Genetic contribution to microglial activation in schizophrenia.

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1ß) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

Development and initial validation of the THL Adverse Childhood Experiences Questionnaire (ACE-THL).

BACKGROUND: The research on adverse childhood experiences (ACEs) has deepened our understanding of the long-lasting and cumulative effects of childhood adversities. However, the instruments measuring ACEs have several shortcomings, including limited item coverage, collapsing of items and response options, simplistic scoring, and inadequate psychometric assessments. OBJECTIVE: To design and conduct preliminarily psychometric testing for a brief new self-report instrument-the THL Adverse Childhood Experiences questionnaire (ACE-THL)-with a comprehensive set of clearly formulated items and appropriate response options. METHODS: A previously published process model was applied to develop the ACE-THL questionnaire, which was validated by cognitive interviews (N = 20). Interviewers and interviewees completed the questionnaire separately for a cross-informant comparison. In a separate survey panel validation, the respondents filled out the ACE-THL twice, two weeks apart (N = 513, with 426 in the follow-up). Interview data were used to improve item clarity, and test-retest reliability and structural validity were assessed with repeated survey data. RESULTS: The final 14-item questionnaire, including 12 ACE items and two items measuring protective experiences, was highly acceptable to the respondents. In the factor analysis of the quantitative data, a sufficiently single-dimensional construct was found, remaining stable in retesting two weeks later. The internal consistency (omega) of the a priori one-dimensional model was 0.89 and 0.90 at baseline and follow-up, respectively. The high test-retest reliability (mean score rank order correlation 0.93) of the ACE-THL indicated that the probed perceptions of childhood experiences are stable. CONCLUSION: Based on the initial validation, the 14-item ACE-THL questionnaire is a reliable and valid instrument to measure adverse childhood experiences, as well as protective experiences.

Exploring the structure and psychometric properties of the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) in a representative adult population sample.

This article reports the psychometric properties of both full and the abbreviated (Short) Warwick-Edinburgh Mental Well-being Scales (WEMWBS; SWEMWBS) in the Finnish general population. A large cross-sectional dataset (N = 5,335) was collected as part of the nationally representative FinHealth Study in 2017. Exploratory and confirmatory factor analyses of the data evaluated one-, two-, three-, and bi-factorial solutions with a split-half approach. McDonald's omega was used to assess internal consistency and convergent validity was evaluated using four established mental health and well-being scales (BDI-6, GHQ-12, MHI-5, EUROHIS-QOL8). Contrary to previous findings, our results supported a three-factor model of the full scale with separate, yet highly correlated, mental, social, and eudemonic well-being factors. For the SWEMWBS, the bi-factor model showed the best fit, with a strong general mental well-being factor and a weaker specific eudemonic well-being factor. In this sampling context, the social aspect of mental well-being may be considered a separable construct from other mental well-being dimensions and the shorter 7-item version might thus be a preferable option when assessing overall mental well-being.

Sense of mastery in first-episode psychosis-a one-year follow-up study.

Introduction: A sense of mastery refers to beliefs about having control over one's life and has been found to protect health and buffer the effect of stressful experiences. Methods: We investigated sense of mastery in first-episode psychosis (FEP) patients and population controls at baseline and at one-year follow-up. Pearlin and Schooler's Sense of Mastery scale was completed by 322 participants at baseline and by 184 participants at follow-up. Results: People having experienced FEP reported lower mastery than controls at both time points, but a modest increase was seen in patients at follow-up. The strongest correlates of high baseline mastery in FEP were lower depressive symptoms and higher perceived social support, whereas positive or negative psychotic symptoms did not associate with mastery. Current depressive symptoms also correlated with mastery at the follow-up point, and change in depressive symptoms correlated with change in mastery. Higher mastery at treatment entry predicted remission of psychotic symptoms one year later. Sense of mastery was also found to mediate the association of perceived social support with depressive symptoms. Discussion: The usefulness of mastery measures should be further tested for estimations of patient prognosis in early psychosis.

Factor and network analysis of psychosis-like experiences and depressive symptoms in a sample of Finnish adolescents entering psychiatric services.

AIM: Psychosis-Like Experiences (PLEs) and depressive symptoms are correlated in clinical adolescent populations. However, symptom-level associations between the two phenomena are not clear. METHODS: We analysed factor structures of a PLE instrument, the Prodromal Questionnaire-Brief (PQ-B), based on dimensions of positive symptoms of schizophrenia, and a depression measurement instrument, the Beck Depression Inventory (BDI-21A) and performed a network analysis of item-level associations between the two measures. The sample consisted of 417 adolescents (range 13-18 years of age, mean 14.9 years, 72.4% females) entering secondary psychiatric services at Helsinki metropolitan area, Finland. RESULTS: Confirmatory factor analysis resulted in adequately fitting 2-factor solution, one for PQ-B and one for BDI-21, with a strong correlation coefficient of 0.605 between the two factors. In the network analysis, PQ-B and BDI-21 both formed their own clusters, and two significant pathways were estimated between PQ-B and BDI-21 clusters: 1. the association between paranoid thinking and distorted body image, and 2. the association between somatic preoccupation and worry about problems of one's mind. CONCLUSIONS: Even though on a general, factor level, PLEs and depressive symptoms were strongly correlated, unique associations between symptoms of the two constructs were sparse. These findings should be considered in the psychiatric assessment and in the care of adolescents.

The associations between metabolic profiles and sexual and physical abuse in depressed adolescent psychiatric outpatients: an exploratory pilot study.

Background: Sexual and physical abuse have been associated with long-term systemic alterations such as low-grade inflammation and changes in brain morphology that may be reflected in the metabolome. However, data on the metabolic consequences of sexual and physical abuse remain scarce.Objective: This pilot study sought to investigate changes in the metabolite profile related to sexual and physical abuse in depressed adolescent psychiatric outpatients.Method: The study included 76 patients aged 14-18 years, whose serum samples were analysed with a targeted metabolite profiling methodology. We estimated the associations between metabolite concentrations and the Trauma and Distress Scale (TADS) Sexual and Physical Abuse factor scores using three linear regression models (one unadjusted and two adjusted) per metabolite and trauma type pair. Additional variables in the two adjusted models were 1) the lifestyle indicators body mass index, tobacco use, and alcohol use, and 2) depression scores and the chronicity of depression.Results: TADS Sexual Abuse scores associated positively with homogentisic acid, as well as cystathionine, and negatively with choline in linear regression analysis, whereas TADS Physical Abuse scores associated negatively with AMP, choline, γ-glutamyl cysteine and succinate, and positively with D-glucuronic acid.Conclusions: This pilot study did not include a healthy control group for comparison and the cohort was relatively small. Nevertheless, we observed alterations in metabolites related to one-carbon metabolism, mitochondrial dysfunction, oxidative stress, and inflammation in depressed patients with a history of sexual or physical abuse.

Metabolomic profiles associate with sexual or physical abuse.Metabolites relate to mitochondria, one-carbon, oxidative stress, and inflammation.Metabolomics a possible tool for precision psychiatry in the future.

Generalized anxiety among Finnish youth from 2013 to 2021-Trend and the impact of COVID-19.

BACKGROUND: Alarming levels of emotional symptoms among youth were reported during the COVID-19 pandemic. Studies assessing these figures against the pre-pandemic developments are rare. We examined the trend of generalized anxiety (GA) in adolescents in the 2010s and the effect of the COVID-19 pandemic against this trend. METHODS: Data from the Finnish School Health Promotion study with 750,000 participants aged 13-20 between 2013 and 2021 was analyzed using GAD-7 to measure self-reported GA (cut-off ≥10). Inquiries were made about remote learning arrangements. Effects of time and COVID-19 were analyzed with logistic regression. RESULTS: Among females, an increasing trend in GA between 2013 and 2019 was found (OR per year 1.05), and the prevalence increased from 15.5 % to 19.7 %. Among males, the trend was decreasing (OR = 0.98), with prevalence from 6.0 % to 5.5 %. Increase in GA from 2019 to 2021 was stronger in females (19.7 % to 30.2 %) than males (5.5 % to 7.8 %), while the effect of COVID-19 on GA was equally strong (OR = 1.59 vs. OR = 1.60) against the pre-pandemic trends. Remote learning was associated with elevated levels of GA, especially among those with unmet needs for learning support. LIMITATIONS: The design of repeated cross-sectional surveys doesn't allow analyses of within individual changes. CONCLUSIONS: Given the pre-pandemic trends of GA, the COVID-19 effect on it appeared equal in both sexes. The increasing pre-pandemic trend among adolescent females and the strong effect of COVID-19 on GA among both sexes warrants constant monitoring of mental health of the youth in the aftermath of the COVID-19 pandemic.

Predictive validity of psychosis risk models when applied to adolescent psychiatric patients.

BACKGROUND: Several multivariate algorithms have been developed for predicting psychosis, as attempts to obtain better prognosis prediction than with current clinical high-risk (CHR) criteria. The models have typically been based on samples from specialized clinics. We evaluated the generalizability of 19 prediction models to clinical practice in an unselected adolescent psychiatric sample. METHODS: In total, 153 adolescent psychiatric patients in the Helsinki Prodromal Study underwent an extensive baseline assessment including the SIPS interview and a neurocognitive battery, with 50 participants (33%) fulfilling CHR criteria. The adolescents were followed up for 7 years using comprehensive national registers. Assessed outcomes were (1) any psychotic disorder diagnosis (n = 18, 12%) and (2) first psychiatric hospitalization (n = 25, 16%) as an index of overall deterioration of functioning. RESULTS: Most models improved the overall prediction accuracy over standard CHR criteria (area under the curve estimates ranging between 0.51 and 0.82), although the accuracy was worse than that in the samples used to develop the models, also when applied only to the CHR subsample. The best models for transition to psychosis included the severity of positive symptoms, especially delusions, and negative symptoms. Exploratory models revealed baseline negative symptoms, low functioning, delusions, and sleep problems in combination to be the best predictor of psychiatric hospitalization in the upcoming years. CONCLUSIONS: Including the severity levels of both positive and negative symptomatology proved beneficial in predicting psychosis. Despite these advances, the applicability of extended psychosis-risk models to general psychiatric practice appears limited.

Specific adolescent prodromal symptoms associated with onset of psychosis in the Northern Finland Birth Cohort 1986.

BACKGROUND: Several psychological symptoms in adolescence associate with later development of psychosis. However, it is unclear which symptoms specifically predict psychotic disorders rather than psychiatric disorders in general. We conducted a prospective study comparing how specific adolescent psychotic-like symptoms, predicted psychotic and non-psychotic hospital-treated psychiatric disorders in the population-based Northern Finland Birth Cohort 1986 (NFBC1986). METHODS: At age 15-16 years, 6632 members of the NFBC1986 completed the PROD-screen questionnaire. New hospital-treated mental disorders of the NFBC1986 participants were detected between age 17 and 30 years from the Finnish Care Register for Health Care. Multiple covariates were used in the analysis. RESULTS: During the follow-up, 1.1% of the participants developed a psychotic and 3.2% a non-psychotic psychiatric disorder. Three symptoms were specifically associated with onset of psychosis compared to non-psychotic psychiatric disorders: 'Difficulty in controlling one's speech, behaviour or facial expression while communicating' (adjusted OR 4.00; 95% CI 1.66-9.92), 'Difficulties in understanding written text or heard speech' (OR 2.25; 1.12-4.51), and 'Difficulty or uncertainty in making contact with other people' (OR 2.20; 1.03-4.67). Of these, the first one remained statistically significant after Bonferroni correction for multiple comparisons. CONCLUSION: To our knowledge, this is the first general-population-based prospective study exploring psychiatric symptoms predicting the onset of hospital-treated first-episode psychosis in comparison to non-psychotic disorders. We found three symptoms related with difficulties in social interaction which predicted onset of psychosis. This is a novel finding and should be replicated.

Extrapyramidal symptoms predict cognitive performance after first-episode psychosis.

Extrapyramidal (EP) symptoms such as tremor, rigidity, and bradykinesia are common side effects of most antipsychotics, and may associate with impaired performance in neurocognitive testing. We studied EP symptoms in first-episode psychosis (FEP; n = 113). Cognitive testing and EP symptoms (three items of the Simpson-Angus Scale) were assessed at baseline and follow-up (mean follow-up time 12 months). Mild EP symptoms were present at treatment onset in 40% of the participants. EP symptoms were related with lower performance in neurocognitive testing at baseline and at follow-up, especially among those with nonaffective psychotic disorder, and especially in tasks requiring speed of processing. No associations between EP symptoms and social cognition were detected. In linear regression models, when positive and negative symptom levels and chlorpromazine equivalents were accounted for, baseline EP symptoms were associated with worse baseline global neurocognition and visuomotor performance. Baseline EP symptoms also longitudinally predicted global, verbal, and visuomotor cognition. However, there were no cross-sectional associations between EP symptoms and cognitive performance at follow-up. In sum, we found both cross-sectional and longitudinal associations between EP symptoms and neurocognitive task performance in the early course of psychosis. Those without EP symptoms at the start of treatment had higher baseline and follow-up neurocognitive performance. Even mild EP symptoms may represent early markers of long-term neurocognitive impairment.

Factor Structure, Measurement Invariance, and Abbreviated Versions of The Adolescent Dissociative Experiences Scale (A-DES).

The purpose of this study was to examine the factor structure of the Adolescent Dissociative Experiences Scale (A-DES) questionnaire with item response theory (IRT) methods, including an assessment of measurement invariance with differential item functioning (DIF) analysis. Three abbreviated versions of the A-DES (with 20, 10, and 5 items) were constructed based on the IRT and DIF statistics. The respondents in this population-based study (N = 4,072) were 12- to 19-year-old Finnish junior and senior high school students. A one-factor model of the A-DES was best supported, and the original theoretical four-factor model showed poor fit. The A-DES turned out to have high measurement invariance with respect to age, gender, transgender tendencies, having multiple friends, the use of illegal substances, and experience of being bullied. Compared to the full 30-item A-DES, abbreviated versions of the questionnaire retained acceptable information value and empirical reliability in the clinically relevant range of symptomatology. Further psychometric studies are needed especially with regards to clinical use.

Psychotic-like experiences of young adults in the general population predict mental disorders.

Psychotic-like experiences (PLEs) have been identified as risk markers for psychotic disorders and may indicate an individual's susceptibility to mental disorders in general. We examined whether 23 PLEs (assessed with M-CIDI questionnaire) reported in young adulthood (n = 1313) predict subsequent psychotic or any mental disorders in the general population. We also investigated whether these possible associations are explained by general psychological distress assessed with the General Health Questionnaire-12 (GHQ-12). The register follow-up period spanned 10-12 years. In Cox regression models, PLEs predicted subsequent psychotic disorders (n = 12) when the effects of age, sex, education, and marital status were adjusted for, but not when general psychological distress was added to the model. Having any mental disorders during follow-up (n = 91) was predicted by PLEs reported at a younger age, when controlling for age, sex, education, marital status, and general psychological distress. In line with earlier results in other age groups, PLEs can be seen as a sign of vulnerability to not just psychotic but all mental disorders during the following years also among young adults in the general population. PLEs were a predictive marker of general psychopathology independently from general psychological distress.

Subjective mental well-being among higher education students in Finland during the first wave of COVID-19.

AIMS: Increased mental health problems during the COVID-19 pandemic have become a major concern among young adults. Our aim was to understand which COVID-19-related questions predicted mental well-being during the outbreak. METHODS: Two cross-sectional datasets were used. The primary dataset was collected in May 2020 (n = 1001), during the initial COVID-19 outbreak, and the secondary in April 2019 (n = 10866), before the pandemic. Mental well-being was assessed with the Short Warwick-Edinburgh Mental Well-Being Scale. Relationships between mental well-being and COVID-19-related questions were investigated with lasso regression. As an exploratory analysis, two-way ANOVAs were used to compare mental well-being before and during the outbreak. RESULTS: Higher levels of mental well-being were associated with lower levels of academic stress and COVID-19-related worry, along with a higher satisfaction with the procedures and information provided by the higher education institutions and the government. COVID-19-related symptoms and infections did not have an impact on students' mental well-being during the outbreak. Small to moderate effect sizes across the time points were detected, indicating an overall decrease in mental well-being across age and gender during the outbreak. CONCLUSIONS: COVID-19 had an impact on higher education students' mental well-being. Higher education institutes may play a crucial role in protecting their students' well-being during uncertain times.

Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia.

Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)-derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron-astrocyte co-cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.

Validation of the Finnish version of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and evaluation of the applicability of the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) and the Fatigue Scale for Motor and Cognitive Functions (FSMC).

OBJECTIVES: Cognitive impairment is frequent in multiple sclerosis (MS) as approximately half of the patients manifest some degree of cognitive impairment. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been designed for brief cognitive evaluation. The purpose of the study was to validate the BICAMS along with the Finnish versions of one self-rating questionnaire each for cognition and fatigue. METHODS: A total of 65 MS patients and 45 healthy controls (HC) were assessed with the BICAMS, the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), and the Fatigue Scale for Motor and Cognitive Functions (FSMC) twice, approximately within nine days. RESULTS: MS patients scored markedly lower than the HCs on each of the three tests of the BICAMS. Of the patients, 60% scored at least 1.5 SD below the mean of the HCs on at least one test; 49% on the SDMT, 26% on the CVLT-II, and 28% on the BVMT-R. Correlation coefficients for the repeated measurement were between 0.75 and 0.89 for the three tests in the whole study sample. MS patients reported more cognitive symptoms and more fatigue than the HCs. Cronbach's alpha was 0.94 for the MSNQ and 0.98 for the FSMC. Correlation coefficient for the repeated measurement was 0.91 for the MSNQ and between 0.92 and 0.94 for the FSMC scores for the whole study sample. CONCLUSIONS: The present study supports the validity of the Finnish version of the BICAMS. The SDMT was the most sensitive of the three BICAMS tests and showed cognitive impairment in half of the patients. The Finnish versions of the MSNQ and the FSMC proved useful tools in approaching concerns related to cognition and fatigue.

Molecular signaling pathways underlying schizophrenia.

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA-related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1-/- mouse model for schizophrenia - could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population.

We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06-1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07-1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

The Attenuated Psychosis Syndrome and Facial Affect Processing in Adolescents With and Without Autism.

BACKGROUND: Autism and schizophrenia spectrum disorders both represent severely disabling neurodevelopmental disorders with marked impairments in social functioning. Despite an increased incidence of psychosis in autism, and substantial overlap in symptoms and cognitive markers, it is unclear whether such phenotypes are specifically related to risk for psychosis or perhaps reflect more general, idiosyncratic autism traits. The attenuated psychosis syndrome (APS) is primarily defined by the presence of attenuated psychotic symptoms, which currently constitute the best and most-replicated clinical predictors of psychosis, and are common in clinical youth with and without autism. The aims of this study were to test the hypothesis that facial affect processing is impaired in adolescents with APS and to explore whether such deficits are more indicative of psychotic or autistic phenotypes on a categorical and dimensional level. MATERIALS AND METHOD: Fifty-three adolescents with APS and 81 typically developing controls (aged 12-18) were included. The APS group consisted of adolescents with (n = 21) and without (n = 32) a diagnosis of autism spectrum disorder. Facial affect recognition was assessed with the Amsterdam Neuropsychological Tasks using a cascade model of cognitive processing, in which disturbances in "lower-level" cognitive abilities (pattern recognition), affect "higher-level" cognitive processes (face recognition and facial affect recognition). For associations with schizotypal and autistic-like traits the Schizotypal Personality Questionnaire and Social Communication Questionnaire were used in a confirmatory item factor analysis framework. RESULTS: Contrary to expectation, APS in adolescents was not associated with impairments in pattern, face, or facial affect recognition. However, the APS group with autism spectrum disorder showed a general latency in response time to social and non-social stimuli. Dimensionally assessed schizotypal and autistic-like traits did not predict the accuracy or the speed of face or facial affect recognition. CONCLUSION: Facial affect processing performance was not associated with APS in adolescence and represents an unlikely early vulnerability marker for psychosis. APS individuals with a more autistic-like profile were characterized by slower responses to social- and non-social stimuli, suggesting that the combined effect of APS and autism spectrum disorder on cognition is larger than for APS alone.

Elevated serum chemokine CCL22 levels in first-episode psychosis: associations with symptoms, peripheral immune state and in vivo brain glial cell function.

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p < 0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (ρ = 0.20) and disorganization (ρ = 0.23), and with worse verbal performance (ρ = -0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [11C]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (VT) of [11C]PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.