results suggest that citalopram enantiomers contributed differentially to treatment outcomes. (R)-citalopram accounted for a greater proportion of the adverse consequences associated with racemic citalopram treatment in patients with AD including a decreased probability of treatment response as measured by the CGIC and a reduction in MMSE scores. The S-enantiomer was associated with increased probability of response based on the CGIC.
    Article · May 2016 · British Journal of Clinical Pharmacology
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: Citalopram has been shown to improve agitation in patients with Alzheimer's disease. The authors evaluated whether other neuropsychiatric symptoms improve with citalopram treatment compared with placebo. Method: In this planned secondary analysis of the Citalopram for Agitation in Alzheimer's Disease study, the authors evaluated the effect of citalopram on the 12 neuropsychiatric symptomdomainsassessedbytheNeuropsychiatricInventory (NPI). They compared caregiver-reported NPI scores at week 9 in patients receiving citalopram(30mg/day) or placebowith regard to both the presence or absence of individual neuropsychiatric symptoms and individualdomain scores (reflecting severity) in participants who had symptoms at week 9. Results: At week 9, participants treated with citalopram were significantly less likely to be reported as showing delusions (odds ratio=0.40), anxiety (odds ratio=0.43), and irritability/ lability (odds ratio=0.38). A comparison of median scores of participants with symptoms present at week 9 showed significant differences favoring citalopram for hallucinations and favoring placebo for sleep/nighttime behavior disorders. Conclusions: While dosage constraints must be considered because of citalopram's adverse effect profile, this agent's overall therapeutic effects in patients with Alzheimer's disease and agitation, in addition to efficacy for agitation/ aggression, included reductions in the frequency of irritability, anxiety, and delusions; among patients who had these symptoms at week 9, they included a reduction in the severity of hallucinations but an increase in the severity of sleep/ nighttime behavior disorders.
    Article · May 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer's disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOADassociated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly.
    Full-text Article · Apr 2016 · Scientific Reports
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    Jerome A. Yesavage · Joy L. Taylor · Leah Friedman · [...] · Art Noda
    [Show abstract] [Hide abstract] ABSTRACT: Background: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory. Methods: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects. Results: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62). Conclusions: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure.
    Full-text Article · Apr 2016 · Journal of Psychiatric Research
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    [Show abstract] [Hide abstract] ABSTRACT: Background Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression (“RAD”) project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time. Methods and design Here we present the protocol for the “RAD” project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who “walk through the door” of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain–based subgroups over time and to assess whether these subgroups predict real–world functional capacity over time. First enrollment was August 2013, and is ongoing. Discussion This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward. Trial registration Identifier: NCT02220309. Registered: August 13, 2014.
    Full-text Article · Mar 2016 · BMC Psychiatry
  • Jerome A. Yesavage · Elmira Yessengaliyeva · Beatriz Hernandez · [...] · Leah Friedman
    Article · Mar 2016
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    Wendy Thanassi · Art Noda · Beatriz Hernandez · [...] · Jerome Yesavage
    [Show abstract] [Hide abstract] ABSTRACT: QuantiFERON tuberculosis tests (QFT) reverted in (612) 77% of 1,094 low-risk healthcare workers (HCW) testing less than 1.16 IU/mL. Of HCW testing greater than 1.1 IU/mL, 33 (59%) of 56 with negative tuberculin skin tests (TST) reverted vs 8 (6%) of 125 with positive TSTs. Retesting low-risk QFT-positive and TST-negative HCW is prudent. Infect. Control Hosp. Epidemiol. 2016;1–5
    Full-text Article · Jan 2016 · Infection Control and Hospital Epidemiology
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed. Method: In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each. Results: Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam. Conclusions: Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.
    Article · Jan 2016 · American Journal of Psychiatry
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    [Show abstract] [Hide abstract] ABSTRACT: Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.
    Full-text Article · Jan 2016 · Scientific Reports
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    Full-text Dataset · Jan 2016
  • [Show abstract] [Hide abstract] ABSTRACT: There is a complex relationship between posttraumatic stress disorder and traumatic brain injury. To understand and treat these conditions, it is necessary to apply an integrated physical and mental health care approach to postdeployment care.
    Article · Dec 2015 · Federal practitioner for the health care professionals of the VA, DoD, and PHS
  • Jeffery Newell · Jerome A. Yesavage · Joy L. Taylor · [...] · Art Noda
    [Show abstract] [Hide abstract] ABSTRACT: Background: We found a benefit of citalopram for agitation in the Citalopram for Agitation in Alzheimer's Disease study (CitAD), and wondered if this was mediated by a sedative effect. CitAD was a randomized, placebo-controlled, double-blind, parallel group trial conducted at 8 academic centers in the United States and Canada from August 2009 to January 2013. One hundred sixty-two participants with probable Alzheimer's disease (AD) and clinically significant agitation were analyzed in this study. Participants received a psychosocial intervention and were randomized to receive either citalopram or placebo (approximately half assigned to each group). Participants were rated on the Neurobehavioral Rating Scale Agitation subscale and measures of sedation (i.e., fatigue and somnolence). Methods: Using the MacArthur Foundation procedures for documenting a mediator effect, we performed a secondary analysis examining whether sedation mediates the effect of treatment on agitation outcome. Results: We found a statistically significant mediating effect of sedation on agitation outcomes, but the magnitude of the effect was small, only explaining 11% of the variance in agitation, with a significant, but modest effect size of 0.16 (95% CI: 0.08 to 0.22). Conclusions: The benefit of citalopram was partly due to sedation but largely due to other mechanisms of action.
    Article · Dec 2015 · Journal of Psychiatric Research
  • Dataset · Nov 2015
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    [Show abstract] [Hide abstract] ABSTRACT: The citalopram for Alzheimer’s disease trial evaluated citalopram for the management for agitation in Alzheimer’s disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower than the clearance of the S-enantiomer. Without accounting for any patient-specific covariates, the population estimate of the metabolic clearance of citalopram was 8.6 (R-citalopram) and 14 L/h (S-citalopram). The population estimate of the clearance of desmethylcitalopram was 23.8 (R-Dcit) and 38.5 L/h (S-Dcit). Several patient-specific covariates were found to have a significant effect on the pharmacokinetics of R,S-citalopram and desmethylcitalopram. A significant difference in the metabolic clearance of R-citalopram between males and females (13 vs 9.05 L/h) was identified in this analysis. Both R- and S-citalopram metabolic clearance decreased with age. Additionally, consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was significantly influenced by CYPC19 genotype, with a difference of 5.8 L/h between extensive/rapid and intermediate/poor metabolizers. R,S-desmethylcitalopram clearance increased with increasing body weight. This model may allow for the opportunity to delineate the effect of R- and S-citalopram on pharmacodynamics outcomes related to the management of agitation in Alzheimer’s disease. Electronic supplementary material The online version of this article (doi:10.1007/s10928-015-9457-6) contains supplementary material, which is available to authorized users.
    Full-text Article · Nov 2015 · Journal of Pharmacokinetics and Pharmacodynamics
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To determine the point prevalence of sleep disordered breathing (SDB) in a community-based sample of older male veterans and to determine if common markers of SDB apply to this population. Methods: Two hundred fourteen older male Veterans (age 55-89 years) were recruited for a study on post-traumatic stress disorder and cognitive decline. Questionnaires concerning anthropomorphic and psychological variables were obtained, as was an overnight polysomnographic examination of sleep. Results: Only 13% of the participants lacked clinically meaningful SDB, whereas 33% had moderate SDB and 54% had severe SDB. Being overweight, self-reported snoring, and excessive daytime sleepiness all had good sensitivity (0.86-0.92) but very poor specificity (0.10-0.28) for the prediction of SDB. Conclusions: Undiagnosed SDB was more than threefold higher than expected in these community-dwelling older veterans. Traditional markers of SDB were not specific for predicting clinically relevant SDB.
    Article · Sep 2015 · The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry
  • L Posecion · G Goodale · D La · [...] · L Kinoshita
    Article · Sep 2015 · Archives of Clinical Neuropsychology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD). Methods: In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression. Results: Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure. Conclusions: We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
    Article · Aug 2015 · International Psychogeriatrics

Publication Stats

19k Citations


  • 1997-2015
    • VA Palo Alto Health Care System
      Palo Alto, California, United States
  • 1985-2015
    • Stanford University
      • Department of Psychiatry and Behavioral Sciences
      Palo Alto, California, United States
    • Palo Alto Research Center
      Palo Alto, California, United States
  • 2012
    • University of California, San Diego
      San Diego, California, United States