Ruth O'Hara

All Publications

• A Cognitive Biotype of Depression and Symptoms, Behavior Measures, Neural Circuits, and Differential Treatment Outcomes: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA network open Hack, L. M., Tozzi, L., Zenteno, S., Olmsted, A. M., Hilton, R., Jubeir, J., Korgaonkar, M. S., Schatzberg, A. F., Yesavage, J. A., O'Hara, R., Williams, L. M. 2023; 6 (6): e2318411

  Abstract

  Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes.To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities.This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023.Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging.A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse.Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction.ClinicalTrials.gov Identifier: NCT00693849.

  View details for DOI 10.1001/jamanetworkopen.2023.18411

  View details for PubMedID 37318808

• Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature communications Ollila, H. M., Sharon, E., Lin, L., Sinnott-Armstrong, N., Ambati, A., Yogeshwar, S. M., Hillary, R. P., Jolanki, O., Faraco, J., Einen, M., Luo, G., Zhang, J., Han, F., Yan, H., Dong, X. S., Li, J., Zhang, J., Hong, S. C., Kim, T. W., Dauvilliers, Y., Barateau, L., Lammers, G. J., Fronczek, R., Mayer, G., Santamaria, J., Arnulf, I., Knudsen-Heier, S., Bredahl, M. K., Thorsby, P. M., Plazzi, G., Pizza, F., Moresco, M., Crowe, C., Van den Eeden, S. K., Lecendreux, M., Bourgin, P., Kanbayashi, T., Martínez-Orozco, F. J., Peraita-Adrados, R., Benetó, A., Montplaisir, J., Desautels, A., Huang, Y. S., Jennum, P., Nevsimalova, S., Kemlink, D., Iranzo, A., Overeem, S., Wierzbicka, A., Geisler, P., Sonka, K., Honda, M., Högl, B., Stefani, A., Coelho, F. M., Mantovani, V., Feketeova, E., Wadelius, M., Eriksson, N., Smedje, H., Hallberg, P., Hesla, P. E., Rye, D., Pelin, Z., Ferini-Strambi, L., Bassetti, C. L., Mathis, J., Khatami, R., Aran, A., Nampoothiri, S., Olsson, T., Kockum, I., Partinen, M., Perola, M., Kornum, B. R., Rueger, S., Winkelmann, J., Miyagawa, T., Toyoda, H., Khor, S. S., Shimada, M., Tokunaga, K., Rivas, M., Pritchard, J. K., Risch, N., Kutalik, Z., O'Hara, R., Hallmayer, J., Ye, C. J., Mignot, E. J. 2023; 14 (1): 2709

  Abstract

  Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

  View details for DOI 10.1038/s41467-023-36120-z

  View details for PubMedID 37188663

  View details for PubMedCentralID PMC10185546

• THE IMPACT OF CORTICAL OXYGENATION DURING SLEEP-DISORDERED BREATHING ON COGNITION Kawai, M., O'hara, R. OXFORD UNIV PRESS INC. 2023: A27

  View details for Web of Science ID 001008232900057

• Association between mental health symptoms and behavioral performance in younger vs. older online workers. Frontiers in psychiatry Mills-Finnerty, C., Staggs, H., Hogoboom, N., Naparstek, S., Harvey, T., Beaudreau, S. A., O'Hara, R. 2023; 14: 995445

  Abstract

  The COVID-19 pandemic has been associated with increased rates of mental health problems, particularly in younger people.We quantified mental health of online workers before and during the COVID-19 pandemic, and cognition during the early stages of the pandemic in 2020. A pre-registered data analysis plan was completed, testing the following three hypotheses: reward-related behaviors will remain intact as age increases; cognitive performance will decline with age; mood symptoms will worsen during the pandemic compared to before. We also conducted exploratory analyses including Bayesian computational modeling of latent cognitive parameters.Self-report depression (Patient Health Questionnaire 8) and anxiety (General Anxiety Disorder 7) prevalence were compared from two samples of Amazon Mechanical Turk (MTurk) workers ages 18-76: pre-COVID 2018 (N = 799) and peri-COVID 2020 (N = 233). The peri-COVID sample also completed a browser-based neurocognitive test battery.We found support for two out of three pre-registered hypotheses. Notably our hypothesis that mental health symptoms would increase in the peri-COVID sample compared to pre-COVID sample was not supported: both groups reported high mental health burden, especially younger online workers. Higher mental health symptoms were associated with negative impacts on cognitive performance (speed/accuracy tradeoffs) in the peri-COVID sample. We found support for two hypotheses: reaction time slows down with age in two of three attention tasks tested, whereas reward function and accuracy appear to be preserved with age.This study identified high mental health burden, particularly in younger online workers, and associated negative impacts on cognitive function.

  View details for DOI 10.3389/fpsyt.2023.995445

  View details for PubMedID 37065893

  View details for PubMedCentralID PMC10090330

• Needles in a Haystack: Finding Qualitative and Quantitative Collaborators in Academic Medical Centers. Academic medicine : journal of the Association of American Medical Colleges Pomann, G. M., Truong, T., Boulos, M., Boulware, L. E., Brouwer, R. N., Curtis, L. H., Kapphahn, K., Khalatbari, S., McKeel, J., Messinger, S., O'Hara, R., Pencina, M. J., Samsa, G. P., Spino, C., Yang, L. Z., Desai, M. 2023

  Abstract

  Translational research is a data-driven process that involves transforming scientific laboratory- and clinic-based discoveries into products and activities with real-world impact to improve individual and population health. Successful execution of translational research requires collaboration between clinical and translational science researchers, who have expertise in a wide variety of domains across the field of medicine, and qualitative and quantitative scientists, who have specialized methodologic expertise across diverse methodologic domains. While many institutions are working to build networks of these specialists, a formalized process is needed to help researchers navigate the network to find the best match and to track the navigation process to evaluate an institution's unmet collaborative needs. In 2018, a novel analytic resource navigation process was developed at Duke University to connect potential collaborators, leverage resources, and foster a community of researchers and scientists. This analytic resource navigation process can be readily adopted by other academic medical centers. The process relies on navigators with broad qualitative and quantitative methodologic knowledge, strong communication and leadership skills, and extensive collaborative experience. The essential elements of the analytic resource navigation process are as follows: (1) strong institutional knowledge of methodologic expertise and access to analytic resources, (2) deep understanding of research needs and methodologic expertise, (3) education of researchers on the role of qualitative and quantitative scientists in the research project, and (4) ongoing evaluation of the analytic resource navigation process to inform improvements. Navigators help researchers determine the type of expertise needed, search the institution to find potential collaborators with that expertise, and document the process to evaluate unmet needs. Although the navigation process can create a basis for an effective solution, some challenges remain, such as having resources to train navigators, comprehensively identifying all potential collaborators, and keeping updated information about resources as methodologists join and leave the institution.

  View details for DOI 10.1097/ACM.0000000000005212

  View details for PubMedID 36940408

• Beyond maintaining safety: Examining the benefit of emotion-centered problem solving therapy added to safety planning for reducing late life suicide risk. Contemporary clinical trials Beaudreau, S. A., Lutz, J., Wetherell, J. L., Nezu, A. M., Nezu, C. M., O'Hara, R., Gould, C. E., Roelk, B., Jo, B., Hernandez, B., Samarina, V., Otero, M. C., Gallagher, A., Hirsch, J., Funderburk, J., Pigeon, W. R. 2023: 107147

  Abstract

  Few clinical trials have examined brief non-pharmacological treatments for reducing suicide risk in older Veterans, a high-risk group. Problem Solving Therapy (PST) is a promising psychosocial intervention for reducing late life suicide risk by increasing adaptive coping to problems through effective problem solving and related coping skills. The current randomized clinical trial will compare the efficacy of six telephone-delivered sessions of Safety Planning (enhanced usual care; EUC) only or an updated version of PST (emotion-centered PST [EC-PST]) + EUC to determine the added clinical benefit of EC-PST for reducing severity of suicidal ideation and for increasing reasons for living, a critical protective factor. Participants randomized to EC-PST + EUC or EUC only will be 150 Veterans (75 each) with active suicidal ideation who are aged 60 or older; have a current DSM-5 anxiety, depressive, and/or trauma-related disorder; and without significant cognitive impairment. Primary outcomes (Geriatric Suicide Ideation Scale and Reasons for Living-Older Adults scale) will be assessed at 11 timepoints: baseline, after each of 6 treatment sessions, posttreatment, and at follow-up at 1, 3, and 6 months posttreatment, and analyzed using mixed effects modeling. Additionally, moderators and mediators of primary outcomes will be examined-functional disability, executive dysfunction, and problem-solving ability. Qualitative feedback from participants will identify potential Veteran-centric changes to the EC-PST protocol and to EUC. Ultimately, the goal of this study is to inform the evidence-based clinical practice guidelines for treatments to reduce suicide risk in older Veterans and specifically to inform clinical decision-making regarding the merit of adding EC-PST to EUC.

  View details for DOI 10.1016/j.cct.2023.107147

  View details for PubMedID 36921689

• Decoding the heterogeneity of Alzheimer's disease diagnosis and progression using multilayer networks. Molecular psychiatry Avelar-Pereira, B., Belloy, M. E., O'Hara, R., Hosseini, S. M. 2022

  Abstract

  Alzheimer's disease (AD) is a multifactorial and heterogeneous disorder, which makes early detection a challenge. Studies have attempted to combine biomarkers to improve AD detection and predict progression. However, most of the existing work reports results in parallel or compares normalized findings but does not analyze data simultaneously. We tested a multi-dimensional network framework, applied to 490 subjects (cognitively normal [CN] = 147; mild cognitive impairment [MCI] = 287; AD = 56) from ADNI, to create a single model capable of capturing the heterogeneity and progression of AD. First, we constructed subject similarity networks for structural magnetic resonance imaging, amyloid-β positron emission tomography, cerebrospinal fluid, cognition, and genetics data and then applied multilayer community detection to find groups with shared similarities across modalities. Individuals were also followed-up longitudinally, with AD subjects having, on average, 4.5 years of follow-up. Our findings show that multilayer community detection allows for accurate identification of present and future AD (≈90%) and is also able to identify cases that were misdiagnosed clinically. From all MCI participants who developed AD or reverted to CN, the multilayer model correctly identified 90.8% and 88.5% of cases respectively. We observed similar subtypes across the full sample and when examining multimodal data from subjects with no AD pathology (i.e., amyloid negative). Finally, these results were also validated using an independent testing set. In summary, the multilayer framework is successful in detecting AD and provides unique insight into the heterogeneity of the disease by identifying subtypes that share similar multidisciplinary profiles of neurological, cognitive, pathological, and genetics information.

  View details for DOI 10.1038/s41380-022-01886-z

  View details for PubMedID 36539525

• Sleep architecture is associated with core symptom severity in autism spectrum disorder. Sleep Kawai, M., Buck, C., Chick, C. F., Anker, L., Talbot, L., Schneider, L., Linkovski, O., Cotto, I., Parker-Fong, K., Phillips, J., Hardan, A., Hallmayer, J., O'Hara, R. 2022

  Abstract

  OBJECTIVE: While caregiver-reported sleep disturbances are common in children and adolescents with autism spectrum disorder (ASD), few studies have measured objective sleep in ASD compared to controls, and their findings are mixed. We investigated 1) differences in sleep architecture, specifically slow-wave sleep (SWS) and rapid eye movement sleep (REM), between ASD and typically developing controls (TD); and 2) if any observed differences in sleep were associated with core ASD symptoms.METHODS: We used ambulatory polysomnography (PSG) in 53 participants with ASD (ages 6 to 18) and 66 age-matched TD in their home sleeping environment. The primary outcome measures were SWS and REM sleep. Core behavioral ASD symptoms were assessed using the Autism Diagnostic Interview-Revised (ADI-R). Spectral power bands during sleep, and additional behavioral measures, were examined in exploratory analyses.RESULTS: Compared to TD, participants with ASD exhibited a higher SWS ratio and lower REM ratio. Within the ASD group, higher SWS was associated with more severe symptoms on the Restricted, Repetitive, and Stereotyped Behaviors subscale of the ADI-R. No association was observed between REM ratio and any ASD symptom.CONCLUSIONS: Increased SWS and reduced REM sleep ratio differentiated ASD from TD. However, only increased SWS was associated with more severe core ASD symptoms. Increased SWS may reflect neuronal immaturity specific to ASD in this age group. These findings may inform the underlying mechanisms of clinical symptoms observed in children and adolescents with ASD.

  View details for DOI 10.1093/sleep/zsac273

  View details for PubMedID 36385326

• Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy. Nature communications Parikh, V. N., Ioannidis, A. G., Jimenez-Morales, D., Gorzynski, J. E., De Jong, H. N., Liu, X., Roque, J., Cepeda-Espinoza, V. P., Osoegawa, K., Hughes, C., Sutton, S. C., Youlton, N., Joshi, R., Amar, D., Tanigawa, Y., Russo, D., Wong, J., Lauzon, J. T., Edelson, J., Mas Montserrat, D., Kwon, Y., Rubinacci, S., Delaneau, O., Cappello, L., Kim, J., Shoura, M. J., Raja, A. N., Watson, N., Hammond, N., Spiteri, E., Mallempati, K. C., Montero-Martín, G., Christle, J., Kim, J., Kirillova, A., Seo, K., Huang, Y., Zhao, C., Moreno-Grau, S., Hershman, S. G., Dalton, K. P., Zhen, J., Kamm, J., Bhatt, K. D., Isakova, A., Morri, M., Ranganath, T., Blish, C. A., Rogers, A. J., Nadeau, K., Yang, S., Blomkalns, A., O'Hara, R., Neff, N. F., DeBoever, C., Szalma, S., Wheeler, M. T., Gates, C. M., Farh, K., Schroth, G. P., Febbo, P., deSouza, F., Cornejo, O. E., Fernandez-Vina, M., Kistler, A., Palacios, J. A., Pinsky, B. A., Bustamante, C. D., Rivas, M. A., Ashley, E. A. 2022; 13 (1): 5107

  Abstract

  The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

  View details for DOI 10.1038/s41467-022-32397-8

  View details for PubMedID 36042219

• THE CIRCADIAN MISALIGNMENT IS ASSOCIATED WITH REDUCED SLOW-WAVE SLEEP IN INDIVIDUALS WITH AUTISM SPECTRUM DISORDER Ishii, T., Chen, J., Parker-Fong, K., Kawai, M., O'hara, R. OXFORD UNIV PRESS INC. 2022: A301

  View details for Web of Science ID 000838094800682

• Mental Health Symptoms Predict Cognitive Performance in Online Gig Economy Workers Mills-Finnerty, C., Staggs, H., Hogoboom, N., Khadr, M., Furst, A., O'Hara, R. ELSEVIER SCIENCE INC. 2022: S187

  View details for Web of Science ID 000789022200457

• Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine. Nature immunology Li, C., Lee, A., Grigoryan, L., Arunachalam, P. S., Scott, M. K., Trisal, M., Wimmers, F., Sanyal, M., Weidenbacher, P. A., Feng, Y., Adamska, J. Z., Valore, E., Wang, Y., Verma, R., Reis, N., Dunham, D., O'Hara, R., Park, H., Luo, W., Gitlin, A. D., Kim, P., Khatri, P., Nadeau, K. C., Pulendran, B. 2022

  Abstract

  Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-gamma levels 1d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-gamma. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

  View details for DOI 10.1038/s41590-022-01163-9

  View details for PubMedID 35288714

• Preparing the Next Generation of Academic Researchers During the Pandemic: Lessons from a National Mental Health Research Postdoctoral Fellowship. Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry Hantke, N. C., Samarina, V., Hallmayer, J., Anker, L., O'Hara, R., Beaudreau, S. A. 2022

  Abstract

  OBJECTIVE: The COVID-19 pandemic has severely disrupted all aspects of academic medicine, including post-doctoral research fellowship training. The current survey examined ways in which research fellows across 28 U.S. nationally diverse sites have been impacted.METHODS: Survey participants included 62 M.D. and Ph.D. post-doctoral fellows and 27 local fellowship center directors within the Veterans Affairs (VA) Advanced Fellowship in Mental Illness Research and Treatment (MIRT), a national fellowship program tasked to develop academic clinician researchers within the field of mental health. Survey questions focused on productivity and challenges experienced by fellows during the pandemic.RESULTS: Half of fellows reported working entirely off-site during the COVID-19 pandemic. All fellows reported some level of disruption in productivity during the pandemic; 73% reported a disruption in data collection, 69% reported decreased scholarly output, 41% reported disruption in grant writing, and 73% reported disruption in ability to provide clinical care. Yet, the majority of fellows (66%) reported not having to change their research goals, pivoting to telehealth-based data collection, and employing extant data for research projects and peer-reviewed publications.CONCLUSIONS: The results of the fellow and director surveys highlight the associated disruption of the COVID-19 pandemic on fellowship-related activities and parallel ingenuity of programs to continue conducting research and clinical services in a modified fashion. While many research goals continued unabated, the findings suggest alterations in data collection methodology and a focus on using extant data, which may have a residual influence on future early career research grant applications.

  View details for DOI 10.1007/s40596-022-01613-4

  View details for PubMedID 35257319

• Increased activation product of complement 4 protein in plasma of individuals with schizophrenia. Translational psychiatry Kalinowski, A., Liliental, J., Anker, L. A., Linkovski, O., Culbertson, C., Hall, J. N., Pattni, R., Sabatti, C., Noordsy, D., Hallmayer, J. F., Mellins, E. D., Ballon, J. S., O'Hara, R., Levinson, D. F., Urban, A. E. 2021; 11 (1): 486

  Abstract

  Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood-brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean=654±16ng/mL, 557±94 respectively, p=0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

  View details for DOI 10.1038/s41398-021-01583-5

  View details for PubMedID 34552056

• Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System. JAMA network open Warren, C. M., Snow, T. T., Lee, A. S., Shah, M. M., Heider, A., Blomkalns, A., Betts, B., Buzzanco, A. S., Gonzalez, J., Chinthrajah, R. S., Do, E., Chang, I., Dunham, D., Lee, G., O'Hara, R., Park, H., Shamji, M. H., Schilling, L., Sindher, S. B., Sisodiya, D., Smith, E., Tsai, M., Galli, S. J., Akdis, C., Nadeau, K. C. 2021; 4 (9): e2125524

  Abstract

  Importance: As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported.Objective: To characterize the immunologic mechanisms underlying allergic reactions to these vaccines.Design, Setting, and Participants: This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing.Exposures: FDA-authorized mRNA COVID-19 vaccines.Main Outcomes and Measures: Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms.Results: Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine.Conclusions and Relevance: Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.

  View details for DOI 10.1001/jamanetworkopen.2021.25524

  View details for PubMedID 34533570

• A timely reminder of the complexities and burden facing caregivers of patients with bvFTD. International psychogeriatrics Chick, C. F., O'Hara, R. 2021; 33 (9): 853-855

  View details for DOI 10.1017/S1041610220003646

  View details for PubMedID 34607623

• Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. The Journal of experimental medicine Wilk, A. J., Lee, M. J., Wei, B., Parks, B., Pi, R., Martinez-Colon, G. J., Ranganath, T., Zhao, N. Q., Taylor, S., Becker, W., Stanford COVID-19 Biobank, Jimenez-Morales, D., Blomkalns, A. L., O'Hara, R., Ashley, E. A., Nadeau, K. C., Yang, S., Holmes, S., Rabinovitch, M., Rogers, A. J., Greenleaf, W. J., Blish, C. A. 2021; 218 (8)

  Abstract

  Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-kappaB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

  View details for DOI 10.1084/jem.20210582

  View details for PubMedID 34128959

• The COVID-19 Outpatient Pragmatic Platform Study (COPPS): Study design of a multi-center pragmatic platform trial. Contemporary clinical trials Bunning, B., Hedlin, H., Purington, N., Sundaram, V., Kapphahn, K., Weng, Y., Cunanan, K., Maldonado, Y., Singh, U., Khosla, C., O'Hara, R., Nicolls, M., Springman, E., Parsonnet, J., Rogers, A., Levitt, J., Desai, M. 2021: 106509

  Abstract

  More than 3000 clinical trials related to COVID-19 have been registered through clinicaltrials.gov. With so many trials, there is a risk that many will be inconclusive due to being underpowered or due to an inability to recruit patients. At academic medical centers, multiple trials are competing for the same resources; the success of one may come at the expense of another. The COVID-19 Outpatient Pragmatic Protocol Study (COPPS) is a flexible phase 2, multi-site, randomized, blinded trial based at Stanford University designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls. This approach reduces the overall number of patients required for statistical power, while improving the likelihood that any enrolled patient receives active treatment. The platform study has two main domains designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain), measured with self-collected nasal swabs, or improve clinical outcomes (Clinical Domain), measured through self-reported symptomology data. Data are collected on both domains for all participants enrolled. Participants are followed over a 28-day period. COPPS has the advantage of pragmatism created around its workflow that is also appealing to potential participants because of a lower probability of inactive treatment. At the conclusion of this clinical trial we expect to have identified potentially effective therapeutic strategy/ies for treating COVID-19 in the outpatient setting, which will have a transformative impact on medicine and public health.

  View details for DOI 10.1016/j.cct.2021.106509

  View details for PubMedID 34274494

• A school-based health and mindfulness curriculum improves children's objectively measured sleep: a prospective observational cohort study. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Chick, C. F., Singh, A., Anker, L. A., Buck, C., Kawai, M., Gould, C., Cotto, I., Schneider, L., Linkovski, O., Karna, R., Pirog, S., Parker-Fong, K., Nolan, C. R., Shinsky, D. N., Hiteshi, P. N., Leyva, O., Flores, B., Matlow, R., Bradley, T., Jordan, J., Carrion, V., O'Hara, R. 2021

  Abstract

  STUDY OBJECTIVES: Poor sleep impedes children's cognitive, emotional, and psychosocial development. Pediatric sleep dysregulation is common, and children who live in communities of low socioeconomic status (SES) experience additional risk factors for short sleep duration and poor sleep quality. School-based training in mindfulness and yoga-informed practices can improve children's behavior and well-being, but effects on objectively measured sleep are unknown.METHODS: Effects of a school-based health and mindfulness curriculum, which taught practices such as paced breathing, on sleep and stress were examined in 115 children (49 girls, ages eight to 11 at baseline). 58 children in a community of low socioeconomic status (SES) received the curriculum twice weekly for two years. 57 children in an SES-matched community engaged in their usual physical education class instead. In-home ambulatory polysomnography and perceived social stress were measured from all children at three timepoints: at baseline (i.e., prior to curriculum exposure) and at two yearly follow-ups.RESULTS: Children receiving the curriculum gained an average of 74 minutes of total sleep time, and 24 minutes of rapid eye movement (REM) sleep, per night over the two-year study period. Children not receiving the curriculum experienced a decrease in total sleep time averaging 64 minutes per night, with no changes in REM sleep. Sleep improved within the first three months of curriculum exposure, in a dose-dependent fashion. Higher curriculum engagement (e.g., using the breathing exercises outside of class) was associated with larger gains in total and REM sleep duration. Aggregate within-group changes in social stress were not significant. However, among children receiving the curriculum, those who experienced larger gains in total and REM sleep duration also experienced larger increases in perceived social stress.CONCLUSIONS: A school-based health and mindfulness curriculum improved children's objectively measured sleep over two years. Social stress did not mediate these effects; instead, mindfulness training may have increased awareness of environmental stressors, while developing tools to reduce stress vulnerability.

  View details for DOI 10.5664/jcsm.9508

  View details for PubMedID 34170222

• Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19. Allergy Eggert, L. E., He, Z., Collins, W., Lee, A. S., Dhondalay, G., Jiang, S. Y., Fitzpatrick, J., Snow, T. T., Pinsky, B. A., Artandi, M., Barman, L., Puri, R., Wittman, R., Ahuja, N., Blomkalns, A., O'Hara, R., Cao, S., Desai, M., Sindher, S. B., Nadeau, K., Chinthrajah, R. S. 2021

  Abstract

  BACKGROUND: It is unclear if asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2.METHODS: All patients over 28 days oldtesting positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms.RESULTS: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4.15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1.12 [95% CI 0.86, 1.45], p=0.40). Among SARS-CoV-2 positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared to non-allergic asthma (OR 0.52 (0.28, 0.91), p=0.026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared to patients with mild or asymptomatic disease, independent of asthma status (p=0.0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms.CONCLUSIONS: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with a more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.

  View details for DOI 10.1111/all.14972

  View details for PubMedID 34080210

• Quantitative Measurement of Macromolecular Tissue Properties in White and Gray Matter in Healthy Aging and Amnestic MCI. NeuroImage Gozdas, E., Fingerhut, H., Wu, H., Bruno, J. L., Dacorro, L., Jo, B., O'Hara, R., Reiss, A. L., Hosseini, S. M. 2021: 118161

  Abstract

  Healthy and pathological aging influence brain microstructure via complex processes. Discerning these processes require measurements that are sensitive to specific biological properties of brain tissue. We integrated a novel quantitative R1 measure with multi-shell diffusion weighted imaging to map age-associated changes in macromolecular tissue volume (MTV) along major white matter tracts in healthy older adults and patients with amnestic Mild Cognitive Impairment (aMCI). Reduced MTV in association tracts was associated with older age in healthy aging, was correlated with memory performance, and distinguished aMCI from controls. We also mapped changes in gray matter tissue properties using quantitative R1 measurements. We documented a widespread decrease in R1 with advancing age across cortex and decreased R1 in aMCI compared with controls in regions implicated in episodic memory. Our data are the first to characterize MTV loss along major white matter tracts in aMCI and suggest that qMRI is a sensitive measure for detecting subtle degeneration of white and gray matter tissue that cannot be detected by conventional MRI and diffusion measures.

  View details for DOI 10.1016/j.neuroimage.2021.118161

  View details for PubMedID 34000394

• Aging Online: Characterizing Attention, Reward Function, and Mental Health in Older Online Workers Mills-Finnerty, C., Hogoboom, N., Cline, C., Rolle, C., Naparstek, S., Khadr, M., Zimmermon-Thompson, T., Harvey, T., O'Hara, R. ELSEVIER SCIENCE INC. 2021: S215

  View details for Web of Science ID 000645683800516

• A SCHOOL-BASED HEALTH AND MINDFULNESS CURRICULUM IMPROVES CHILDREN'S OBJECTIVELY MEASURED SLEEP Chick, C., Anker, L., Singh, A., Buck, C., Kawai, M., Gould, C., Cotto, I., Schneider, L., Linkovski, O., Matlow, R., Bradley, T., Carrion, V., O'Hara, R. OXFORD UNIV PRESS INC. 2021: A251

  View details for Web of Science ID 000698984300640

• SARS-CoV-2 RNAemia predicts clinical deterioration and extrapulmonary complications from COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Ram-Mohan, N. n., Kim, D. n., Zudock, E. J., Hashemi, M. M., Tjandra, K. C., Rogers, A. J., Blish, C. A., Nadeau, K. C., Newberry, J. A., Quinn, J. V., O'Hara, R. n., Ashley, E. n., Nguyen, H. n., Jiang, L. n., Hung, P. n., Blomkalns, A. L., Yang, S. n. 2021

  Abstract

  The determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between SARS-CoV-2 RNAemia and disease severity, clinical deterioration, and specific EPCs.We used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the Emergency Department (ED) with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression.23.0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1.4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAaemic patients were more likely to manifest severe disease (OR 6.72 [95% CI, 2.45 - 19.79]), worsening of disease severity (OR 2.43 [95% CI, 1.07 - 5.38]), and EPCs (OR 2.81 [95% CI, 1.26 - 6.36]). RNA load correlated with maximum severity (r = 0.47 [95% CI, 0.20 - 0.67]).dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

  View details for DOI 10.1093/cid/ciab394

  View details for PubMedID 33949665

• Depression, health comorbidities, cognitive symptoms and their functional impact: Not just a geriatric problem. Journal of psychiatric research Schüssler-Fiorenza Rose, S. M., Bott, N. T., Heinemeyer, E. E., Hantke, N. C., Gould, C. E., Hirst, R. B., Jordan, J. T., Beaudreau, S. A., O'Hara, R. 2021; 139: 185-192

  Abstract

  To compare the prevalence of cognitive symptoms and their functional impact by age group accounting for depression and number of other health conditions.We analyzed data from the 2011 Behavioral Risk Factor Surveillance System, a population-based, cross-sectional telephone survey of US adults. Twenty-one US states asked participants (n = 131, 273) about cognitive symptoms (worsening confusion or memory loss in the past year) and their functional impact (interference with activities and need for assistance). We analyzed the association between age, depression history and cognitive symptoms and their functional impact using logistic regression and adjusted for demographic characteristics and other health condition count.There was a significant interaction between age and depression (p < 0.0001). In adults reporting depression, the adjusted odds of cognitive symptoms in younger age groups (<75 years) were comparable or greater to those in the oldest age group (≥75 years) with a peak in the middle age (45-54 years) group (OR 1.9 (95% Confidence Interval: 1.4-2.5). In adults without depression, adults <75 years had a significantly lower adjusted odds of cognitive symptoms compared to the oldest age group with the exception of the middle-aged group where the difference was not statistically significant. Over half of adults under age 65 with depression reported that cognitive symptoms interfered with life activities compared to 35.7% of adults ≥65 years.Cognitive symptoms are not universally higher in older adults; middle-aged adults are also particularly vulnerable. Given the adverse functional impact associated with cognitive symptoms in younger adults, clinicians should assess cognitive symptoms and their functional impact in adults of all ages and consider treatments that impact both cognition and functional domains.

  View details for DOI 10.1016/j.jpsychires.2021.05.013

  View details for PubMedID 34087515

• BRIEF VIDEO-DELIVERED INTERVENTIONS TO REDUCE ANXIETY IN OLDER VETERANS: A PILOT RCT Gould, C., Carlson, C., Anker, L., O'Hara, R., Wetherell, J., Goldstein, M., Beaudreau, S. OXFORD UNIV PRESS. 2021: 567

  View details for Web of Science ID 000842009902628

• Brain health registry GenePool study: A novel approach to online genetics research. Alzheimer's & dementia (New York, N. Y.) Fockler, J., Kwang, W., Ashford, M. T., Flenniken, D., Hwang, J., Truran, D., Mackin, R. S., Jin, C., O'Hara, R., Hallmayer, J. F., Yesavage, J. A., Weiner, M. W., Nosheny, R. L. 2021; 7 (1): e12118

  Abstract

  Introduction: Remote data collection, including the establishment of online registries, is a novel approach to efficiently identify risk for cognitive decline and Alzheimer's disease (AD) in older adults, with growing evidence for feasibility and validity. Addition of genetic data to online registries has the potential to facilitate identification of older adults at risk and to advance the understanding of genetic contributions to AD.Methods: 573 older adult participants with longitudinal online Brain Health Registry (BHR) data underwent apolipoprotein E (APOE) genotyping using remotely collected saliva samples and a novel, automated Biofluid Collection Management Portal. We evaluated acceptability of genetic sample collection and estimated associations between (1) sociodemographic variables and willingness to participate in genetics research and (2) APOE results and online cognitive and functional assessments. We also assessed acceptance of hypothetical genetics research participation by surveying a larger sample of 25,888 BHR participants.Results: 51% of invited participants enrolled in the BHR genetics study, BHR-GenePool Study (BHR-GPS); 27% of participants had at least one APOE epsilon4 allele. Older participants and those with higher educational attainment were more likely to participate. In the remotely administered Cogstate Brief Battery, APOE epsilon4/epsilon4 homozygotes (HM) had worse online learning scores, and greater decline in processing speed and attention, compared to epsilon3/epsilon4 heterozygotes (HT) and epsilon4 non-carriers (NC).Discussion: APOE genotyping of more than 500 older adults enrolled in BHR supports the feasibility and validity of a novel, remote biofluids collection approach from a large cohort of older adults, with data linkage to longitudinal online cognitive data. This approach can be expanded for efficient collection of genetic data and other information from biofluids in the future.

  View details for DOI 10.1002/trc2.12118

  View details for PubMedID 33614891

• Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19 European Journal of Allergy and Clinical Immunology Eggert, L. E., He, Z., Collins, W., Lee, A. S., Nadeau, K., Chinthrajah, R. 2021

  View details for DOI 10.1111/all.14972

• Neurocognitive markers of passive suicidal ideation in late-life depression. International psychogeriatrics Jordan, J. T., Chick, C. F., Rolle, C. E., Hantke, N., Gould, C. E., Lutz, J., Kawai, M., Cotto, I., Karna, R., Pirog, S., Berk, M., Sudheimer, K., O'Hara, R., Beaudreau, S. A. 2020: 1–11

  Abstract

  OBJECTIVES: (1) To delineate whether cognitive flexibility and inhibitory ability are neurocognitive markers of passive suicidal ideation (PSI), an early stage of suicide risk in depression and (2) to determine whether PSI is associated with volumetric differences in regions of the prefrontal cortex (PFC) in middle-aged and older adults with depression.DESIGN: Cross-sectional study.SETTING: University medical school.PARTICIPANTS: Forty community-dwelling middle-aged and older adults with depression from a larger study of depression and anxiety (NIMH R01 MH091342-05 PI: O'Hara).MEASUREMENTS: Psychiatric measures were assessed for the presence of a DSM-5 depressive disorder and PSI. A neurocognitive battery assessed cognitive flexibility, inhibitory ability, as well as other neurocognitive domains.RESULTS: The PSI group (n = 18) performed significantly worse on cognitive flexibility and inhibitory ability, but not on other neurocognitive tasks, compared to the group without PSI (n = 22). The group with PSI had larger left mid-frontal gyri (MFG) than the no-PSI group. There was no association between cognitive flexibility/inhibitory ability and left MFG volume.CONCLUSIONS: Findings implicate a neurocognitive signature of PSI: poorer cognitive flexibility and poor inhibitory ability not better accounted for by other domains of cognitive dysfunction and not associated with volumetric differences in the left MFG. This suggests that there are two specific but independent risk factors of PSI in middle- and older-aged adults.

  View details for DOI 10.1017/S1041610220003610

  View details for PubMedID 33118918

• The 5-HTTLPR Long, not Short, Allele Predicts Two-year Longitudinal Increases in Cortisol and Declines in Verbal Memory in Older Adults. International journal of geriatric psychiatry Hirst, R. B., Jordan, J. T., Miryam Schussler-Fiorenza Rose, S., Schneider, L., Kawai, M., Gould, C., Anker, L., Chick, C. F., Beaudreau, S., Hallmayer, J., O'Hara, R. 2020

  Abstract

  OBJECTIVES: The short form or s-allele variant of the serotonin transporter polymorphism (5-HTTLPR), as compared with the long form or l-allele variant, has been associated with the presence of cognitive dysfunction, and particularly memory impairment in older adults. This body of cross-sectional work has culminated in the hypothesis that presence of the s-allele predicts greater memory decline in older adults (1). Yet, to date, there are no longitudinal studies which have investigated this issue.METHODS/DESIGN: Here we examine 109 community-dwelling older adults (mean and SD of age=70.7±8.7years) who underwent blood draw for genotyping, cognitive, and psychological testing at baseline, 12-month, and 24-month follow-up.RESULTS: Multilevel modeling found that s-allele carriers (ss or ls) performed worse than ll homozygotes at baseline on delayed verbal recall. Yet, s-allele carriers' memory performance was stable over the two-year follow-up period, while l-allele homozygotes experienced significant memory decline. l-allele homozygote status was associated with both increased cortisol and decreased memory over time, resulting in attenuated verbal memory performance differences compared to s-allele carriers with age.CONCLUSIONS: Overall, our findings do not support the hypothesis that presence of the 5-HTTLPR s-allele is a marker for memory decline in older adults. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/gps.5319

  View details for PubMedID 32400901

• Guided self-management targeting anxiety and activity participation in older Veterans. Aging & mental health Gould, C. E., Carlson, C., Wetherell, J. L., O'Hara, R., Goldstein, M. K., Loup, J. R., Ma, F., Beaudreau, S. A. 2020: 1–10

  Abstract

  Objectives: This study examined the acceptance, feasibility, and preliminary effects of a guided self-management intervention using video delivery and a telephone coach on anxiety and activity engagement.Method: Ten Veterans aged 60years or older with anxiety disorders determined by Structured Clinical Interview for Diagnostic and Statistical Manual 5th edition (SCID-5) at baseline visit participated in this non-randomized study examining a 4-week guided self-management intervention for anxiety. Feasibility was examined using participation engagement with the intervention. Measures of anxiety (Geriatric Anxiety Scale, PROMIS Anxiety Scale, Anxiety Control Questionnaire), depression (Patient Health Questionnaire 9-item), and activity participation (modified Activity Card Sort) administered at baseline and final (week 8) visit provided estimates of preliminary intervention effects. The Geriatric Anxiety Scale also was administered by phone at week 4. Participants completed a semi-structured qualitative interview at the final visit, which provided information about the acceptability, benefits of intervention, and barriers to engagement.Results: All participants (N=10) reported that the intervention somewhat or completely met their expectations, demonstrating intervention acceptability. Intervention completers (n=9) experienced reduced anxiety over the first 4weeks, alongside significant improvements in anxiety control and personalized activity goals across 8weeks. However, anxiety symptoms tended to return to baseline at follow-up. Participants identified the relaxation videos and promotion of a daily relaxation routine as the most helpful intervention components.Conclusions: Findings indicate that the intervention may improve activity participation and reduce anxiety. Thus, guided self-management interventions show promise for reducing distress and maintaining engagement later in life.

  View details for DOI 10.1080/13607863.2020.1758905

  View details for PubMedID 32397822

• The Effects of Cortisol on Subgenual Cingulate Activity in Depression Sudheimer, K., Duvio, D., Shols, E., Heinemeyer, E., Williams, N., O'Hara, R., Schatzberg, A. ELSEVIER SCIENCE INC. 2020: S449

  View details for Web of Science ID 000535308201342

• IMPORTANCE OF SLEEP IN GERIATRIC MENTAL HEALTH: SLEEP RESEARCH IN SCHIZOPHRENIA, COGNITIVE DISORDERS, AND AFFECTIVE DISORDERS O'Hara, R., Gebara, M., Lee, E., Jeste, D. ELSEVIER SCIENCE INC. 2020: S46

  View details for Web of Science ID 000520017700062

• Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nature medicine Khan, T. A., Revah, O. n., Gordon, A. n., Yoon, S. J., Krawisz, A. K., Goold, C. n., Sun, Y. n., Kim, C. H., Tian, Y. n., Li, M. Y., Schaepe, J. M., Ikeda, K. n., Amin, N. D., Sakai, N. n., Yazawa, M. n., Kushan, L. n., Nishino, S. n., Porteus, M. H., Rapoport, J. L., Bernstein, J. A., O'Hara, R. n., Bearden, C. E., Hallmayer, J. F., Huguenard, J. R., Geschwind, D. H., Dolmetsch, R. E., Paşca, S. P. 2020

  Abstract

  22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.

  View details for DOI 10.1038/s41591-020-1043-9

  View details for PubMedID 32989314

• High-Resolution Spectral Sleep Analysis Reveals a Novel Association Between Slow Oscillations and Memory Retention in Elderly Adults. Frontiers in aging neuroscience Kawai, M. n., Schneider, L. D., Linkovski, O. n., Jordan, J. T., Karna, R. n., Pirog, S. n., Cotto, I. n., Buck, C. n., Giardino, W. J., O'Hara, R. n. 2020; 12: 540424

  Abstract

  Objective: In recognition of the mixed associations between traditionally scored slow wave sleep and memory, we sought to explore the relationships between slow wave sleep, electroencephalographic (EEG) power spectra during sleep and overnight verbal memory retention in older adults. Design, Setting, Participants, and Measurements: Participants were 101 adults without dementia (52% female, mean age 70.3 years). Delayed verbal memory was first tested in the evening prior to overnight polysomnography (PSG). The following morning, subjects were asked to recall as many items as possible from the same List (overnight memory retention; OMR). Partial correlation analyses examined the associations of delayed verbal memory and OMR with slow wave sleep (SWS) and two physiologic EEG slow wave activity (SWA) power spectral bands (0.5-1 Hz slow oscillations vs. 1-4 Hz delta activity). Results: In subjects displaying SWS, SWS was associated with enhanced delayed verbal memory, but not with OMR. Interestingly, among participants that did not show SWS, OMR was significantly associated with a higher slow oscillation relative power, during NREM sleep in the first ultradian cycle, with medium effect size. Conclusions: These findings suggest a complex relationship between SWS and memory and illustrate that even in the absence of scorable SWS, older adults demonstrate substantial slow wave activity. Further, these slow oscillations (0.5-1 Hz), in the first ultradian cycle, are positively associated with OMR, but only in those without SWS. Our findings raise the possibility that precise features of slow wave activity play key roles in maintaining memory function in healthy aging. Further, our results underscore that conventional methods of sleep evaluation may not be sufficiently sensitive to detect associations between SWA and memory in older adults.

  View details for DOI 10.3389/fnagi.2020.540424

  View details for PubMedID 33505299

  View details for PubMedCentralID PMC7829345

• Focal white matter disruptions along the cingulum tract explain cognitive decline in amnestic mild cognitive impairment (aMCI). Scientific reports Gozdas, E. n., Fingerhut, H. n., Chromik, L. C., O'Hara, R. n., Reiss, A. L., Hosseini, S. M. 2020; 10 (1): 10213

  Abstract

  White matter abnormalities of the human brain are implicated in typical aging and neurodegenerative diseases. However, our understanding of how fine-grained changes in microstructural properties along white matter tracts are associated with memory and cognitive decline in normal aging and mild cognitive impairment remains elusive. We quantified tract profiles with a newer method that can reliably measure fine-grained changes in white matter properties along the tracts using advanced multi-shell diffusion magnetic resonance imaging in 25 patients with amnestic mild cognitive impairment (aMCI) and 23 matched healthy controls (HC). While the changes in tract profiles were parallel across aMCI and HC, we found a significant focal shift in the profile at specific locations along major tracts sub-serving memory in aMCI. Particularly, our findings depict white matter alterations at specific locations on the right cingulum cingulate, the right cingulum hippocampus and anterior corpus callosum (CC) in aMCI compared to HC. Notably, focal changes in white matter tract properties along the cingulum tract predicted memory and cognitive functioning in aMCI. The results suggest that white matter disruptions at specific locations of the cingulum bundle may be a hallmark for the early prediction of Alzheimer's disease and a predictor of cognitive decline in aMCI.

  View details for DOI 10.1038/s41598-020-66796-y

  View details for PubMedID 32576866

• SARS-CoV-2 RNAaemia predicts clinical deterioration and extrapulmonary complications from COVID-19. medRxiv : the preprint server for health sciences Ram-Mohan, N. n., Kim, D. n., Zudock, E. J., Hashemi, M. M., Tjandra, K. C., Rogers, A. J., Blish, C. A., Nadeau, K. C., Newberry, J. A., Quinn, J. V., O'Hara, R. n., Ashley, E. n., Nguyen, H. n., Jiang, L. n., Hung, P. n., Blomkalns, A. L., Yang, S. n. 2020

  Abstract

  The determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterise the relationships between SARS-CoV-2 RNAaemia and disease severity, clinical deterioration, and specific EPCs.We used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from nasopharyngeal swabs and plasma in 191 patients presenting to the Emergency Department (ED) with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterised the role of RNAaemia in predicting clinical severity and EPCs using elastic net regression.23·0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1·4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAaemia 10 days after onset of symptoms, but took 16 days to reach maximum severity, and 33 days for symptoms to resolve. Initially RNAaemic patients were more likely to manifest severe disease (OR 6·72 [95% CI, 2·45 - 19·79]), worsening of disease severity (OR 2·43 [95% CI, 1·07 - 5·38]), and EPCs (OR 2·81 [95% CI, 1·26 - 6·36]). RNA load correlated with maximum severity ( r = 0·47 [95% CI, 0·20 - 0·67]).dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAaemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAaemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.NIH/NIAID (Grants R01A153133, R01AI137272, and 3U19AI057229 - 17W1 COVID SUPP #2) and a donation from Eva Grove.Evidence before this study: The varied clinical manifestations of COVID-19 have directed attention to the distribution of SARS-CoV-2 in the body. Although most concentrated and tested for in the nasopharynx, SARS-CoV-2 RNA has been found in blood, stool, and numerous tissues, raising questions about dissemination of viral RNA throughout the body, and the role of this process in disease severity and extrapulmonary complications. Recent studies have detected low levels of SARS-CoV-2 RNA in blood using either quantitative reverse transcriptase real-time PCR (qPCR) or droplet digital PCR (dPCR), and have associated RNAaemia with disease severity and biomarkers of dysregulated immune response.Added value of this study: We quantified SARS-CoV-2 RNA in the nasopharynx and plasma of patients presenting to the Emergency Department with COVID-19, and found an array-based dPCR platform to be markedly more sensitive than qPCR for detection of SARS-CoV-2 RNA, with a simplified workflow well-suited to clinical adoption. We collected serial plasma samples during patients' course of illness, and showed that SARS-CoV-2 RNAaemia peaks early, while clinical condition often continues to worsen. Our findings confirm the association between RNAaemia and disease severity, and additionally demonstrate a role for RNAaemia in predicting future deterioration and specific extrapulmonary complications.Implications of all the available evidence: Variation in SARS-CoV-2 RNAaemia may help explain disparities in disease severity and extrapulmonary complications from COVID-19. Testing for RNAaemia with dPCR early in the course of illness may help guide patient triage and management.

  View details for DOI 10.1101/2020.12.19.20248561

  View details for PubMedID 33398290

  View details for PubMedCentralID PMC7781329

• Technology Use and Preferences for Mental Health Self-Management Interventions among Older Veterans. International journal of geriatric psychiatry Gould, C. E., Loup, J., Kuhn, E., Beaudreau, S. A., Ma, F., Goldstein, M. K., Wetherell, J. L., Zapata, A. M., Choe, P., O'Hara, R. 2019

  Abstract

  OBJECTIVES: The United States Department of Veterans Affairs offers numerous technology-delivered interventions to self-manage mental health problems. It is unknown, however, what barriers older military veterans face to using these technologies and how willing they would be to use technologies for mental health concerns.METHODS: Seventy-seven veterans (Mage =69.16years; SD=7.10) completed interviews in a concurrent mixed methods study. Interviewers asked about technology ownership and described four modalities of delivering self-management interventions: printed materials, DVDs, Internet, and mobile apps. Interviewers obtained feedback about each modality's benefits, barriers, and facilitators. Participants ranked their self-management modalities preferences alone and compared with counseling. Multi-variable adjusted logistic regression and qualitative analyses were conducted to investigate the reasons contributing to preferences.RESULTS: Most reported owning a computer (84.4%), having home Internet (80.5%), and a smartphone (70.1%). Participants preferred printed materials (35.1%) over mobile apps (28.6%), Internet (24.7%), and DVDs (13.0%). Lower computer proficiency was associated with preferring DVDs; higher proficiency was associated with Internet and mobile interventions. Residing in an urban area was associated with mobile apps. When counseling was an option, 66% identified this as their first preference. Qualitative findings showed veterans' desire for information, training, and provider support with technology.CONCLUSIONS: Older veterans reported high technology ownership rates, but varied preferences for self-management interventions. Notably, two-thirds preferred some form of technology, which points to the importance of ensuring that providers offer existing technology-delivered interventions to older veterans. Veterans' strong preference for counseling emphasizes the need for human support alongside self-management. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/gps.5252

  View details for PubMedID 31854029

• The Future of Dementia Biomarkers Needs Better Neuropsychology. The American journal of psychiatry Naparstek, S., Linkovski, O., O'Hara, R. 2019; 176 (12): 1050

  View details for DOI 10.1176/appi.ajp.2019.19080791

  View details for PubMedID 31787015

• Sleep-wake disorders in Alzheimer's disease: further genetic analyses in relation to objective sleep measures. International psychogeriatrics Yesavage, J. A., Noda, A., Heath, A., McNerney, M. W., Domingue, B. W., Hernandez, Y., Benson, G., Hallmayer, J., O'Hara, R., Williams, L. M., Goldstein-Piekarski, A. N., Zeitzer, J. M., Fairchild, J. K. 2019: 1–7

  Abstract

  This paper presents updated analyses on the genetic associations of sleep disruption in individuals with Alzheimer's disease (AD). We published previously a study of the association between single nucleotide polymorphisms (SNPs) found in eight genes related to circadian rhythms and objective measures of sleep-wake disturbances in 124 individuals with AD. Here, we present new relevant analyses using polygenic risk scores (PRS) and variable number tandem repeats (VNTRs) enumerations. PRS were calculated using the genetic data from the original participants and relevant genome wide association studies (GWAS). VNTRs for the same circadian rhythm genes studied with SNPs were obtained from a separate cohort of participants using whole genome sequencing (WGS). Objectively (wrist actigraphy) determined wake after sleep onset (WASO) was used as a measure of sleep disruption. None of the PRS were associated with sleep disturbance. Computer analyses using VNTRseek software generated a total of 30 VNTRs for the circadian-related genes but none appear relevant to our objective sleep measure. In addition, of 71 neurotransmitter function-related genes, 29 genes had VNTRs that differed from the reference VNTR, but it was not clear if any of these might affect circadian function in AD patients. Although we have not found in either the current analyses or in our previous published analyses of SNPs any direct linkages between identified genetic factors and WASO, research in this area remains in its infancy.

  View details for DOI 10.1017/S1041610219001777

  View details for PubMedID 31739820

• Development of VM-REACT: Verbal memory RecAll computerized test JOURNAL OF PSYCHIATRIC RESEARCH Naparstek, S., El-Said, D., Eisenberg, M. L., Jordan, J. T., O'Hara, R., Etkin, A. 2019; 114: 170–77

  View details for DOI 10.1016/j.jpsychires.2019.04.023

  View details for Web of Science ID 000472127300025

• Rediscovering an old friend: a role for insulin growth factor-2 in reducing neurodegeneration, decreasing amyloid beta, and improving memory INTERNATIONAL PSYCHOGERIATRICS O'Hara, R., Hallmayer, J. 2019; 31 (7): 925–27

  View details for DOI 10.1017/S1041610219000930

  View details for Web of Science ID 000514156700004

• Human 3D cellular model of hypoxic brain injury of prematurity NATURE MEDICINE Pasca, A. M., Park, J., Shin, H., Qi, Q., Revah, O., Krasnoff, R., O'Hara, R., Willsey, A., Palmer, T. D., Pascz, S. P. 2019; 25 (5): 784-+

  View details for DOI 10.1038/s41591-019-0436-0

  View details for Web of Science ID 000468247800022

• Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder SCIENCE TRANSLATIONAL MEDICINE Etkin, A., Maron-Katz, A., Wu, W., Fonzo, G. A., Huemer, J., Vertes, P. E., Patenaude, B., Richiardi, J., Goodkind, M. S., Keller, C. J., Ramos-Cejudo, J., Zaiko, Y., Peng, K. K., Shpigel, E., Longwell, P., Toll, R. T., Thompson, A., Zack, S., Gonzalez, B., Edelstein, R., Chen, J., Akingbade, I., Weiss, E., Hart, R., Mann, S., Durkin, K., Baete, S. H., Boada, F. E., Genfi, A., Autea, J., Newman, J., Oathes, D. J., Lindley, S. E., Abu-Amara, D., Arnow, B. A., Crossley, N., Hallmayer, J., Fossati, S., Rothbaum, B. O., Marmar, C. R., Bullmore, E. T., O'Hara, R. 2019; 11 (486)

  View details for DOI 10.1126/scitranslmed.aal3236

  View details for Web of Science ID 000463186500002

• Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder. Science translational medicine Etkin, A., Maron-Katz, A., Wu, W., Fonzo, G. A., Huemer, J., Vertes, P. E., Patenaude, B., Richiardi, J., Goodkind, M. S., Keller, C. J., Ramos-Cejudo, J., Zaiko, Y. V., Peng, K. K., Shpigel, E., Longwell, P., Toll, R. T., Thompson, A., Zack, S., Gonzalez, B., Edelstein, R., Chen, J., Akingbade, I., Weiss, E., Hart, R., Mann, S., Durkin, K., Baete, S. H., Boada, F. E., Genfi, A., Autea, J., Newman, J., Oathes, D. J., Lindley, S. E., Abu-Amara, D., Arnow, B. A., Crossley, N., Hallmayer, J., Fossati, S., Rothbaum, B. O., Marmar, C. R., Bullmore, E. T., O'Hara, R. 2019; 11 (486)

  Abstract

  A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

  View details for PubMedID 30944165

• ULTRADIAN CYCLE OF SLOW-WAVE ACTIVITY IN OLDER ADULTS. Kawai, M., Schneider, L., O'Hara, R. OXFORD UNIV PRESS INC. 2019

  View details for Web of Science ID 000471071001051

• Does Cognition Predict Treatment Response and Remission in Psychotherapy for Late-Life Depression? (vol 23, pg 215, 2015) AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Beaudreau, S. A., Rideaux, T., O'Hara, R., Arean, P. 2019; 27 (4): 461

  View details for DOI 10.1016/j.jagp.2018.12.020

  View details for Web of Science ID 000461900400017

• Human 3D cellular model of hypoxic brain injury of prematurity. Nature medicine Pașca, A. M., Park, J. Y., Shin, H. W., Qi, Q. n., Revah, O. n., Krasnoff, R. n., O'Hara, R. n., Willsey, A. J., Palmer, T. D., Pașca, S. P. 2019

  Abstract

  Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.

  View details for PubMedID 31061540

• Factors Associated with Supportive Care Service Use Among California Alzheimer's Disease Patients and Their Caregivers. Journal of Alzheimer's disease : JAD Newkirk, L. A., Dao, V. L., Jordan, J. T., Alving, L. I., Davies, H. D., Hewett, L. n., Beaudreau, S. A., Schneider, L. D., Gould, C. E., Chick, C. F., Hirst, R. B., Rose, S. M., Anker, L. A., Tinklenberg, J. R., O'Hara, R. n. 2019

  Abstract

  Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services.To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use.California Alzheimer's Disease Center patients with AD (n = 220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users.Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p < 0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p < 0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services.Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use.

  View details for DOI 10.3233/JAD-190438

  View details for PubMedID 31743997

• IPSCS - A PLATFORM TO STUDY AUTISM SPECTRUM DISORDER Hallmayer, J., Bernstein, J., O'Hara, R., Pasca, S. ELSEVIER SCIENCE BV. 2019: S764–S765

  View details for DOI 10.1016/j.euroneuro.2017.06.121

  View details for Web of Science ID 000462156400105

• Development of VM-REACT: Verbal memory RecAll computerized test. Journal of psychiatric research Naparstek, S. n., El-Said, D. n., Eisenberg, M. L., Jordan, J. T., O'Hara, R. n., Etkin, A. n. 2019; 114: 170–77

  Abstract

  When tracking the progression of neuropsychiatric or neurodegenerative diseases, assessment tools that enable repeated measures of cognition and require little examiner burden are increasingly important to develop. In the current study, we describe the development of the VM-REACT (Verbal Memory REcAll Computerized Test), which assesses verbal memory recall abilities using a computerized, automated version. Four different list versions of the test were applied on a cohort of 798 healthy adults (ages 20-80). Recall and learning scores were computed and compared to existing gender- and age-matched published norms for a similar paper-and-pencil test. Performance was similar to existing age-matched norms for all but the two oldest age groups. These adults (ages 60-80) outperformed their age-matched norms. Processing speed, initiation speed, and number of recall errors are also reported for each age group. Our findings suggest that VM-REACT can be utilized to study verbal memory abilities in a standardized and time efficient manner, and thus holds great promise for assessment in the 21st century.

  View details for PubMedID 31096177

• Commentary on "High Occurrence of Psychiatric Disorders and Suicidal Behavior Across Dementia Subtypes" AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Beaudreau, S. A., Jordan, J. T., O'Hara, R. 2018; 26 (12): 1202–3

  View details for DOI 10.1016/j.jagp.2018.09.008

  View details for Web of Science ID 000452865000002

• Commentary on "High Occurrence of Psychiatric Disorders and Suicidal Behavior Across Dementia Subtypes". The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry Beaudreau, S. A., Jordan, J. T., O'Hara, R. 2018

  View details for PubMedID 30401607

• Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans A Randomized Clinical Trial JAMA PSYCHIATRY Yesavage, J. A., Fairchild, J., Mi, Z., Biswas, K., Davis-Karim, A., Phibbs, C. S., Forman, S. D., Thase, M., Williams, L. M., Etkin, A., O'Hara, R., Georgette, G., Beale, T., Huang, G. D., Noda, A., George, M. S., VA Cooperative Studies Program Stu 2018; 75 (9): 884–93

  Abstract

  Treatment-resistant major depression (TRMD) in veterans is a major clinical challenge given the high risk for suicidality in these patients. Repetitive transcranial magnetic stimulation (rTMS) offers the potential for a novel treatment modality for these veterans.To determine the efficacy of rTMS in the treatment of TRMD in veterans.A double-blind, sham-controlled randomized clinical trial was conducted from September 1, 2012, to December 31, 2016, in 9 Veterans Affairs medical centers. A total of 164 veterans with TRD participated.Participants were randomized to either left prefrontal rTMS treatment (10 Hz, 120% motor threshold, 4000 pulses/session) or to sham (control) rTMS treatment for up to 30 treatment sessions.The primary dependent measure of the intention-to-treat analysis was remission rate (Hamilton Rating Scale for Depression score ≤10, indicating that depression is in remission and not a clinically significant burden), and secondary analyses were conducted on other indices of posttraumatic stress disorder, depression, hopelessness, suicidality, and quality of life.The 164 participants had a mean (SD) age of 55.2 (12.4) years, 132 (80.5%) were men, and 126 (76.8%) were of white race. Of these, 81 were randomized to receive active rTMS and 83 to receive sham. For the primary analysis of remission, there was no significant effect of treatment (odds ratio, 1.16; 95% CI, 0.59-2.26; P = .67). At the end of the acute treatment phase, 33 of 81 (40.7%) of those in the active treatment group achieved remission of depressive symptoms compared with 31 of 83 (37.4%) of those in the sham treatment group. Overall, 64 of 164 (39.0%) of the participants achieved remission.A total of 39.0% of the veterans who participated in this trial experienced clinically significant improvement resulting in remission of depressive symptoms; however, there was no evidence of difference in remission rates between the active and sham treatments. These findings may reflect the importance of close clinical surveillance, rigorous monitoring of concomitant medication, and regular interaction with clinic staff in bringing about significant improvement in this treatment-resistant population.ClinicalTrials.gov Identifier: NCT01191333.

  View details for PubMedID 29955803

• Subjective but Not Objective Sleep is Associated with Subsyndromal Anxiety and Depression in Community-Dwelling Older Adults AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Gould, C. E., Karna, R., Jordan, J., Kawai, M., Hirst, R., Hantke, N., Pirog, S., Cotto, I., Rose, S., Beaudreau, S. A., O'Hara, R. 2018; 26 (7): 806–11

  View details for DOI 10.1016/j.jagp.2018.03.010

  View details for Web of Science ID 000436629200010

• Subjective but Not Objective Sleep is Associated with Subsyndromal Anxiety and Depression in Community-Dwelling Older Adults. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry Gould, C. E., Karna, R., Jordan, J., Kawai, M., Hirst, R., Hantke, N., Pirog, S., Cotto, I., Schussler-Fiorenza Rose, S. M., Beaudreau, S. A., O'Hara, R. 2018

  Abstract

  OBJECTIVE: To examine the relationship between subclinical anxiety and depressive symptoms and objective sleep architecture measures and subjective sleep reports in older adults.METHODS: Community-dwelling older adults (N=167) self-rated their current severity of anxiety symptoms, depressive symptoms, daytime sleepiness, and global sleep quality. Participants received overnight ambulatory polysomnography to assess sleep architecture. Multivariate linear regression models examined associations between anxiety and depressive symptoms and objective and subjective sleep measures.RESULTS: Significant findings emerged for subjective sleep, with higher depression and anxiety scores associated with worse global sleep quality and greater anxiety scores associated with greater daytime sleepiness. No significant associations were observed between subclinical levels of anxiety or depressive symptoms with sleep architecture.CONCLUSION: Subclinical levels of late-life anxiety and depression have distinct associations with subjective sleep disturbance. Findings implicate subjective measures of sleep quality and daytime sleepiness as stronger trait markers for subthreshold psychiatric symptoms than objective sleep biomarkers.

  View details for PubMedID 29709510

• Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation PLOS ONE McNerney, M., Sheng, T., Nechvatal, J. M., Lee, A. G., Lyons, D. M., Soman, S., Liao, C., O'Hara, R., Hallmayer, J., Taylor, J., Ashford, J., Yesavage, J., Adamson, M. M. 2018; 13 (2): e0192222

  Abstract

  Many Veterans exposed to physical and psychological trauma experience symptoms of posttraumatic stress disorder (PTSD). As the etiology of PTSD symptoms is complex, a better understanding of the underlying biological mechanisms may improve preventative care and treatment for PTSD. Recent findings from the fields of neuroimaging and epigenetics offer important insights into the potential brain structures and biochemical pathways of modified gene expression associated with PTSD. We combined neuroimaging and epigenetic measures to assess current PTSD symptoms by measuring overall hippocampal volume and methylation of the glucocorticoid receptor (GR) gene (promoter region). Multiple regression analyses indicated that the hippocampal volume/GR methylation interaction was a predictor of PTSD symptoms. Our findings suggest that neuroimaging and epigenetic measures contribute interactively to PTSD symptoms. Incorporation of these metrics may aid in the identification and treatment of PTSD patients.

  View details for DOI 10.1371/journal.pone.0192222

  View details for Web of Science ID 000424325300060

  View details for PubMedID 29415058

  View details for PubMedCentralID PMC5802910

• Information-Seeking about Anxiety and Perceptions about Technology to Teach Coping Skills in Older Veterans CLINICAL GERONTOLOGIST Zapata, A. L., Beaudreau, S. A., O'Hara, R., Merrell, S., Bruce, J., Garrison-Diehn, C., Gould, C. E. 2018; 41 (4): 346–56

  Abstract

  We sought to learn where older veterans seek information about anxiety and coping. Due to increasing use of technology in health care, we also explored benefits and barriers of using technology to teach coping skills.Twenty veterans (mean age = 69.5 years, SD = 7.3) participated in semi-structured interviews in which we inquired about where they seek information about anxiety. We explored quantitative and qualitative differences for veterans with high versus low anxiety. In follow-up focus groups, we examined opinions about learning coping skills using technology.Though veterans primarily named health care professionals as sources of information about anxiety, online searches and reading books were frequently mentioned. Reported benefits of using technology were convenience and standardized instruction of coping skills. Barriers included lack of interaction and frustration with technology usability.Older veterans use multiple sources, heavily rely on interpersonal sources (e.g., professionals, friends), and employ varied search strategies regarding how to cope with anxiety. Using technology to teach coping skills was generally acceptable to older veterans.Health care professionals could guide patients towards credible online and book sources. Providing instruction about using technology may help older adults use technology to learn coping skills.

  View details for PubMedID 28967837

• Neuropsychological Functioning in Older Adults with Mild Cognitive Impairment and Insomnia Randomized to CBT-I or Control Group CLINICAL GERONTOLOGIST Cassidy-Eagle, E., Siebern, A., Unti, L., Glassman, J., O'Hara, R. 2018; 41 (2): 136–44

  Abstract

  Improving the sleep of older adults with mild cognitive impairment (MCI) represents a first step in discovering whether interventions directed at modifying this risk factor also have the potential to alter the cognitive decline trajectory.A six-session, adapted version of a cognitive behavioral therapy for insomnia (CBT-I) was administered to older adults (N = 28; 14 per group) with MCI across two residential facilities. Participants were randomly assigned to either the sleep intervention or an active control group and completed a neuropsychological battery at three time points (e.g., baseline-T1, post-intervention-T2, 4 month follow-up-T3).Results showed a significant improvement in sleep and a change (p < .05) on a key measure of executive functioning sub task of inhibition (Condition 3 of D-KEF Color-Word Interference Test), a positive trend on the inhibition-switching task (p < .10; Condition 4 of D-KEF Color-Word Interference Test), an no change in a measure of verbal memory (HVLT-R Delayed Recall) compared with the active control group.CBT-I is a nonpharmacological intervention that has the potential to cognitively benefit individuals with MCI suffering from comorbid insomnia.Results suggest that a non-pharmacological intervention to improve sleep in older adults with MCI also improve cognitive functioning. Further exploration of the mechanisms underlying these improvements is warranted.

  View details for PubMedID 29220627

• Unlocking Neurocognitive Substrates of Late-Life Affective Symptoms Using the Research Domain Criteria: Worry Is an Essential Dimension FRONTIERS IN AGING NEUROSCIENCE Beaudreau, S. A., Hantke, N. C., Mashal, N., Gould, C. E., Henderson, V. W., O'Hara, R. 2017; 9: 380

  Abstract

  While investigations have sought to identify the distinct and shared contributions of anxiety and depression to neurocognitive processes in late life, less is known regarding the further contribution of worry, a unique and critical dimension of affective dysregulation. Capturing the full range of symptoms, as inspired by the NIH Research Domain Criteria (RDoC), may provide finer-grained information on inter-relationships among worry, anxiety and depression on neurocognitive processing in later life. The objective of this study was to determine if the dimensional trait of worry intensifies known negative associations of dimensional measures of anxiety and depressive symptoms with neurocognitive processes, specifically cognitive control and memory processes. Using a cross-sectional and observational design, this study was conducted within a translational research center located with a Veterans medical center in Northern California. One hundred and nineteen community-residing older adults ages 65-91 years participated, and were characterized with psychiatric and neurocognitive dimensional measures. Affective symptom severity was assessed with the Penn State Worry Questionnaire, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory-II. Primary neurocognitive outcomes were inhibitory control assessed using a Stroop paradigm and delayed verbal memory assessed with the Rey Auditory Verbal Learning Test. Secondary outcomes included other less frequently examined cognitive control mechanisms (working memory, information processing, and verbal fluency) and memory processes (visual delayed memory). Contrary to prediction, the dimensional trait of worry attenuated negative associations between anxiety and depressive symptoms and inhibitory control on the one hand, and between depressive symptoms and delayed verbal memory processes on the other. In the secondary models, symptom dimensions were not associated with other cognitive control or visual delayed memory processes. Our fine-grained approach, in line with the NIMH RDoC model, suggests the neurocognitive processes associated with dimensional measures of late-life affective symptoms are dissociable. Specifically, dimensional measures of worry operate independently from other anxiety and depression symptoms to reveal differential patterns of neurocognitive processes associated with affective dysregulation.

  View details for PubMedID 29249958

• Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease The Multi-Ethnic Study of Atherosclerosis ANNALS OF THE AMERICAN THORACIC SOCIETY Johnson, D. A., Lane, J., Wang, R., Reid, M., Djonlagic, I., Fitzpatrick, A. L., Rapp, S. R., Charles, L. E., O'Hara, R., Saxena, R., Redline, S. 2017; 14 (11): 1697–1705

  Abstract

  There are conflicting findings regarding the link between sleep apnea and cognitive dysfunction.Investigate associations between indicators of sleep-disordered breathing (SDB) and cognitive function in the Multi-Ethnic Study of Atherosclerosis and assess effect modification by the apolipoprotein ε-4 (APOE-ε4) allele.A diverse population (N = 1,752) underwent type 2 in-home polysomnography, which included measurement of percentage sleep time less than 90% oxyhemoglobin saturation (%Sat < 90%) and apnea-hypopnea index (AHI). Epworth Sleepiness Scale score (ESS) and sleep apnea syndrome (SAS; AHI ≥ 5 and ESS > 10) were also analyzed. Cognitive outcomes included the Cognitive Abilities Screening Instrument; Digit Symbol Coding (DSC) test; and Digit Span Tests (DST) Forward and Backward.Participants were 45.4% men, aged 68.1 years (SD, 9.1 yr) with a median AHI of 9.0 and mean ESS of 6.0. Approximately 9.7% had SAS, and 26.8% had at least one copy of the APOE-ε4 allele. In adjusted analyses, a 1-SD increase in %Sat < 90% and ESS score were associated with a poorer attention and memory assessed by the DST Forward score (β = -0.12 [SE, 0.06] and β = -0.13 [SE, 0.06], respectively; P ≤ 0.05). SAS and higher ESS scores were also associated with poorer attention and processing speed as measured by the DSC (β = -0.69 [SE, 0.35] and β = -1.42 [SE, 0.35], respectively; P < 0.05). The presence of APOE-ε4 allele modified the associations of %Sat < 90% with DST forward and of ESS with DSC (Pinteraction ≤ 0.05).Overnight hypoxemia and sleepiness were associated with cognition. The average effect estimates were small, similar to effect estimates for several other individual dementia risk factors. Associations were strongest in APOE-ε4 risk allele carriers. Our results (1) suggest that SDB be considered among a group of modifiable dementia risk factors, and (2) highlight the potential vulnerability of APOE-ε4 risk allele carriers with SDB.

  View details for PubMedID 28731362

  View details for PubMedCentralID PMC5711280

• Development of a video-delivered relaxation treatment of late-life anxiety for veterans. International psychogeriatrics Gould, C. E., Zapata, A. M., Bruce, J., Bereknyei Merrell, S., Wetherell, J. L., O'Hara, R., Kuhn, E., Goldstein, M. K., Beaudreau, S. A. 2017: 1-13

  Abstract

  Behavioral treatments reduce anxiety, yet many older adults may not have access to these efficacious treatments. To address this need, we developed and evaluated the feasibility and acceptability of a video-delivered anxiety treatment for older Veterans. This treatment program, BREATHE (Breathing, Relaxation, and Education for Anxiety Treatment in the Home Environment), combines psychoeducation, diaphragmatic breathing, and progressive muscle relaxation training with engagement in activities.A mixed methods concurrent study design was used to examine the clarity of the treatment videos. We conducted semi-structured interviews with 20 Veterans (M age = 69.5, SD = 7.3 years; 55% White, Non-Hispanic) and collected ratings of video clarity.Quantitative ratings revealed that 100% of participants generally or definitely could follow breathing and relaxation video instructions. Qualitative findings, however, demonstrated more variability in the extent to which each video segment was clear. Participants identified both immediate benefits and motivation challenges associated with a video-delivered treatment. Participants suggested that some patients may need encouragement, whereas others need face-to-face therapy.Quantitative ratings of video clarity and qualitative findings highlight the feasibility of a video-delivered treatment for older Veterans with anxiety. Our findings demonstrate the importance of ensuring patients can follow instructions provided in self-directed treatments and the role that an iterative testing process has in addressing these issues. Next steps include testing the treatment videos with older Veterans with anxiety disorders.

  View details for DOI 10.1017/S1041610217000928

  View details for PubMedID 28592349

• Association of Anxiety Symptom Clusters with Sleep Quality and Daytime Sleepiness. journals of gerontology. Series B, Psychological sciences and social sciences Gould, C. E., Spira, A. P., Liou-Johnson, V., Cassidy-Eagle, E., Kawai, M., Mashal, N., O'Hara, R., Beaudreau, S. A. 2017

  Abstract

  To better understand links between anxiety and sleep disturbances in older adults, we examined the association of different phenotypic presentations of anxiety (i.e., affective, cognitive, and somatic clusters) with global sleep quality and daytime sleepiness.109 community-dwelling adults aged 66-92 years old (57% female) completed assessments of global sleep quality (Pittsburgh Sleep Quality Index), daytime sleepiness (Epworth Sleepiness Scale), affective anxiety symptoms (Geriatric Anxiety Scale (GAS) affective subscale), cognitive anxiety symptoms (GAS cognitive subscale), and somatic anxiety symptoms (GAS somatic subscale).In hierarchical regression models adjusted for depressive symptoms and health status, greater affective and somatic anxiety were associated with poorer global sleep quality (affective B = 0.30, p = .01; somatic B = 0.41, p = .01). Somatic and cognitive anxiety were associated with greater daytime sleepiness (somatic B = 0.74, p < .001; cognitive B = 0.30, p = .03), but these associations were attenuated by covariates added to the models.These findings indicate that anxiety symptom clusters are differentially associated with specific sleep-related disturbances, underscoring the complex relationship of late-life anxiety to sleep. Results suggest that personalized treatments, such as targeted sleep interventions, may improve specific anxiety-symptom domains, or vice versa.

  View details for DOI 10.1093/geronb/gbx020

  View details for PubMedID 28379498

• Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome). Journal of psychiatric research Reierson, G., Bernstein, J., Froehlich-Santino, W., Urban, A., Purmann, C., Berquist, S., Jordan, J., O'Hara, R., Hallmayer, J. 2017; 91: 139-144

  Abstract

  To describe the frequency and characteristics of developmental regression in a sample of 50 patients with Phelan McDermid Syndrome (PMS) and investigate the possibility of association between regression, epilepsy, and electroencephalogram (EEG) abnormalities and deletion size.The Autism Diagnostic Interview-Revised (ADI-R) was used to evaluate regression in patients with a confirmed diagnosis of PMS. Information on seizure history and EEGs was obtained from medical record review. Deletion size was determined by DNA microarray.A history of regression at any age was present in 43% of all patients. Among those exhibiting regression, 67% had onset after the age of 30 months, affecting primarily motor and self-help skills. In 63% of all patients there was a history of seizures and a history of abnormal EEG was also present in 71%. No significant associations were found between regression and seizures or EEG abnormalities. Deletion size was significantly associated with EEG abnormalities, but not with regression or seizures.This study found a high rate of regression in PMS. In contrast to regression in autism, that often occurs earlier in development and affects language and social skills, we found regression in PMS most frequently has an onset in mid-childhood, affecting motor and self-help skills. We also found high rates of seizures and abnormal EEGs in patients with PMS. However, a history of abnormal EEG and seizures was not associated with an increased risk of regression. Larger deletion sizes were found to be significantly associated with a history of abnormal EEG.

  View details for DOI 10.1016/j.jpsychires.2017.03.010

  View details for PubMedID 28346892

• Handling clinical comorbidity in randomized clinical trials in psychiatry. Journal of psychiatric research O'Hara, R., Beaudreau, S. A., Gould, C. E., Froehlich, W., Kraemer, H. C. 2017; 86: 26-33

  Abstract

  The purpose of this paper is to a) outline the importance of including patients with clinical comorbidities in Randomized Clinical Trials (RCTs) of psychiatric treatments; and b) to propose a specific approach for best handling, analyzing and interpreting the data on clinical comorbidities in terms of their impact on treatment outcomes. To do this we first define and describe clinical comorbidity and differentiate it from other forms of comorbidity. We then describe the methodological and analytical problems associated with excluding patients with clinically comorbid conditions from RCTs, including the impact on the outcomes of RCTs in psychiatry and the impact on evidence-based clinical decision-making. We then address the challenges inherent to including patients with clinical comorbidities in RCTs. Finally, we propose a methodological and analytic approach to deal with these issues in RCTs which aims to significantly improve the information yielded from RCTs in psychiatry, and thus improve clinical decision-making.

  View details for DOI 10.1016/j.jpsychires.2016.11.006

  View details for PubMedID 27886637

• Sleep Disturbances in Individuals With Phelan-McDermid Syndrome: Correlation With Caregivers' Sleep Quality and Daytime Functioning SLEEP Bro, D., O'Hara, R., Primeau, M., Hanson-Kahn, A., Hallmayer, J., Bernstein, J. A. 2017; 40 (2)

  Abstract

  The aims of this study were to document sleep disturbances in individuals with Phelan-McDermid syndrome (PMS), to assess whether these individuals had been evaluated for sleep disorders, and to examine relationships between the sleep behavior of these individuals and the sleep behavior and daytime functioning of their caregivers.Participants were 193 caregivers of individuals with PMS recruited by the Phelan-McDermid Syndrome Foundation. Data were collected through a survey comprising 2 questionnaires: the Children's Sleep Habits Questionnaire (CSHQ) and the Parents' Sleep Habits Questionnaire. Data were analyzed using multiple linear regression analyses, Pearson correlation analyses, and independent-samples t-tests.Ninety percent of individuals with PMS showed evidence of marked sleep disturbance based on caregiver responses to the CSHQ. However, only 22% of individuals had undergone a formal sleep assessment. Reported increased sleep disturbance in individuals with PMS was a statistically significant predictor of reported increased sleep disturbance and daytime sleepiness in their caregivers.Sleep disturbance may be present in a substantial proportion of individuals with PMS and is negatively associated with caregivers' well-being. However, most individuals with PMS have not been evaluated for sleep disorders. When properly diagnosed, many sleep disorders can be alleviated with intervention. Thus, routine screening for and evaluation of sleep disturbances in individuals with PMS may have long-term positive impacts on the well-being of these individuals and their caregivers.

  View details for DOI 10.1093/sleep/zsw062

  View details for PubMedID 28364490

• A Longitudinal Pilot Study of Behavioral Abnormalities in Children with Autism. Journal of psychiatry and psychiatric disorders Libove, R. A., Frazier, T. W., O'Hara, R. n., Phillips, J. M., Jo, B. n., Hardan, A. Y. 2017; 1 (4): 215–23

  Abstract

  This longitudinal investigation examined the development of emotional and behavioral functioning in school-age children with autism. The Child Behavior Checklist was obtained at baseline and after an average interval of 28.5 months from 13 boys with autism and 14 age- and gender-matched controls between the ages of 7 and 12 years at baseline. Children with autism demonstrated clinically significant elevations in several domains including Social, Thought, and Attention Problems. Children with autism exhibited significant improvements over time in Total, Externalizing, Social, and Oppositional Defiant Problems and Aggressive Behavior, while there were no changes over time in the controls. These findings suggest that children with autism may demonstrate improvements over time in some clinical domains such as social and behavioral functioning.

  View details for DOI 10.26502/jppd.2572-519X0022

  View details for PubMedID 32587950

  View details for PubMedCentralID PMC7316392

• Genetics of the HPA-Axis Predict Limbic Connectivity Patterns Sudheimer, K., Keller, J., O'Hara, R., Hantke, N., Karna, R., Duvio, D., Beaudreau, S., Heinemeyer, E., Reiss, A., Murphy, G., Gomez, R., Garrett, A., Tennakoon, L., Schatzberg, A. NATURE PUBLISHING GROUP. 2016: S164

  View details for Web of Science ID 000440365600297

• Sleep Disturbances in Individuals with Phelan-McDermid Syndrome: Correlation with Caregivers' Sleep Quality and Daytime Functioning. Sleep Bro, D., O'Hara, R., Primeau, M., Hanson-Kahn, A., Hallmayer, J., Bernstein, J. A. 2016

  Abstract

  The aims of this study were: to document sleep disturbances in individuals with Phelan-McDermid syndrome, to assess whether these individuals had been evaluated for sleep disorders, and to examine relationships between the sleep behavior of these individuals and the sleep behavior and daytime functioning of their caregivers.Participants were 193 caregivers of individuals with Phelan-McDermid Syndrome recruited by the Phelan-McDermid Syndrome Foundation. Data were collected via a survey comprising two questionnaires: the Children's Sleep Habits Questionnaire and the Parents' Sleep Habits Questionnaire. Data were analyzed using multiple linear regression analyses, Pearson correlation analyses, and independent-samples t-tests.Ninety percent of individuals with Phelan-McDermid Syndrome showed evidence of marked sleep disturbance based on caregiver responses to the Children's Sleep Habits Questionnaire. However, only 22% of individuals had undergone a formal sleep assessment. Reported increased sleep disturbance in individuals with Phelan-McDermid Syndrome was a statistically significant predictor of reported increased sleep disturbance and daytime sleepiness in their Caregivers.Sleep disturbance may be present in a substantial proportion of individuals with Phelan-McDermid Syndrome and is negatively associated with caregivers' wellbeing. However, most individuals with Phelan-McDermid Syndrome have not been evaluated for sleep disorders. When properly diagnosed, many sleep disorders can be alleviated with intervention. Thus, routine screening for and evaluation of sleep disturbances in individuals with Phelan-McDermid Syndrome may have long-term positive impacts on the wellbeing of these individuals and their caregivers.

  View details for PubMedID 27923425

• Longitudinal association of delta activity at sleep onset with cognitive and affective function in community-dwelling older adults. International journal of geriatric psychiatry Kawai, M., Beaudreau, S. A., Gould, C. E., Hantke, N. C., Cotto, I., Jordan, J. T., Hirst, R. B., O'Hara, R. 2016; 31 (10): 1124-1135

  Abstract

  This investigation sought to determine whether delta activity at sleep onset (DASO) in the sleep electroencephalography of older adults represents normal variation or is associated with clinical pathology. To this end, we examined its longitudinal associations with cognitive and affective function in older adults without dementia.Participants were 153 community-dwelling older adults without dementia. We evaluated polysomnography (PSG), cognitive performance, and affective function at four time points: baseline, 12, 24, and 36 months. All participants completed PSG and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, visuospatial ability, and measures of anxiety and depression. DASO was defined as sequences of rhythmic anterior delta activity on PSG in the transition from awake to sleep during the baseline assessment (Figure ).At the baseline, 83 women and 70 men, mean age 71.3 ± 0.6 years participated and 19.6% of participants exhibited DASO. Age, years of education, gender, and body mass index did not differ according to DASO status. Linear mixed modeling showed that the presence of DASO was actually associated with lower levels of anxiety and depression. Further, participants with DASO, versus those without DASO, exhibited a trend towards better cognitive performance over time, although none of these associations reached statistical significance.Whereas DASO was associated with better affective function, no significant association was found between DASO and cognitive change over time. These longitudinal findings support the view that the presence of DASO in healthy older adults represents normal variation rather than pathological aging. Copyright © 2016 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/gps.4554

  View details for PubMedID 27554208

• Multimorbidity is associated with anxiety in older adults in the Health and Retirement Study. International journal of geriatric psychiatry Gould, C. E., O'Hara, R., Goldstein, M. K., Beaudreau, S. A. 2016; 31 (10): 1105-1115

  Abstract

  The present study determined whether the number of medical conditions was associated with increased occurrence of anxiety and whether triads of medical conditions were associated with anxiety in a nationally representative sample of older Americans. We determined whether multimorbidity findings were unique to anxiety as compared with depressive symptoms.A sample of 4219 participants (65 years or older) completed anxiety and depression measures in the Health and Retirement Study 2006 wave. The logistic regression models' outcome was elevated anxiety (≥12 on five-item Beck Anxiety Inventory) or depressive symptoms (≥12 on eight-item Center for Epidemiological Studies Depression Scale). The predictor variable was a tally of seven self-report of doctor-diagnosed conditions: arthritis, cancer, diabetes, heart conditions, high blood pressure, lung disease, and stroke. Analyses were adjusted for age, gender, and depressive or anxiety symptoms. Associations among elevated anxiety or depressive symptoms and 35 triads of medical conditions were examined using Bonferroni corrected chi-square analyses.Three or more medical conditions conferred a 2.30-fold increase in elevated anxiety (95% confidence interval: 1.44-4.01). Twenty triads were associated with elevated anxiety as compared with 13 associated with depressive symptoms. Six of seven medical conditions, with the exception being stroke, were present in the majority of triads.Number of medical conditions and specific conditions are associated with increased occurrence of elevated anxiety. Compared with elevated depressive symptoms, anxiety is associated with greater multimorbidity. As anxiety and depression cause significant morbidity, it may be beneficial to consider these mental health symptoms when evaluating older adults with multimorbidity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  View details for DOI 10.1002/gps.4532

  View details for PubMedID 27441851

• Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. Journal of Alzheimer's disease : JAD Durazzo, T. C., Korecka, M., Trojanowski, J. Q., Weiner, M. W., O' Hara, R., Ashford, J. W., Shaw, L. M. 2016; 54 (1): 99-107

  Abstract

  Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD). Smoking and non-smoking CN (n = 83), MCI (n = 164), and probable AD (n = 101) were compared on cerebrospinal fluid (CSF) iPF2α-III and 8,12, iso-iPF2α-VI F2-isoprostane concentrations. Associations between F2-isoprostane levels and hippocampal volumes were also evaluated. In CN and AD, smokers had higher iPF2α-III concentration; overall, smoking AD showed the highest iPF2α-III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2α-III concentration. No group differences were apparent on 8,12, iso-iPF2α-VI concentration, but across AD, higher 8,12, iso-iPF2α-VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2-isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan.

  View details for DOI 10.3233/JAD-160413

  View details for PubMedID 27472882

• Disentangling cognition and emotion in older adults: the role of cognitive control and mental health in emotional conflict adaptation. International journal of geriatric psychiatry Hantke, N. C., Gyurak, A., Van Moorleghem, K., Waring, J. D., Adamson, M. M., O'Hara, R., Beaudreau, S. A. 2016

  Abstract

  Recent research suggests cognition has a bidirectional relationship with emotional processing in older adults, yet the relationship is still poorly understood. We aimed to examine a potential relationship between late-life cognitive function, mental health symptoms, and emotional conflict adaptation. We hypothesized that worse cognitive control abilities would be associated with poorer emotional conflict adaptation. We further hypothesized that a higher severity of mental health symptoms would be associated with poorer emotional conflict adaptation.Participants included 83 cognitively normal community-dwelling older adults who completed a targeted mental health and cognitive battery, and emotion and gender conflict-adaptation tasks.Consistent with our hypothesis, poorer performance on components of cognitive control, specifically attention and working memory, was associated with poorer emotional conflict adaptation. This association with attention and working memory was not observed in the non-affective-based gender conflict adaptation task. Mental health symptoms did not predict emotional conflict adaptation, nor did performance on other cognitive measures.Our findings suggest that emotion conflict adaptation is disrupted in older individuals who have poorer attention and working memory. Components of cognitive control may therefore be an important potential source of inter-individual differences in late-life emotion regulation and cognitive affective deficits. Copyright © 2016 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/gps.4535

  View details for PubMedID 27445036

• Delta Activity at Sleep Onset and Cognitive Performance in Community-Dwelling Older Adults SLEEP Kawai, M., Beaudreau, S. A., Gould, C. E., Hantke, N. C., Jordan, J. T., O'Hara, R. 2016; 39 (4): 907-914

  Abstract

  Frontal intermittent rhythmic delta activity (FIRDA) has long been considered to be an abnormal variant in the electroencephalogram (EEG) among older adults. Prior work also indicates a predominance of slow wave EEG activity among patients with dementia. However, instability of state control occurring with aging generally and among many neurodegenerative diseases raises the possibility that FIRDA might represent the intrusion of sleep related elements of the EEG into the waking state. We examined delta activity at sleep onset (DASO) in community-dwelling, older adults without dementia, and examined whether this activity is related to poorer cognitive performance.153 community-dwelling, older adults without dementia underwent overnight polysomnography and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, and visuospatial ability. Delta activity during sleep/wake transitions (scored either as Waking or N1) was analyzed visually.Participants were 83 women and 70 men, mean age 71.3 ± 0.6 y. DASO was present in 30 participants (19.6%). Age, years of education, sex, and body mass index did not differ between DASO (+) and (-) groups. Multiple regression analyses indicated faster reading of the Stroop color words in DASO (+) subjects (P = 0.007). None of the other cognitive domains differed between the two groups.DASO was relatively common in our sample of community-dwelling, older adults without dementia. DASO was not associated with poorer performance on any cognitive domain. Instead, individuals with DASO demonstrated better performance on a simple reading task. Although these findings suggest that an abnormal EEG activity may represent normal variation, our work underscores the importance of distinguishing DASO from FIRDA when examining sleep in older adults.A commentary on this article appears in this issue on page 725.

  View details for DOI 10.5665/sleep.5652

  View details for Web of Science ID 000373186900022

  View details for PubMedCentralID PMC4791624

• The impact of executive function on response to cognitive behavioral therapy in late-life depression. International journal of geriatric psychiatry Goodkind, M. S., Gallagher-Thompson, D., Thompson, L. W., Kesler, S. R., Anker, L., Flournoy, J., Berman, M. P., Holland, J. M., O'Hara, R. M. 2016; 31 (4): 334-339

  Abstract

  Late-life depression (LLD) is a common and debilitating condition among older adults. Cognitive behavioral therapy (CBT) has strong empirical support for the treatment of depression in all ages, including in LLD. In teaching patients to identify, monitor, and challenge negative patterns in their thinking, CBT for LLD relies heavily on cognitive processes and, in particular, executive functioning, such as planning, sequencing, organizing, and selectively inhibiting information. It may be that the effectiveness of CBT lies in its ability to train these cognitive areas.Participants with LLD completed a comprehensive neuropsychological battery before enrolling in CBT. The current study examined the relationship between neuropsychological function prior to treatment and response to CBT.When using three baseline measures of executive functioning that quantify set shifting, cognitive flexibility, and response inhibition to predict treatment response, only baseline Wisconsin Card Sort Task performance was associated with a significant drop in depression symptoms after CBT. Specifically, worse performance on the Wisconsin Card Sort Task was associated with better treatment response.These results suggest that CBT, which teaches cognitive techniques for improving psychiatric symptoms, may be especially beneficial in LLD if relative weaknesses in specific areas of executive functioning are present. Copyright © 2015 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/gps.4325

  View details for PubMedID 26230057

• Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project BMC PSYCHIATRY Williams, L. M., Goldstein-Piekarski, A. N., Chowdhry, N., Grisanzio, K. A., Haug, N. A., Samara, Z., Etkin, A., O'Hara, R., Schatzberg, A. F., Suppes, T., Yesavage, J. 2016; 16

  Abstract

  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.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.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.ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014.

  View details for DOI 10.1186/s12888-016-0771-3

  View details for Web of Science ID 000372738400001

  View details for PubMedCentralID PMC4793523

• Delta Activity at Sleep Onset and Cognitive Performance in Community-Dwelling Older Adults. Sleep Kawai, M., Beaudreau, S. A., Gould, C. E., Hantke, N. C., Jordan, J. T., O'Hara, R. 2016; 39 (4): 907-914

  Abstract

  Frontal intermittent rhythmic delta activity (FIRDA) has long been considered to be an abnormal variant in the electroencephalogram (EEG) among older adults. Prior work also indicates a predominance of slow wave EEG activity among patients with dementia. However, instability of state control occurring with aging generally and among many neurodegenerative diseases raises the possibility that FIRDA might represent the intrusion of sleep related elements of the EEG into the waking state. We examined delta activity at sleep onset (DASO) in community-dwelling, older adults without dementia, and examined whether this activity is related to poorer cognitive performance.153 community-dwelling, older adults without dementia underwent overnight polysomnography and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, and visuospatial ability. Delta activity during sleep/wake transitions (scored either as Waking or N1) was analyzed visually.Participants were 83 women and 70 men, mean age 71.3 ± 0.6 y. DASO was present in 30 participants (19.6%). Age, years of education, sex, and body mass index did not differ between DASO (+) and (-) groups. Multiple regression analyses indicated faster reading of the Stroop color words in DASO (+) subjects (P = 0.007). None of the other cognitive domains differed between the two groups.DASO was relatively common in our sample of community-dwelling, older adults without dementia. DASO was not associated with poorer performance on any cognitive domain. Instead, individuals with DASO demonstrated better performance on a simple reading task. Although these findings suggest that an abnormal EEG activity may represent normal variation, our work underscores the importance of distinguishing DASO from FIRDA when examining sleep in older adults.A commentary on this article appears in this issue on page 725.

  View details for DOI 10.5665/sleep.5652

  View details for PubMedID 26943464

  View details for PubMedCentralID PMC4791624

• Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers JOURNAL OF ALZHEIMERS DISEASE Durazzo, T. C., Korecka, M., Trojanowski, J. Q., Weiner, M. W., Hara, R. O., Ashford, J. W., Shaw, L. M. 2016; 54 (1): 99-107

  Abstract

  Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD). Smoking and non-smoking CN (n = 83), MCI (n = 164), and probable AD (n = 101) were compared on cerebrospinal fluid (CSF) iPF2α-III and 8,12, iso-iPF2α-VI F2-isoprostane concentrations. Associations between F2-isoprostane levels and hippocampal volumes were also evaluated. In CN and AD, smokers had higher iPF2α-III concentration; overall, smoking AD showed the highest iPF2α-III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2α-III concentration. No group differences were apparent on 8,12, iso-iPF2α-VI concentration, but across AD, higher 8,12, iso-iPF2α-VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2-isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan.

  View details for DOI 10.3233/JAD-160413

  View details for Web of Science ID 000383838400009

• Perceived anxiety control is associated with sleep disturbance in young and older adults AGING & MENTAL HEALTH Gould, C. E., Beaudreau, S. A., O'Hara, R., Edelstein, B. A. 2016; 20 (8): 856-860

  Abstract

  This study examined the extent to which perceived anxiety control was related to subjective sleep disturbance in young and older adults.Fifty-one young adults (18 to 30 years old) and 48 older adults (aged 65 years and older) completed questionnaires including the Pittsburgh Sleep Quality Index (PSQI) to assess sleep disturbance, Anxiety Control Questionnaire to assess perceived control over anxiety, a perceived health rating, and demographic questionnaire. Correlation and multivariable adjusted hierarchical regression analyses examined the extent to which anxiety control was associated with sleep disturbance.Anxiety control and health status were associated with global sleep quality on the PSQI, but no age differences in PSQI scores were found. In post hoc analyses, greater anxiety control was related to shorter sleep latency. Both older age and greater anxiety control were associated with less daytime dysfunction, whereas only older age was associated with better sleep quality.Although some variations in sleep quality by age were found, overall findings suggest that perceived anxiety control contributes to sleep disturbance in young and older adults. Greater anxiety control could lead to shorter sleep latency through reduced anxiety and worry symptoms at bedtime. Future studies should examine whether improved anxiety control with psychological treatments is one mechanism through which beneficial and lasting effects on sleep disturbance can be achieved.

  View details for DOI 10.1080/13607863.2015.1043617

  View details for Web of Science ID 000379246300011

  View details for PubMedID 26023761

• Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography JOURNAL OF CLINICAL SLEEP MEDICINE Primeau, M., Gershon, A., Talbot, L., Cotto, I., Lotspeich, L., Hardan, A., Hallmayer, J., O'Hara, R. 2016; 12 (3): 357-362

  Abstract

  Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

  View details for DOI 10.5664/jcsm.5584

  View details for Web of Science ID 000374139600013

  View details for PubMedCentralID PMC4773615

• Cortisol Administration Inhibits Sadness-Related Subgenual Cingulate Activity in Depression Sudheimer, K., Heinemeyer, E., O'Hara, R., Duvio, D., Schatzberg, A. NATURE PUBLISHING GROUP. 2015: S326–S327

  View details for Web of Science ID 000366597700555

• Narcolepsy in African Americans SLEEP Kawai, M., O'Hara, R., Einen, M., Lin, L., Mignot, E. 2015; 38 (11): 1673-1681

  Abstract

  Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States.Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level.182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy.Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%).Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy.

  View details for DOI 10.5665/sleep.5140

  View details for Web of Science ID 000363740100006

  View details for PubMedCentralID PMC4813366

• Narcolepsy in African Americans. Sleep Kawai, M., O'Hara, R., Einen, M., Lin, L., Mignot, E. 2015; 38 (11): 1673-81

  Abstract

  Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States.Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level.182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy.Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%).Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy.

  View details for DOI 10.5665/sleep.5140

  View details for PubMedID 26158891

  View details for PubMedCentralID PMC4813366

• Impact of 5-HTTLPR on hippocampal subregional activation in older adults TRANSLATIONAL PSYCHIATRY Garrett, A., Gupta, S., Reiss, A. L., Waring, J., Sudheimer, K., Anker, L., Sosa, N., Hallmayer, J. F., O'Hara, R. 2015; 5

  Abstract

  Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein ɛ4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.

  View details for DOI 10.1038/tp.2015.131

  View details for Web of Science ID 000367663000002

  View details for PubMedCentralID PMC5068801

• Personalizing the Treatment of Depression: Emotional Reactivity and Early Life Stress Predict Antidepressant Outcomes Goldstein-Piekarski, A. N., Yesavage, J., Schatzberg, A., Etkin, A., O'hara, R., Suppes, T., Korgaonkar, M., Williams, L. ELSEVIER SCIENCE INC. 2015

  View details for Web of Science ID 000352207501255

• Genetic Variations in the Glucocorticoid and Mineralcorticoid Receptor Genes are Associated with Disrupted Hypothalamic Functional Connectivity and Elevated Nocturnal Cortisol Secretion in Depression Sudheimer, K., Keller, J., O'Hara, R., Schatzberg, A. ELSEVIER SCIENCE INC. 2015

  View details for Web of Science ID 000352207501290

• Donepezil treatment in ethnically diverse patients with Alzheimer disease. American journal of geriatric psychiatry Tinklenberg, J. R., Kraemer, H. C., Yaffe, K., O'Hara, R., Ringman, J. M., Ashford, J. W., Yesavage, J. A., Taylor, J. L. 2015; 23 (4): 384-390

  Abstract

  To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil.Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity.The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data.Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

  View details for DOI 10.1016/j.jagp.2014.09.007

  View details for PubMedID 25747405

• Anxiety Symptom Clusters Predict Sleep Quality Gould, C. E., O'Hara, R., Cassidy-Eagle, E. L., Liou-Johnson, V., Beaudreau, S. A. ELSEVIER SCIENCE INC. 2015: S144–S145

  View details for DOI 10.1016/j.jagp.2014.12.150

  View details for Web of Science ID 000350829500143

• Elevated Worry Is Associated with Better, Not Worse, Cognitive Performance in Old Community-Residing Adults Reporting Elevated Symptoms of Anxiety or Depression Beaudreau, S. A., Hantke, N. C., O'Hara, R. ELSEVIER SCIENCE INC. 2015: S166

  View details for DOI 10.1016/j.jagp.2014.12.173

  View details for Web of Science ID 000350829500165

• Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Sudheimer, K., Keller, J., Gomez, R., Tennakoon, L., Reiss, A., Garrett, A., Kenna, H., O'Hara, R., Schatzberg, A. F. 2015; 40 (4): 849-860

  Abstract

  Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

  View details for DOI 10.1038/npp.2014.259

  View details for PubMedID 25292261

  View details for PubMedCentralID PMC4330499

• Does cognitive-behavioural therapy promote meaning making? A preliminary test in the context of geriatric depression. Psychology and psychotherapy Holland, J. M., Chong, G., Currier, J. M., O'Hara, R., Gallagher-Thompson, D. 2015; 88 (1): 120-124

  Abstract

  This study examined the extent to which cognitive-behavioural therapy (CBT) for geriatric depression promoted meaning made of stress.Fifty-one participants received CBT and were assessed at pre- and post-treatment.The primary outcome was the Integration of Stressful Life Experiences Scale (ISLES) and demographic factors were examined as moderators of changes over time.Those with more education showed improvement in their ability to regain positive values, worldviews, and purpose in life after a stressor.It appears that CBT promotes some forms of meaning made of stress for those with higher education.Cognitive-behavioural therapy as it is routinely practiced may help highly educated older adults regain their Footing in the World (e.g., maintain positive values, worldviews, and purpose in life) in the aftermath of a stressful life event. Cognitive-behavioural therapy appears to offer fewer gains for less educated older adults (in terms of Footing in the World) as well as for other aspects of meaning-making, such as the ability to 'make sense' of a significant stressor. Although more empirical work is necessary, meaning-oriented interventions (e.g., 're-authoring' a fragmented self-narrative; Neimeyer, 2009, p. 97) hold promise as useful adjuncts to routine therapy that could augment outcomes.

  View details for DOI 10.1111/papt.12030

  View details for PubMedID 24839175

  View details for PubMedCentralID PMC4233192

• Does cognition predict treatment response and remission in psychotherapy for late-life depression? American journal of geriatric psychiatry Beaudreau, S. A., Rideaux, T., O'Hara, R., Arean, P. 2015; 23 (2): 215-219

  Abstract

  To identify cognitive predictors of geriatric depression treatment outcome.Older participants completed baseline measures of memory and executive function, health, and baseline and post-treatment Hamilton Depression Scales (HAM-D) in a 12-week trial comparing psychotherapies (problem-solving vs. supportive; N = 46). We examined cognitive predictors to identify treatment responders (i.e., HAM-D scores reduced by ≥50%) and remitters (i.e., post-treatment HAM-D score ≤10).Empirically derived decision trees identified poorer performance on switching (i.e., Trails B), with a cut-score of ≥82 predicting psychotherapy responders. No other cognitive or health variables predicted psychotherapy outcomes in the decision trees.Psychotherapies that support or improve the executive skill of switching may augment treatment response for older patients exhibiting executive dysfunction in depression. If replicated, Trails B has potential as a brief cognitive tool for clinical decision-making in geriatric depression.

  View details for DOI 10.1016/j.jagp.2014.09.003

  View details for PubMedID 25441055

  View details for PubMedCentralID PMC4289644

• fMRI Activation During Executive Function Predicts Response to Cognitive Behavioral Therapy in Older, Depressed Adults AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Thompson, D. G., Kesler, S. R., Sudheimer, K., Mehta, K. M., Thompson, L. W., Marquett, R. M., Holland, J. M., Reiser, R., Rasgon, N., Schatzberg, A., O'Hara, R. M. 2015; 23 (1): 13-22

  Abstract

  To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients.Clinical cohort study.University-affiliated hospital.Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures.The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable.67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor.These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.

  View details for DOI 10.1016/j.jagp.2014.02.001

  View details for Web of Science ID 000346204400003

  View details for PubMedID 24656506

• Biology of Positive Psychiatry POSITIVE PSYCHIATRY: A CLINICAL HANDBOOK Moore, R. C., Eyler, L. T., Mills, P. J., O'Hara, R. M., Wachmann, K., Lavretsky, H., Jeste, D. V., Palmer, B. W. 2015: 261–83

  View details for Web of Science ID 000383142600014

• Posttraumatic Stress Disorder Symptom Severity and Socioeconomic Factors Associated with Veterans Health Administration Use among Women Veterans. Women's health issues : official publication of the Jacobs Institute of Women's Health Lehavot, K. n., O'Hara, R. n., Washington, D. L., Yano, E. M., Simpson, T. L. 2015; 25 (5): 535–41

  Abstract

  The Veterans Health Administration (VA) has historically focused on treating men. Although women veterans' VA use is increasing, they remain more likely than male veterans to receive their care in non-VA settings. To date, there is limited research on factors associated with VA use among women. We examined the relationship between demographic, civilian, military, and health-related variables with past-year VA use among women veterans.Women veterans were recruited over the internet to participate in an anonymous national survey (n = 617) in 2013. An empirically derived decision tree was computed using signal detection software for iterative receiver operator characteristics (ROC) to identify variables with the best sensitivity/specificity balance associated with past-year VA use.ROC analysis indicated that 85% of participants with high posttraumatic stress disorder (PTSD) and depressive symptoms and who were younger than 54 years of age used VA in the past year. Of those who were 54 years of age or older and had very high PTSD symptoms, 94% used the VA in the last year. By contrast, only 40% of participants with relatively lower PTSD symptoms had VA past-year use, although among these individuals, VA past-year use increased to 65% for those with a relatively lower income.Findings suggest that greater PTSD symptoms, depressive symptoms, and low income correlate with VA use, with very high PTSD symptoms in older groups, high PTSD symptoms coupled with high depressive symptoms in younger groups, and low income in those with lower PTSD symptoms each associated with greater past-year VA use. Ensuring PTSD assessment and treatment, and addressing socioeconomic factors, may be key strategies for health care delivered directly or through contract with VA facilities.

  View details for PubMedID 26123641

• Individuals with Autism Spectrum Disorders Have Equal Success Rate But Require Longer Periods of Systematic Desensitization than Control Patients to Complete Ambulatory Polysomnography. Journal of clinical sleep medicine Primeau, M., Gershon, A., Talbot, L., Cotto, I., Lotspeich, L., Hardan, A., Hallmayer, J., O'Hara, R. 2015; 12 (3): 357-362

  Abstract

  Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

  View details for DOI 10.5664/jcsm.5584

  View details for PubMedID 26564388

  View details for PubMedCentralID PMC4773615

• Reduced Hypothalamic Functional Connectivity to the Subgenual Cortex is Associated with Genetic Variations in the Glucocorticoid and Mineralcorticoid Receptor Genes Sudheimer, K., Keller, J., O'Hara, R., Schatzberg, A. NATURE PUBLISHING GROUP. 2014: S283–S284

  View details for Web of Science ID 000345905000468

• The prediction of study-emergent suicidal ideation in bipolar disorder: a pilot study using ecological momentary assessment data BIPOLAR DISORDERS Thompson, W. K., Gershon, A., O'Hara, R., Bernert, R. A., Depp, C. A. 2014; 16 (7): 669-677

  Abstract

  Bipolar disorder is associated with idiosyncratic precursors of clinically important states such as suicidal ideation. Ecological momentary assessment (EMA) - high frequency data collection in a subject's usual environment - provides the potential for development of temporal, individualized prediction of risk states. The present study tested the ability of EMA data to predict individual symptom change in clinician-rated suicidal ideation.Thirty-five adults diagnosed with inter-episode bipolar disorder completed daily measures of affect in their home environments using diaries administered over an eight-week assessment timeline. Suicidal ideation was assessed monthly at in-person visits using the Inventory of Depressive Symptomatology-Clinician Rated. We used a novel application of functional linear models (FLMs) to generate prospective predictions of suicidal ideation at in-person clinician assessments based on intensively sampled trajectories of daily affect.Eight instances of suicidal ideation scores > 0 were recorded during the study period on six participants. Utilizing trajectories of negative and positive affect, cross-validated predictions attained 88% sensitivity with 95% specificity for elevated suicidal ideation one week prior to in-person clinician assessment. This model strongly outperformed prediction models using cross-sectional data obtained at study visits alone.Utilizing EMA data with FLM prediction models substantially increases the accuracy of prediction of study-emergent suicidal ideation. Prediction algorithms employing intensively sampled longitudinal EMA data could sensitively detect the warning signs of suicidal ideation to facilitate improved suicide risk assessment and the timely delivery of preventative interventions.

  View details for DOI 10.1111/bdi.12218

  View details for Web of Science ID 000344373100001

• The prediction of study-emergent suicidal ideation in bipolar disorder: a pilot study using ecological momentary assessment data. Bipolar disorders Thompson, W. K., Gershon, A., O'Hara, R., Bernert, R. A., Depp, C. A. 2014; 16 (7): 669-677

  Abstract

  Bipolar disorder is associated with idiosyncratic precursors of clinically important states such as suicidal ideation. Ecological momentary assessment (EMA) - high frequency data collection in a subject's usual environment - provides the potential for development of temporal, individualized prediction of risk states. The present study tested the ability of EMA data to predict individual symptom change in clinician-rated suicidal ideation.Thirty-five adults diagnosed with inter-episode bipolar disorder completed daily measures of affect in their home environments using diaries administered over an eight-week assessment timeline. Suicidal ideation was assessed monthly at in-person visits using the Inventory of Depressive Symptomatology-Clinician Rated. We used a novel application of functional linear models (FLMs) to generate prospective predictions of suicidal ideation at in-person clinician assessments based on intensively sampled trajectories of daily affect.Eight instances of suicidal ideation scores > 0 were recorded during the study period on six participants. Utilizing trajectories of negative and positive affect, cross-validated predictions attained 88% sensitivity with 95% specificity for elevated suicidal ideation one week prior to in-person clinician assessment. This model strongly outperformed prediction models using cross-sectional data obtained at study visits alone.Utilizing EMA data with FLM prediction models substantially increases the accuracy of prediction of study-emergent suicidal ideation. Prediction algorithms employing intensively sampled longitudinal EMA data could sensitively detect the warning signs of suicidal ideation to facilitate improved suicide risk assessment and the timely delivery of preventative interventions.

  View details for DOI 10.1111/bdi.12218

  View details for PubMedID 24903771

• Connectivity Underlying Emotion Conflict Regulation in Older Adults with 5-HTTLPR Short Allele: A Preliminary Investigation. American journal of geriatric psychiatry Waring, J. D., Etkin, A., Hallmayer, J. F., O'Hara, R. 2014; 22 (9): 946-950

  Abstract

  The serotonin transporter polymorphism short (s) allele is associated with heightened emotional reactivity and reduced emotion regulation, which increases vulnerability to depression and anxiety disorders. We investigated behavioral and neural markers of emotion regulation in community-dwelling older adults, contrasting s allele carriers and long allele homozygotes.Participants (N = 26) completed a face-word emotion conflict task during functional magnetic resonance imaging, in which facilitated regulation of emotion conflict was observed on face-word incongruent trials following another incongruent trial (i.e., emotional conflict adaptation).There were no differences between genetic groups in behavioral task performance or neural activation in postincongruent versus postcongruent trials. By contrast, connectivity between dorsal anterior cingulate cortex (ACC) and pregenual ACC, regions previously implicated in emotion conflict regulation, was impaired in s carriers for emotional conflict adaptation.This is the first demonstration of an association between serotonin transporter polymorphism and functional connectivity in older adults. Poor dorsal ACC-pregenual ACC connectivity in s carriers may be one route by which these individuals experience greater difficulty in implementing effective emotional regulation, which may contribute to their vulnerability for affective disorders.

  View details for DOI 10.1016/j.jagp.2013.08.004

  View details for PubMedID 24119861

  View details for PubMedCentralID PMC4006319

• Psychosocial predictors of salivary cortisol among older adults with depression INTERNATIONAL PSYCHOGERIATRICS Holland, J. M., Rengifo, J., Currier, J. M., O'Hara, R., Sudheimer, K., Gallagher-Thompson, D. 2014; 26 (9): 1531-1539

  View details for DOI 10.1017/S1041610214000489

  View details for Web of Science ID 000341780900015

• Prenatal and perinatal risk factors in a twin study of autism spectrum disorders. Journal of psychiatric research Froehlich-Santino, W., Londono Tobon, A., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., Miller, J., Fedele, A., Collins, J., Smith, K., Lotspeich, L., Croen, L. A., Ozonoff, S., LaJonchere, C., Grether, J. K., O'Hara, R., Hallmayer, J. 2014; 54: 100-108

  Abstract

  Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently.Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed.Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74).Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.

  View details for DOI 10.1016/j.jpsychires.2014.03.019

  View details for PubMedID 24726638

• Psychosocial predictors of salivary cortisol among older adults with depression. International psychogeriatrics Holland, J. M., Rengifo, J., Currier, J. M., O'Hara, R., Sudheimer, K., Gallagher-Thompson, D. 2014: 1-9

  Abstract

  ABSTRACT Background: Previous studies have identified a number of psychosocial risk factors of dysregulated cortisol (frequently referred to as the "stress hormone") among older adults with depression. However, these studies have typically only examined a handful of risk factors at a time and have sometimes yielded inconsistent results. Method: This study aims to address this gap in the literature by simultaneously examining a range of relevant psychosocial predictors of diurnal cortisol among 54 older adults with a depressive disorder. Salivary cortisol was assessed upon awakening, at 5 PM, and at 9 PM across two consecutive days. Participants also completed measures of global psychosocial stress, current psychiatric symptomatology, pervasive distress (e.g. history of past depression), and protective factors (e.g. social support, resiliency, extent to which one has "made sense" of a significant stressor). Results: High levels of current depressive symptoms, psychiatric comorbidities, past depressive episodes, trait anxiety, and poorer ability to make sense of one's stress were found to be associated with flatter (more abnormal) cortisol slopes. However, when all of these variables were entered simultaneously in a multiple regression analysis, only history of past depression and the degree of sense made of stress emerged as unique predictors of cortisol in the model. Conclusions: These findings have important implications for identifying depressed elderly individuals with dysregulated cortisol patterns who may be most at risk for health complications. Treatments that aim to limit the chronicity of depression and help to increase the sense made of stress could potentially have a positive impact on health.

  View details for PubMedID 24735686

• Serotonin transporter polymorphism is associated with increased apnea-hypopnea index in older adults. International journal of geriatric psychiatry Schröder, C. M., Primeau, M. M., Hallmayer, J. F., Lazzeroni, L. C., Hubbard, J. T., O'Hara, R. 2014; 29 (3): 227-235

  Abstract

  RATIONALE: A functional polymorphism of the serotonin transporter gene (5-HTTLPR) has previously been related to upper airway pathology, but its contribution to obstructive sleep apnea (OSA), a highly prevalent sleep disorder in older adults, remains unclear. OBJECTIVES: We aimed to investigate the relationship between apnea-hypopnea index (AHI) and genetic variations in the promoter region of the 5-HTTLPR in older adults. METHODS: DNA samples from 94 community-dwelling older adults (57% female, mean age 72 ± 8) were genotyped for the 5-HTTLPR polymorphism. All participants were assessed in their homes with full ambulatory polysomnography in order to determine AHI and related parameters such as hypoxia, sleep fragmentation, and self-reported daytime sleepiness. RESULTS: The 5-HTT l allele was significantly associated with AHI (p = 0.019), with l allele carriers displaying a higher AHI than s allele homozygotes. A single allele change in 5-HTTLPR genotype from s to l resulted in an increase of AHI by 4.46 per hour of sleep (95% CI, 0.75-8.17). The l allele was also associated with increased time during sleep spent at oxygen saturation levels below 90% (p = 0.014). CONCLUSIONS: The observed significant association between the 5-HTTLPR l allele and severity of OSA in older adults suggests that the l allele may be important to consider when assessing for OSA in this age group. This association may also explain some of the observed variability among serotonergic pharmacological treatment studies for OSA, and 5-HTT genotype status may have to be taken into account in future therapeutic trials involving serotonergic agents. Copyright © 2013 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/gps.3994

  View details for PubMedID 23754303

• COGNITION, BIOMARKERS, AND OUTCOMES IN GERIATRIC MOOD Lavretsky, H., Aizenstein, H., O'Hara, R., Alexopoulos, G. S. ELSEVIER SCIENCE INC. 2014: S8–S9

  View details for DOI 10.1016/j.jagp.2013.12.013

  View details for Web of Science ID 000336081800007

• Effects of body mass index-related disorders on cognition: preliminary results. Diabetes, metabolic syndrome and obesity : targets and therapy Yesavage, J. A., Kinoshita, L. M., Noda, A., Lazzeroni, L. C., Fairchild, J. K., Taylor, J., Kulick, D., Friedman, L., Cheng, J., Zeitzer, J. M., O'Hara, R. 2014; 7: 145-151

  Abstract

  Well-known risk factors for cognitive impairment are also associated with obesity. Research has highlighted genetic risk factors for obesity, yet the relationship of those risk factors with cognitive impairment is unknown. The objective of this study was to determine the associations between cognition, hypertension, diabetes, sleep-disordered breathing, and obesity. Genetic risk factors of obesity were also examined.The sample consisted of 369 nondemented individuals aged 50 years or older from four community cohorts. Primary outcome measures included auditory verbal memory, as measured by the Rey Auditory Verbal Learning Test, and executive functioning, as measured by the Color-Word Interference Test of the Delis-Kaplan Executive Function System battery. Apnea-hypopnea index indicators were determined during standard overnight polysomnography. Statistical analyses included Pearson correlations and linear regressions.Poor executive function and auditory verbal memory were linked to cardiovascular risk factors, but not directly to obesity. Genetic factors appeared to have a small but measureable association to obesity.A direct linkage between obesity and poor executive function and auditory verbal memory is difficult to discern, possibly because nonobese individuals may show cognitive impairment due to insulin resistance and the "metabolic syndrome".

  View details for DOI 10.2147/DMSO.S60294

  View details for PubMedID 24855383

• Effects of body mass index-related disorders on cognition: preliminary results DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY Yesavage, J. A., Kinoshita, L. M., Noda, A., Lazzeroni, L. C., Fairchild, J., Taylor, J., Kulick, D., Friedman, L., Cheng, J., Zeitzer, J. M., O'Hara, R. 2014; 7: 145–51

  View details for DOI 10.2147/DMSO.S60294

  View details for Web of Science ID 000213948100014

• Coming of age of genetic investigations in late-life mental health. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry O'Hara, R. n., Hallmayer, J. n. 2014; 22 (10): 953–56

  View details for PubMedID 25217024

• Commentary on "Individual and societal wisdom: explaining the paradox of human aging and high well-being" by Dilip V. Jeste and Andrew J. Oswald: uncovering the genetic basis of well-being in older adults. Psychiatry O'Hara, R. n. 2014; 77 (4): 340–43

  View details for PubMedID 25386774

• Cortisol, cytokines, and hippocampal volume interactions in the elderly. Frontiers in aging neuroscience Sudheimer, K. D., O'Hara, R., Spiegel, D., Powers, B., Kraemer, H. C., Neri, E., Weiner, M., Hardan, A., Hallmayer, J., Dhabhar, F. S. 2014; 6: 153-?

  Abstract

  Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  View details for DOI 10.3389/fnagi.2014.00153

  View details for PubMedID 25071562

  View details for PubMedCentralID PMC4079951

• Cortisol, cytokines, and hippocampal volume interactions in the elderly. Frontiers in aging neuroscience Sudheimer, K. D., O'Hara, R., Spiegel, D., Powers, B., Kraemer, H. C., Neri, E., Weiner, M., Hardan, A., Hallmayer, J., Dhabhar, F. S. 2014; 6: 153-?

  Abstract

  Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  View details for DOI 10.3389/fnagi.2014.00153

  View details for PubMedID 25071562

  View details for PubMedCentralID PMC4079951

• The unique impact of late-life bereavement and prolonged grief on diurnal cortisol. journals of gerontology. Series B, Psychological sciences and social sciences Holland, J. M., Rozalski, V., Thompson, K. L., Tiongson, R. J., Schatzberg, A. F., O'Hara, R., Gallagher-Thompson, D. 2014; 69 (1): 4-11

  Abstract

  This study expands on previous research by examining the effects of prolonged grief disorder (PGD) symptoms and bereavement on diurnal cortisol patterns above and beyond depressive symptomatology.Drawing on information from 56 depressed older adults, 3 groups were compared: (1) a depressed nonbereaved group, (2) a depressed bereaved without elevated PGD symptoms group, and (3) a depressed bereaved with elevated PGD symptoms group. Multilevel modeling was used to examine differences in diurnal cortisol profiles between these 3 groups, controlling for demographic factors and depressive symptoms.Results revealed that those who were bereaved had more dysregulated cortisol patterns, but PGD symptomatology seemed to have little effect. Subsidiary analysis with just the bereaved participants suggests that those who were recently widowed may have had greater cortisol dysregulation compared with other bereaved individuals in the sample.These findings suggest that the circumstance of being bereaved may be associated with more dysregulated cortisol, regardless of PGD symptomatology. This pattern of results might reflect greater disturbance in daily routines among bereaved individuals and acute stress in the case of those experiencing the recent loss of a spouse, which leads to disruption in circadian rhythms and the diurnal cycle of cortisol.

  View details for DOI 10.1093/geronb/gbt051

  View details for PubMedID 23740094

  View details for PubMedCentralID PMC3894130

• Pretreatment cortisol levels predict posttreatment outcomes among older adults with depression in cognitive behavioral therapy. Psychiatry research Holland, J. M., Schatzberg, A. F., O'Hara, R., Marquett, R. M., Gallagher-Thompson, D. 2013; 210 (2): 444-450

  Abstract

  Previous studies suggest that individuals with elevated levels of cortisol (the "stress hormone") could be particularly resistant to treatment for depression. However, most of these studies have been conducted in the context of antidepressant medications, and no study has examined pretreatment cortisol levels as a predictor of treatment outcomes among older adults with depression in cognitive-behavioral therapy (CBT), despite the relevance of this population for such a research question. The current study includes 54 older adults with depression who provided salivary cortisol samples at baseline and completed measures of depression at pretreatment and posttreatment, following a 12-week course of CBT. Structural equation modeling results suggest that those with higher daily outputs of cortisol and flatter diurnal slopes were less likely to benefit from CBT-a finding which if replicated could have important implications for clinical practice and future research.

  View details for DOI 10.1016/j.psychres.2013.07.033

  View details for PubMedID 23953171

  View details for PubMedCentralID PMC3818434

• Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy BRAIN IMAGING AND BEHAVIOR Kesler, S. R., Watson, C., Koovakkattu, D., Lee, C., O'Hara, R., Mahaffey, M. L., Wefel, J. S. 2013; 7 (4): 501-510

  Abstract

  Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using (1)H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy.

  View details for DOI 10.1007/s11682-013-9228-1

  View details for Web of Science ID 000328853800010

  View details for PubMedID 23536015

  View details for PubMedCentralID PMC3731420

• A neurobiological approach to the cognitive deficits of psychiatric disorders. Dialogues in clinical neuroscience Etkin, A., Gyurak, A., O'Hara, R. 2013; 15 (4): 419-429

  Abstract

  Deficits in brain networks that support cognitive regulatory functions are prevalent in many psychiatric disorders. Findings across neuropsychology and neuroimaging point to broad-based impairments that cross traditional diagnostic boundaries. These dysfunctions are largely separate from the classical symptoms of the disorders, and manifest in regulatory problems in both traditional cognitive and emotional domains. As such, they relate to the capacity of patients to engage effectively in their daily lives and activity, often persist even in the face of symptomatically effective treatment, and are poorly targeted by current treatments. Advances in cognitive neuroscience now allow us to ground an understanding of these cognitive regulatory deficits in the function and interaction of key brain networks. This emerging neurobiological understanding furthermore points to several promising routes for novel neuroscience-informed treatments targeted more specifically at improving cognitive function in a range of psychiatric disorders.

  View details for PubMedID 24459409

• DSM-5 Sleep-Wake Disorders Classification: Overview for Use in Clinical Practice AMERICAN JOURNAL OF PSYCHIATRY Reynolds, C. F., O'Hara, R. 2013; 170 (10): 1099–1101

  Abstract

  Mental health clinicians should appreciate that sleep is a fundamental human behavior and that inadequate sleep has adverse medical, psychiatric, and psychosocial consequences. Sleep disturbances interact with common mental disorders; the two are mutually exacerbating, and both must be appropriately addressed to ensure optimal outcomes for our patients. Sleep is by the brain, of the brain, and for the brain.

  View details for DOI 10.1176/appi.ajp.2013.13010058

  View details for Web of Science ID 000325383700007

  View details for PubMedID 24084814

• Early Exposure to Traumatic Stressors Impairs Emotional Brain Circuitry PLOS ONE Korgaonkar, M. S., Antees, C., Williams, L. M., Gatt, J. M., Bryant, R. A., Cohen, R., Paul, R., O'Hara, R., Grieve, S. M. 2013; 8 (9)

  Abstract

  Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder.

  View details for DOI 10.1371/journal.pone.0075524

  View details for PubMedID 24073270

• Psychosocial predictors of treatment response to cognitive-behavior therapy for late-life depression: an exploratory study AGING & MENTAL HEALTH Marquett, R. M., Thompson, L. W., Reiser, R. P., Holland, J. M., O'Hara, R. M., Kesler, S. R., Stepanenko, A., Bilbrey, A., Rengifo, J., Majoros, A., Thompson, D. G. 2013; 17 (7): 830-838

  Abstract

  Objective: The primary objective of this study was to examine a variety of potential predictors of response to Cognitive Behavioral Therapy (CBT) in depressed older adults. Method: Sixty older adults with a clinical diagnosis of major or minor depression or dysthymic disorder received 12 individual sessions of CBT over a three- to four-month-period. The BDI-II was administered pre- and post-intervention to assess change in the level of depression. A cutoff score of 13 or less at post was used to determine positive treatment response. A variety of measures (obtained at baseline) were evaluated using hierarchical regression techniques to predict improvement following treatment. Results: Individuals who showed greater improvement were: (a) more open to new experiences; (b) less negatively affected by past stressors; (c) less inclined to have an external locus of control but more likely to cite others as responsible for negative stress in their lives; and (d) were more likely to seek emotional support when symptomatic. Lower education level and reported use of active coping strategies at baseline were associated with less improvement. Other variables (e.g., age, overall physical health, and cognitive status) were not associated with treatment response. Use of logistic regression to predict responders vs. nonresponders yielded a similar pattern. Conclusion: These findings agree with prior research confirming the effectiveness of a brief CBT intervention for older depressed persons and suggest further exploration of several psychosocial factors that may contribute to a stronger response to CBT.

  View details for DOI 10.1080/13607863.2013.791661

  View details for Web of Science ID 000323476600008

  View details for PubMedID 23631698

• Neuropsychiatric symptoms, apolipoprotein E gene, and risk of progression to cognitive impairment, no dementia and dementia: the Aging, Demographics, and Memory Study (ADAMS). International journal of geriatric psychiatry Beaudreau, S. A., Kaci Fairchild, J., Spira, A. P., Lazzeroni, L. C., O'Hara, R. 2013; 28 (7): 672-680

  Abstract

  OBJECTIVE: To examine the relationship of neuropsychiatric symptoms and apolipoprotein E (APOE) ε4 allele status to dementia at baseline and progression to dementia in older adults with and without cognitive impairment, no dementia (CIND). METHODS: Adults (n = 856) 71 years and older (mean age = 79.15 years), 12.8% ethnic minority and 60.6% women, completed neuropsychological tests and APOE genotyping, and a proxy informant completed the Neuropsychiatric Inventory. RESULTS: After adjusting for age and education, neuropsychiatric symptoms and APOE ε4 were independently associated with CIND and dementia status at baseline (compared with cognitively normal). Further, neuropsychiatric symptoms predicted progression to dementia at 16- to 18-month follow-up among participants with CIND at baseline; the presence of these symptoms decreased the risk of progression from normal to CIND or dementia at 36 to 48 months. CONCLUSION: Findings provide cross-sectional and longitudinal support for the role of neuropsychiatric symptoms in the prediction of cognitive impairment, particularly dementia. APOE ε4, although important, may be a less robust predictor. This investigation highlights the importance of behavioral symptoms, such as neuropsychiatric symptom status or frequency/severity, as predictors of future cognitive decline. Copyright © 2012 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/gps.3868

  View details for PubMedID 22927174

  View details for PubMedCentralID PMC3665735

• Neuropsychiatric symptoms, apolipoprotein E gene, and risk of progression to cognitive impairment, no dementia and dementia: the Aging, Demographics, and Memory Study (ADAMS) INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Beaudreau, S. A., Fairchild, J. K., Spira, A. P., Lazzeroni, L. C., O'Hara, R. 2013; 28 (7): 672-680

  Abstract

  OBJECTIVE: To examine the relationship of neuropsychiatric symptoms and apolipoprotein E (APOE) ε4 allele status to dementia at baseline and progression to dementia in older adults with and without cognitive impairment, no dementia (CIND). METHODS: Adults (n = 856) 71 years and older (mean age = 79.15 years), 12.8% ethnic minority and 60.6% women, completed neuropsychological tests and APOE genotyping, and a proxy informant completed the Neuropsychiatric Inventory. RESULTS: After adjusting for age and education, neuropsychiatric symptoms and APOE ε4 were independently associated with CIND and dementia status at baseline (compared with cognitively normal). Further, neuropsychiatric symptoms predicted progression to dementia at 16- to 18-month follow-up among participants with CIND at baseline; the presence of these symptoms decreased the risk of progression from normal to CIND or dementia at 36 to 48 months. CONCLUSION: Findings provide cross-sectional and longitudinal support for the role of neuropsychiatric symptoms in the prediction of cognitive impairment, particularly dementia. APOE ε4, although important, may be a less robust predictor. This investigation highlights the importance of behavioral symptoms, such as neuropsychiatric symptom status or frequency/severity, as predictors of future cognitive decline. Copyright © 2012 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/gps.3868

  View details for Web of Science ID 000319944200002

  View details for PubMedCentralID PMC3665735

• Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA neurology Andlauer, O., Moore, H., Jouhier, L., Drake, C., Peppard, P. E., Han, F., Hong, S., Poli, F., Plazzi, G., O'Hara, R., Haffen, E., Roth, T., Young, T., Mignot, E. 2013; 70 (7): 891-902

  Abstract

  Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically.To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency.Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels.Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level.Short REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%).Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.

  View details for DOI 10.1001/jamaneurol.2013.1589

  View details for PubMedID 23649748

• BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenetics and genomics Murphy, G. M., Sarginson, J. E., Ryan, H. S., O'Hara, R., Schatzberg, A. F., Lazzeroni, L. C. 2013; 23 (6): 301-313

  Abstract

  Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF.We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped.BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition.These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.

  View details for DOI 10.1097/FPC.0b013e328360b175

  View details for PubMedID 23619509

• Impact of Life Stress and Genetics on Vulnerability to Age-Related Neuropsychiatric Decline O'Hara, R. ELSEVIER SCIENCE INC. 2013: 7S

  View details for Web of Science ID 000318671800021

• The long-term impact of early adversity on late-life psychiatric disorders. Current psychiatry reports Gershon, A., Sudheimer, K., Tirouvanziam, R., Williams, L. M., O'Hara, R. 2013; 15 (4): 352-?

  Abstract

  Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research.

  View details for DOI 10.1007/s11920-013-0352-9

  View details for PubMedID 23443532

• The long-term impact of early adversity on late-life psychiatric disorders. Current psychiatry reports Gershon, A., Sudheimer, K., Tirouvanziam, R., Williams, L. M., O'Hara, R. 2013; 15 (4): 352-?

  Abstract

  Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research.

  View details for DOI 10.1007/s11920-013-0352-9

  View details for PubMedID 23443532

• COGNITION AND MOOD DISORDER: IS THERE A CONNECTION TO NEURODEGENERATION AND COGNITIVE DECLINE? Evans, J. D., Lavretsky, H., O'Hara, R., Gildengers, A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S8–S9

  View details for DOI 10.1016/j.jagp.2012.12.033

  View details for Web of Science ID 000330358400007

• Characterizing trajectories of cognitive functioning in older adults with schizophrenia: Does method matter? SCHIZOPHRENIA RESEARCH Thompson, W. K., Savla, G. N., Vahia, I. V., Depp, C. A., O'Hara, R., Jeste, D. V., Palmer, B. W. 2013; 143 (1): 90-96

  Abstract

  Heterogeneity in clinical outcomes may be caused by factors working at multiple levels, e.g., between groups, between subjects, or within subjects over time. A more nuanced assessment of differences in variation among schizophrenia patients and between patients and healthy comparison subjects can clarify etiology and even facilitate the identification of patient subtypes with common neuropathology and clinical course.We compared trajectories (mean duration of 3.5years) of cognitive impairments in a sample of 201 community-dwelling schizophrenia (SCZ) patients (aged 40-100years) with 67 healthy comparison (HC) subjects. We employed growth mixture models to discover subclasses with more homogenous between-subject variation in cognitive trajectories. Post hoc analyses determined factors associated with class membership and class-specific correlates of cognitive trajectories.Three latent classes were indicated: Class 1 (85% HC and 50% SCZ) exhibited relatively high and stable trajectories of cognition, Class 2 (15% HC and 40% SCZ) exhibited lower, modestly declining trajectories, and Class 3 (10% SCZ) exhibited lower, more rapidly declining trajectories. Within the patient group, membership in Classes 2-3 was associated with worse negative symptoms and living in a board and care facility.These results bridge the gap between schizophrenia studies demonstrating cognitive decline and those demonstrating stability. Moreover, a finer-grained characterization of heterogeneity in cognitive trajectories has practical implications for interventions and for case management of patients who show accelerated cognitive decline. Such a characterization requires study designs and analyses sensitive to between- and within-patient heterogeneity in outcomes.

  View details for DOI 10.1016/j.schres.2012.10.033

  View details for Web of Science ID 000313118700017

  View details for PubMedID 23218560

  View details for PubMedCentralID PMC3540183

• Children of Former Child Soldiers and Never-Conscripted Civilians: A Preliminary Intergenerational Study in Burundi JOURNAL OF AGGRESSION MALTREATMENT & TRAUMA Song, S. J., de Jong, J., O'Hara, R., Koopman, C. 2013; 22 (7): 757-772

  View details for DOI 10.1080/10926771.2013.813881

  View details for Web of Science ID 000209303700005

• Sleep Disturbance in Pediatric PTSD: Current Findings and Future Directions JOURNAL OF CLINICAL SLEEP MEDICINE Kovachy, B., O'Hara, R., Hawkins, N., Gershon, A., Primeau, M. M., Madej, J., Carrion, V. 2013; 9 (5): 503-512

  View details for DOI 10.5664/jcsm.2678

  View details for Web of Science ID 000319199100014

• Sleep Disturbance in Pediatric PTSD: Current Findings and Future Directions. Journal of clinical sleep medicine Kovachy, B., O'Hara, R., Hawkins, N., Gershon, A., Primeau, M. M., Madej, J., Carrion, V. 2013; 9 (5): 501-510

  Abstract

  Many studies have provided strong evidence of a fundamental and complex role for sleep disturbances in adult posttraumatic stress disorder (PTSD). Investigations of adult PTSD using subjective and objective measures document sleep architecture abnormalities and high prevalence of sleep disordered breathing, periodic limb movement disorder, nightmares, and insomnia. PTSD treatment methods do appear to significantly improve sleep disturbance, and also studies suggest that treatments for sleep disorders often result in improvements in PTSD symptoms. Further, the most recent evidence suggests sleep abnormalities may precede the development of PTSD. Given the importance of sleep disorders to the onset, course, and treatment of adult PTSD, examination of sleep disturbances far earlier in the life course is imperative. Here we review the literature on what we know about sleep disturbances and disorders in pediatric PTSD. Our review indicates that the extant, empirical data examining sleep disturbance and disorders in pediatric PTSD is limited. Yet, this literature suggests there are significantly higher reports of sleep disturbances and nightmares in children and adolescents exposed to trauma and/or diagnosed with PTSD than in non-trauma-exposed samples. Sleep questionnaires are predominantly employed to assess sleep disorders in pediatric PTSD, with few studies utilizing objective measures. Given the important, complex relationship being uncovered between adult PTSD and sleep, this review calls for further research of sleep in children with PTSD using more specific subjective measures and also objective measures, such as polysomnography and eventually treatment trial studies. CITATION: Kovachy B; O'Hara R; Hawkins N; Gershon A; Primeau MM; Madej J; Carrion V. Sleep disturbance in pediatric PTSD: current findings and future directions. J Clin Sleep Med 2013;9(5):501-510.

  View details for DOI 10.5664/jcsm.2678

  View details for PubMedID 23674943

  View details for PubMedCentralID PMC3629326

• Modeling the effects of obstructive sleep apnea and hypertension in Vietnam veterans with PTSD SLEEP AND BREATHING Kinoshita, L. M., Yesavage, J. A., Noda, A., Jo, B., Hernandez, B., Taylor, J., Zeitzer, J. M., Friedman, L., Fairchild, J. K., Cheng, J., Kuschner, W., O'Hara, R., Holty, J. C., Scanlon, B. K. 2012; 16 (4): 1201-1209

  Abstract

  The present work aimed to extend models suggesting that obstructive sleep apnea (OSA) is associated with worse cognitive performance in community-dwelling older adults. We hypothesized that in addition to indices of OSA severity, hypertension is associated with worse cognitive performance in such adults.The PTSD Apnea Clinical Study recruited 120 community-dwelling, male veterans diagnosed with PTSD, ages 55 and older. The Rey Auditory Verbal Learning Test (RAVLT) and Color-Word Interference Test (CWIT) were measures of auditory verbal memory and executive function, respectively. Apnea-hypopnea index (AHI), minimum and mean pulse oximeter oxygen saturation (min SpO(2), mean SpO(2)) indicators were determined during standard overnight polysomnography. Multivariate linear regression and receiver operating characteristic (ROC) curve analyses were performed.In regression models, AHI (β = -4.099; p < 0.01) and hypertension (β = -4.500; p < 0.05) predicted RAVLT; hypertension alone (β = 9.146; p < 0.01) predicted CWIT. ROC analyses selected min SpO(2) cut-points of 85% for RAVLT (κ = 0.27; χ² = 8.23, p < 0.01) and 80% for CWIT (κ = 0.25; χ² = 12.65, p < 0.01). Min SpO(2) cut-points and hypertension were significant when added simultaneously in a regression model for RAVLT (min SpO(2), β = 4.452; p < 0.05; hypertension, β = -4.332; p < 0.05), and in separate models for CWIT (min SpO(2), β = -8.286; p < 0.05; hypertension, β = -8.993; p < 0.01).OSA severity and presence of self-reported hypertension are associated with poor auditory verbal memory and executive function in older adults.

  View details for DOI 10.1007/s11325-011-0632-8

  View details for Web of Science ID 000311301700038

  View details for PubMedID 22193972

• The Reciprocal Relationship of Neurocognitive and Neuropsychiatric Function in Late Life AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY O'Hara, R. 2012; 20 (12): 1001-1005

  View details for DOI 10.1097/JGP.0b013e318275d60f

  View details for Web of Science ID 000311715500001

  View details for PubMedID 23089977

• Epidemiology of restless legs syndrome: A synthesis of the literature SLEEP MEDICINE REVIEWS Ohayon, M. M., O'Hara, R., Vitiello, M. V. 2012; 16 (4): 283-295

  Abstract

  Restless legs syndrome (RLS) has gained considerable attention in the recent years: nearly 50 community-based studies have been published in the last decade around the world. The development of strict diagnostic criteria in 1995 and their revision in 2003 helped to stimulate research interest on this syndrome. In community-based surveys, RLS has been studied as: 1) a symptom only, 2) a set of symptoms meeting minimal diagnostic criteria of the international restless legs syndrome study group (IRLSSG), 3) meeting minimal criteria accompanied with a specific frequency and/or severity, and 4) a differential diagnosis. In the first case, prevalence estimates in the general adult population ranged from 9.4% to 15%. In the second case, prevalence ranged from 3.9% to 14.3%. When frequency/severity is added, prevalence ranged from 2.2% to 7.9% and when differential diagnosis is applied prevalence estimates are between 1.9% and 4.6%. In all instances, RLS prevalence is higher in women than in men. It also increases with age in European and North American countries but not in Asian countries. Symptoms of anxiety and depression have been consistently associated with RLS. Overall, individuals with RLS have a poorer health than non-RLS but evidence for specific disease associations is mixed. Future epidemiological studies should focus on systematically adding frequency and severity in the definition of the syndrome in order to minimize the inclusion of cases mimicking RLS.

  View details for DOI 10.1016/j.smrv.2011.05.002

  View details for Web of Science ID 000306096700002

  View details for PubMedID 21795081

  View details for PubMedCentralID PMC3204316

• 5-HTTLPR Short Allele, Resilience, and Successful Aging in Older Adults AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY O'Hara, R., Marcus, P., Thompson, W. K., Flournoy, J., Vahia, I., Lin, X., Hallmayer, J., Depp, C., Jeste, D. V. 2012; 20 (5): 452-456

  Abstract

  Resilience is proposed as a significant component of successful aging. Young adult carriers of the Serotonin Transporter Polymorphism (5-HTTLPR) short(s) allele appear to have reduced resilience to stress. We examined whether the presence of the short allele was associated with poorer emotional resilience in older adults.In a cross-sectional study of 99 healthy, community-dwelling, older adults, we determined 5-HTTLPR genotype status and administered the Connor-Davidson Resilience Scale and self-reported measures of successful aging, cognition, and health.There was no significant association between the 5-HTTLPR s allele and resilience. S allele carriers had worse cognition and self-report ratings of successful aging.These findings suggest that the impact of the 5-HTTLPR s allele on stress-related outcomes may attenuate with older age. However, s allele status appears to be a biomarker of poorer self-rated successful aging, and cognitive performance in older adults.

  View details for DOI 10.1097/JGP.0b013e31823e2d03

  View details for Web of Science ID 000303295900010

  View details for PubMedID 22233775

  View details for PubMedCentralID PMC3326186

• Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Tirouvanziam, R., Obukhanych, T. V., Laval, J., Aronov, P. A., Libove, R., Banerjee, A. G., Parker, K. J., O'Hara, R., Herzenberg, L. A., Herzenberg, L. A., Hardan, A. Y. 2012; 42 (5): 827-836

  Abstract

  The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

  View details for DOI 10.1007/s10803-011-1314-x

  View details for Web of Science ID 000302771500017

  View details for PubMedID 21713591

• Validity of RLS diagnosis in epidemiologic research: Time to move on SLEEP MEDICINE Lee, H., Cho, Y., O'Hara, R. 2012; 13 (4): 325–26

  View details for DOI 10.1016/j.sleep.2011.11.016

  View details for Web of Science ID 000303346300001

  View details for PubMedID 22425682

• Sleep-Disordered Breathing in Vietnam Veterans with Posttraumatic Stress Disorder AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Yesavage, J. A., Kinoshita, L. M., Kimball, T., Zeitzer, J., Friedman, L., Noda, A., David, R., Hernandez, B., Lee, T., Cheng, J., O'Hara, R. 2012; 20 (3): 199-204

  Abstract

  : To study the prevalence of sleep-disordered breathing (SDB) in Vietnam- era veterans.: This was an observational study of Vietnam-era veterans using unattended, overnight polysomnography, cognitive testing, and genetic measures.: A sample of 105 Vietnam-era veterans with posttraumatic stress disorder: 69% had an Apnea Hypopnea Index >10. Their mean body mass index was 31, "obese" by Centers for Disease Control and Prevention criteria, and body mass index was significantly associated with Apnea Hypopnea Index (Spearman r = 0.41, N = 97, p < 0.0001). No significant effects of sleep-disordered breathing or apolipoprotein status were found on an extensive battery of cognitive tests.: There is a relatively high prevalence of SDB in these patients which raises the question of to what degree excess cognitive loss in older PTSD patients may be due to a high prevalence of SDB.

  View details for DOI 10.1097/JGP.0b013e3181e446ea

  View details for Web of Science ID 000300642300002

  View details for PubMedID 20808112

• DIMENSIONAL APPROACHES TO GERIATRIC MENTAL HEALTH DIAGNOSIS: RDOC AND DSM-5 Cuthbert, B. N., Jeste, D. V., O'Hara, R., Niederehe, G. ELSEVIER SCIENCE INC. 2012: S20–S21

  View details for Web of Science ID 000209846500017

• Utility of the Abbreviated Fuld Object Memory Evaluation and MMSE for Detection of Dementia and Cognitive Impairment not Dementia in Diverse Ethnic Groups JOURNAL OF ALZHEIMERS DISEASE Rideaux, T., Beaudreau, S. A., Fernandez, S., O'Hara, R. 2012; 31 (2): 371-386

  Abstract

  To address the growing need for ethnically unbiased cognitive screening, we examined whether the Mini Mental State Exam (MMSE), the abbreviated Fuld Object Memory Evaluation (FOME), or a combination of the two provided optimal detection of dementia in an ethnically diverse group of older adults with no cognitive impairment (normal); cognitive impairment not dementia (CIND); and dementia. Participants included 509 Caucasians, 124 African Americans, and 68 Latinos (>70 years old) from the Aging, Demographics, and Memory Study who completed the MMSE and FOME. Empirically derived decision trees were computed using signal detection software for receiver operator characteristics (ROC). Among the three ethnic groups, ROC analyses revealed that lower scores on both the MMSE and FOME provided better detection of CIND or dementia. Sensitivity and specificity of the MMSE was augmented by the addition of the FOME among Caucasian and African American older adults. The MMSE alone was the best screen in Latino older adults to distinguish any cognitive impairment from normal. When comparing CIND versus dementia, however, the FOME alone was best for detecting dementia among Latinos. The abbreviated FOME is recommended to increase clinical validity and thus minimize ethnic biases when administering the MMSE to Caucasian and African American older adults. The MMSE alone is preferred for older Latinos unless comparing CIND and dementia, in which case the FOME alone would then be recommended. Findings suggest that ethnicity is important in the selection of an appropriate cognitive screen and cut-score to use with older adults.

  View details for DOI 10.3233/JAD-2012-112180

  View details for Web of Science ID 000307377300013

  View details for PubMedID 22555374

• Gender differences in sexual behaviors of AD patients and their relationship to spousal caregiver well-being AGING & MENTAL HEALTH Davies, H. D., Sridhar, S. B., Newkirk, L. A., Beaudreau, S. A., O'Hara, R. 2012; 16 (1): 89-101

  Abstract

  Little is known about gender differences in sexuality among community-dwelling heterosexual couples in which one partner has Alzheimer's disease (AD). Few studies have examined gender differences in specific sexual behaviors or their associations with caregiver well-being. This study evaluated the impact of gender differences on intimacy and sexual satisfaction in marital relationships in which one partner has AD.Baseline measures were collected from 162 AD patients and their partners enrolled in a multi-site study between 2001 and 2009 to evaluate gender differences in measures of intimacy, caregiver well-being, and patient sexual behaviors.While over 70% of all patients initiated physically intimate activities (i.e., kissing, hugging, and intercourse), most did not initiate intercourse specifically. Female caregivers reported higher levels of stress and depressive symptoms than male caregivers (p < 0.01). Satisfaction with intimacy was significantly associated with fewer stress and depressive symptoms in female caregivers (r = -0.29, p < 0.01). Caregiver gender, satisfaction with intimacy, and caring for a patient with mild AD were significant predictors of caregiver depressive symptoms (p's < 0.05).The majority of couples dealing with AD reported engaging in intimacy, suggesting its importance in the relationship. Female caregivers who reported less sexual satisfaction reported more frequent stress and depressive symptoms. Caregiver gender, satisfaction with intimacy, and the AD patient's level of cognitive functioning significantly contributed to caregiver well-being. Gender-specific therapies to address patient sexual difficulties and caregiver well-being could potentially maintain or improve the marital relationship.

  View details for DOI 10.1080/13607863.2011.609532

  View details for Web of Science ID 000301535800009

  View details for PubMedID 21999712

  View details for PubMedCentralID PMC3358115

• Prefrontal Cortex and Executive Function Impairments in Primary Breast Cancer ARCHIVES OF NEUROLOGY Kesler, S. R., Kent, J. S., O'Hara, R. 2011; 68 (11): 1447-1453

  Abstract

  To examine differences in prefrontal-executive function between breast cancer (BC) survivors with and without a history of chemotherapy treatment compared with healthy control women and to determine the associations between prefrontal cortex deficits and behavioral impairments, as well as certain demographic and disease variables.Observational study.University-based research facility.Twenty-five women with BC who had received chemotherapy, 19 women with BC who had not received chemotherapy, and 18 healthy female controls, all matched for age and other demographic variables.Women with BC demonstrated significantly reduced activation in the left middle dorsolateral prefrontal cortex and premotor cortex compared with healthy controls. The chemotherapy group also demonstrated significantly reduced left caudal lateral prefrontal cortex activation and increased perseverative errors and reduced processing speed compared with the other 2 groups. Reduced left caudal lateral prefrontal cortex activation was significantly correlated with higher disease severity and elevated subjective executive dysfunction in the chemotherapy-treated women. Older age and lower educational level were associated with increased executive function impairment in the chemotherapy group.These findings provide further evidence of neurological impairment associated with primary BC irrespective of treatment history. The left caudal lateral prefrontal region may be particularly vulnerable to the effects of chemotherapy and/or disease severity and may represent a novel biomarker of subjective executive dysfunction in chemotherapy-treated women. Furthermore, negative effects of chemotherapy on brain function may be exacerbated by such factors as increased age and lower educational level.

  View details for Web of Science ID 000297014900013

  View details for PubMedID 22084128

• PERFORMANCE OF APPOINTMENT TASKS SCALE (PATS): A STAFF-RATED INSTRUMENT FOR ASSESSING OLDER ADULTS' PERFORMANCE OF EVERYDAY TASKS Holland, J. M., Anker, L., Jo, B., Kesler, S., Marquett, R., O'Hara, R., Pritchard-Berman, M., Gallagher-Thompson, D. OXFORD UNIV PRESS INC. 2011: 55–55

  View details for Web of Science ID 000303602000252

• Design Considerations for Characterizing Psychiatric Trajectories Across the Lifespan: Application to Effects of APOE-epsilon 4 on Cerebral Cortical Thickness in Alzheimer's Disease AMERICAN JOURNAL OF PSYCHIATRY Thompson, W. K., Hallmayer, J., O'Hara, R. 2011; 168 (9): 894-903

  Abstract

  Characterization of developmental trajectories across the lifespan is integral to understanding the prodromal course of many neuropsychiatric illnesses and the significant risk factors for disease onset or unfavorable outcomes. However, the standard experimental designs used in psychiatric research are not ideal for this purpose. The authors review the limitations of the most commonly employed designs in studies that make developmental or lifespan inferences in psychiatry: cross-sectional, single-cohort longitudinal, and unstructured multicohort longitudinal designs. Cross-sectional studies completely confound within- and between-subject sources of variation and hence rely on the presence of parallel trajectories and negligible sampling and age cohort differences for making valid developmental inferences. Delineating trajectories of within-individual change over substantial periods of time requires data covering long age spans that often cannot be covered using single-cohort longitudinal designs. Unstructured multicohort longitudinal designs are a commonly used alternative that can cover a longer age span in a shorter interval than necessary for a single-cohort design. However, the impact of cohort and sampling effects is often minimized or ignored in unstructured multicohort longitudinal designs. The authors propose that structured multicohort longitudinal designs are a particularly viable and underutilized class of designs in psychiatry that represents a significant improvement over cross-sectional designs and unstructured multicohort longitudinal designs for making developmental inferences while being more practical to implement than single-cohort longitudinal designs. As an example of this approach, the authors analyze changes in entorhinal cortex thickness in Alzheimer's disease in relation to APOE-ε4 genotype.

  View details for DOI 10.1176/appi.ajp.2011.10111690

  View details for Web of Science ID 000294484100009

  View details for PubMedID 21724665

• Circadian Clock Gene Polymorphisms and Sleep-Wake Disturbance in Alzheimer Disease AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Yesavage, J. A., Noda, A., Hernandez, B., Friedman, L., Cheng, J. J., Tinklenberg, J. R., Hallmayer, J., O'Hara, R., David, R., Robert, P., Landsverk, E., Zeitzer, J. M. 2011; 19 (7): 635-643

  Abstract

  One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

  View details for DOI 10.1097/JGP.0b013e31820d92b2

  View details for PubMedID 21709609

• MR Spectroscopy for Assessment of Memantine Treatment in Mild to Moderate Alzheimer Dementia JOURNAL OF ALZHEIMERS DISEASE Ashford, J. W., Adamson, M., Beale, T., La, D., Hernandez, B., Noda, A., Rosen, A., O'Hara, R., Fairchild, J. K., Spielman, D., Yesavage, J. A. 2011; 26: 331-336

  Abstract

  Magnetic Resonance Spectroscopy (MRS) may provide a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) and Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimer's disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients.A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr ratio in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores.This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/Cr ratio, or the secondary outcome measures.More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology.

  View details for DOI 10.3233/JAD-2011-0021

  View details for Web of Science ID 000297842800025

  View details for PubMedID 21971472

• A Method to Combine Cognitive and Neurophysiological Assessments of the Elderly DEMENTIA AND GERIATRIC COGNITIVE DISORDERS Gevins, A., Ilan, A. B., Jiang, A., Chan, C. S., Gelinas, D., Smith, M. E., McEvoy, L. K., Schwager, E., Padilla, M., Davis, Z., Meador, K. J., Patterson, J., O'Hara, R. 2011; 31 (1): 7-19

  Abstract

  The development of better treatments for brain diseases of the elderly will necessitate more sensitive and efficient means of repeatedly assessing an individual's neurocognitive status.To illustrate the development of an assessment combining episodic memory and working memory tasks with simultaneous electroencephalography and evoked potential (EP) brain function measures.Data from matched groups of elderly subjects with mildly impaired episodic verbal memory on neuropsychological tests and those with no objective signs of impairment were used for scale development. An exploratory multivariate divergence analysis selected task performance and neurophysiological variables that best recognized impairment. Discriminant validity was then initially assessed on separate impaired and unimpaired groups.Decreased response accuracy and parietal late positive component EP amplitude in the episodic memory task best characterized impaired subjects. Sensitivity in recognizing impairment in the validation analysis was 89% with 79% specificity (area under the curve = 0.94). Retest reliability was 0.89 for the unimpaired and 0.74 for the impaired validation groups.These promising initial results suggest that with further refinement and testing, an assessment combining cognitive task performance with simultaneous neurofunctional measures could eventually provide an important benefit for clinicians and researchers.

  View details for DOI 10.1159/000322108

  View details for Web of Science ID 000286425500002

  View details for PubMedID 21109739

  View details for PubMedCentralID PMC3019365

• Non-pharmacologic management of sleep disturbance in Alzheimer's disease JOURNAL OF NUTRITION HEALTH & AGING David, R., Zeitzer, J., Friedman, L., Noda, A., O'Hara, R., Robert, P., Yesavage, J. A. 2010; 14 (3): 203-206

  Abstract

  Sleep and wake in Alzheimer's disease (AD) are often fragmented as manifested by bouts of wakefulness at night and napping during the day. Management of sleep disturbances in AD is important because of their negative impact on both patients and caregivers. Pharmacological treatments, mainly sedative-hypnotics and antipsychotics, are often used but can be associated with significant adverse effects. Non-pharmacological treatments represent a beneficial alternative approach to the management of sleep disturbances in AD since they are associated with fewer adverse effects and their efficacy can be sustained after treatment has been completed. The aim of this article is to review non-pharmacological treatments, such as sleep hygiene, sleep restriction therapy (SRT), cognitive behavioral therapy (CBT), light therapy, and continuous positive airway pressure (CPAP), for the management of sleep/wake disturbances in AD.

  View details for DOI 10.1007/s12603-010-0050-9

  View details for Web of Science ID 000276527000006

  View details for PubMedID 20191254

• Increasing the Ranks of Academic Researchers in Mental Health: A Multisite Approach to Postdoctoral Fellowship Training ACADEMIC MEDICINE O'Hara, R., Cassidy-Eagle, E. L., Beaudreau, S. A., Eyler, L. T., Gray, H. L., Giese-Davis, J., Hubbard, J., Yesavage, J. A. 2010; 85 (1): 41-47

  Abstract

  This report highlights the use of multisite training for psychiatry and psychology postdoctoral fellows developing careers in academic clinical research in the field of mental health. The objective is to describe a model of training for young investigators to establish independent academic clinical research careers, including (1) program structure and eligibility, (2) program goals and development of a multisite curriculum, (3) use of technology for implementing the program across multiple sites, and (4) advantages and challenges of this multisite approach. In 2000, in collaboration with the Veterans Affairs (VA) Mental Illness Research, Education and Clinical Centers (MIRECCs), the VA Office of Academic Affiliations launched the Special Fellowship Program in Advanced Psychiatry and Psychology. Each of the 10 currently participating VA sites across the United States is affiliated with a MIRECC and an academic medical institution. In the first five years of this fellowship program, 83 fellows (34 psychiatrists and 49 psychologists) have participated. The success of this multisite approach is evidenced by the 58 fellows who have already graduated from the program: 70% have entered academic clinical research positions, and over 25 have obtained independent extramural grant support from the VA or the National Institutes of Health. Multisite training results in a greater transfer of knowledge and capitalizes on the nationwide availability of experts, creating unique networking and learning opportunities for trainees. The VA's multisite fellowship program plays a valuable role in preparing substantial numbers of psychiatry and psychology trainees for a range of academic clinical research and leadership positions in the field of mental health.

  View details for DOI 10.1097/ACM.0b013e3181c47c51

  View details for Web of Science ID 000276131300015

  View details for PubMedID 20042819

• Memory Before and After Sleep in Patients with Moderate Obstructive Sleep Apnea JOURNAL OF CLINICAL SLEEP MEDICINE Kloepfer, C., Riemann, D., Nofzinger, E. A., Feige, B., Unterrainer, J., O'Hara, R., Sorichter, S., Nissen, C. 2009; 5 (6): 540–48

  Abstract

  The aim of this study was to investigate the effects of obstructive sleep apnea (OSA) on procedural and declarative memory encoding in the evening prior to sleep, on memory consolidation during subsequent sleep, and on retrieval in the morning after sleep.Memory performance (procedural mirror-tracing task, declarative visual and verbal memory task) and general neuropsychological performance were assessed before and after one night of polysomnographic monitoring in 15 patients with moderate OSA and 20 age-, sex-, and IQ-matched healthy subjects.Encoding levels prior to sleep were similar across groups for all tasks. Conventional analyses of averaged mirror tracing performance suggested a significantly reduced overnight improvement in OSA patients. Single trial analyses, however, revealed that this effect was due to significantly flattened learning curves in the evening and morning session in OSA patients. OSA patients showed a significantly lower verbal retention rate and a non-significantly reduced visual retention rate after sleep compared to healthy subjects. Polysomnography revealed a significantly reduced REM density, increased frequency of micro-arousals, elevated apnea-hypopnea index, and subjectively disturbed sleep quality in OSA patients compared to healthy subjects.The results suggest that moderate OSA is associated with a significant impairment of procedural and verbal declarative memory. Future work is needed to further determine the contribution of structural or functional alterations in brain circuits relevant for memory, and to test whether OSA treatment improves or normalizes the observed deficits in learning.

  View details for Web of Science ID 000272780400009

  View details for PubMedID 20465021

  View details for PubMedCentralID PMC2792970

• The Career Development Institute for Psychiatry: An Innovative, Longitudinal Program for Physician-Scientists ACADEMIC PSYCHIATRY Kupfer, D. J., Schatzberg, A. F., Grochocinski, V. J., Dunn, L. O., Kelley, K. A., O'Hara, R. M. 2009; 33 (4): 313-318

  Abstract

  The Research Career Development Institute for Psychiatry is a collaboration between the University of Pittsburgh and Stanford University to recruit and train a broad-based group of promising junior physicians by providing the necessary skills and support for successful research careers in academic psychiatry.Participants whose interests span the spectrum of clinical and intervention research attend a multiday career development institute workshop and follow-up annual booster sessions conducted with the American College of Neuropsychopharmacology. The program identifies and trains 20 new physician-researchers each year, with particular emphasis on women, minorities, and those from less research-intensive psychiatry departments, and provides booster sessions for all trainees. An annual evaluation is used to renew and update the content of the institutes and to measure the long-term value in research and career success.This report is based on the results of 77 participants from the first four Career Development Institute classes. Qualitative assessment of the program content and process led to improvements in each successive year's workshop. Preliminary quantitative follow-up assessment of participants indicated successful career progress toward individual objectives.By providing early career investigators with skills to cope with local and national forces in academic medical centers, the Career Development Institute is significantly contributing to the development of the next generation of leading academic clinical researchers in mental health and can serve as a model for other biomedical research arenas.

  View details for Web of Science ID 000269055600010

  View details for PubMedID 19690113

  View details for PubMedCentralID PMC2758049

• The Association of Anxiety and Depressive Symptoms With Cognitive Performance in Community-Dwelling Older Adults PSYCHOLOGY AND AGING Beaudreau, S. A., O'Hara, R. 2009; 24 (2): 507-512

  Abstract

  The authors examined the association of anxiety, depressive symptoms, and their co-occurrence on cognitive processes in 102 community-dwelling older adults. Participants completed anxiety and depression questionnaires as well as measures of episodic and semantic memory, word fluency, processing speed/shifting attention, and inhibition. Participants with only increased anxiety had poorer processing speed/shifting attention and inhibition, but depressive symptoms alone were not associated with any cognitive deficits. Although coexisting anxiety and depressive symptoms were associated with deficits in 3 cognitive domains, reductions in inhibition were solely attributed to anxiety. Findings suggest an excess cognitive load on inhibitory ability in normal older adults reporting mild anxiety.

  View details for DOI 10.1037/a0016035

  View details for Web of Science ID 000266580700022

  View details for PubMedID 19485667

  View details for PubMedCentralID PMC2725021

• Genetic Influences on Late-Life Mental Health: Do Genes Determine Destiny? Lenze, E. J., O'Hara, R., Sweet, R. A., Taylor, W. D. LIPPINCOTT WILLIAMS & WILKINS. 2009: A25

  View details for Web of Science ID 000207905900025

• Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT O'Hara, R., Luzon, A., Hubbard, J., Zeitzer, J. M. 2009; 46 (6): 837-850

  Abstract

  Sleep apnea is prevalent among patients with traumatic brain injuries (TBIs), and initial studies suggest it is associated with cognitive impairments in these patients. Recent studies found that the apolipoprotein epsilon 4 (APOE epsilon 4) allele increases the risk for sleep disordered breathing, particularly sleep apnea. The APOE epsilon 4 allele is associated with cognitive decline and the development of dementia in the general population as well as in patients with TBI. These findings raise the question of whether patients with TBI who are APOE epsilon 4 allele carriers are more vulnerable to the negative effects of sleep apnea on their cognitive functioning. While few treatments are available for cognitive impairment, highly effective treatments are available for sleep apnea. Here we review these different lines of evidence, making a case that the interactive effects of sleep apnea and the APOE epsilon 4 allele represent an important mechanism by which patients with TBI may develop a range of cognitive and neurobehavioral impairments. Increased understanding of the relationships among sleep apnea, the APOE epsilon 4 allele, and cognition could improve our ability to ameliorate one significant source of cognitive impairment and risk for dementia associated with TBI.

  View details for DOI 10.1682/JRRD.2008.10.0140

  View details for Web of Science ID 000272638100015

  View details for PubMedID 20104407

• Insomnia in the context of traumatic brain injury JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT Zeitzer, J. M., Friedman, L., O'Hara, R. 2009; 46 (6): 827-835

  Abstract

  Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the United States. One of the most common comorbidities of TBI is the disruption of normal sleep. While often viewed as a nuisance symptom, sleep disruption can delay TBI recovery and negatively affect many of the psychological (e.g., anxiety, depression) and neuromuscular (e.g., pain) sequelae of TBI, decreasing quality of life. Treatment of sleep disruption in the context of TBI is complicated by issues of an altered neuronal milieu, polypharmacy, and the complex relationship between the various comorbidities often found in patients with TBI. Given the growing number of veterans returning from combat with TBI and the elevated risk of comorbid disrupted sleep, both caused by and independent of TBI, a comprehensive review of sleep disruption and its treatment is of great relevance to the Department of Veterans Affairs.

  View details for DOI 10.1682/JRRD.2008.08.0099

  View details for Web of Science ID 000272638100014

  View details for PubMedID 20104406

• Late-life anxiety and cognitive impairment: A review AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Beaudreau, S. A., O'Hara, R. 2008; 16 (10): 790-803

  Abstract

  Emerging research implicates a consistent reciprocal relationship between late-life anxiety and cognition. Understanding this relationship may clarify pathophysiological substrates of cognitive impairment and why co-occurring anxiety and cognitive impairment relates to poorer treatment prognosis for both conditions. This article critically reviews evidence of more prevalent anxiety in cognitively impaired older adults, elevated anxiety related to poorer cognitive performance, and more severe anxiety symptoms predicting future cognitive decline. It considers pathophysiologic mediators and moderators, and the influence of comorbid depression or medical illness in anxiety. Identified directions for future research includes use of in-depth anxiety assessment comparing normal and mild cognitively impaired older adults and use of challenging neuropsychological tests to determine if specific cognitive domains suffer in anxious older adults.

  View details for Web of Science ID 000259703400002

  View details for PubMedID 18827225

• 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

• Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP) ANNALS OF NEUROLOGY Gothelf, D., Furfaro, J. A., Hoeft, F., Eckert, M. A., Hall, S. S., O'Hara, R., Erba, H. W., Ringel, J., Hayashi, K. M., Patnaik, S., Golianu, B., Kraemer, H. C., Thompson, P. M., Piven, J., Reiss, A. L. 2008; 63 (1): 40-51

  Abstract

  To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.

  View details for DOI 10.1002/ana.21243

  View details for Web of Science ID 000253008700007

  View details for PubMedID 17932962

  View details for PubMedCentralID PMC2773141

• Long-term effects of mnemonic training in community-dwelling older adults JOURNAL OF PSYCHIATRIC RESEARCH O'Hara, R., Brooks, J. O., Friedman, L., Schroder, C. M., Morgan, K. S., Kraemer, H. C. 2007; 41 (7): 585-590

  Abstract

  The purpose of our study was to investigate the long-term effect of mnemonic training on memory performance in older adults. Five years after participation in a mnemonic training study, we followed-up 112 community-dwelling older adults, 60 years of age and over. Delayed recall of a word list was assessed prior to, and immediately following mnemonic training, and at the 5-year follow-up. Overall, there was no significant difference between word recall prior to training and that exhibited at follow-up. However, pre-training performance, gain scores in performance immediately post-training and use of the mnemonic predicted performance at follow-up. Individuals who self-reported using the mnemonic exhibited the highest performance overall, with scores significantly higher than at pre-training. Our findings suggest that mnemonic training has long-term benefits for some older adults, particularly those who continue to employ the mnemonic.

  View details for DOI 10.1016/j.jpsychires.2006.04.010

  View details for Web of Science ID 000245426800006

  View details for PubMedID 16780878

• Should one use medications in combination with cognitive training? If so, which ones? JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES Yesavage, J., Hoblyn, J., Friedman, L., Mumenthaler, M., Schneider, B., O'Hara, R. 2007; 62: 11-18

  Abstract

  In this article, we review current research regarding diagnosis of cognitive impairment in nondemented adults and discuss why medications and cognitive training together may be more beneficial than either alone. We also review potential cognitive enhancers and future research challenges. There are major reasons for such research: (a) Large numbers of older adults without dementia but with cognitive problems are not treatable with current cognitive training techniques; (b) some medications offer a rationale (i.e., cognitive enhancement) and some evidence that they might be a useful adjunct; and (c) there are unanswered questions about which population to target, which medications to use, how to administer them, and issues regarding tolerance and use of appropriate (active) placebo controls. As the number of cognitively impaired older adults grows, it is likely that there will be pressure to treat more broadly with both medications and cognitive training.

  View details for Web of Science ID 000253836500002

  View details for PubMedID 17565161

• Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol MOLECULAR PSYCHIATRY O'Hara, R., Schroder, C. M., Mahadevan, R., Schatzberg, A. F., Lindley, S., Fox, S., Weiner, M., Kraemer, H. C., Noda, A., Lin, X., Gray, H. L., Hallmayer, J. F. 2007; 12 (6): 544-555

  Abstract

  The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.

  View details for DOI 10.1038/sj.mp.4001978

  View details for Web of Science ID 000246906200003

  View details for PubMedID 17353910

  View details for PubMedCentralID PMC2084475

• Serotonin transporter polymorphism and stress: a view across the lifespan. Current psychiatry reports O'Hara, R., Hallmayer, J. F. 2007; 9 (3): 173-175

  View details for PubMedID 17521511

• Should older adults be screened for dementia? It is important to screen for evidence of dementia! ALZHEIMERS & DEMENTIA Ashford, J. W., Borson, S., O'Hara, R., Dash, P., Frank, L., Robert, P., Shankle, W. R., Tierney, M. C., Brodaty, H., Schmitt, F. A., Kraemer, H. C., Buschke, H., Fillit, H. 2007; 3 (2): 75-80

  Abstract

  Multiple arguments for considering routine dementia screening have been presented. Furthermore, dementia diagnoses are widely unrecognized. As a result, persons with dementia are missing important clinical care and treatment interventions. By distinction, the problems of defining, diagnosing, and treating mild cognitive impairment (MCI) are not yet resolved, and MCI is not ready for a screening recommendation. Dementia screening approaches, including cognitive testing and functional assessment, must be evaluated on their scientific merits, including sensitivity and specificity for recognizing affected individuals in at-risk populations. Screening tests must be "cost-worthy", with the benefits of true-positive test results justifying the costs of testing and resolving false-positive cases, with due consideration for proper diagnostic evaluation and potential harms. With the tremendous number of new cases projected in the near future and the expected emergence of beneficial therapies, considerably more research is needed to develop more efficient screening systems.

  View details for DOI 10.1016/j.jalz.2007.03.005

  View details for Web of Science ID 000249579900002

  View details for PubMedID 19595920

  View details for PubMedCentralID PMC2804947

• The impact of autobiographic writing on memory performance in older adults: A preliminary investigation AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY de Medeiros, K., Kennedy, Q., Cole, T., Lindley, R., Hara, R. O. 2007; 15 (3): 257-261

  Abstract

  In this pilot study, the authors examined whether participation in a structured autobiographic writing workshop positively influenced memory performance in a group of community-dwelling older adults. Eighteen subjects, aged 62-84 years, were enrolled in an eight-week writing workshop. At baseline and follow up, they completed five memory assessments and submitted two writing samples, which were evaluated for linguistic complexity. The authors found a significant increase in follow-up scores on tests of verbal memory and attention, indicating a possible positive influence of the writing workshop. The authors also found a decline in idea density, suggesting that more research is needed to better understand how interpretation of the language assessment tool may be affected by improvements in writing.

  View details for Web of Science ID 000244993200010

  View details for PubMedID 17322137

• COMT genotype, gender and cognition in community-dwelling, older adults NEUROSCIENCE LETTERS O'Hara, R., Miller, E., Liao, C., Way, N., Lin, X., Hallmayer, J. 2006; 409 (3): 205-209

  Abstract

  A common polymorphism (Val158Met) in the gene encoding for the catechol-O-methyltransferase (COMT) enzyme has been associated with differences in prefrontal cognitive function in schizophrenic patients and healthy adults. While several studies indicate that the Met allele is associated with better performance on measures of executive function, working memory and verbal fluency, results have been inconsistent. Furthermore, fewer studies have investigated this relationship in older adults, a group known to experience impairments in prefrontal cognitive functions. Additionally, findings vary according to the gender distribution of study participants. We examined whether COMT genotype interacted with gender to impact cognition in a cohort of 163 healthy, older adults. Memory, verbal ability and areas of prefrontal cognitive function, including attention, speed-of-processing, and executive function, were assessed. We found no significant association between COMT genotype and any cognitive measure. However, gender interacted with COMT genotype to impact cognitive performance. Males homozygous for the Val allele performed better than both the Val/Met and Met/Met groups on measures of delayed recall. Heterozygous women performed better than their homozygous counterparts on the measure of verbal ability. These findings suggest that gender may be an important variable in consideration of the impact of COMT on cognition. Further, when gender is taken into consideration, any negative impact of COMT genotype may extend to cognitive domains other than those associated with prefrontal regions.

  View details for DOI 10.1016/j.neulet.2006.09.047

  View details for Web of Science ID 000242448500010

  View details for PubMedID 17029783

  View details for PubMedCentralID PMC1892791

• Stress, aging, and mental health AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY O'Hara, R. 2006; 14 (4): 295-298

  View details for Web of Science ID 000236540800001

  View details for PubMedID 16582037

• Should older adults be screened for dementia? Alzheimer's & dementia : the journal of the Alzheimer's Association Ashford, J. W., Borson, S., O'Hara, R., Dash, P., Frank, L., Robert, P., Shankle, W. R., Tierney, M. C., Brodaty, H., Schmitt, F. A., Kraemer, H. C., Buschke, H. 2006; 2 (2): 76-85

  Abstract

  The question of whether to screen for dementia and Alzheimer's disease (AD) has been discussed in many forums throughout the world. Generally, medical advisory groups and policy-making groups have recognized the importance of early diagnosis but have uniformly avoided making recommendations to screen at-risk populations. This presentation reflects the support for reconsidering the importance of screening individuals at risk or above a certain age. In this statement, the majority of the authors support the consideration of dementia risk factors in individuals at age 50, with routine yearly screening after 75. Other authors remain concerned that the benefits of treatments of early disease do not yet support a general screening recommendation. These statements are made to encourage progress toward the development of a consensus regarding the widespread institution of screening policy. Accordingly, members of the worldwide scientific community are invited to add their perspective by contributing short commentaries (1500 words) on this subject.

  View details for DOI 10.1016/j.jalz.2006.02.005

  View details for PubMedID 19595860

• Design decisions to optimize reliability of daytime cortisol slopes in an older population 26th Annual Meeting of the Society-for-Behavioral-Medicine Kraemer, H. C., Giese-Davis, J., Yutsis, M., Neri, E., Gallagher-Thompson, D., Taylor, C. B., Spiegel, D. LIPPINCOTT WILLIAMS & WILKINS. 2006: 325–33

  Abstract

  The daytime log-cortisol slope appears to be of growing importance in studying the relationship between stress and health. How best to estimate that slope with minimal burden to the participants and the cost of the study is a decision often made without empiric foundation.In 50 older participants, the authors examined cortisol assay comparability across laboratories, assay reliability, test-retest reliability of slopes, and comparability of slope estimates for two, three, and four samples per day.The authors demonstrate in an older sample that 1) assay reliability is a relatively minor issue, that one assay per saliva sample suffices; 2) the use of a sample obtained at wake time for each participant appears to be a preferred anchor for the slope estimate in comparison to a sample 30 minutes postwake time; 3) self-reported times appear preferable to automatic time recording; and 4) test-retest reliability of slopes, however, is not sufficiently high to base a slope estimate on one day; minimally two days and preferably three should be required.Whether these conclusions apply to other populations, or using other protocols, is not assured, but the study itself provides a model that can be used to check research decisions. Unnecessarily imposing a burdensome protocol has both ethical and scientific ramifications and should be carefully avoided.

  View details for Web of Science ID 000236540800005

  View details for PubMedID 16582041

• 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

• Factors in choosing atypical antipsychotics: Toward understanding the bases of physicians' prescribing decisions JOURNAL OF PSYCHIATRIC RESEARCH Hoblyn, J., Noda, A., Yesavage, J. A., Brooks, J. O., Sheikh, J., Lee, T., Tinklenberg, J. R., Schneider, B., O'Hara, R., Leslie, D. L., Rosenheck, R. A., Kraemer, H. C. 2006; 40 (2): 160-166

  Abstract

  Off-label prescribing of medications, polypharmacy, and other questionable prescribing practices have led investigators to examine a large VA pharmacy database to determine if physician prescribing decisions appear reasonable.The current study addresses the question of physician prescribing of atypical antipsychotics in 34,925 veterans with schizophrenia, using a series of signal detection analyses.These results suggest that only three factors (hospital size, age, and secondary diagnosis) allow classification of patients prescribed atypicals into three groups with frequencies of use of atypicals ranging from 43% to 79%, and that these results are consistent with reasonable clinical practice.Results of two-stage signal detection analyses are readily interpretable by clinicians and administrators who are faced with the task of evaluating how physicians prescribe medications in clinical practice. Physicians' decisions to prescribe atypical antipsychotics are based on both patient and fiscal considerations. This likely reflects a combination of clinical judgment and institutional guidelines.

  View details for DOI 10.1016/j.jpsychires.2005.06.004

  View details for Web of Science ID 000235641200009

  View details for PubMedID 16150458

• Unraveling the relationship of obstructive sleep-disordered breathing to major depressive disorder SLEEP MEDICINE O'Hara, R. 2006; 7 (2): 101-103

  View details for DOI 10.1016/j.steep.2005.11.011

  View details for Web of Science ID 000236490900002

  View details for PubMedID 16458604

• Hormone replacement therapy and longitudinal cognitive performance in postmenopausal women AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY O'Hara, R., Schroder, C. M., Bloss, C., Bailey, A. M., Alyeshmerni, A. M., Mumenthaler, M. S., Friedman, L. F., Yesavage, J. A. 2005; 13 (12): 1107-1110

  Abstract

  The authors examined the impact of hormone replacement therapy (HRT) on longitudinal cognitive performance (controlling for mood state) in 69 community-dwelling, postmenopausal women.The authors conducted a 5-year follow-up of cognitive performance in 37 postmenopausal HRT users and 32 non-users. The groups did not differ with respect to age, years of education, or inter-test interval.No main effect of HRT was observed on any of the cognitive measures, and depressive symptomatology did not affect the relationship between HRT and cognition.Overall, our findings do not suggest that HRT affects longitudinal cognitive performance in postmenopausal, community-dwelling older women.

  View details for Web of Science ID 000233614500011

  View details for PubMedID 16319304

• The role of hypoxia in apolipoprotein E4-associated cognitive impairment: Implications for neurodegeneration and sleep-disordered breathing SLEEP O'Hara, R. 2005; 28 (11): 1355–57

  View details for Web of Science ID 000233103500003

  View details for PubMedID 16335323

• 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

• Relating medial temporal lobe volume to frontal fMRI activation for memory encoding in older adults CORTEX Rosen, A. C., Gabrieli, J. D., Stoub, T., Prull, M. W., O'Hara, R., Yesavage, J., DeToledo-Morrell, L. 2005; 41 (4): 595-602

  Abstract

  Neuroimaging research on the brain basis of memory decline in older adults typically has examined age-related changes either in structure or in function. Structural imaging studies have found that smaller medial temporal lobe (MTL) volumes are associated with lower memory performance. Functional imaging studies have found that older adults often exhibit bilateral frontal-lobe activation under conditions where young adults exhibit unilateral frontal activation. As yet, no one has examined whether these MTL structural and frontal-lobe functional findings are associated. In this study, we tested whether these findings were correlated in a population of healthy older adults in whom we previously demonstrated verbal memory performance was positively associated with left entorhinal cortex volume in the MTL (Rosen et al., 2003) and right frontal lobe activation during memory encoding (Rosen et al., 2002). Thirteen, non-demented, community-dwelling older adults participated both in a functional MRI (fMRI) study of verbal memory encoding and structural imaging. MRI-derived left entorhinal volume was measured on structural images and entered as a regressor against fMRI activation during verbal memory encoding. Right frontal activation (Brodmann's Area 47/insula) was positively correlated with left entorhinal cortex volume. These findings indicate a positive association between MTL volume and right frontal-lobe function that may underlie variability in memory performance among the elderly, and also suggest a two-stage model of memory decline in aging.

  View details for Web of Science ID 000230574200015

  View details for PubMedID 16042035

• Underreporting of behavioral problems in older hospitalized patients GERONTOLOGIST Davies, H. D., O'Hara, R., Mumenthaler, M. S., Cassidy, E. L., Buffum, M., Kim, J. M., Danielsen, C. E., Noda, A., Kraemer, H. C., Sheikh, J. I. 2005; 45 (4): 535-538

  Abstract

  This descriptive study examined reports of behavioral problems among older patients hospitalized in acute care medical settings. Greater numbers of behavioral problems were reported by nursing staff on the Neuropsychiatric Inventory-Questionnaire than were documented in medical charts over the same time period. Such underreporting may have clinical and administrative implications.

  View details for Web of Science ID 000230872100012

  View details for PubMedID 16051916

• Depression and Obstructive Sleep Apnea (OSA). Annals of general psychiatry Schröder, C. M., O'Hara, R. 2005; 4: 13-?

  Abstract

  For over two decades clinical studies have been conducted which suggest the existence of a relationship between depression and Obstructive Sleep Apnea (OSA). Recently, Ohayon underscored the evidence for a link between these two disorders in the general population, showing that 800 out of 100,000 individuals had both, a breathing-related sleep disorder and a major depressive disorder, with up to 20% of the subjects presenting with one of these disorders also having the other. In some populations, depending on age, gender and other demographic and health characteristics, the prevalence of both disorders may be even higher: OSA may affect more than 50% of individuals over the age of 65, and significant depressive symptoms may be present in as many as 26% of a community-dwelling population of older adults. In clinical practice, the presence of depressive symptomatology is often considered in patients with OSA, and may be accounted for and followed-up when considering treatment approaches and response to treatment. On the other hand, sleep problems and specifically OSA are rarely assessed on a regular basis in patients with a depressive disorder. However, OSA might not only be associated with a depressive syndrome, but its presence may also be responsible for failure to respond to appropriate pharmacological treatment. Furthermore, an undiagnosed OSA might be exacerbated by adjunct treatments to antidepressant medications, such as benzodiazepines. Increased awareness of the relationship between depression and OSA might significantly improve diagnostic accuracy as well as treatment outcome for both disorders. In this review, we will summarize important findings in the current literature regarding the association between depression and OSA, and the possible mechanisms by which both disorders interact. Implications for clinical practice will be discussed.

  View details for PubMedID 15982424

• The effect of oxybutynin treatment on cognition in children with diurnal incontinence Annual Meeting of the Section on Urology of the American-Academy-of-Pediatrics Sommer, B. R., O'Hara, R., Askari, N., Kraemer, H. C., Kennedy, W. A. ELSEVIER SCIENCE INC. 2005: 2125–27

  Abstract

  Oxybutynin is a powerful anticholinergic drug already known to impair cognition in the elderly. The impact of this drug on cognitive functioning in the pediatric population is unknown. We report the results of a study designed to assess the effect of oxybutynin on cognitive function in children.A total of 25 patients presenting with the primary symptom of daytime enuresis were recruited for this nonrandomized trial. All subjects initially received 4 weeks of behavior modification, followed by an additional 4 weeks of behavior modification either alone or with oxybutynin for continued treatment of enuresis. Neuropsychological testing was performed at baseline (4 weeks) and after additional therapy (8 weeks).Patient demographics included a male-to-female ratio of 11:14 and a mean age of 7.2 +/- 1.8 years. A total of 10 patients were assigned to the control group receiving behavior modification, and 15 patients were assigned to the treatment group receiving behavior modification plus oxybutynin. The oxybutynin treated patients had a lower overall performance at baseline pretreatment testing. However, performance in this group improved following treatment with oxybutynin.Oxybutynin, a commonly used pharmacological agent in pediatric urology, was not associated with cognitive impairment following treatment. However, we observed lower baseline cognitive functioning in patients whose parents chose oxybutynin over behavior modification alone. This finding may represent a selection bias. However, it also supports the need for a multidisciplinary approach to the treatment of patients with dysfunctional voiding, as some may have cognitive difficulties that have not previously been explored.

  View details for PubMedID 15879864

• Cognitive ability, expertise, and age differences in following air-traffic control instructions 9th Biennial Cognitive Aging Conference Taylor, J. L., O'Hara, R., Mumenthaler, M. S., Rosen, A. C., Yesavage, J. A. AMER PSYCHOLOGICAL ASSOC. 2005: 117–33

  Abstract

  Differences in cognitive ability and domain-specific expertise may help explain age differences in pilot performance. Pilots heard air-traffic controller messages and then executed them while "flying" in a simulator. Messages varied in length and speech rate. Age was associated with lower accuracy, but the expected Age x Message Difficulty interactions were not obtained. Expertise, as indexed by pilot ratings, was associated with higher accuracy; yet expertise did not reduce age differences in accuracy. The effect of age on communication task accuracy was largely explainable as an age-associated decrease in working memory span, which in turn was explainable as decreases in both speed and interference control. Results are discussed within frameworks of deliberate practice and cognitive mediation of age differences.

  View details for DOI 10.1037/0882-7974.20.1.117

  View details for Web of Science ID 000227731300009

  View details for PubMedID 15769218

• The role of hypoxia in apolipoprotein E4-associated cognitive impairment: implications for neurodegeneration and sleep-disordered breathing Sleep O'Hara R 2005; 28 (11): 1355-57
• Stress and neuroendocrine reactivity among caucasian and hispanic women: A preliminary comparison of family dementia caregivers and non-caregivers Gallagher-Thompson, D., Rider, K. L., Shurgot, G. R., O'Hara, R., Kraemer, H. C., Yesavage, J. A. ELSEVIER SCIENCE INC. 2004: S344

  View details for DOI 10.1016/S0197-4580(04)81131-X

  View details for Web of Science ID 000223058701129

• 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

• Categorical versus dimensional approaches to diagnosis: methodological challenges Conference on Non Schizophrenic Psychoses Kraemer, H. C., Noda, A., O'Hara, R. PERGAMON-ELSEVIER SCIENCE LTD. 2004: 17–25

  Abstract

  The arguments pitting categorical versus dimensional approaches to psychiatric diagnosis have been long ongoing with little sign of imminent resolution. We argue that categorical and dimensional approaches are fundamentally equivalent, but that one or other approach is more appropriate depending on the clinical circumstances and research questions being addressed. This paper aims to demonstrate (a) how these two approaches necessarily interdigitate, (b) to clarify the conditions under which one should utilize one approach over the other, and (c) to alert psychiatric clinicians and researchers to issues in the methodology literature that might facilitate their considerations. Using an example from the Infant Health and Development Program (IHDP), we illustrate the importance of using dimensional approaches for hypothesis testing, identify the problems with power and with interpretation that arise from employing a categorical approach, and underscore the importance of identifying the appropriate cutpoints when a categorical approach is necessitated. We argue that failure to utilize the correct approach under the appropriate circumstances can result in impaired clinical and research decision-making.

  View details for DOI 10.1016/S0022-3956(03)00097-9

  View details for Web of Science ID 000220190700003

  View details for PubMedID 14690767

• Unipolar late-onset depression: A comprehensive review. Annals of general hospital psychiatry Fountoulakis, K. N., O'Hara, R., Iacovides, A., Camilleri, C. P., Kaprinis, S., Kaprinis, G., Yesavage, J. 2003; 2 (1): 11-?

  Abstract

  BACKGROUND: The older population increases all over the world and so also does the number of older psychiatric patients, which manifest certain specific and unique characteristics. The aim of this article is to provide a comprehensive review of the international literature on unipolar depression with onset at old age. METHODS: The authors reviewed several pages and books relevent to the subject but did not search the entire literature because of it's overwhelming size. They chose to review those considered most significant. RESULTS: The prevalence of major depression is estimated to be 2% in the general population over 65 years of age. The clinical picture of geriatric depression differs in many aspects from depression in younger patients. It is not yet clear whether it also varies across cultures and different socio-economic backgrounds. Biological data suggest that it is associated with an increased severity of subcortical vascular disease and greater impairment of cognitive performance. Many authors consider the existence of a somatic disorder to be related to the presence of depression in late life, even constituting a negative prognostic factor for the outcome of depression. Most studies support the opinion that geriatric depression carries a poorer prognosis than depression in younger patients. The therapeutic intervention includes pharmacotherapy, mainly with antidepressants, which is of established value and psychotherapy which is not equally validated. CONCLUSION: A significant number of questions regarding the assessment and treatment of geriatric depression remain unanswered, empirical data are limited, and further research is necessary.

  View details for PubMedID 14675492

• Differential associations between entorhinal and hippocampal volumes and memory performance in older adults BEHAVIORAL NEUROSCIENCE Rosen, A. C., Prull, M. W., Gabrieli, J. D., Stoub, T., O'Hara, R., Friedman, L., Yesavage, J. A., DeToledo-Morrell, L. 2003; 117 (6): 1150-1160

  Abstract

  Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r= .79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r= .57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults.

  View details for DOI 10.1037/0735-7044.117.6.1150

  View details for Web of Science ID 000187402300004

  View details for PubMedID 14674836

• Age and disease severity predict choice of atypical neuroleptic: a signal detection approach to physicians' prescribing decisions JOURNAL OF PSYCHIATRIC RESEARCH Yesavage, J. A., Hoblyn, J., Sheikh, J., Tinklenberg, J. R., Noda, A., O'Hara, R., Fenn, C., Mumenthaler, M. S., Friedman, L., Kraemer, H. C. 2003; 37 (6): 535-538

  Abstract

  We used a novel application of a signal detection technique, receiver operator characteristics (ROC), to describe factors entering a physician's decision to switch a patient from a typical high potency neuroleptic to a particular atypical, olanzapine (OLA) or risperidone (RIS).ROC analyses were performed on pharmacy records of 476 VA patients who had been treated on a high potency neuroleptic then changed to either OLA or RIS.Overall 68% patients switched to OLA and 32% to RIS. The best predictor of neuroleptic choice was age at switch, with 78% of patients aged less than 55 years receiving OLA and 51% of those aged greater than or equal to 55 years receiving OLA (chi(2)=38.2, P<0.001). Further analysis of the former group indicated that adding the predictor of one or more inpatient days to age increased the likelihood of an OLA switch from 78% to 85% (chi(2)=7.3, P<0.01) while further analysis of the latter group indicated that adding the predictor of less than 10 inpatients days to age decreased the likelihood of an OLA switch from 51% to 45% (chi(2)=7.0, P<0.01).ROC analyses have the advantage over other analyses, such as regression techniques, insofar as their "cut-points" are readily interpretable, their sequential use forms an intuitive "decision tree" and allows the potential identification of clinically relevant "subgroups". The software used in this analysis is in the public domain (http://mirecc.stanford.edu).

  View details for DOI 10.1016/S0022-3956(03)00053-0

  View details for Web of Science ID 000186239700010

  View details for PubMedID 14563385

• Psychoactive drugs and pilot performance: A comparison of nicotine, donepezil, and alcohol effects NEUROPSYCHOPHARMACOLOGY Mumenthaler, M. S., Yesavage, J. A., Taylor, J. L., O'Hara, R., Friedman, L., LEE, H., Kraemer, H. C. 2003; 28 (7): 1366-1373

  Abstract

  The cholinergic system plays a major role in cognitive abilities that are essential to piloting an aircraft: attention, learning, and memory. In previous studies, drugs that enhance the cholinergic system through different pharmacologic mechanisms have shown beneficial effects on cognition; but dissimilar cognitive measures were used and samples were not comparable. A comparison within the same cognitive tasks, within comparable samples appears desirable. Toward this aim, we compared effect sizes (ES) of performance-enhancing doses of nicotine (a nicotinic receptor agonist) and donepezil (an acetylcholinesterase inhibitor) as found in our prior work on pilot performance. We also compared cholinergic ES to those of performance-impairing doses of alcohol. In three randomized, placebo-controlled trials, we assessed the flight performance of aircraft pilots in a Frasca 141 simulator, testing I: the acute effects of nicotine gum 2 mg; II: the effects of administration of 5 mg donepezil/day for 30 days; and III: the acute and 8 h-carryover effects of alcohol after a target peak BAC of 0.10%. We calculated the ES of nicotine, donepezil, and alcohol on a flight summary score and on four flight component scores. Compared to placebo, nicotine and donepezil significantly improved, while alcohol significantly impaired overall flight performance: ES (nicotine)=0.80; ES (donepezil)=1.02; ES (alcohol acute)=-3.66; ES (alcohol 8 h)=-0.82. Both cholinergic drugs showed the largest effects on flight tasks requiring sustained visual attention. Although the two tested cholinergic drugs have different pharmacologic mechanisms, their effects on flight performance were similar in kind and size. The beneficial effects of the cholinergic drugs on overall flight performance were large and the absolute (ie nondirectional) sizes were about one-fourth of the absolute ES of acute alcohol intoxication and roughly the same as the absolute 8 h-carryover ES of alcohol.

  View details for DOI 10.1038/sj.npp.1300202

  View details for Web of Science ID 000183773000018

  View details for PubMedID 12784106

• 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

• Variable effects of aging on frontal lobe contributions to memory NEUROREPORT Rosen, A. C., Prull, M. W., O'Hara, R., Race, E. A., Desmond, J. E., Glover, G. H., Yesavage, J. A., Gabrieli, J. D. 2002; 13 (18): 2425-2428

  Abstract

  Declarative memory declines with age, but there is profound variation in the severity of this decline. Healthy elderly adults with high or low memory scores and young adults viewed words under semantic or non-semantic encoding conditions while undergoing fMRI. Young adults had superior memory for the words, and elderly adults with high memory scores had better memory for the words than those with low memory scores. The elderly with high scores had left lateral and medial prefrontal activations for semantic encoding equal to the young, and greater right prefrontal activation than the young. The elderly with low scores had reduced activations in all three regions relative to the elderly with high memory scores. Thus, successful aging was characterized by preserved left prefrontal and enhanced right prefrontal activation that may have provided compensatory encoding resources.

  View details for DOI 10.1097/01.wnr.0000048001.96487.05

  View details for Web of Science ID 000180673200010

  View details for PubMedID 12499842

• Cognitive status and behavioral problems in older hospitalized patients. Annals of general hospital psychiatry O'Hara, R., Mumenthaler, M. S., Davies, H., Cassidy, E. L., Buffum, M., Namburi, S., Shakoori, R., Danielsen, C. E., Tsui, P., Noda, A., Kraemer, H. C., Sheikh, J. I. 2002; 1 (1): 1-?

  Abstract

  OBJECTIVES: (a) To determine the quantity and quality of behavioral problems in older hospitalized patients on acute care units; (b) to determine the burden of these behaviors on staff; and (c) to identify predictors of behavioral problems. METHODS: Upon admission, patients performed the Mini-Mental State Exam (MMSE), the Geriatric Depression Scale (GDS), and information was obtained on age, ethnicity, level of education, living arrangement, and psychiatric history. Two days post-admission, a clinical staff member caring for each patient, performed the Neuropsychiatric Inventory-Questionnaire (NPI-Q) to assess patients' behavioral problems and staff distress. PARTICIPANTS AND SETTING : Forty-two patients, over 60 years of age, admitted to medical and surgical units of the Veterans Affairs Hospitals in Palo Alto and San Francisco, participated. RESULTS: Twenty-three of 42 (55%) patients exhibited behavioral problems. Anxiety, depression, irritability, and agitation/aggression were the most frequently observed behaviors. The severity of the behavioral problems was significantly correlated with staff distress. Lower performance on the MMSE at admission was significantly associated with higher NPI-Q ratings. Specifically, of those cases with scores less than or equal to 27 on the MMSE, 66% had behavioral problems during hospitalization, compared to only 31% of those with scores greater than 27. CONCLUSION: Behavioral problems in older hospitalized patients appear to occur frequently, are a significant source of distress to staff, and can result in the need for psychiatric consultation. Assessment of the mental status of older adults at admission to hospital may be valuable in identifying individuals at increased risk for behavioral problems during hospitalization.

  View details for PubMedID 12537601

• Modeling the prevalence and incidence of Alzheimer's disease and mild cognitive impairment European Winter Conference on Brain Research Yesavage, J. A., O'Hara, R., Kraemer, H., Noda, A., Taylor, J. L., Ferris, S., Gely-Nargeot, M. C., Rosen, A., Friedman, L., Sheikh, J., Derouesne, C. PERGAMON-ELSEVIER SCIENCE LTD. 2002: 281–86

  Abstract

  A number of systems have been proposed for classifying older adults who suffer from cognitive impairment or decline but do not yet meet criteria for Alzheimer's disease (AD). The classification, Mild Cognitive Impairment (MCI), has attracted much attention. It uses relatively specific diagnostic criteria and individuals who meet these criteria appear to be at substantial risk for the development of AD. However, little data is available to define the prevalence of MCI in any age group. We propose a simple mathematical model for the progression of patients from Non-Affected (NA) to MCI to AD. This first-order Markov model defines the likely prevalence of MCI at specific ages. Primary assumptions of the model include an AD prevalence of 1% at age 60 increasing to 25% at age 85 and a conversion rate from MCI to AD of 10% constant across all ages considered. We used the best available information for our model and found (1) that the MCI prevalence increased from 1% at age 60 to 42% at age 85 and (2) that the conversion rate from NA to MCI increased from 1% per year at age 60 to 11% at age 85. In conclusion, this model allows estimation of prevalence of MCI and conversion from NA to MCI based upon known prevalences of AD, conversion rates of MCI to AD, and death rates. Due to its substantial prevalence, MCI may be an important target for screening and possible intervention.

  View details for Web of Science ID 000178254700002

  View details for PubMedID 12127595

• Donepezil and flight simulator performance: Effects on retention of complex skills NEUROLOGY Yesavage, J. A., Mumenthaler, M. S., Taylor, J. L., Friedman, L., O'Hara, R., Sheikh, J., Tinklenberg, J., Whitehouse, P. J. 2002; 59 (1): 123-125

  Abstract

  We report a randomized, double-blind, parallel group, placebo-controlled study to test the effects of the acetylcholinesterase inhibitor, donepezil (5 mg/d for 30 days), on aircraft pilot performance in 18 licensed pilots with mean age of 52 years. After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p < 0.05. Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.

  View details for Web of Science ID 000176622600025

  View details for PubMedID 12105320

• Which Alzheimer patients are at risk for rapid cognitive decline? JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY O'Hara, R., Thompson, J. M., Kraemer, H. C., Fenn, C., Taylor, J. L., Ross, L., Yesavage, J. A., Bailey, A. M., Tinklenberg, J. R. 2002; 15 (4): 233-238

  Abstract

  In the current study of 1062 Alzheimer's disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimer's Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease.

  View details for Web of Science ID 000179584400009

  View details for PubMedID 12489920

• 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

• Therapeutic approaches to age-associated neurocognitive disorders. Dialogues in clinical neuroscience O'Hara, R., Derouesné, C., Fountoulakis, K. N., Yesavage, J. A. 2001; 3 (3): 191-213

  Abstract

  The United Nations projects that the number of individuals with dementia in developed countries alone will be approximately 36,7 million by the year 2050. International recognition of the significant emotional and economic burden of Alzheimer's disease has been matched by a dramatic increase in the development of pharmacological and nonpharmacological approaches to this illness in the past decade. Changing demographics have underscored the necessity to develop similar approaches for the remediation of the cognitive impairment associated with more benign syndromes, such as mild cognitive impairment (MCI) and age-associated cognitive decline (AACD). The present article aims to provide an overview of the most current therapeutic approaches to age-associated neurocognitive disorders. Additionally, it discusses the conceptual and methodological issues that surround the design, implementation, and interpretation of such approaches.

  View details for PubMedID 22033831

  View details for PubMedCentralID PMC3181653

• Influence of the menstrual cycle on flight simulator performance after alcohol ingestion JOURNAL OF STUDIES ON ALCOHOL Mumenthaler, M. S., O'Hara, R., Taylor, J. L., Friedman, L., Yesavage, J. A. 2001; 62 (4): 422-433

  Abstract

  Previous studies investigating the influence of the menstrual cycle on cognitive functioning of women after alcohol ingestion have obtained inconsistent results. The present study tested the hypothesis that flight simulator performance during acute alcohol intoxication and 8 hours after drinking differs between the menstrual and the luteal phase of the menstrual cycle.White female pilots (N = 24) were tested during the menstrual and the luteal phases of their menstrual cycles. On each test day they performed a baseline simulator flight, consumed 0.67 g/kg ethanol, and performed an acute-intoxication and an 8-hour-carryover simulator flight.Subjects reached highly significant increases in estradiol (E2) as well as progesterone (P) levels during the luteal test day. Yet, there were no significant differences in overall flight performance after alcohol ingestion between the menstrual and luteal phases during acute intoxication or at 8-hour carryover. We found no correlations between E, or P levels and overall flight performance. However, there was a statistically significant Phase x Order interaction: Pilots who started the experiment with their menstrual day were less susceptible to the effects of alcohol during the second test day than were pilots who started with their luteal day.The tested menstrual cycle phases and varying E2 and P levels did not significantly influence postdrink flight performance. Because the present study included a comparatively large sample size and because it involved complex "real world" tasks (piloting an aircraft), we believe that the present findings are important. We hope that our failure to detect menstrual cycle effects will encourage researchers to include women in their investigations of alcohol effects and human performance.

  View details for Web of Science ID 000170348900002

  View details for PubMedID 11523532

• Relationship between variations in estradiol and progesterone levels across the menstrual cycle and human performance PSYCHOPHARMACOLOGY Mumenthaler, M. S., O'Hara, R., Taylor, J. L., Friedman, L., Yesavage, J. A. 2001; 155 (2): 198-203

  Abstract

  Studies about whether or not the cognitive performance of women is influenced by changes in levels of sex steroid hormones across the menstrual cycle have produced ambiguous results.This study tested whether flight simulator performance differs significantly between the menstrual and the luteal phase of the menstrual cycle.In a within-subjects design, 24 female pilots were tested twice during their menstrual cycle: once during the menstrual and once during the luteal phase. On both test days they performed a 75-min simulator flight in a Frasca 141, a popular pilot training device.Despite highly significant differences in estradiol (E2) as well as progesterone (P) levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analyses, there were no significant differences in overall flight performance between the menstrual and luteal phases. We found no significant correlations between E2 or P levels and flight performance.We found no evidence that the tested menstrual cycle phases and their associated E2 and P levels significantly influence flight simulator performance. We consider these negative findings based on 24 subjects meaningful because previous studies on the influence of menstrual cycle on cognitive performance have not involved complex "real world" tasks such as piloting an aircraft and they obtained inconsistent results.

  View details for Web of Science ID 000168778000013

  View details for PubMedID 11401010

• 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

• Relationship of CogScreen-AE to flight simulator performance and pilot age AVIATION SPACE AND ENVIRONMENTAL MEDICINE Taylor, J. L., O'Hara, R., Mumenthaler, M. S., Yesavage, J. A. 2000; 71 (4): 373-380

  Abstract

  We report on the relationship between CogScreen-Aeromedical Edition (AE) factor scores and flight simulator performance in aircraft pilots aged 50-69.Some 100 licensed, civilian aviators (average age 58+/-5.3 yr) performed aviation tasks in a Frasca model 141 flight simulator and the CogScreen-AE battery. The aviation performance indices were: a) staying on course; b) dialing in communication frequencies; c) avoiding conflicting traffic; d) monitoring cockpit instruments; e) executing the approach; and f) a summary score, which was the mean of these scores. The CogScreen predictors were based on a factor structure reported by Kay (11), which comprised 28 CogScreen scores. Through principal components analysis of Kay's nine factors, we reduced the number of predictors to five composite CogScreen scores: Speed/Working Memory (WM), Visual Associative Memory, Motor Coordination, Tracking, and Attribute Identification.Speed/WM scores had the highest correlation with the flight summary score, Spearman r(rho) = 0.57. A stepwise-forward multiple regression analysis indicated that four CogScreen variables could explain 45% of the variance in flight summary scores. Significant predictors, in order of entry, were: Speed/WM, Visual Associative Memory, Motor Coordination, and Tracking (p<0.05). Pilot age was found to significantly improve prediction beyond that which could be predicted by the four cognitive variables. In addition, there was some evidence for specific ability relationships between certain flight component scores and CogScreen scores, such as approach performance and tracking errors.These data support the validity of CogScreen-AE as a cognitive battery that taps skills relevant to piloting.

  View details for Web of Science ID 000086061300002

  View details for PubMedID 10766461

• Update on Alzheimer's disease: recent findings and treatments WESTERN JOURNAL OF MEDICINE O'Hara, R., Mumenthaler, M. S., Yesavage, J. A. 2000; 172 (2): 115-120

  View details for Web of Science ID 000085217100020

  View details for PubMedID 10693374

• Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass CIRCULATION Fitch, J. C., Rollins, S., Matis, L., Alford, B., Aranki, S., Collard, C. D., Dewar, M., Elefteriades, J., Hines, R., Kopf, G., Kraker, P., Li, L., O'Hara, R., Rinder, C., Rinder, H., Shaw, R., Smith, B., Stahl, G., Shernan, S. K. 1999; 100 (25): 2499-2506

  Abstract

  Cardiopulmonary bypass (CPB) induces a systemic inflammatory response that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We examined the capability of a novel therapeutic complement inhibitor to prevent pathological complement activation and tissue injury in patients undergoing CPB.A humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinase-MB release, P=0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (P<0. 05) in patients who received 1 or 2 mg/kg.A single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.

  View details for Web of Science ID 000084391400065

  View details for PubMedID 10604887

• The validation of the short form of the Geriatric Depression Scale (GDS) in Greece AGING CLINICAL AND EXPERIMENTAL RESEARCH Fountoulakis, K. N., Tsolaki, M., Iacovides, A., Yesavage, J., O'Hara, R., Kazis, A., Ierodiakonou, C. 1999; 11 (6): 367-372

  Abstract

  The Geriatric Depression Scale-15 (GDS-15) is a short, 15-item instrument specifically designed to assess depression in geriatric populations. Its items require a yes/no response. The Geriatric Depression Scale was first introduced by Yesavage et al. in 1983, and the short form (GDS-15) was developed by Sheikh and Yesavage in 1986. The aim of the current study was the standardization of the GDS-15 for use in Greece. Subjects were divided into Group A: 168 control subjects, and Group B: 103 patients suffering from clinically diagnosed depression. All were over 65 years of age. A score of 6/7 on the GDS-15 was found to be the best cut-off point for diagnosing depression in an elderly Greek population, with Sensitivity = 92.23 and Specificity = 95.24. GDS-15 manifests high internal consistency with Cronbach's alpha = 0.94, and all items seem to be equivalent. Factor Analysis of the GDS-15 revealed 4 factors: a cognitive (thought content), an affective, a functional, and a factor that reflects helplessness and fear for the future. The two diagnostic groups differed on all 4 factors scores at p-value <0.001.

  View details for Web of Science ID 000085695000004

  View details for PubMedID 10738851

• Relationship of age and simulated flight performance JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Yesavage, J. A., Taylor, J. L., Mumenthaler, M. S., Noda, A., O'Hara, R. 1999; 47 (7): 819-823

  Abstract

  To determine the relationship between age and aviator performance on a flight simulator.A cross-sectional observational study.The sample consisted of 100 aviators aged 50 to 69 (mean = 58).Pilots were tested on a Frasca 141 flight simulator (Urbana, IL), linked to a UNIX-based IRIS 4D computer (Silicon Graphics, Mountain View, CA), which both generated graphics of the environment in which the pilots flew and collected data concerning the aircraft's flight conditions.We found that increased age was significantly associated with decreased aviator performance on a flight simulator.Although there was a significant relationship between increased age and decreased aviator performance, age explained 22% or less of the variance of performance on different flight tasks; hence, other factors are also important in explaining the performance of older pilots.

  View details for Web of Science ID 000081323400007

  View details for PubMedID 10404925

• Relationship between brain electrical activity and cortical perfusion in normal subjects PSYCHIATRY RESEARCH-NEUROIMAGING Leuchter, A. F., Uijtdehaage, S. H., Cook, I. A., O'Hara, R., Mandelkern, M. 1999; 90 (2): 125–40

  Abstract

  Cerebral glucose uptake and perfusion are accepted as tightly coupled measures of energy utilization in both normal and diseased brain. The coupling of brain electrical activity to perfusion has been demonstrated, however, only in the presence of chronic brain disease. Very few studies have examined the relationship between cerebral electrical activity and energy utilization in normal brain tissue. To clarify this relationship, we performed 33 H2(15)O-positron emission tomography (PET) scans in six normal subjects both at rest and during a simple motor task, and acquired surface-recorded quantitative electroencephalogram (QEEG) data simultaneously with isotope injection. We examined the associations between cerebral perfusion directly underlying each recording electrode and three QEEG measures (absolute power, relative power, and cordance). All EEG measures had moderately strong coupling with perfusion at most frequency bands, although the directions of the associations differed from those previously reported in subjects with stroke or dementia. Of the three QEEG measures examined, cordance had the strongest relationship with perfusion (multiple R2 = 0.58). Cordance and PET were equally effective in detecting lateralized activation associated with the motor task, while EEG power did not detect this activation. Electrodes in the concordant state had a significantly higher mean perfusion than those in the discordant state. These results indicate that normal brain electrical activity has a moderately strong association with cerebral perfusion. Cordance may be the most useful QEEG measure for monitoring cerebral perfusion in subjects without chronic brain disease.

  View details for DOI 10.1016/S0925-4927(99)00006-2

  View details for Web of Science ID 000080631000005

  View details for PubMedID 10482384

• Effects of menstrual cycle and female sex steroids on ethanol pharmacokinetics ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Mumenthaler, M. S., Taylor, J. L., O'Hara, R., Fisch, H. U., Yesavage, J. A. 1999; 23 (2): 250-255

  Abstract

  This study investigated the influence of menstrual cycle and female sex steroid levels on ethanol pharmacokinetics. In a within-subjects design, 24 female volunteers each consumed 0.67 g x kg(-1) ethanol during the menstrual and luteal phases of their menstrual cycle. On each test day, we collected blood samples before ethanol administration to determine estradiol (E2) and progesterone (P) levels and to confirm ovulation. We took 20 or more postdrink breath ethanol concentration readings and examined pharmacokinetic differences between the two phases, using classical pharmacokinetic measures, as well as Michaelis-Menten measures. Despite highly significant differences in measured E2 as well as P levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analysis, there were no significant differences between menstrual and luteal phases for any of the pharmacokinetic variables. We found no correlation between E2 or P levels and any of the pharmacokinetic measures. In summary, we found no evidence that the tested menstrual cycle phases or varying E2 and progesterone levels significantly influence ethanol pharmacokinetics. Because previous studies about the topic have used few subjects and revealed controversial results, we consider our negative findings based on 24 subjects meaningful.

  View details for Web of Science ID 000078678700009

  View details for PubMedID 10069553

• Gender differences in moderate drinking effects ALCOHOL RESEARCH & HEALTH Mumenthaler, M. S., Taylor, J. L., O'Hara, R., Yesavage, J. A. 1999; 23 (1): 55-?

  Abstract

  Women appear to become more impaired than men after drinking equivalent amounts of alcohol, achieving higher blood alcohol concentrations even when doses are adjusted for body weight. This finding may be attributable in part to gender differences in total body water content. Men and women appear to eliminate approximately the same total amount of alcohol per unit body weight per hour. However, women seem to eliminate significantly more alcohol per unit of lean body mass per hour than men. Some studies report that women are more susceptible than men to alcohol-related impairment of cognitive performance, especially in tasks involving delayed memory or divided attention functions. Psychomotor performance impairment, however, does not appear to be affected by gender. This article provides an overview of alcohol metabolism (pharmacokinetics) and reviews recent studies on gender differences in alcohol absorption, distribution, elimination, and impairment. Speculation that gender differences in alcohol pharmacokinetics or alcohol-induced performance impairment may be caused by the menstrual cycle and variations in female sex hormones are discussed. It is concluded that the menstrual cycle is unlikely to influence alcohol pharmacokinetics.

  View details for Web of Science ID 000084105600008

  View details for PubMedID 10890798

• 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

• Assessing the accuracy of topographic EEG mapping for determining local brain function ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY Cook, I. A., O'Hara, R., Uijtdehaage, S. H., Mandelkern, M., Leuchter, A. F. 1998; 107 (6): 408–14

  Abstract

  There has been considerable discussion regarding the accuracy of topographic electroencephalographic (EEG) maps for assessing local cerebral function. We performed this study to test the accuracy of EEG mapping by examining the association between electrical activity and the perfusion under each electrode as another measure of local cerebral function.EEG mapping was performed simultaneously with (H15)2O positron emission tomography (PET) scanning in 6 normal adult subjects, both at rest and during a simple motor task. EEG data were processed using 3 different montages; two EEG power measures (absolute and relative power) were examined.Relative power had much stronger associations with perfusion than did absolute power. In addition, calculating power for bipolar electrode pairs and averaging power over electrode pairs sharing a common electrode yielded stronger associations with perfusion than data from referential or single source montages.These findings indicate (1) that topographic EEG mapping can accurately reflect local brain function in a way that is comparable to other methods, and (2) that the choice of EEG measure and montage have a significant influence on the degree with which maps reflect this local activity and function.

  View details for DOI 10.1016/S0013-4694(98)00092-3

  View details for Web of Science ID 000077930100005

  View details for PubMedID 9922086

• Influence of nicotine on simulator flight performance in non smokers PSYCHOPHARMACOLOGY Mumenthaler, M. S., Taylor, J. L., O'Hara, R., Yesavage, J. A. 1998; 140 (1): 38-41

  Abstract

  In a placebo-controlled study, we investigated the influence of nicotine on late-day aviation performance in 15 non-smoking subjects. In a within-subjects design, subjects were tested on 2 days, each lasting 8 h and consisting of three 75-min simulator flights (late-afternoon practice, evening test, night test). Prior to each test, subjects received either nicotine polacrilex 2 mg or placebo gum. As expected, overall performance was significantly better after nicotine, compared to placebo (P < 0.01). Post-hoc analysis of individual flight tasks showed that nicotine improved scores on approach to landing, a task which appears to require sustained attention. We conclude that nicotine may improve late-day flight performance in non-smoking aviators.

  View details for Web of Science ID 000077151700005

  View details for PubMedID 9862400