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Background: Persons with schizophrenia and schizoaffective disorder (PwS) have high rates of cardiometabolic pathology that contributes to premature mortality. Adiponectin is a metabolic hormone affecting insulin sensitivity and inflammation, and is active in the brain. High-molecular weight (HMW) adiponectin is considered a more sensitive marker of metabolic dysfunction than total adiponectin, but has been poorly studied in schizophrenia., Methods: This was a cross-sectional study of 100 PwS, age range 26-68 years (46 women), and 93 age- and sex-comparable non-psychiatric comparison (NC) subjects. Assessments included measures of psychopathology, physical health, cognitive function, and circulating biomarkers of metabolic dysfunction (HMW adiponectin, lipids, insulin resistance) and inflammation (high-sensitivity C-reactive protein or hs-CRP, Tumor Necrosis Factor-α, Interleukin-6, and Interleukin-10)., Results: HMW adiponectin levels were lower in PwS compared to NCs. Lower HMW adiponectin levels were associated with higher body mass index (BMI), higher Framingham risk for coronary heart disease, higher number of metabolic syndrome criteria, greater insulin resistance, lower HDL cholesterol, and higher hs-CRP in both groups. Only in PwS, lower HMW adiponectin correlated with younger age. In the best-fit regression models of HMW adiponectin, lower levels were associated with lower HDL cholesterol and minority race/ethnicity in both groups; but with younger age, non-smoking, higher insulin resistance, and a diagnosis of schizoaffective disorder only among PwS, and with male sex, better cognitive functioning, and higher hs-CRP levels in NCs only., Discussion: HMW adiponectin may be a promising biomarker of cardiometabolic health, especially among PwS. Adiponectin is a potential target for lifestyle and pharmacological interventions. Research on the possible role of HMW adiponectin in modifying cardiometabolic pathology in schizophrenia is needed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Sleep disturbances are common in bipolar disorder (BD) and are often assessed by self-report at clinic visits over the course of BD treatment. Self-report may be subject to recall bias based upon current mood/affect states. This study sought to identify the degree of inaccuracy between subjective and objective measures of sleep duration in those with and without BD, and to assess the demographic and clinical correlates of this inaccuracy., Methods: Thirty-one individuals with BD and 54 healthy control (HC) participants reported on the number of hours slept a night over the past month and subsequently completed up to 14 days/nights of wrist actigraphy which provided an objective measure of sleep duration. We compared the subjective rating to the average of all nights of objective sleep duration, and correlated the magnitude of inaccuracy with demographic and clinical characteristics in the BD and HC groups., Results: On average, both BD and HC groups overestimated their sleep, and there were no differences in inaccuracy between groups. In the BD group, greater inaccuracy was associated with lower functioning, even after controlling individually for objective and subjective sleep measures., Limitations: Cross-sectional study, only focus on sleep duration, and less severe bipolar symptoms of sample., Conclusions: Inaccuracy in reports of sleep duration was associated with lower functioning among BD patients. Better identifying discrepancies in reports of sleep duration in clinical practice could help in more efficient monitoring and management of BD symptoms., (Copyright © 2019. Published by Elsevier B.V.)

Higher prevalence of physical comorbidity and premature mortality in persons with schizophrenia (PwS) results primarily from heightened cardiovascular and metabolic risks. The literature suggests that insulin resistance precedes the development of obesity, smoking, and use of antipsychotic medications, although these likely play a compounding role later in the course of the disorder. It is thus important to discover the clinical characteristics of PwS with high insulin resistance, as these individuals may represent an etiopathologically distinct subgroup with a distinct course and treatment needs. We conducted a cross-sectional study and compared insulin resistance between 145 PwS and 140 nonpsychiatric comparison (NC) participants, similar in age, sex, and race distribution. In addition, we examined correlates of insulin resistance in PwS. As expected, PwS had higher levels of insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] and body mass index (BMI) compared to the NC participants. HOMA-IR in the PwS was most associated with negative symptoms, BMI, and non-White race/ethnicity. The mechanistic relationships between insulin resistance and negative symptoms in schizophrenia patients warrant further investigation, and future studies should examine outcomes of PwS with this cluster of physical and mental symptoms and determine how management of insulin resistance might improve health of these individuals.

The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T 1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T 1 -weighted images., (© 2018 Wiley Periodicals, Inc.)

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Black emerging adult women (ages 18-25 years) are among the fastest growing demographics of HIV infection, second only to men who have sex with men. Black women account for nine of 10 new HIV cases, whereas 84% of these cases are reported to be from heterosexual contact with infected male partners. Heterosexual Black college women (BCW) have been nearly ignored in the HIV literature despite having shared (e.g., risky alcohol use, multiple and concurrent sex partnerships, and inconsistent condom use) and unique (e.g., segregating dating practices and high sexually transmitted infection rates) risk factors when compared with broader college student demographics., Method: This conceptual paper uses a multiple risk factor framework to underscore shared and unique risk factors that may work to increase the potential HIV infection risk burden in this understudied population., Conclusions: Prevention and intervention implications and recommendations for future research that have potential to impact the ways in which colleges, universities, and researchers engage this population are presented. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objectives: Persons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. The sleep-inflammation link has been reported to be stronger in women within the general population. This study sought to examine the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical and cognitive variables., Design: Cross-sectional case-control study., Participants: Community-dwelling outpatients with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26-65 years., Measurements: Reported sleep disturbances (sleep quality and duration), and mental and physical health were assessed. Cognitive assessments included executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status - modified.) Inflammatory biomarkers included pro-inflammatory cytokines [high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-α (TNF-α)] and an anti-inflammatory cytokine (IL-10)., Results: The schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-α compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels., Conclusions: Sleep disturbances and increased inflammation, which were common in schizophrenia, were associated in persons with schizophrenia. Moreover, women with schizophrenia had worse sleep quality and inflammation than men. Further examination of the sleep-inflammation links, their contribution to clinical outcomes, and sex-specific factors is warranted., (Copyright © 2018. Published by Elsevier Inc.)

Background: Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach., Objective: We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups., Methods: PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences., Results: Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies., Conclusions: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.

Sixty percent of Hispanics/Latinos are bilingual which research suggests may confer certain cognitive advantages. Female sex confers cognitive advantages in verbal learning and memory compared to male sex, regardless of race or ethnicity. Understanding the independent and interactive associations of bilingualism and sex with cognition may aid in predicting cognitive aging in Hispanics/Latinos. We examined baseline (2008-2011) data from the Hispanic Community Health Study/Study of Latinos, a multicenter, prospective community-based study. Our analyses included 6,110 males and females ≥45 years old who self-reported birth and parents' origin outside of the continental US, Spanish as their first language, and were evaluated in Spanish. Bilingualism was assessed along a Likert scale (1 = only Spanish to 4 = English>Spanish) for language proficiency (reading/spoken) and patterns of use (thinking/socializing). Cognitive testing included verbal learning, memory, fluency, and Digit Symbol Substitution (DSS). Linear regression models adjusted for relevant confounders, the complex survey design, and sampling weights. Participants' self-reported language proficiency was Spanish better than English, while patterns of use suggested more Spanish than English. Higher language proficiency was associated with higher performance on all cognitive indices while higher patterns of use associated with higher fluency and DSS scores (p-values < 0.01). Female sex was associated with higher performance on all cognitive indices (p-values < 0.05). There were no significant interactions with bilingualism (regardless of metric) by sex on cognition. For Hispanics/Latinos residing in the continental US and reporting birth and parents' origin elsewhere, bilingualism and female sex have independent cognitive benefits that are important to consider when evaluating cognitive performance.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case-control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A "vascular endothelial index" (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62 years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: More than 50% of people with bipolar disorder will be age 60 years or older by 2030. There is a need for more data to guide assessment and treatment in older age bipolar disorder (OABD); however, interpretation of findings from small, single-site studies may not be generalizable and there are few large trials. As a step in the direction of coordinated large-scale OABD data collection, it is critical to identify which measurements are currently used and identify potential gaps in domains typically assessed., Methods: An international group of OABD experts performed a systematic literature review to identify studies examining OABD in the past 6 years. Relevant articles were assessed to categorize the types of clinical, cognitive, biomarker, and neuroimaging OABD tools routinely used in OABD studies., Results: A total of 53 papers were identified, with a broad range of assessments. Most studies evaluated demographic and clinical domains, with fewer studies assessing cognition. There are relatively few biomarker and neuroimaging data, and data collection methods were less comprehensively covered., Conclusion: Assessment tools used in the recent OABD literature may help to identify both a minimum and a comprehensive dataset that should be evaluated in OABD. Our review also highlights gaps where key clinical outcomes have not been routinely assessed. Biomarker and neuroimaging assessment could be further developed and standardized. Clinical data could be combined with neuroimaging, genetic, and other biomarkers in large-scale coordinated data collection to further improve our understanding of OABD phenomenology and biology, thereby contributing to research that advances care., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To determine the clinical and biological characteristics of an exceptionally high functioning index person (IP) with schizophrenia in her mid-50s, which may represent compensatory mechanisms, and potentially, avoidance of the accelerated aging typically associated with schizophrenia., Method: IP, 11 other women with schizophrenia, and 11 non-psychiatric comparison (NC) women were assessed with standard ratings of psychopathology, neurocognitive function, decisional capacity, and functional brain imaging. IP was also compared to a sample of demographically similar NCs (N=45) and persons with schizophrenia (N=42) on a set of blood-based biomarkers of aging related to metabolic function, oxidative stress, and inflammation., Results: IP's scores on working memory, and levels of brain activation during an affective face matching task in the left fusiform, right lingual, and left precentral gyri, exceeded NCs. IP was similar to NCs in severity of negative symptoms, most neurocognitive functions, decisional capacity, and brain activation in the left inferior occipital gyrus during a selective stopping task. IP's levels on 11 of 14 metabolic and inflammatory biomarkers of aging were better than NCs and the schizophrenia group., Conclusion: Although speculative, results suggest a possible model in which superior working memory permits a person to be aware of the potentially psychotic nature of a thought or perception, and adjust response accordingly. Compensatory overactivity of brain regions during affective processing may also reflect heightened meta-awareness in emotional situations. Biomarker levels raise the possibility that IP partially avoided the accelerated biological aging associated with schizophrenia., (Published by Elsevier B.V.)

Individuals with schizophrenia have higher mortality rates than the population at large. General mortality rates have declined in developed countries since the early 1970s, extending average lifespan by nearly a decade. This review of eight longitudinal studies of mortality in schizophrenia found that the mean standardized mortality ratio (SMR, a measure of mortality rate in schizophrenia compared to the general population) increased 37%, from 2.2 in the pre-1970s studies to 3.0 in the post-1970s reports. Major changes in societal stigma, healthcare, and economic policy are urgently warranted to ensure that this vulnerable segment of the population participates in the longevity revolution., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Insomnia is prevalent in bipolar disorder (BD) even during periods of euthymic mood. We compared resting state brain activity and cognitive function between euthymic BD with and without insomnia, and secondarily to healthy individuals. BD patients with insomnia symptoms showed a significantly lower functional connectivity within the task-positive network, compared to those without insomnia. They also showed significantly slower cognitive processing speed. These two features of BD with insomnia appeared relatively independent of each other. Preliminary findings suggest that exploration of the mechanisms of sleep disturbance in BD could lead to improved understanding and treatment of inattention in BD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD., (© 2018 Wiley Periodicals, Inc.)

Background and Aims: Disentangling the putative impact of cannabis on brain morphology from other comorbid substance use is critical. After controlling for the effects of nicotine, alcohol and multi-substance use, this study aimed to determine whether frequent cannabis use is associated with significantly smaller subcortical grey matter volumes., Design: Exploratory analyses using mixed linear models, one per region of interest (ROI), were performed whereby individual differences in volume (outcome) at seven subcortical ROIs were regressed onto cannabis and comorbid substance use (predictors)., Setting: Two large population-based twin samples from the United States and Australia., Participants: A total of 622 young Australian adults [66% female; μ age  = 25.9, standard deviation SD) = 3.6] and 474 middle-aged US males (μ age  = 56.1 SD = 2.6 ) of predominately Anglo-Saxon ancestry with complete substance use and imaging data. Subjects with a history of stroke or traumatic brain injury were excluded., Measurements: Magnetic resonance imaging (MRI) and volumetric segmentation methods were used to estimate volume in seven subcortical ROIs: thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala and nucleus accumbens. Substance use measurements included maximum nicotine and alcohol use, total life-time multi-substance use, maximum cannabis use in the young adults and regular cannabis use in the middle-aged males., Findings: After correcting for multiple testing (P = 0.007), cannabis use was unrelated to any subcortical ROI. However, maximum nicotine use was associated with significantly smaller thalamus volumes in middle-aged males., Conclusions: In exploratory analyses based on young adult and middle-aged samples, normal variation in cannabis use is unrelated statistically to individual differences in brain morphology as measured by subcortical volume., (© 2018 Society for the Study of Addiction.)

Schizophrenia and bipolar disorder are among the leading causes of disability, morbidity, and mortality worldwide. In addition to being serious mental illnesses, these disorders are associated with considerable systemic physiological dysfunction, including chronic inflammation and elevated oxidative stress. The advent of sophisticated sequencing techniques has led to a growing interest in the potential role of gut microbiota in human health and disease. Advances in this area have transformed our understanding of a number of medical conditions and have generated a new perspective suggesting that gut microbiota might be involved in the development and maintenance of brain/mental health. Animal models have demonstrated strong though indirect evidence for a contributory role of intestinal microbiota in psychiatric symptomatology and have linked the microbiome with neuropsychiatric conditions. We present a systematic review of clinical studies of microbiome in schizophrenia and bipolar disorder. The published literature has a number of limitations; however, the investigations suggest that these disorders are associated with reduced microbial diversity and show global community differences compared to non-psychiatric comparison samples. In some reports, specific microbial taxa were associated with clinical disease characteristics, including physical health, depressive and psychotic symptoms, and sleep, but little information on the functional potential of those community changes. Studies also suggest increased intestinal inflammation and permeability, which may be among the principal mechanisms by which microbial dysbiosis impacts systemic physiological functioning. We highlight gaps in the current literature and implications for diagnosis and therapeutic interventions, and outline future directions for microbiome research in psychiatry., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Positive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors with mental and physical health in schizophrenia., Method: One hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26-65 years, were evaluated with scales of resilience, optimism, happiness, and perceived stress. Measures of mental and physical health were also obtained. Regression analyses examined associations of a PPF composite with health variables., Results: Relative to the HCs, the schizophrenia group had lower levels of PPFs. However, there was considerable heterogeneity, with over one-third of schizophrenia participants having values within the 'normative' range. The PPF composite was positively related to mental and physical health variables and with biomarkers of inflammation and insulin resistance. The relationship between PPFs and mental health was particularly strong for individuals with schizophrenia., Conclusion: A sizable minority of adults with chronic schizophrenia have levels of resilience, optimism, happiness, and perceived stress similar to HCs. Psychosocial interventions to enhance PPFs should be tested in patients with serious mental illnesses, with the goal of improving their mental health (beyond controlling symptoms of psychosis) and their physical health.

Background: Schizophrenia is associated with increased physical morbidity and early mortality, suggesting that the aging process may be accelerated in schizophrenia. However, the biological underpinnings of these alterations in aging in schizophrenia are unclear., Method: We conducted a detailed search of peer-reviewed empirical studies to evaluate evidence for accelerated biological aging in schizophrenia based on systemic, age-related biomarkers. We included studies that investigated differences between persons with schizophrenia and healthy comparison subjects in levels of biomarkers known to be associated with aging and examined the relationship of these biomarkers to age in the 2 groups., Results: Forty-two articles that met our selection criteria were reviewed. Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia, including indices of inflammation, cytotoxicity, oxidative stress, metabolic health, gene expression, and receptor/synaptic function, with medium to large effect sizes reported in many studies. Twenty-nine percent of the studies observed differential age-related decline in schizophrenia. Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia. Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length., Conclusions: Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging. Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis.

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56-66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9-28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage.

Pupillary responses during cognitive tasks are linked to functioning of the locus coeruleus (LC). The LC is an early site of abnormal tau deposition, which may contribute to key aspects of Alzheimer's disease (AD) pathophysiology. We previously found attenuation of pupillary responses to increases in cognitive load in individuals with mild cognitive impairment (MCI), suggesting pupillary responses may provide a biomarker of early risk for AD associated with LC dysfunction. The LC modulates cortical activity through two modes of operation: tonic and phasic. Early LC damage has been predicted to result in a state of persistent high tonic LC activity that may disrupt task-related phasic activity. To further examine whether pupillary responses are associated with early LC dysfunction, we measured pupil dilation during a digit span task as a measure of phasic activity, and low frequency BOLD variance (LFBV) during resting-state fMRI in key nodes of the ventral attention network (VAN) as a measure of cortical reactivity related to LC tonic activity in 358 middle-aged men. Individuals with greater LFBV in VAN nodes, i.e., higher tonic brain activity at rest, showed a smaller increase in pupil dilation from low to moderate cognitive loads. Thus, higher tonic LFBV activity at rest was related to reduced task-appropriate phasic dilation increases. The results support predictions from prominent models of LC functioning in which early LC dysfunction leads to persistent high tonic rates of activity during rest and lower signal-to-noise of phasic responses during task performance. Taken together with previous findings of early AD pathophysiology in LC and reduced phasic dilation responses to increased cognitive load in individuals with MCI, the present results suggest that pupillary responses may index early LC dysfunction and should receive further study as a potential biomarker of risk for AD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to examine the feasibility, acceptability, and initial validity of using smartphone-based ecological momentary assessment (EMA) to assess daily functioning and other behavioral factors among older HIV+ adults., Methods: Twenty older HIV+ adults (mean age: 59 years) completed laboratory-based neurobehavioral and functional assessments then completed EMA surveys via smartphones five times per day for one week., Results: Excellent EMA adherence (86.4%) was found, and participants rated their experience with EMA methods positively. Time-use data indicated participants were spending 74% of their waking-sampled time at home, 63% of their time alone, and 32% of their time engaged in passive leisure activities (e.g., watching TV). Better neurocognitive and functional capacity abilities were correlated with less time spent in passive leisure activities. Lastly, mood and cognitive symptom data collected via EMA were significantly associated with scores from laboratory-based assessments of these same constructs., Conclusions: EMA via smartphones is a feasible and acceptable data collection method among older HIV+ adults and appears to be a promising mobile tool to assess daily functioning behaviors in HIV. These preliminary findings indicate older HIV+ adults are spending a considerable amount of time at home, alone, and engaged in passive leisure activities, primarily watching TV. EMA may contribute to future research examining functional disability among the growing population of older HIV+ adults., (Published by Elsevier Inc.)

Objectives: Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging., Design: Cross-sectional study., Setting: University of California San Diego and the Veterans Administration San Diego Healthcare System., Participants: 33 euthymic BD and 38 HC participants., Measurements: Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test., Results: BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently., Conclusions: Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Increased mean diffusivity (MD) is hypothesized to reflect tissue degeneration and may provide subtle indicators of neuropathology as well as age-related brain changes in the absence of volumetric differences. Our aim was to determine the degree to which genetic and environmental variation in subcortical MD is distinct from variation in subcortical volume. Data were derived from a sample of 387 male twins (83 MZ twin pairs, 55 DZ twin pairs, and 111 incomplete twin pairs) who were MRI scanned as part of the Vietnam Era Twin Study of Aging. Quantitative estimates of MD and volume for 7 subcortical regions were obtained: thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens. After adjusting for covariates, bivariate twin models were fitted to estimate the size and significance of phenotypic, genotypic, and environmental correlations between MD and volume at each subcortical region. With the exception of the amygdala, familial aggregation in MD was entirely explained by additive genetic factors across all subcortical regions with estimates ranging from 46 to 84%. Based on bivariate twin modeling, variation in subcortical MD appears to be both genetically and environmentally unrelated to individual differences in subcortical volume. Therefore, subcortical MD may be an alternative biomarker of brain morphology for complex traits worthy of future investigation. Hum Brain Mapp 38:2589-2598, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Chemokines are promising biomarkers of immune activation and inflammation, but evidence for chemokine abnormalities in schizophrenia and their relationship to clinical factors remains inconclusive. We aimed to understand chemokine-related diagnostic differences and clinical correlates using a comprehensive panel and studying a large, well-characterized sample of adults with and without schizophrenia. We studied 134 outpatients with schizophrenia or schizoaffective disorder and 112 healthy comparison (HC) individuals, 26 to 65years of age. Clinical measures were obtained, and plasma levels of 11 chemokines were assessed using multiplex immunoassay. Schizophrenia vs. HC differences were tested for each chemokine, adjusting for age, gender, body mass index, and current smoking status. We also examined whether age and gender relationships differed between diagnostic groups. Using logistic regression, we created a Chemokine Index (CI) and explored its clinical correlates. Levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1β (MIP-1β/CCL4), Eotaxin-1 (CCL11), thymus and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22) were significantly higher in persons with schizophrenia than HCs. Group differences in TARC were reduced after adjusting for covariates. The CI, a linear combination of Eotaxin-1 and MDC levels, was positively associated with age, duration of schizophrenia, and severity of negative symptoms. Levels of chemokines with neuroimmune regulatory effects were higher in individuals with schizophrenia, particularly in older and chronic patients. Treatments aimed at normalizing chemokine levels might improve mental and physical health among schizophrenia patients as they age., (Published by Elsevier B.V.)

Objective: Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called 'inflammaging.' Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults., Methods: Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP)., Results: Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load., Conclusions: These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: Bipolar disorder (BD) is associated with cognitive deficits, yet little is known about associations between cognition, vascular risk (VR), and age in this population. This study investigated whether BD patients with VR demonstrate stronger apparent age-related decline in inhibitory performance and processing speed (PS)., Methods: A full medical history was obtained for 34 euthymic BD and 41 healthy comparison (HC) individuals. The Delis-Kaplan Executive Functions Color Word Interference Subtests were administered to all participants to assess for inhibitory performance (condition 3) and PS (conditions 1 and 2). VR positive (VRPos) and VR negative (VRNeg) groups were created based on the presence of one or more VR factors., Results: VRPos-BD participants demonstrated significantly worse inhibitory performance with older age, whereas age and inhibition were not significantly related in the VRPos-HC group or in those who were VRNeg. The same was not true for PS., Conclusion: BD patients with VR may also be at risk for greater decline in inhibitory performance, but not PS, with age. Longitudinal studies are needed to further investigate the contributions of VR to cognitive decline among older BD patients., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To identify key mood, social, and functional correlates of current participation in mental health treatment and barriers to participation in mental health treatment among older HIV infected (HIV+) veterans., Methods: HIV+ veterans (N = 150) aged ≥ 50 years receiving HIV-related medical care at the VA San Diego Healthcare System, San Diego, California, anonymously completed a survey assessing current self-reported mood, social support, daily functioning problems, mental health service utilization, and barriers to participating in mental health services. Veterans also completed the 2-item Patient Health Questionnaire (PHQ-2), a validated depression screening instrument frequently used in primary care settings. Data were collected from February 2014 to May 2014., Results: Overall, 44% of participants screened positive for depressive symptomatology on the PHQ-2; 55% of those who screened positive were participating in mental health treatment. Of the 45% of veterans who screened positive on the PHQ-2 and were not in treatment, two-thirds (66%) stated they had been offered services; however, they were not engaging in or accepting the services. Regardless of PHQ-2 status, current self-reported depressive symptoms emerged as an independent, significant positive predictor of participation in mental health treatment (odds ratio = 5.98; 95% CI, 1.16-30.72; P = .03), whereas anxiety, HIV-related stigma, sufficiency of social support, and daily functioning problems were not associated with mental health treatment utilization. Primary reported barriers to mental health treatment included scheduling/availability, travel time and transportation, and discomfort with group settings., Conclusions: Results of this study suggest there may be a need to better engage older HIV+ veterans in depression-related treatment. The use of telehealth technology, such as teletherapy, electronic devices, and cell phone-based programs, may be beneficial in helping older HIV+ veterans overcome many barriers that restrict their participation in mental health treatment., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Objective: Develop a novel theatre-based program and test its feasibility, tolerability, and preliminary efficacy for improving empathy/compassion and well-being among older adults., Method: Thirteen older adults were randomized to a 6-week Drama Workshop (DW) program or time-equivalent Backstage Pass (BP) control condition. Pre- and post-treatment measures included empathy, compassion, and mood scales. Additional post-treatment measures included self-rated change in empathy/compassion, confidence, and affect. Participants also rated their mood/affect after each session., Results: The program was successfully completed and well-liked. No pre-to-post-treatment changes in empathy/compassion or mood symptoms were found in either group. Compared to BP, DW weekly ratings indicated higher levels of anxiety and lower happiness; however, the DW program had higher self-ratings of positive change in self-esteem, confidence, and happiness post-treatment., Discussion: While the DW may not promote empathy/compassion and was personally challenging during the program, engagement in dramatic exercises and rehearsing and performing a dramatic piece was seen by participants as a positive growth experience, as indicated by the post-treatment ratings of enhanced self-esteem, confidence and happiness. Thus, such a program might be useful for counteracting some of the potential negative aspects of aging, including reduced self-efficacy due to physical limitations and negative affect due to losses., Competing Interests: Declaration of Conflicting Interests No conflicts of interest were declared.

Magnetic resonance imaging (MRI) has become an important tool in the early detection of age-related and neuropathological brain changes. Recent studies suggest that changes in mean diffusivity (MD) of cortical gray matter derived from diffusion MRI scans may be useful in detecting early effects of Alzheimer's disease (AD), and that these changes may be detected earlier than alterations associated with standard structural MRI measures such as cortical thickness. Thus, due to its potential clinical relevance, we examined the genetic and environmental influences on cortical MD in middle-aged men to provide support for the biological relevance of this measure and to guide future gene association studies. It is not clear whether individual differences in cortical MD reflect neuroanatomical variability similarly detected by other MRI measures, or whether unique features are captured. For instance, variability in cortical MD may reflect morphological variability more commonly measured by cortical thickness. Differences among individuals in cortical MD may also arise from breakdowns in myelinated fibers running through the cortical mantle. Thus, we investigated whether genetic influences on variation in cortical MD are the same or different from those influencing cortical thickness and MD of white matter (WM) subjacent to the cortical ribbon. Univariate twin analyses indicated that cortical MD is heritable in the majority of brain regions; the average of regional heritability estimates ranged from 0.38 in the cingulate cortex to 0.66 in the occipital cortex, consistent with the heritability of other MRI measures of the brain. Trivariate analyses found that, while there was some shared genetic variance between cortical MD and each of the other two measures, this overlap was not complete (i.e., the correlation was statistically different from 1). A significant amount of distinct genetic variance influences inter-individual variability in cortical MD; therefore, this measure could be useful for further investigation in studies of neurodegenerative diseases and gene association studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Disturbances in functional connectivity have been suggested to contribute to cognitive and emotion processing deficits observed in bipolar disorder (BD). Functional connectivity between medial prefrontal cortex (mPFC) and other brain regions may be particularly abnormal. The goal of the present study was to characterize the temporal dynamics of the default mode network (DMN) connectivity in BD and examine its association with cognition., Method: In a preliminary study, euthymic BD (n = 15) and healthy comparison (HC, n = 19) participants underwent resting-state functional MRI, using high-resolution sequences adapted from the Human Connectome Project, and completed neuropsychological measures of processing speed and executive function. A seed-based approach was used to measure DMN correlations in each participant, with regions of interest in the mPFC, posterior cingulate cortex (PCC), and lateral parietal cortex. Subsequently, to characterize temporal dynamics, correlational analyses between the mPFC and other DMN nodes were repeated using a sliding-window correlational analysis with subsets of the time series., Results: When averaged across the entire scan, there were no group differences in overall connectivity strength between the mPFC and other regions of the DMN. However, dynamic connectivity between the mPFC and PCC was altered in BD, such that connectivity was less variable (i.e., more rigid) over time. Decreased connectivity variability was associated with slower processing speed and reduced cognitive set-shifting in BD patients., Conclusions: Variability in resting-state functional connectivity may be an index of internetwork flexibility that is reduced in BD and a correlate of ongoing cognitive impairment during periods of euthymia. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Objective: Inflammation may play a role in the accelerated physical aging reported in schizophrenia, though biomarker findings and associations with demographic and clinical factors are inconsistent., Methods: In a cross-sectional, case-control design, 95 outpatients with schizophrenia (mean age ± SD: 48.1 ± 10.2 years) and 95 demographically comparable healthy comparison subjects (HCs) (mean age ± SD: 48.1 ± 12.1 years) were studied. Sociodemographic and clinical data were collected, and plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed. The authors compared cytokine levels, examined demographic and clinical associations, and adjusted for relevant variables with linear models., Results: Individuals with schizophrenia had higher levels of TNF-α and IL-6 but not IFN-γ than HCs. Age was not related to cytokine levels, and age relationships did not differ between diagnostic groups. Women had higher levels of IL-6. TNF-α and IL-6 levels were significantly correlated with depressive symptoms, and adjustment for depression reduced the group effect for both. Within the HCs, TNF-α levels were associated with physical comorbidity and body mass index. IL-6 levels were significantly correlated with body mass index and within schizophrenia patients, with worse mental and physical well-being. Accounting for physical morbidity and mental well-being reduced group differences in TNF-α and IL-6 levels, respectively. Worse positive symptoms were associated with higher IL-6 levels., Conclusion: Higher TNF-α and IL-6 levels in schizophrenia patients were associated with depression, physical comorbidity, and mental well-being. Further longitudinal studies are warranted to assess inflammation as a potential treatment target for a subgroup of schizophrenia., Competing Interests: The authors declare no relevant conflicts of interest., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E- ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age ( t  = 1.9, p  = 0.05) and hypertension ( t  = 2.9, p  = 0.004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled ( t  = 3.0, p  = 0.003) and normotensive ( t  = 4.0, p  = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a 2  = 0.81) and shared some genetic influences with systolic blood pressure (r A  = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery.

Background: Schizophrenia is one of the most disabling psychiatric disorders with increased morbidity and mortality. Both schizophrenia and oxidative stress have been associated with accelerated aging. Previous studies found increased oxidative stress in individuals with schizophrenia, though only one study measured F2-isoprostanes and did so in urine. To our knowledge, the present study is the first to assess plasma F2-isoprostane levels, the putative gold standard measure of systemic oxidative stress in vivo, in schizophrenia., Methods: We compared plasma F2-isoprostane levels in 134 stable outpatients with schizophrenia and 120 age- and gender-matched healthy comparison (HC) subjects. Sociodemographic and clinical data were collected in both groups., Results: Plasma F2-isoprostane levels were significantly higher in the schizophrenia group than in the HC group. Women had higher F2-isoprostane levels compared to men, and those with higher body mass index (BMI) had higher levels, within each group. F2-isoprostane levels correlated with BMI, physical functioning, and medical comorbidity but not with severity of psychopathology or executive function. Linear models showed significant effects of diagnosis, gender, and BMI on F2-isoprostane levels, but no interactions., Discussion: Our finding of increased oxidative stress in schizophrenia is consistent with reports of increased morbidity and mortality as well as accelerated aging in schizophrenia. The significant associations between F2-isoprostane levels and both gender and BMI warrant further study., Competing Interests: The authors declare no relevant conflicts of interest., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Sleep disturbances are prevalent, persistent, and impairing features of bipolar disorder. However, the near-term and cumulative impact of the severity and variability of sleep disturbances on symptoms and functioning remains unclear. We examined self-reported daily sleep duration and variability in relation to mood symptoms, medication adherence, cognitive functioning, and concurrent daily affect., Methods: Forty-one outpatients diagnosed with bipolar disorder were asked to provide daily reports of sleep duration and affect collected via ecological momentary assessment with smartphones over eleven weeks. Measures of depressive and manic symptoms, medication adherence, and cognitive function were collected at baseline and concurrent assessment of affect were collected daily. Analyses examined whether sleep duration or variability were associated with baseline measures and changes in same-day or next-day affect., Results: Greater sleep duration variability (but not average sleep duration) was associated with greater depressive and manic symptom severity, and lower medication adherence at baseline, and with lower and more variable ratings of positive affect and higher ratings of negative affect. Sleep durations shorter than 7-8 h were associated with lower same-day ratings of positive and higher same-day ratings of negative affect, however this did not extend to next-day affect., Conclusions: Greater cumulative day-to-day sleep duration variability, but not average sleep duration, was related to more severe mood symptoms, lower self-reported medication adherence and higher levels of negative affect. Bouts of short- or long-duration sleep had transient impact on affect. Day-to-day sleep variability may be important to incorporate into clinical assessment of sleep disturbances in bipolar disorder., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical "bigger is better" view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Impulsivity is frequently linked with bipolar disorder and is associated with mania and negative outcomes. The temporal dynamics of subjective impulsivity are unclear, in particular whether impulsivity precedes or follows changes in positive or negative affect., Methods: A total of 41 outpatients with bipolar disorder (I or II) were provided with mobile devices for 11 weeks and completed twice-daily surveys about affective states and subjective impulsivity. We examined the association between aggregate subjective impulsivity with baseline global cognitive function, suicide risk ratings, and medication adherence, as well as concurrent and lagged associations with momentary positive and negative affect ratings., Results: A total of 2902 ratings were available across study subjects. Higher aggregate mean ratings of impulsivity were associated with worse baseline global cognitive function, prior suicide attempts, and self-reported problems with medication adherence, as well as more severe manic (but not depressive) symptoms. Time-lagged models indicated that greater negative affect, but not positive affect, predicted subsequent increases in subjective impulsivity, which, in turn, predicted diminished positive affect., Limitations: Other measures of impulsivity with which to validate subjective ratings were unavailable and the sample was restricted to generally clinically stable outpatients., Conclusions: Subjective impulsivity as measured by daily monitoring was associated with worse cognitive function and self-rated medication adherence, and higher suicide risk ratings. Impulsivity may be a maladaptive strategy to regulate negative affect in bipolar disorder., (Copyright © 2016. Published by Elsevier B.V.)

Depression and cognitive impairment are pervasive and highly disabling aspects of bipolar disorder. Although cognitive impairment is partially independent from mood episodes, depressive symptoms may increase the risk of cognitive impairment in bipolar disorder through inflammatory processes as well as health risks such as obesity and sedentary behavior. Novel treatment avenues at the intersection of bipolar depression and cognitive impairment target inflammation directly or indirectly health behaviors such as diet, physical activity, and sleep hygiene., (Published by Elsevier Inc.)

Cortical surface area (CSA) has particular relevance for understanding development, behavior, and the connection between brain structure and function. Little is known about genetic and environmental determinants of CSA during development. We utilized bivariate twin methods to identify global and regionally specific genetic factors which influence CSA in a preliminary sample of typically-developing adolescents, with hypotheses based on findings in middle-aged adults. Similar to previous findings, we observed high heritability for total CSA. There was also significant evidence for genetic influences on regional CSA, particularly when these were not adjusted for total CSA, with highest heritability in frontal cortex and relatively fewer genetic contributions to medial temporal cortical structures. Adjustment for total CSA reduced regional CSA heritability dramatically, but a moderate influence of genetic factors remained in some regions. Both global and regionally-specific genetic factors influence regional CSA during adolescence.

Objectives: Affective dysregulation is a core feature of bipolar disorder (BD). Abnormalities in neural circuits underlying affect regulation have been observed in BD, specifically in the structure and function of the amygdala and orbital frontal cortex (OFC). Fear extinction is an automatic affect regulatory process relying on neural circuits that are abnormal in BD. Thus, fear extinction might be useful in probing automatic affect regulation deficits in BD. We tested the hypothesis that BD is associated with reduced ability to extinguish fear responses., Methods: We examined fear conditioning, extinction, and extinction memory recall in a sample of stable, euthymic participants with BD (n=19) vs. healthy comparison participants (n=32). A limited number of subjects (BD: n=12; healthy comparison: n=11) underwent structural MRI scanning to examine cortical size associations with extinction recall., Results: Both healthy comparison and BD participants were successful in acquiring a fear response, but BD participants responded with greater startle to both threat and safety cues. Both groups showed significant extinction. The BD group showed superior extinction recall. Extinction recall was associated with right rostral middle frontal cortex thickness across groups, whereas right OFC surface area was associated with recall only in healthy comparisons., Limitations: Limitations include use of a stable, highly screened sample and a relatively small number of participants available for MRI analysis., Conclusions: Increased fear reactivity may be related to a "trait" disruption in BD patients similar to that previously described in anxiety disorders. This task may be useful for probing automatic affect regulatory processes in BD, and understanding treatment response., (Published by Elsevier B.V.)

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques-biometrical genetic modeling, cluster analysis, and graph theory-to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several of the genetic parcellations. Cluster analysis suggested small distinct groupings of genetic covariance; networks highlighted several significant negative and positive genetic correlations between bilateral parcellations. Graph theoretical analysis suggested that small world, but not rich club, network properties may characterize the genetic relationships between these regional size measures. These findings suggest that cortical genetic parcellations exhibit short characteristic path lengths across a broad network of connections. This property may be protective against network failure. In contrast, previous research with structural data has observed strong rich club properties with tightly interconnected hub networks. Future studies of these genetic networks might provide powerful phenotypes for genetic studies of normal and pathological brain development, aging, and function.

Most studies examining associations between hypertension and brain white matter microstructure have focused on older adults or on cohorts with a large age range. Because hypertension effects on the brain may vary with age, it is important to focus on middle age, when hypertension becomes more prevalent. We used linear mixed-effect models to examine differences in white matter diffusion metrics as a function of hypertension in a well-characterized cohort of middle-aged men (n=316; mean, 61.8 years; range, 56.7-65.6). Diffusion metrics were examined in 9 tracts reported to be sensitive to hypertension in older adults. Relative to normotensive individuals, individuals with long-standing hypertension (>5.6 years) showed reduced fractional anisotropy or increased diffusivity in most tracts. Effects were stronger among carriers than among noncarriers of the apolipoprotein E ε4 allele for 2 tracts connecting frontal regions with other brain areas. Significant differences were observed even after adjustment for potentially related lifestyle and cardiovascular risk factors. Shorter duration of hypertension or better blood pressure control among hypertensive individuals did not lessen the adverse effects. These findings suggest that microstructural white matter alterations appear early in the course of hypertension and may persist despite adequate treatment. Although longitudinal studies are needed to confirm these findings, the results suggest that prevention-rather than management-of hypertension may be vital to preserving brain health in aging., (© 2015 American Heart Association, Inc.)

Total gray matter volume is associated with general cognitive ability (GCA), an association mediated by genetic factors. It is expectable that total neocortical volume should be similarly associated with GCA. Neocortical volume is the product of thickness and surface area, but global thickness and surface area are unrelated phenotypically and genetically in humans. The nature of the genetic association between GCA and either of these 2 cortical dimensions has not been examined. Humans possess greater cognitive capacity than other species, and surface area increases appear to be the primary driver of the increased size of the human cortex. Thus, we expected neocortical surface area to be more strongly associated with cognition than thickness. Using multivariate genetic analysis in 515 middle-aged twins, we demonstrated that both the phenotypic and genetic associations between neocortical volume and GCA are driven primarily by surface area rather than thickness. Results were generally similar for each of 4 specific cognitive abilities that comprised the GCA measure. Our results suggest that emphasis on neocortical surface area, rather than thickness, could be more fruitful for elucidating neocortical-GCA associations and identifying specific genes underlying those associations., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)