Nonpsychiatric Comparison Subjects Research Articles

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p < 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01–0.77, R² = 0.18, p < 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p < 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

Differential regulation of MAP2 by phosphorylation events in proline-rich versus C-terminal domains.

MAP2 is a critical cytoskeletal regulator in neurons. The phosphorylation of MAP2 (MAP2-P) is well known to regulate core functions of MAP2, including microtubule (MT)/actin binding and facilitation of tubulin polymerization. However, site-specific studies of MAP2-P function in regions outside of the MT-binding domain (MTBD) are lacking. We previously identified a set of MAP2 phosphopeptides which are differentially expressed and predominantly increased in the cortex of individuals with schizophrenia relative to nonpsychiatric comparison subjects. The phosphopeptides originated not from the MTBD, but from the flanking proline-rich and C-terminal domains of MAP2. We sought to understand the contribution of MAP2-P at these sites on MAP2 function. To this end, we isolated a series of phosphomimetic MAP2C constructs and subjected them to cell-free tubulin polymerization, MT-binding, actin-binding, and actin polymerization assays. A subset of MAP2-P events significantly impaired these functions, with the two domains displaying different patterns of MAP2 regulation: proline-rich domain mutants T293E and T300E impaired MT assembly and actin-binding affinity but did not affect MT-binding, while C-terminal domain mutants S426E and S439D impaired all three functions. S443D also impaired MT assembly with minimal effects on MT- or actin-binding. Using heterologous cells, we also found that S426E but not T293E had a lower capability for process formation than the wild-type protein. These findings demonstrate the functional utility of MAP2-P in the proline-rich and C-terminal domains and point to distinct, domain-dependent regulations of MAP2 function, which can go on to affect cellular morphology.

Self-compassion, but not compassion toward others, is associated with better physical health: A cross-sectional study.

Compassion is a modifiable construct that is associated with better physical health outcomes but, to our knowledge, has seldom been studied in people with schizophrenia (PwS) despite its applicability to counteract widespread depression in this community that might prevent positive health behaviors. We hypothesized that, compared to non-psychiatric comparison subjects (NCs), PwS would have lower compassion toward self (CTS), lower compassion toward others (CTO), and a positive association between compassion and health outcomes, such as physical wellbeing, comorbidities, and plasma hs-CRP. This cross-sectional study examined differences in physical health, CTS, and CTO in 189 PwS and 166 NCs. We used general linear models to analyze the relationship between compassion and health. As hypothesized, PwS had lower levels of CTS and CTO, worse physical well-being, more comorbidities, and higher levels of plasma hs-CRP than NCs. In the combined sample, higher CTS was significantly associated with better physical well-being and fewer comorbidities, while higher CTO was significantly associated with more comorbidities. In PwS alone, higher CTS was significantly associated with better physical well-being and lower levels of hs-CRP. CTS seemed to have a larger positive association with physical health than CTO, with depression acting as a potential mediator for CTS. Exploring effects of CTS interventions on physical health and health behaviors could be a promising next step.

Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk

DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.

Associations between inflammatory marker profiles and neurocognitive functioning in people with schizophrenia and non-psychiatric comparison subjects

BackgroundCognitive dysfunction in schizophrenia is the key predictor of functional disability and drives economic burden. Inflammation has been increasingly implicated in the pathogenesis of schizophrenia, yet its role in cognitive decline has not been evaluated. This study explores the association between inflammation and cognitive functioning in persons with schizophrenia. MethodsParticipants included 143 persons with schizophrenia (PwS) and 139 non-psychiatric comparison subjects (NCs) from an ongoing study of aging. Cognitive assessments included validated measures for executive functioning, processing speed, and visuospatial skills. Plasma levels of nine biomarkers associated with inflammation (high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, interleukin-8, interferon gamma-induced protein-10, monocyte chemotactic protein-1, fractalkine, and brain-derived neurotrophic factor) were quantified using commercially available, enzyme-linked immunosorbent assays. Partial least squares regression was used to develop a composite “inflammatory profile” to maximize correlations with the cognitive outcomes. We then constructed a best-fit model using these composites and their interactions with diagnosis and sex as the predictors, controlling for covariates. ResultsThe biomarker composite, which best correlated with scores on cognitive testing, included high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, and brain-derived neurotrophic factor, for a 5-biomarker “inflammatory profile.” The best-fit model showed a significant biomarker composite by diagnosis by sex three-way interaction, for executive function and processing speed, but not visuospatial skill. ConclusionsThis approach to building an “inflammatory profile” may provide insight into inflammatory pathways affecting brain function and potential targets for anti-inflammatory interventions to improve cognition in schizophrenia.

The viability of the frequency following response characteristics for use as biomarkers of cognitive therapeutics in schizophrenia

Deficits in early auditory information processing contribute to cognitive and psychosocial disability; this has prompted development of interventions that target low-level auditory processing, which may alleviate these disabilities. The frequency following response (FFR) is a constellation of event-related potential and frequency characteristics that reflect the processing of acoustic stimuli at the level of the brainstem and ascending portions of the auditory pathway. While FFR is a promising candidate biomarker of response to auditory-based cognitive training interventions, the psychometric properties of FFR in schizophrenia patients have not been studied. Here we assessed the psychometric reliability and magnitude of group differences across 18 different FFR parameters to determine which of these parameters demonstrate adequate internal consistency. Electroencephalography from 40 schizophrenia patients and 40 nonpsychiatric comparison subjects was recorded during rapid presentation of an auditory speech stimulus (6000 trials). Patients showed normal response amplitudes but longer latencies for most FFR peaks and lower signal-to-noise ratios (SNRs) than healthy subjects. Analysis of amplitude and latency estimates of peaks, however, indicated a need for a substantial increase in task length to obtain internal consistency estimates above 0.80. In contrast, excellent internal consistency (>0.95) was shown for FFR sustained responses. Only SNR scores reflecting the FFR sustained response yielded significant group differences and excellent internal consistency, suggesting that this measure is a viable candidate for use in clinical treatment studies. The present study highlights the use of internal consistency estimates to select FFR characteristics for use in future intervention studies interested in individual differences among patients.

Associations Between Inflammatory Marker Profiles and Cognitive Functioning in Adults With Schizophrenia and Non-Psychiatric Comparison Subjects

Cognitive dysfunction in schizophrenia is the key predictor of functional disability and drives the economic burden, though its etiology remains unclear. This study explores the role of inflammation in cognitive functioning in schizophrenia using a data-driven approach.

Plasma Levels of Neuron- and Astrocyte-Derived Exosomal Amyloid Beta1-42, Amyloid Beta1-40, and Phosphorylated Tau Levels in Schizophrenia Patients and Non-psychiatric Comparison Subjects: Relationships With Cognitive Functioning and Psychopathology.

Introduction: Cognitive deficits in people with schizophrenia (PWS) are a major predictor of disability and functioning, yet the underlying pathophysiology remains unclear. A possible role of amyloid and tau biomarkers (hallmarks of Alzheimer's disease) is still speculative in schizophrenia. Exosomes or extracellular vesicles, involved with cell-to-cell communication and waste removal, can be used to assay brain-based proteins from peripheral blood. To our knowledge, this is the first study of exosomal amyloid and tau protein levels in PWS.Methods: This cross-sectional study included 60 PWS and 60 age- and sex-comparable non-psychiatric comparison subjects (NCs), age range 26–65 years. Assessments of global cognitive screening, executive functioning, psychopathology, and physical measures were conducted. Exosomes were extracted and precipitated from fasting plasma and identified as neuron-derived exosomes (NDEs) or astrocyte-derived exosomes (ADEs). Human-specific ELISAs were used to assay levels of amyloid-beta 1-42 (Aβ42), amyloid-beta 1-40 (Aβ40), and phosphorylated T181 tau (P-T181-tau). Plasma assays for aging biomarkers (C-reactive protein and F2-isoprostanes) were also performed.Results: ADE-Aβ42 levels were higher in PWS compared to NCs, though the other exosomal markers were similar between the two groups. Higher ADE-P-T181-tau levels were associated with worse executive functioning. Among PWS, higher ADE-P-T181-tau levels were associated with less severe negative symptoms and increased F2-isoprostane levels. Astrocyte-derived Aβ marker levels were sensitive and specific in differentiating between diagnostic groups. Among PWS, Aβ40 levels differed most by exosomal origin.Discussion: Exosomal markers may provide novel insights into brain-based processes (e.g., aging, oxidative stress) from peripheral blood samples.

Links between objective sleep and sleep variability measures and inflammatory markers in adults with bipolar disorder

Premature mortality and increased physical comorbidity associated with bipolar disorder (BD) may be related to accelerated biological aging. Sleep disturbances and inflammation may be key mechanisms underlying accelerated aging in adults with BD. To our knowledge, these relationships have not been examined rigorously. This cross-sectional study included 50 adults with BD and 73 age- and sex-comparable non-psychiatric comparison (NC) subjects, age 26–65 years. Participants were assessed with wrist-worn actigraphy for total sleep time (TST), percent sleep (PS), and bed/wake times for 7 consecutive nights as well as completing scales for subjective sleep quality. Within-individual variability in sleep measures included intra-individual standard deviation (iSD) and atypicality of one evening's sleep. Blood-based inflammatory biomarkers included interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). Linear regression analyses tested relationships of mean and iSD sleep variables with inflammatory marker levels; time-lagged analyses tested the influence of the previous evening's sleep on inflammation. BD participants had worse subjective sleep quality, as well as greater TST iSD and wake time iSD compared to the NC group. In all participants, higher TST iSD and lower mean PS were associated with higher IL-6 levels (p = 0.04, ηp2 = 0.042; p = 0.05, ηp2 = 0.039, respectively). Lower mean PS was associated with higher CRP levels (p = 0.05, ηp2 = 0.039). Atypicality of the previous night's TST predicted next day IL-6 levels (p = 0.05, ηp2 = 0.04). All of these relationships were present in both BD and NC groups and remained significant even after controlling for sleep medications. Overall, sleep measures and their variability may influence inflammatory markers in all adults. Thus, sleep may be linked to the inflammatory processes believed to underlie accelerated aging in BD.

Gut microbiome in Schizophrenia: Altered functional pathways related to immune modulation and atherosclerotic risk

Emerging evidence has linked the gut microbiome changes to schizophrenia. However, there has been limited research into the functional pathways by which the gut microbiota contributes to the phenotype of persons with chronic schizophrenia. We characterized the composition and functional potential of the gut microbiota in 48 individuals with chronic schizophrenia and 48 matched (sequencing plate, age, sex, BMI, and antibiotic use) non-psychiatric comparison subjects (NCs) using 16S rRNA sequencing. Patients with schizophrenia demonstrated significant beta-diversity differences in microbial composition and predicted genetic functional potential compared to NCs. Alpha-diversity of taxa and functional pathways were not different between groups. Random forests analyses revealed that the microbiome predicts differentiation of patients with schizophrenia from NCs using taxa (75% accuracy) and functional profiles (67% accuracy for KEGG orthologs, 70% for MetaCyc pathways). We utilized a new compositionally-aware method incorporating reference frames to identify differentially abundant microbes and pathways, which revealed that Lachnospiraceae is associated with schizophrenia. Functional pathways related to trimethylamine-N-oxide reductase and Kdo2-lipid A biosynthesis were altered in schizophrenia. These metabolic pathways were associated with inflammatory cytokines and risk for coronary heart disease in schizophrenia. Findings suggest potential mechanisms by which the microbiota may impact the pathophysiology of the disease through modulation of functional pathways related to immune signaling/response and lipid and glucose regulation to be further investigated in future studies.

Compassion Toward Self Versus Compassion Toward Others in People With Schizophrenia: Associations With Biomarkers and Mental, Cognitive, and Physical Health

People with schizophrenia (PWS) have impaired social cognition and deficits in empathy. Associations of compassion toward self (CTS) and compassion toward others (CTO) with health and biomarkers in PWS have not been investigated. Our hypotheses for this cross-sectional study of PWS and non-psychiatric comparison (NC) subjects were: 1) PWS have lower CTS and CTO scores. 2) Women have higher CTS and CTO. 3) CTS and CTO are related to mental, cognitive and physical health. We also explored the relationships of CTS and CTO with biomarkers.

Gut microbiome in serious mental illnesses: A systematic review and critical evaluation

Schizophrenia and bipolar disorder (BD) are associated with debilitating psychiatric and cognitive dysfunction, worse health outcomes, and shorter life expectancies. The pathophysiological understanding of and therapeutic resources for these neuropsychiatric disorders are still limited. Humans harbor over 1000 unique bacterial species in our gut, which have been linked to both physical and mental/cognitive health. The gut microbiome is a novel and promising avenue to understand the attributes of psychiatric diseases and, potentially, to modify them. Building upon our previous work, this systematic review evaluates the most recent evidence of the gut microbiome in clinical populations with serious mental illness (SMI). Sixteen articles that met our selection criteria were reviewed, including cross-sectional cohort studies and longitudinal treatment trials. All studies reported alterations in the gut microbiome of patients with SMI compared to non-psychiatric comparison subjects (NCs), and beta-diversity was consistently reported to be different between schizophrenia and NCs. Ruminococcaceae and Faecalibacterium were relatively decreased in BD, and abundance of Ruminococcaceae was reported across several investigations of SMI to be associated with better clinical characteristics. Lactic acid bacteria were relatively more abundant in SMI and associated with worse clinical outcomes. There was very limited evidence for the efficacy of probiotic or prebiotic interventions in SMI. As microbiome research in psychiatry is still nascent, the extant literature has several limitations. We critically evaluate the current data, including experimental approaches. There is a need for more unified methodological standards in order to arrive at robust biological understanding of microbial contributions to SMI.

MAP2 immunoreactivity deficit is conserved across the cerebral cortex within individuals with schizophrenia

Several postmortem studies have reported lower levels of immunoreactivity (IR) for microtubule-associated protein 2 (MAP2) in several cortical regions of individuals with schizophrenia (SZ). However, whether this effect is conserved across multiple brain areas within an individual with SZ or if it is regionally-specific remains unclear. We characterized patterns of MAP2-IR across three cortical regions at different levels of the rostral-caudal axis within individual subjects with and without SZ. MAP2-IR levels were measured in deep layer 3 of dorsolateral prefrontal cortex (DLPFC), lateral intraparietal cortex (LIP), and primary visual cortex (V1). Postmortem tissue containing each cortical region was derived from 20 pairs of SZ subjects and nonpsychiatric comparison (NPC) subjects matched perfectly for sex, and as closely as possible for age and postmortem interval. MAP2-IR was assessed by quantitative fluorescence microscopy. We observed significantly lower levels of MAP2-IR in SZ subjects relative to NPC subjects, without a significant region by diagnosis interaction. Logs of the within-pair ratios (SZ:NPC) of MAP2-IR were significantly correlated across the three regions. These findings demonstrate that MAP2-IR deficits in SZ are consistent across three neocortical regions within individual subjects. This pattern of MAP2-IR deficit has implications for therapeutic development and future investigations of MAP2 pathology in SZ.

A novel biomarker of cardiometabolic pathology in schizophrenia?

BackgroundPersons 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. MethodsThis 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). ResultsHMW 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. DiscussionHMW 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.

EFFECT OF SEX DIFFERENCES ON INFLAMMATION IN SCHIZOPHRENIA: RELATIONSHIPS WITH SLEEP DISTURBANCES, COGNITIVE FUNCTIONING, AND CARDIOMETABOLIC RISK

Introduction Persons with schizophrenia (SZ) have life expectancies that are 15-20 years shorter than the general population, primarily due to cardiovascular-related deaths. In addition to premature mortality, persons with SZ have high rates of disability largely due to cognitive deficits. While cardiometabolic risk as well as cognition are known to be associated with poor sleep and inflammation in the general population, this has not been systematically examined in persons with SZ, although SZ is associated with inflammatory pathology and sleep disturbances that predate the use of antipsychotic medications and accumulation of poor lifestyle habits. Within the general population, women have higher inflammatory marker levels and are more likely to have sleep disturbances and cognitive decline as they age. This study examines the link between sleep, cognition and cardiometabolic risk within persons with SZ, focusing on sex differences. Methods The sample included 152 subjects with SZ (DSM-IV-TR criteria) and 141 non-psychiatric comparison (NC) subjects (age range 26 to 65 years; mean 48), with comparable sex and race distribution. We examined sleep (self-reported duration and quality), cardiometabolic risk [Framingham 10-year Risk of cardiovascular disease, high-sensitivity C-reactive protein or hs-CRP, insulin resistance using the Homeostatic Model of Assessment for Insulin Resistance or HOMA-IR], cognition [executive functioning (D-KEFS), overall cognitive functioning (TICS - modified)]; and blood-based inflammatory markers (TNF-a, IL-6, IL-10). In a subset of subjects, we also examined objective measures of sleep (total sleep time (TST), wake after sleep onset (WASO), latency, and efficiency) using wrist-worn actigraphy. The sleep-inflammation-cardiometabolic risk links were examined using Spearman's correlations and general linear models with a backward elimination approach to trim the models. Results The SZ group reported higher total sleep time and worse sleep quality, worse cardiometabolic risk, and increased levels of inflammatory markers compared to NCs. Within the SZ group, SZ men had higher Framingham Risk, lower hs-CRP and IL-6 levels, as well as better overall cognitive functioning than SZ women (Cohen's d = -0.65, 0.48, 0.38, and -0.33, respectively.) In SZ men, shorter sleep duration and poor sleep quality was associated with higher IL-6 and TNF-a levels and better executive functioning. Within the SZ group, Framingham Risk was associated with sex (as expected), age, IL-6, TNF-a, and overall cognition such that younger women with lower levels of IL-6 and TNF-a as well as better overall cognition had lower Framingham Risk (partial eta-squared = 0.19, 0.27, 0.03, 0.04, and 0.02, respectively). The levels of hs-CRP and HOMA-IR were not associated with sex. The levels of hs-CRP was associated with age, IL-6 and overall cognition (partial eta-squared = 0.02, 0.19, and 0.08, respectively). HOMA-IR was associated with age, duration of sleep, sleep quality, IL-6, and overall cognition such that younger persons with longer sleep duration, better sleep quality, lower inflammation and better cognitive functioning had less insulin resistance (partial eta-squared = 0.02, 0.02, 0.05, 0.03, and 0.08, respectively.) Objective measures of sleep disturbances (TST, WASO) were associated with HOMA-IR, executive functioning, as well as levels of hs-CRP and IL-6. Conclusions There are complexities in the associations of different inflammatory biomarkers with clinically meaningful measures of sleep, cardiometabolic health and cognition that reveal sex differences in SZ. Self-reported sleep disturbances and increased inflammation are associated in persons with SZ. Levels of inflammation and sleep disturbances, and their relationships, were sex-dependent in the SZ group, but not the NC group. Longitudinal examination of the sleep-inflammation links, their contribution to clinical outcomes, and the relationship with objective sleep measures and sex-specific factors is warranted. This research was funded by This study was supported, in part, by the National Institutes of Health (grant R01MH094151-01 to DVJ [PI]), by the National Institute of Mental Health T32 Geriatric Mental Health Program (grant MH019934 to DVJ [PI]), by the Stein Institute for Research on Aging at the University of California San Diego, and by the National Institutes of Health, Grant UL1TR001442 of CTSA funding. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

THE ASSOCIATIONS AMONG HISTORY OF PSYCHOSIS, NEUROPSYCHOLOGICAL PERFORMANCE, AND FUNCTIONING IN REMITTED LATER-LIFE MAJOR DEPRESSION

Introduction Observational studies report that people with psychotic major depressive disorder (PMD) have poorer functional outcome than those with non-psychotic major depression (NPMD), but this finding could be explained by less robust recovery and residual symptoms in PMD. In addition, neuropsychological performance is worse in those with PMD than NPMD, both acutely and in remission. The aim of this study was to examine the relative contributions of a history of psychosis and neuropsychological performance to impaired everyday function in patients with remitted later-life major depressive disorder (MDD). We hypothesized that, in later-life patients with MDD, a history of psychotic features and poorer neuropsychological function would be independently associated with poorer everyday functioning, but that poorer neuropsychological performance would be more strongly associated with poorer functioning compared to history of psychosis. In order to place the results in a broader context, we examined everyday functioning in an age- and gender-matched non-psychiatric comparison group. Methods This cross-sectional design study included 73 patients aged 50 years and older with a history of MDD (n = 51 with NPMD and n = 22 with PMD) in sustained remission and 42 non-psychiatric comparison subjects. Sociodemographic, clinical, neuropsychological, and functional data were collected by an investigator blind to the history of psychotic features. Everyday functioning, the dependent variable, was divided into general functioning (measured by participant-report) and IADL performance (measured by observer-rated assessment). The independent variables were i) history of psychosis and ii) neuropsychological performance in the domains of processing speed, memory, and executive function. Relationships between each independent variable and functioning were analyzed using multiple linear regression models. The relative contribution of history of psychosis and neuropsychological performance to functioning was analyzed using multiple regression models with history of psychosis entered in the first step and the neuropsychological variable in the second step. All models included covariates that were potential confounders. We also calculated effect sizes for the difference in functioning between MDD and non-psychiatric comparison participants. Results Patients with PMD exhibited substantial deficits in measures of processing speed and, to a lesser extent, executive function, compared to NPMD patients and to population norms. History of psychosis was independently related to poorer IADL performance (β = 0.262, t = 3.03, p = 0.004) and general functioning (β = -0.29, t = -2.46, p = 0.017). Poorer performance on measures of processing speed (β = -0.468, t = -4.99, p In comparison to non-psychiatric subjects, the effect size of functional impairment in patients with remitted PMD was large (Cohen's d for IADL function = 0.80; Cohen's d for general functioning = 0.97), whereas the impairment was small to moderate in remitted NPMD (Cohen's d for IADL function = 0.10; Cohen's d for general functioning = 0.64). Conclusions Later-life remitted PMD is associated with poorer everyday functioning compared to NPMD, with clinically-significant deficits. However, this relationship is no longer significant when neuropsychological function, especially processing speed, is accounted for. This study advances previous literature by including only patients with rigorously-defined sustained remission and measuring functioning comprehensively using both participant-report and performance-based measures. We will discuss future directions of these research findings, including examining neurobiological correlates of processing speed deficits in remitted PMD. This research was funded by This study was funded by the University Health Network Centre for Mental Health's research grant ($14,000)

RELATIONSHIP OF HAIR CORTISOL CONCENTRATION WITH HISTORY OF PSYCHOSIS, NEUROPSYCHOLOGICAL PERFORMANCE, AND EVERYDAY FUNCTIONING IN REMITTED LATER-LIFE MAJOR DEPRESSIVE DISORDER

Introduction Psychotic features are more prevalent in older adults with depression than in younger depressed adults. Psychotic major depressive disorder (PMD) is associated with poorer neuropsychological performance and poorer everyday functioning, in both acute and remitted states, compared with non-psychotic major depressive disorder (NPMD). In addition, PMD is also associated with more pronounced dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including elevated cortisol levels, but it is not known whether this difference between PMD and NPMD persists in remission. The goal of this exploratory study was to test the hypothesis that a history of psychotic features, poorer neuropsychological performance, and poorer everyday functioning were associated with higher cortisol levels in sustained remission of major depressive disorder. If confirmed, it could suggest a possible mechanism for neuropsychological and functional impairment in remitted PMD. In order to examine the relationship between sustained HPA dysfunction in remission and the aforementioned variables, we measured hair cortisol concentration (HCC), a measure of longer-term cortisol exposure. Methods This study used a cross-sectional design and included 60 participants aged 50 years or older with a history of major depressive disorder (n = 17 with NPMD and n = 43 with PMD) in sustained remission and 36 non-psychiatric comparison participants. Hair samples were collected using standardized methods and cortisol concentrations were determined from the first 3-cm hair segment most proximal to the scalp, or from as much hair as was available for participants with shorter hair. This hair segment represents the hair growth over the 3-month period prior to the sampling. HCC was measured in a research laboratory with extensive experience in this analysis using a validated high sensitivity enzyme immunoassay (EIA) that is standard in the field. In order to examine the relationships between HCC and i) history of psychotic features, ii) neuropsychological performance (processing speed, executive function, and verbal memory), and iii) everyday functioning (participant-report general functioning and observer-rated IADL performance), we performed three sets of correlation analyses, one for each variable of interest (point biserial for psychosis history and HCC; Pearson's r for neuropsychological and functional measures). We calculated effect sizes and 95% confidence limits in order to compare HCC results between patient and non-psychiatric comparison groups. HCC data were highly skewed and were log transformed for all analyses. Results NPMD and PMD groups had mean (SD) HCCs of 18.86 (32.97) pg/mg and 12.48 (11.26) pg/mg, respectively. The correlation between HCC and history of psychosis was weak (r = -0.02), as were the correlations between HCC and the neuropsychological measures (r ranging between -0.11 and 0.1). The correlations between HCC and i) IADL performance (r = -0.04) and ii) general functioning (r = -0.074) were also weak. None of these correlations were statistically significant. The mean (SD) HCC for non-psychiatric comparison subjects was 13.86 (20.06) pg/mg. Both effect sizes for the difference between the clinical and non-psychiatric comparison groups were small (0.26 for NPMD versus Comparison group and 0.25 for PMD versus Comparison group). Conclusions This is the first study to assess HCC in PMD and to examine the relationship between HCC and cognition and between HCC and everyday functioning in MDD. We did not find a correlation between HCC and history of psychosis, neuropsychological performance, or functioning in later-life patients with MDD in sustained remission. Further, there was no substantial difference in mean HCC between the patient and non-psychiatric comparison group. There is variability in the literature regarding HCC in MDD and regarding the relationship between HPA-axis function and neuropsychological performance in remitted MDD. Our findings will be discussed in this context. This research was funded by This study was funded by a research grant from the University Health Network Centre for Mental Health ($14,000)

Nonlinear dynamics underlying sensory processing dysfunction in schizophrenia

Natural systems, including the brain, often seem chaotic, since they are typically driven by complex nonlinear dynamical processes. Disruption in the fluid coordination of multiple brain regions contributes to impairments in information processing and the constellation of symptoms observed in neuropsychiatric disorders. Schizophrenia (SZ), one of the most debilitating mental illnesses, is thought to arise, in part, from such a network dysfunction, leading to impaired auditory information processing as well as cognitive and psychosocial deficits. Current approaches to neurophysiologic biomarker analyses predominantly rely on linear methods and may, therefore, fail to capture the wealth of information contained in whole EEG signals, including nonlinear dynamics. In this study, delay differential analysis (DDA), a nonlinear method based on embedding theory from theoretical physics, was applied to EEG recordings from 877 SZ patients and 753 nonpsychiatric comparison subjects (NCSs) who underwent mismatch negativity (MMN) testing via their participation in the Consortium on the Genetics of Schizophrenia (COGS-2) study. DDA revealed significant nonlinear dynamical architecture related to auditory information processing in both groups. Importantly, significant DDA changes preceded those observed with traditional linear methods. Marked abnormalities in both linear and nonlinear features were detected in SZ patients. These results illustrate the benefits of nonlinear analysis of brain signals and underscore the need for future studies to investigate the relationship between DDA features and pathophysiology of information processing.

Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects

Intestinal microbiome and gut-brain axis have been receiving increasing attention for their role in the regulation of brain/behavior and possible biological basis of psychiatric disorders. Several recent clinical studies have linked the microbiome with neuropsychiatric conditions, although the literature on schizophrenia is quite limited. This study investigated gut microbiome composition in 50 individuals, including 25 persons with chronic schizophrenia and 25 demographically-matched non-psychiatric comparison subjects (NCs). Stool samples were collected and assayed using 16S rRNA sequencing of the V4 region. Examination of unweighted UniFrac and Bray-Curtis dissimilarity revealed significant community-level separation in microbiome composition between the two subject groups. At the phylum level, Proteobacteria were found to be relatively decreased in schizophrenia subjects compared to NCs. At the genus level, Anaerococcus was relatively increased in schizophrenia while Haemophilus, Sutterella, and Clostridium were decreased. Within individuals with schizophrenia, abundance of Ruminococcaceae was correlated with lower severity of negative symptoms; Bacteroides was associated with worse depressive symptoms; and Coprococcus was related to greater risk for developing coronary heart disease. Our findings provide evidence of altered gut microbial composition in persons with chronic schizophrenia and suggest a need for larger and longitudinal studies of microbiome in schizophrenia.

Loneliness in schizophrenia: Construct clarification, measurement, and clinical relevance

Loneliness is a highly prevalent experience in schizophrenia. Theoretical models developed in the general population propose that loneliness is tantamount to a feeling of being unsafe, is accompanied by enhanced environmental threat perception, and leads to poor physical, emotional, and cognitive functioning. Previous research has reported that loneliness is associated with poorer physical and emotional health in schizophrenia; however, few studies have directly compared loneliness and its correlates in persons with schizophrenia and non-psychiatric comparison subjects. The purpose of the current study was to evaluate similarities and differences in the construct of loneliness, the equivalency of the measurement of this construct, and similarities and differences in the pattern of external correlates of loneliness between schizophrenia and non-psychiatric comparison groups. The third version of the University of California, Los Angeles Loneliness Scale (UCLA-3) was administered to 116 individuals with schizophrenia or schizoaffective disorder and 106 non-psychiatric comparison subjects. Additional clinical and positive psychological measures were collected, as well as demographic characteristics of the two groups. Multiple groups confirmatory factor analysis revealed that the UCLA-3 was best characterized by a bifactor model in which all items loaded on a general loneliness dimension as well as one of two orthogonal method factors reflecting item wording in both groups. Furthermore, the UCLA-3 exhibited invariant measurement of these latent constructs across groups. Mean levels of loneliness were nearly a standard deviation higher in the schizophrenia group. Nonetheless, the overall pattern and strength of correlates were largely similar across groups, with loneliness being positively associated with depression, anxiety, and perceived stress, and negatively correlated with mental well-being, happiness, and resilience. Subtle differences in correlates of age, optimism, and satisfaction with life were found. Overall, loneliness appears to be distinct from other schizophrenia-related deficits and operates similarly across schizophrenia and NC groups, suggesting that theoretical models of loneliness developed in the general population may generalize to schizophrenia.