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1.  Characterizing Trajectories of Cognitive Functioning in Older Adults with Schizophrenia: Does Method Matter? 
Schizophrenia research  2012;143(1):90-96.
Background
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.
Methods
We compared trajectories (mean duration 3.5 years) of cognitive impairments in a sample of 201 community-dwelling schizophrenia (SCZ) patients (aged 40–100 years) 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.
Results
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.
Discussion
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.
doi:10.1016/j.schres.2012.10.033
PMCID: PMC3540183  PMID: 23218560
Late-Life Schizophrenia; Cognition; Trajectories; Heterogeneity; Growth Mixture Models
2.  Prediction of transplant-free survival in idiopathic pulmonary fibrosis patients using joint models for event times and mixed multivariate longitudinal data 
Journal of applied statistics  2014;41(10):2192-2205.
SUMMARY
We implement a joint model for mixed multivariate longitudinal measurements, applied to the prediction of time until lung transplant or death in idiopathic pulmonary fibrosis. Specifically, we formulate a unified Bayesian joint model for the mixed longitudinal responses and time-to-event outcomes. For the longitudinal model of continuous and binary responses, we investigate multivariate generalized linear mixed models using shared random effects. Longitudinal and time-to-event data are assumed to be independent conditional on available covariates and shared parameters. A Markov chain Monte Carlo (MCMC) algorithm, implemented in OpenBUGS, is used for parameter estimation. To illustrate practical considerations in choosing a final model, we fit 37 different candidate models using all possible combinations of random effects and employ a Deviance Information Criterion (DIC) to select a best fitting model. We demonstrate the prediction of future event probabilities within a fixed time interval for patients utilizing baseline data, post-baseline longitudinal responses, and the time-to-event outcome. The performance of our joint model is also evaluated in simulation studies.
doi:10.1080/02664763.2014.909784
PMCID: PMC4157686  PMID: 25214700
Idiopathic Pulmonary Fibrosis; Joint model; Mixed continuous and binary data; Multivariate longitudinal data; Prediction model; Shared parameter model; Survival analysis
3.  Boosting the Power of Schizophrenia Genetics by Leveraging New Statistical Tools 
Schizophrenia Bulletin  2013;40(1):13-17.
Genome-wide association studies (GWAS) have identified a large number of gene variants associated with schizophrenia, but these variants explain only a small portion of the heritability. It is becoming increasingly clear that schizophrenia is influenced by many genes, most of which have effects too small to be identified using traditional GWAS statistical methods. By applying recently developed Empirical Bayes statistical approaches, we have demonstrated that functional genic elements show differential contribution to phenotypic variance, with some elements (regulatory regions and exons) showing strong enrichment for association with schizophrenia. Applying related methods, we also showed abundant genetic overlap (pleiotropy) between schizophrenia and other phenotypes, including bipolar disorder, cardiovascular disease risk factors, and multiple sclerosis. We estimated the number of gene variants with effects in schizophrenia and bipolar disorder to be approximately 1.2%. By applying our novel statistical framework, we dramatically improved gene discovery and detected a large number of new gene loci associated with schizophrenia that have not yet been identified with standard GWAS methods. Utilizing independent schizophrenia substudies, we showed that these new loci have high replication rates in de novo samples, indicating that they likely represent true schizophrenia risk genes. The new statistical tools provide a powerful approach for uncovering more of the missing heritability of schizophrenia and other complex disorders. In conclusion, the highly polygenic architecture of schizophrenia strongly suggests the utility of research approaches that recognize schizophrenia neuropathology as a complex dynamic system, with many small gene effects integrated in functional networks.
doi:10.1093/schbul/sbt168
PMCID: PMC3885310  PMID: 24319118
GWAS; polygenicity; pleiotropy; empirical Bayes approach; molecular genetics
4.  The Cumulative Impact of Nonsevere Life Events Predicts Depression Recurrence During Maintenance Treatment with Interpersonal Psychotherapy (IPT-M) 
While much research has focused on the role of severe life events as risk factors for depression onset, less is known about the relationship between nonsevere life events and depression recurrence. The current study examined the cumulative effects of nonsevere and positive life events on depression recurrence in an outpatient sample of recurrently depressed women treated to remission with interpersonal psychotherapy (IPT). A Cox proportional hazards model was used to test this relationship in 124 adult women who entered into the maintenance phase of IPT treatment (IPT-M) and completed at least one Life Events and Difficulties Schedule (LEDS) interview. The cumulative experience of nonsevere life events that were subject- or joint-focused and non-independent was significantly related to depression recurrence during the maintenance treatment phase. None of the other event categories were significantly related to depression recurrence. These findings may help to clarify the mechanisms by which life events contribute to depression recurrence and to guide the development of more efficacious maintenance treatments.
doi:10.1037/a0012862
PMCID: PMC2597551  PMID: 19045966
Major Depressive Disorder; Life Events and Difficulties Schedule; Interpersonal Psychotherapy; stress sensitization; stress generation
5.  Association between higher levels of sexual function, activity, and satisfaction and self-rated successful aging in older postmenopausal women 
Objectives
To determine if measures of successful-aging are associated with sexual activity, satisfaction, and function in older post-menopausal women.
Design
Cross-sectional study using self-report surveys; analyses include chi-square and t-tests and multiple linear regression analyses.
Setting
Community-dwelling older post-menopausal women in the greater San Diego Region.
Participants
1,235 community-dwelling women aged 60-89 years participating at the San Diego site of the Women's Health Initiative.
Measurements
Demographics and self-report measures of sexual activity, function, and satisfaction and successful aging.
Results
Sexual activity and functioning (desire, arousal, vaginal tightness, use of lubricants, and ability to climax) were negatively associated with age, as were physical and mental health. In contrast, sexual satisfaction and self-rated successful aging and quality of life remained unchanged across age groups. Successful aging measures were positively associated with sexual measures, especially self-rated quality of life and sexual satisfaction.
Conclusions
Self-rated successful aging, quality of life, and sexual satisfaction appear to be stable in the face of declines in physical health, some cognitive abilities, and sexual activity and function and are positively associated with each other across ages 60-89 years.
doi:10.1111/j.1532-5415.2011.03495.x
PMCID: PMC4151627  PMID: 21797827
Sexual Activity; Sexual Satisfaction; Sexual Function; Post-menopausal Women; Self-Rated Successful aging
6.  Feeling bad about screwing up: emotion regulation and action monitoring in the anterior cingulate cortex 
This study examined neural features of emotional responses to errors. We specifically examined whether directed emotion regulation of negative emotion associated with error modulates action-monitoring functions of anterior cingulate cortex, including conflict monitoring, error processing, and error prevention. Seventeen healthy adults performed a continuous performance task during assessment by fMRI. In each block, participants were asked either to increase or decrease their negative emotional responses or to react naturally after error commission. Emotion regulation instructions were associated with modulation of rostral and dorsal anterior activity and of their effective connectivity following errors and conflict. Cingulate activity and connectivity predicted subsequent errors. These data may suggest that responses to errors are affected by emotion and that aspects of emotion and cognition are inextricably linked, even during a nominally cognitive task.
doi:10.3758/s13415-011-0028-z
PMCID: PMC4128506  PMID: 21590316
Emotion regulation; Anterior cingulate cortex; Action monitoring; Conflict; Error; fMRI
7.  The role of clusterin in amyloid-β associated neurodegeneration 
JAMA neurology  2014;71(2):180-187.
Importance
Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer's disease (AD) neurodegeneration. However, the precise role of clusterin in AD pathogenesis is still not well understood.
Objective
To elucidate the relationship between clusterin, amyloid-β (Aβ), p-tau, and rate of brain atrophy over time among non-demented older individuals.
Design
A longitudinal cohort of cognitively normal older participants (HC) and individuals with mild cognitive impairment (MCI) assessed with baseline lumbar puncture and longitudinal structural MRI.
Setting
Research centers across the United States and Canada.
Participants
We examined 241 non-demented older individuals (91 participants with a Clinical Dementia Rating (CDR) of 0 and 150 individuals with a CDR of 0.5).
Main Outcome Measures
Using linear mixed effects models, we investigated interactions between CSF clusterin, CSF Aβ1-42 and CSF p-tau181p on atrophy rate of the entorhinal cortex and hippocampus.
Results
Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on entorhinal cortex atrophy rate, but not on hippocampal atrophy rate. CSF clusterin was associated with entorhinal cortex atrophy rate among CSF Aβ1-42 positive individuals, but not among CSF Aβ1-42 negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin and CSF Aβ1-42 and CSF p-tau181p on entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the MCI and HC cohorts.
Conclusions and Relevance
In non-demented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the AD neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
doi:10.1001/jamaneurol.2013.4560
PMCID: PMC4118752  PMID: 24378367
8.  An application of item response theory to fMRI data: Prospects and pitfalls 
Psychiatry research  2013;212(3):167-174.
When using functional brain imaging to study neuropsychiatric patients an important challenge is determining whether the imaging task assesses individual differences with equal precision in healthy control and impaired patient groups. Classical test theory (CTT) requires separate reliability studies of patients and controls to determine equivalent measurement precision with additional studies to determine measurement precision for different levels of disease severity. Unlike CTT, item response theory (IRT) provides estimates of measurement error for different levels of ability, without the need for separate studies, and can determine if different tests are equivalently difficult when investigating differential deficits between groups. To determine the potential value of IRT in functional brain imaging, IRT was applied to behavioral data obtained during a multi-center functional MRI (fMRI) study of working memory (WM). Average item difficulty was approximately one standard deviation below the ability scale mean, supporting the task’s sensitivity to individual differences within the ability range of patients with WM impairment, but not within the range of most controls. The correlation of IRT estimated ability with fMRI activation during the task recognition period supported the linkage of the latent IRT scale to brain activation data. IRT can meaningfully contribute to the design of fMRI tasks.
doi:10.1016/j.pscychresns.2013.01.009
PMCID: PMC3775707  PMID: 23642468
Functional MRI; Item response theory; Bayesian analysis; Task design
9.  APOE ε4 does not modulate amyloid-β associated neurodegeneration in preclinical Alzheimer’s disease 
Background and Purpose
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood.
Materials and Methods
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions.
Results
The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
Conclusions
Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.
doi:10.3174/ajnr.A3267
PMCID: PMC4041629  PMID: 22976236
preclinical AD; neurodegeneration; p-tau; amyloid-β; APOE
10.  Amphetamine effects on MATRICS Consensus Cognitive Battery performance in healthy adults 
Psychopharmacology  2013;227(1):165-176.
Background
Cognitive deficits contribute strongly to functional disability in schizophrenia. The cost of identifying and testing candidate procognitive agents is substantial. Conceivably, candidate drugs might be first identified by positive effects on cognitive domains in sensitive subgroups of healthy subjects. Here, we examined whether the MATRICS Consensus Cognitive Battery (MCCB) detected procognitive drug effects in subgroups of healthy individuals.
Methods
The effects of 20 mg amphetamine (AMPH) on MCCB performance were tested in a double-blind, placebo-controlled crossover study of 60 healthy adults. AMPH effects were compared in subgroups of subjects characterized by low vs. high placebo MCCB scores, and by extreme values on personality subscales associated with schizophrenia-relevant biomarkers.
Results
AMPH produced autonomic and subjective effects, but did not significantly change MCCB composite scores or individual domain scores across the inclusive sample of 60 subjects. AMPH-induced MCCB changes were significantly (inversely) related to placebo MCCB performance: among individuals with lower placebo scores, AMPH enhanced performance, while among individuals with higher placebo scores, it impaired performance. A potential impact of regression to the mean was assessed, and could not be ruled out. Both placebo MCCB performance and AMPH effects on MCCB scores were significantly related to personality domains associated with schizophrenia-linked genetic- and/or neurophysiological substrates.
Conclusions
Among healthy adults, AMPH effects on MCCB performance were detected only among specific subgroups, and in specific cognitive domains. Strategies that utilize drug-induced changes in MCCB performance in healthy subjects to screen for candidate procognitive drugs should consider the use of “enriched” subgroups with specific neurocognitive or personality characteristics.
doi:10.1007/s00213-012-2948-x
PMCID: PMC3624060  PMID: 23314393
amphetamine; cognition; schizophrenia; MCCB; MATRICS; neurocognition
11.  Cognitive Reserve Moderates the Association Between Hippocampal Volume and Episodic Memory in Middle Age 
Neuropsychologia  2013;51(6):1124-1131.
Cognitive reserve is hypothesized to help people withstand greater brain pathology without manifesting clinical symptoms, and may be regarded as a preventive factor of dementia. It is unclear whether the effect of cognitive reserve is evident only among the older adults or after conversion to dementia, or if it can also be seen earlier in life before the prominent effects of cognitive aging become apparent. While finding a main effect of cognitive reserve on cognitive outcome may be consistent with the reserve hypothesis, in our view, it is unnecessary to invoke the idea of reserve if only a main effect is present. Rather, it is the interaction between a measure of reserve and a brain measure on cognitive outcome that is key for confirming that the effects of brain pathology affect people differently according to their cognitive reserve. We studied whether general cognitive ability at an average age of 20 years, as a direct measure of cognitive reserve, moderates the association between hippocampal volume and episodic memory performance in 494 middle-aged men ages 51 to 60. Whereas there was no statistically significant direct relationship between hippocampal volume and episodic memory performance in middle age, we found a statistically significant interaction such that there was a positive association between hippocampal volume and episodic memory only among people with lower general cognitive ability at age 20, i.e., lower levels of cognitive reserve. Our results provide support for the hypothesis that cognitive reserve moderates the relationship between brain structure and cognition in middle age, well before the onset of dementia.
doi:10.1016/j.neuropsychologia.2013.02.022
PMCID: PMC3660613  PMID: 23499725
cognitive reserve; general cognitive ability; episodic memory; hippocampus; verbal learning
12.  Conceptual and Data-based Investigation of Genetic Influences and Brain Asymmetry: A Twin Study of Multiple Structural Phenotypes 
Journal of cognitive neuroscience  2013;26(5):1100-1117.
Right–left regional cerebral differences are a feature of the human brain linked to functional abilities, aging, and neuro-developmental and mental disorders. The role of genetic factors in structural asymmetry has been incompletely studied. We analyzed data from 515 individuals (130 monozygotic twin pairs, 97 dizygotic pairs, and 61 unpaired twins) from the Vietnam Era Twin Study of Aging to answer three questions about genetic determinants of brain structural asymmetry: First, does the magnitude of heritability differ for homologous regions in each hemisphere? Despite adequate power to detect regional differences, heritability estimates were not significantly larger in one hemisphere versus the other, except left > right inferior lateral ventricle heritability. Second, do different genetic factors influence left and right hemisphere size in homologous regions? Inter-hemispheric genetic correlations were high and significant; in only two subcortical regions (pallidum and accumbens) did the estimate statistically differ from 1.0. Thus, there was little evidence for different genetic influences on left and right hemisphere regions. Third, to what extent do genetic factors influence variability in left–right size differences? There was no evidence that variation in asymmetry (i.e., the size difference) of left and right homologous regions was genetically determined, except in pallidum and accumbens. Our findings suggest that genetic factors do not play a significant role in determining individual variation in the degree of regional cortical size asymmetries measured with MRI, although they may do so for volume of some subcortical structures. Despite varying interpretations of existing left–right, we view the present results as consistent with previous findings.
doi:10.1162/jocn_a_00531
PMCID: PMC3999438  PMID: 24283492
13.  Towards clinically useful neuroimaging in depression treatment: Is subgenual cingulate activity robustly prognostic for depression outcome in Cognitive Therapy across studies, scanners, and patient characteristics? 
Archives of general psychiatry  2012;69(9):913-924.
Context
40–60% of unmedicated depressed individuals respond to Cognitive Therapy (CT) in controlled trials. Multiple previous studies suggest that activity in the subgenual anterior cingulate predicts outcome in CT for depression, but there have been no prospective replications.
Objective
This study prospectively examined whether subgenual cingulate activity is a reliable and robust prognostic outcome marker for CT for depression and whether its activity changes in treatment.
Design
Two inception cohorts were assessed with fMRI on different scanners on a task sensitive to sustained emotional information processing before and after 16–20 sessions of CT, along with a sample of control participants tested at comparable intervals.
Setting
Therapy took place in a hospital outpatient clinic.
Patients
Participants included 49 unmedicated depressed adults and 35 healthy control participants.
Main Outcome Measures
Pre-treatment subgenual anterior cingulate activity in an a priori region in response to negative words was correlated with residual severity and used to classify response and remission.
Results
As expected, in both samples, participants with the lowest pre-treatment sustained subgenual cingulate (sgACC; BA25) reactivity in response to negative words displayed the most improvement in CT (R2=.29, >75% correct classification of response, >70% correct classification of remission). Other a priori regions explained additional variance. Response/Remission in Cohort 2 was predicted based on thresholds from Cohort 1. sgACC activity remained low for remitters following treatment.
Conclusions
Neuroimaging provides a quick, valid, and clinically applicable way of assessing neural systems associated with treatment response/remission. sgACC activity, in particular, may reflect processes which interfere with treatment, e.g,. emotion generation in addition to its putative regulatory role; alternately, its absence may facilitate treatment response.
doi:10.1001/archgenpsychiatry.2012.65
PMCID: PMC3951953  PMID: 22945620
Cognitive Therapy; Mood Disorders – Unipolar; Brain Imaging Techniques; Cognitive Neuroscience; Emotion
14.  Subthreshold Depression and Successful Aging in Older Women 
Objectives
Subthreshold Depression (StD) is common in older adults and is associated with poor self-rated health. However, the impact of StD on broader indicators of successful aging, such as positive psychological constructs, cognitive functioning, or quality of well-being, has not been assessed. We compared persons with scores above and below a predetermined threshold on the Center for Epidemiological Studies Scale for Depression (CESD) to non-depressed persons (ND) on measures of multiple domains associated with successful aging.
Design
Cross sectional survey-based psychological assessments.
Participants
1,979 community-dwelling older women participating in the Women’s Health Initiative study.
Measurements
ND was defined as a CESD score below 8, StD as a score between 8 and 15, and CESD Depression (CD) as a score of 16 or above. The study questionnaire consisted of multiple self-reported measures of positive psychological functioning (e.g., optimism, resilience), cognitive functioning and complaints, and quality of well-being. We also obtained a history of diagnosis, treatment, and hospitalization related to mental health problems.
Results
20.2% of women met CES-D criteria for StD and 7% for CD. Women with StD had worse self-rated successful aging, worse physical and emotional functioning, lower optimism, more negative attitudes toward aging, lower personal mastery and self-efficacy, and greater anxiety and hostility than ND women, but scored better on all these measures than women with CD. StD subjects also had higher self-reported rates of previous diagnosis, treatment, and hospitalization for mental health problems than the ND group. StD subjects with depressed mood and/or anhedonia were largely similar to those without these symptoms.
Conclusions
Mild-moderate levels of depressive symptoms that likely fall under a general category of StD were common, and were associated with worse functioning on virtually every component of successful aging that we examined. StD represents a clinical entity that may affect the longitudinal course of successful aging for large numbers of persons and is a potential target for clinical intervention.
doi:10.1097/JGP.0b013e3181b7f10e
PMCID: PMC3937985  PMID: 20224518
15.  The NIH Toolbox Cognition Battery: Results from a Large Normative Developmental Sample (PING) 
Neuropsychology  2013;28(1):1-10.
Objective
The NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance.
Method
The NTCB was administered to a sample of 1020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States.
Results
General additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores.
Conclusions
The results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors.
doi:10.1037/neu0000001
PMCID: PMC3925365  PMID: 24219608
Computerized Assessment; Cognitive Development; Socioeconomic Status
16.  Older Age is Associated with More Successful Aging: Role of Resilience and Depression 
The American journal of psychiatry  2013;170(2):188-196.
Background
There is growing public health interest in understanding and promoting successful aging. While there has been some exciting empirical work on objective measures of physical health, relatively little published research combines physical, cognitive, and psychological assessments in large, randomly selected, community-based samples to assess self-rated successful aging (SRSA).
Methods
In this Successful AGing Evaluation (SAGE) study, we used a structured multi-cohort design to assess successful aging in 1,006 community-dwelling adults in San Diego County, aged 50–99 years, with over-sampling of people over 80. A modified version of random digit dialing was used to recruit subjects. Evaluations included a 25-minute phone interview followed by a comprehensive mail-in survey of physical, cognitive, and psychological domains, including SRSA (scaled from 1 [lowest] to 10 [highest]) and positive psychological traits.
Results
In our sample with mean age of 77.3 years, the mean SRSA score was 8.2, and older age was associated with higher SRSA (R2 = 0.027), despite worsening physical and cognitive functioning. The best multiple regression model achieved, using all the potential correlates, accounted for 30% of variance in SRSA, and included resilience, depression, physical functioning, and age (entering the regression model in that order).
Conclusions
Resilience and depression had a significant association with SRSA with effect sizes comparable to that for physical health. While no causality can be inferred from cross-sectional data, increasing resilience and reducing depression might have as strong effects on successful aging as reducing physical disability, suggesting an important role for psychiatry in promoting successful aging.
doi:10.1176/appi.ajp.2012.12030386
PMCID: PMC3593664  PMID: 23223917
Aging; Resilience; Optimism; Depression; Cognition; Disability
17.  A web-portal for interactive data exploration, visualization, and hypothesis testing 
Clinical research studies generate data that need to be shared and statistically analyzed by their participating institutions. The distributed nature of research and the different domains involved present major challenges to data sharing, exploration, and visualization. The Data Portal infrastructure was developed to support ongoing research in the areas of neurocognition, imaging, and genetics. Researchers benefit from the integration of data sources across domains, the explicit representation of knowledge from domain experts, and user interfaces providing convenient access to project specific data resources and algorithms. The system provides an interactive approach to statistical analysis, data mining, and hypothesis testing over the lifetime of a study and fulfills a mandate of public sharing by integrating data sharing into a system built for active data exploration. The web-based platform removes barriers for research and supports the ongoing exploration of data.
doi:10.3389/fninf.2014.00025
PMCID: PMC3972454  PMID: 24723882
data exploration; data sharing; genetics; data dictionary; imaging; hypothesis testing
18.  Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis 
Liu, Jimmy Z. | Hov, Johannes Roksund | Folseraas, Trine | Ellinghaus, Eva | Rushbrook, Simon M. | Doncheva, Nadezhda T. | Andreassen, Ole A. | Weersma, Rinse K. | Weismüller, Tobias J. | Eksteen, Bertus | Invernizzi, Pietro | Hirschfield, Gideon M. | Gotthardt, Daniel Nils | Pares, Albert | Ellinghaus, David | Shah, Tejas | Juran, Brian D. | Milkiewicz, Piotr | Rust, Christian | Schramm, Christoph | Müller, Tobias | Srivastava, Brijesh | Dalekos, Georgios | Nöthen, Markus M. | Herms, Stefan | Winkelmann, Juliane | Mitrovic, Mitja | Braun, Felix | Ponsioen, Cyriel Y. | Croucher, Peter J. P. | Sterneck, Martina | Teufel, Andreas | Mason, Andrew L. | Saarela, Janna | Leppa, Virpi | Dorfman, Ruslan | Alvaro, Domenico | Floreani, Annarosa | Onengut-Gumuscu, Suna | Rich, Stephen S. | Thompson, Wesley K. | Schork, Andrew J. | Næss, Sigrid | Thomsen, Ingo | Mayr, Gabriele | König, Inke R. | Hveem, Kristian | Cleynen, Isabelle | Gutierrez-Achury, Javier | Ricaño-Ponce, Isis | van Heel, David | Björnsson, Einar | Sandford, Richard N. | Durie, Peter R. | Melum, Espen | Vatn, Morten H | Silverberg, Mark S. | Duerr, Richard H. | Padyukov, Leonid | Brand, Stephan | Sans, Miquel | Annese, Vito | Achkar, Jean-Paul | Boberg, Kirsten Muri | Marschall, Hanns-Ulrich | Chazouillères, Olivier | Bowlus, Christopher L. | Wijmenga, Cisca | Schrumpf, Erik | Vermeire, Severine | Albrecht, Mario | Rioux, John D. | Alexander, Graeme | Bergquist, Annika | Cho, Judy | Schreiber, Stefan | Manns, Michael P. | Färkkilä, Martti | Dale, Anders M. | Chapman, Roger W. | Lazaridis, Konstantinos N. | Franke, Andre | Anderson, Carl A. | Karlsen, Tom H.
Nature genetics  2013;45(6):670-675.
doi:10.1038/ng.2616
PMCID: PMC3667736  PMID: 23603763
genetic association study; disease genetics; immunogenetics; liver
19.  Restless Pillow, Ruffled Mind: Sleep and Affect Coupling in Interepisode Bipolar Disorder 
Journal of abnormal psychology  2012;121(4):863-873.
Disturbances in sleep and affect are prominent features of bipolar disorder, even during interepisode periods. Few longitudinal studies have prospectively examined the relationship between naturally occurring sleep and affect, and no studies to date have done so during interepisode periods of bipolar disorder and using the entire set of “gold standard” sleep parameters. Participants diagnosed with bipolar I disorder who were interepisode (n = 32) and healthy controls (n = 36) completed diagnostic and symptom severity interviews, and a daily sleep and affect diary, as well as an actigraphy sleep assessment, for eight weeks (M = 54 days, ± 8 days). Mutual information analysis was used to assess the degree of statistical dependence, or coupling, between time series data of sleep and affect. As measured by actigraphy, longer sleep onset latency was coupled with higher negative affect more strongly in the bipolar group than in the control group. As measured by sleep diary, longer wakefulness after sleep onset and lower sleep efficiency were coupled with higher negative affect significantly more strongly in the bipolar group than in the control group. By contrast, there were no significant differences between groups in the degree of coupling between any measures of sleep and positive affect. Findings support the coupling of sleep disturbance and negative affect during interepisode bipolar disorder. Ongoing monitoring of sleep-affect coupling may provide an important target for intervention in bipolar disorder.
doi:10.1037/a0028233
PMCID: PMC3612504  PMID: 22845651
bipolar disorder; sleep; mood; ecological momentary assessment
20.  Neuroimaging Correlates of Novel Psychiatric Disorders after Pediatric Traumatic Brain Injury 
Objective
To study magnetic resonance imaging (MRI) correlates of novel (new-onset) psychiatric disorders (NPD) following traumatic brain injury (TBI) and orthopedic injury (OI).
Method
Participants were age 7–17 years at the time of hospitalization for either TBI or OI. The study used a prospective, longitudinal, controlled design with standardized psychiatric assessments conducted at baseline (reflecting pre-injury function) and 3 months post-injury. MRI assessments including diffusion tensor imaging (DTI)–derived fractional anisotropy (FA), volumetric measures of gray and white matter regions, volumetric measures of lesions, and cortical thickness were conducted. Injury severity was assessed by standard clinical scales. The outcome measure was the presence of an NPD identified during the first 3 months following injury.
Results
There were 88 participants (TBI=44; OI=44). NPD occurred more frequently in the TBI (21/44; 48%) versus the OI (6/44; 14%) group (Fisher’s Exact p=.001). NPD in TBI participants was not related to injury severity. Multivariate analysis of covariance of the relationship between FA in hypothesized regions of interest (bilateral frontal and temporal lobes, bilateral centrum semiovale, bilateral uncinate fasciculi) and NPD and group (TBI versus OI) was significant, and both variables (NPD: p<.05; group: p<.001) were jointly significantly related to FA. NPD was not significantly related to volumetric measures of white or gray matter structures, volumetric measures of lesions, or to cortical thickness measures.
Conclusions
Lowered white matter integrity may be more important in the pathophysiology of NPD than indices of gray matter or white matter atrophic changes, macroscopic lesions, and injury severity.
doi:10.1016/j.jaac.2012.08.026
PMCID: PMC3511860  PMID: 23101746
TBI; pediatric; psychiatric disorders; prospective; diffusion tensor imaging
21.  Heart fatty acid binding protein and Aβ-associated Alzheimer’s neurodegeneration 
Background
Epidemiological and molecular findings suggest a relationship between Alzheimer’s disease (AD) and dyslipidemia, although the nature of this association is not well understood.
Results
Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-β (Aβ), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Aβ1–42 and occurred irrespective of phospho-tau181p status.
Conclusions
Our findings indicate that Aβ-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer’s disease neurodegeneration.
doi:10.1186/1750-1326-8-39
PMCID: PMC3850652  PMID: 24088526
Alzheimer’s disease; Fatty acids; Lipids; Amyloid; Tau; Brain atrophy
22.  Right Orbitofrontal Corticolimbic and Left Corticocortical White Matter Connectivity Differentiate Bipolar and Unipolar Depression 
Biological psychiatry  2010;68(6):560-567.
Objectives
The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression.
Methods
We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration.
Results
There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F ≥ 9.8; p ≤ .05, corrected). Whole brain post hoc analyses (all t ≥ 4.2; p ≤ .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC.
Conclusions
White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.
doi:10.1016/j.biopsych.2010.04.036
PMCID: PMC3743239  PMID: 20598288
Depression; diffusion tensor imaging; inferior longitudinal fasciculus; mood disorders; superior longitudinal fasciculus; uncinate fasciculus
23.  To What Factors Do Rural-Dwelling Hispanics Attribute Depressive Symptoms? 
This study is a retrospective chart review comparing rural-dwelling Caucasian and Hispanic outpatients' attribution of depressive symptoms. Based on the data gathered at intake, Hispanics were more likely to attribute depression to curse/spell and supernatural causes, while Caucasians were more likely to attribute symptoms to hereditary factors or job stress. Among both groups, higher CESD score was associated with problems with significant others or how they got along with others. Among Hispanics, depression severity was additionally associated with problems related to job or finances. Our findings point to a consequential role for clinical inquiry into attributed causes of depressive symptoms.
doi:10.1155/2013/781986
PMCID: PMC3677663  PMID: 23781333
24.  5HTTLPR Short Allele, Resilience and Successful Aging in Older Adults 
Objective
Resilience is proposed as a significant component of successful aging. Young adult carriers of the Serotonin Transporter Polymorphism (5HTTLPR) short(s) allele appear to have reduced resilience to stress. We examined if presence of the short allele was associated with poorer emotional resilience in older adults.
Methods
In a cross-sectional study of 99 healthy, community-dwelling, older adults we determined 5HTTLPR genotype status and administered the Connor-Davidson Resilience Scale and self-reported measures of successful aging, cognition and health.
Results
There was no significant association between the 5HTTLPR s allele and resilience. S allele carriers had worse cognition and self-report ratings of successful aging.
Conclusions
These findings suggest that the impact of the 5HTTLPR 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.
doi:10.1097/JGP.0b013e31823e2d03
PMCID: PMC3326186  PMID: 22233775
5-HTT; Serotonin transporter polymorphism; Resilience; Stress; Successful Aging; Cognition
25.  Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate 
PLoS Genetics  2013;9(4):e1003455.
Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the “missing heritability” of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q–Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders.
Author Summary
Genome-wide association studies (GWAS) have thus far identified only a small fraction of the heritability of common complex disorders, such as severe mental disorders. We used a conditional false discovery rate approach for analysis of GWAS data, exploiting “genetic pleiotropy” to increase discovery of common gene variants associated with schizophrenia and bipolar disorders. Leveraging the increased power from combining GWAS of two associated phenotypes, we found a striking overlap in polygenic signals, allowing for the discovery of several new common gene variants associated with bipolar disorder and schizophrenia that were not identified in the original analysis using traditional GWAS methods. Some of the gene variants have been identified in other studies with large targeted replication samples, validating the present findings. Our pleiotropy-informed method may be of significant importance for detecting effects that are below the traditional genome-wide significance level in GWAS, particularly in highly polygenic, complex phenotypes, such as schizophrenia and bipolar disorder, where most of the genetic signal is missing (i.e., “missing heritability”). The findings also offer insights into mechanistic relationships between bipolar disorder and schizophrenia pathogenesis.
doi:10.1371/journal.pgen.1003455
PMCID: PMC3636100  PMID: 23637625

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