Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness.

BACKGROUND: Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. METHODS: We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. RESULTS: We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. CONCLUSION: We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.

Prenatal maternal depressive symptoms and infant DNA methylation: a longitudinal epigenome-wide study.

Background: Prenatal maternal stress increases the risk of offspring developmental and psychological difficulties. The biological mechanisms behind these associations are mostly unknown. One explanation suggests that exposure of the fetus to maternal stress may influence DNA methylation. However, this hypothesis is largely based on animal studies, and human studies of candidate genes from single timepoints. Aim: The aim of this study was to investigate if prenatal maternal stress, in the form of maternal depressive symptoms, was associated with variation in genome-wide DNA methylation at two timepoints. Methods: One-hundred and eighty-four mother-child dyads were selected from a population of pregnant women in the Little-in-Norway study. The Edinburgh Postnatal Depression Scale (EPDS) measured maternal depressive symptoms. It was completed by the pregnant mothers between weeks 17 and 32 of gestation. DNA was obtained from infant saliva cells at two timepoints (age 6 weeks and 12 months). DNA methylation was measured in 274 samples from 6 weeks (n = 146) and 12 months (n = 128) using the Illumina Infinium HumanMethylation 450 BeadChip. Linear regression analyses of prenatal maternal depressive symptoms and infant methylation were performed at 6 weeks and 12 months separately, and for both timepoints together using a mixed model. Results: The analyses revealed no significant genome-wide association between maternal depressive symptoms and infant DNA methylation in the separate analyses and for both timepoints together. Conclusions: This sample of pregnant women and their infants living in Norway did not reveal associations between maternal depressive symptoms and infant DNA methylation.

The impact of ADHD symptoms and global impairment in childhood on working disability in mid-adulthood: a 28-year follow-up study using official disability pension records in a high-risk in-patient population.

BACKGROUND: Individuals with ADHD have been associated with more employment difficulties in early adulthood than healthy community controls. To examine whether this association is attributable specifically to disturbance of activity and attention (ADHD) or to psychopathology in general, we wanted to extend existing research by comparing the rate of mid-adulthood working disabilities for individuals diagnosed with ADHD as children with the rate for clinical controls diagnosed with either conduct disorder, emotional disorder or mixed disorder of conduct and emotions. METHODS: Former Norwegian child-psychiatric in-patients (n = 257) were followed up 17-39 years after hospitalization by record linkage to the Norwegian national registry of disability pension (DP) awards. Based on the hospital records, the patients were re-diagnosed according to ICD-10. Associations between the diagnoses, other baseline factors and subsequent DP were investigated using Kaplan-Meier survival analyses and logrank testing. RESULTS: At follow-up, 19% of the participants had received a DP award. In the logrank testing, ADHD was the only disorder associated with a subsequent DP, with 30% being disabled at follow-up (p = 0.01). Low psychosocial functioning (assessed by the Children's Global Assessment Scale) at admission uniquely predicted future DP (p = 0.04). CONCLUSIONS: ADHD in childhood was highly associated with later receiving a DP. Our finding of worse prognosis in ADHD compared with other internalizing and externalizing disorders in mid-adulthood supports the assumption of ADHD being specifically linked to working disability. Assessment of psychosocial functioning in addition to diagnostic features could enhance prediction of children who are most at risk of future disability.

The impact of ADHD and conduct disorder in childhood on adult delinquency: a 30 years follow-up study using official crime records.

BACKGROUND: Few longitudinal studies have explored lifetime criminality in adults with a childhood history of severe mental disorders. In the present study, we wanted to explore the association between adult delinquency and several different childhood diagnoses in an in-patient population. Of special interest was the impact of disturbance of activity and attention (ADHD) and mixed disorder of conduct and emotions on later delinquency, as these disorders have been variously associated with delinquent development. METHODS: Former Norwegian child psychiatric in-patients (n = 541) were followed up 19-41 years after hospitalization by record linkage to the National Register of Criminality. On the basis of the hospital records, the patients were re-diagnosed according to ICD-10. The association between diagnoses and other baseline factors and later delinquency were investigated using univariate and multivariate Cox regression analyses. RESULTS: At follow-up, 24% of the participants had been convicted of criminal activity. In the multivariate Cox regression analysis, conduct disorder (RR = 2.0, 95%CI = 1.2-3.4) and hyperkinetic conduct disorder (RR = 2.7, 95% CI = 1.6-4.4) significantly increased the risk of future criminal behaviour. Pervasive developmental disorder (RR = 0.4, 95%CI = 0.2-0.9) and mental retardation (RR = 0.4, 95%CI = 0.3-0.8) reduced the risk for a criminal act. Male gender (RR = 3.6, 95%CI = 2.1-6.1) and chronic family difficulties (RR = 1.3, 95% CI = 1.1-1.5) both predicted future criminality. CONCLUSIONS: Conduct disorder in childhood was highly associated with later delinquency both alone or in combination with hyperactivity, but less associated when combined with an emotional disorder. ADHD in childhood was no more associated with later delinquency than the rest of the disorders in the study population. Our finding strengthens the assumption that there is no direct association between ADHD and criminality.

Lower plasma total tau in adolescent psychosis: Involvement of the orbitofrontal cortex.

Schizophrenia is thought to be a neurodevelopmental disorder with neuronal migration, differentiation and maturation disturbances. Tau is a microtubule-associated protein with a crucial role in these processes. Lower circulating tau levels have been reported in adults with schizophrenia, but this association has not been investigated in adolescent psychosis. We aimed to test the hypotheses that a) adolescents with early-onset psychosis (EOP; age of onset <18 years) display lower plasma tau concentrations compared to healthy controls, and b) among patients with psychosis, tau levels are linked to structural brain measures associated with the microtubule-associated tau (MAPT) gene and psychosis. We included 37 adolescent patients with EOP (mean age 16.4 years) and 59 adolescent healthy controls (mean age 16.2 years). We investigated putative patient-control differences in plasma total tau concentrations measured by a Single molecule array (Simoa) immunoassay. We explored the correlations between tau and selected structural brain measures based on T1-weighted MRI scans processed in FreeSurfer v6.0. We found significantly lower plasma tau concentrations in patients compared to healthy controls (p = 0.017, partial eta-squared = 0.061). Tau was not associated with antipsychotic use or the antipsychotic dosage. Among patients but not healthy controls, tau levels were positively correlated with the cortical orbitofrontal surface area (p = 0.013, R-squared = 0.24). The results are suggestive of a tau-related neurodevelopmental disturbance in adolescent psychosis.

Autoantibodies to the N-Methyl-D-Aspartate Receptor in Adolescents With Early Onset Psychosis and Healthy Controls.

BACKGROUND: Autoantibodies to the N-methyl-D-aspartate receptor (NMDAR-Abs) in autoimmune encephalitis have been associated with prominent psychiatric symptoms. The aims of the present study are to identify the prevalence of NMDAR-Abs in adolescents with early onset psychosis disorders (EOP) and healthy controls (HC) and examine its clinical significance. METHOD: Plasma samples were acquired from 46 adolescent EOP patients and 69 age- and sex matched HC, and assessed for the presence of immunoglobulin G NMDAR-Abs. All participants underwent psychiatric evaluation, neurological examination and head magnetic resonance imaging. RESULTS: NMDAR-Abs were detected in three of 46 (6.5%) EOP patients and in two of 69 (2.9%) HC. One NMDAR-Abs EOP patient presented with unusual psychopathology and minor T1 weighted lesions of vasculopathological origin located bi-frontally and in the basal ganglia, and had a recent diagnosis of a separate autoimmune disease. One NMDAR-Ab HC displayed a T2 weighted FLAIR hyperintensity lesion in the left frontal lobe. The remaining three NMDAR-Ab participants were two EOP patients without neurological or radiological findings, and one HC without any clinical findings. CONCLUSIONS: We report that a small number of EOP patients and HC have NMDAR-Abs with a similar frequency in both groups. The presence of the antibodies was not associated with any distinctive clinical or radiological features. Detection of the antibodies had no diagnostic implication, and a positive NMDAR antibody test must be carefully interpreted and reviewed within the individual clinical context.

Healthy Adolescent Performance With Standardized Scoring Tables for the MATRICS Consensus Cognitive Battery: A Multisite Study.

OBJECTIVE: The aim of this study was to develop standardized scores and scoring tables for test performance in healthy adolescents for the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for each year from 11 to 19 years of age, by sex, with T scores and percentile ranks. METHODS: A total of 502 healthy participants (aged 11-19 years) from 7 cohorts from Ireland, Norway, Sweden, and United States, were included in this multisite study. Regression-predicted means for the MCCB tests, except the social cognition subtest, were calculated using the MCCB test scores as outcome variables and age, age2, sex, age × sex as predictors. The regression-predicted means for each combination of age and sex were added with the residuals from the entire cohort to yield the expected distribution of that group. Age effects were examined using regression models with age and age2 as predictors. Sex differences were examined using Student's t-tests. RESULTS: Significant positive age effects were found for all tests, except for the Brief Visuospatial Memory Test, revised (BVMT-R; measure of visual learning). Females performed significantly better than males on BACS Symbol coding (measure of speed of processing) and BVMT-R, while males performed significantly better than females on NAB Mazes (measure of reasoning and problem solving). Based on the regression-predicted distributions of scores, 19 standardized scoring tables for each test and domain were created. CONCLUSIONS: With the results from this study, we have developed an accessible standardized data set of healthy adolescent test performance for the MCCB.

[Urine peptide patterns in children with milder types of autism]. / Peptidmønstre i urin hos barn med mildere former for autisme.

BACKGROUND: Autism is a severe developmental disorder. The condition is probably not homogenous. Elevated urine peptides have been found in individuals affected by autism spectrum disorders. This finding may be explained by characteristics of the samples studied. Autistic children without mental retardation (high-functioning autism) or mild mental retardation may represent a more homogenous group among those suffering from autism spectrum disorders. The purpose of this study is to compare urine peptide patterns in this group of patients with healthy controls. This has never been done before. METHOD: Urine from the first miction was frozen immediately in order to inhibit bacterial growth and enzymatic degeneration. Peptides from the urine samples were later analysed by high pressure liquid chromatography (HPLC). RESULTS: No significant differences in urine peptide values were found between the autism spectrum disorders group and the controls. There was an age dependent decrease in peptides, with values decreasing with the age of the child. Three individuals in the autism group (17%) and one in the familiar control group (0.05%) had high levels of urine peptides. No one in the same age non-familiar control group had elevated levels of urine peptides. INTERPRETATION: This study shows that high-functioning autism cannot be identified by the urine peptide pattern.

The Association between Hair Cortisol and Self-Reported Symptoms of Depression in Pregnant Women.

Depression has been linked to an imbalance in cortisol. Until recently, cortisol has been studied by measuring concentrations at single time points in blood or saliva samples. Cortisol concentrations vary with circadian rhythm and experiences, from time point to time point. The measurement of hair cortisol concentration (HCC) is a new method of accessing mean, long-term cortisol concentrations. Recent studies show positive associations between depression and HCC, and prenatal maternal cortisol is thought to influence the developing fetus. We therefore examined the association between HCC and self-reported symptoms of depression in second trimester pregnant women. Participants were 181 women, recruited between September 2011 and October 2013 to the Little-in-Norway (LiN)-study. These women answered the Edinburgh Postnatal Depression Rating Scale (EPDS) on self-reported symptoms of depression, and one cm maternal scalp hair was collected and analyzed for cortisol concentrations. Multiple regression analyses did not show depressive symptoms as a predictor for HCC in our selection of pregnant women, while gestational age was significantly related. In conclusion, our study indicated that symptoms of depression during pregnancy did not predict HCC, but further studies of clinically depressed, pregnant women using gestational age as an adjustment variable are warranted.

Is long-term prognosis for pervasive developmental disorder not otherwise specified different from prognosis for autistic disorder? Findings from a 30-year follow-up study.

We followed 74 children with autistic disorder (AD) and 39 children with pervasive developmental disorder not otherwise specified (PDD NOS) for 17-38 years in a record linkage study. Rates of disability pension award, marital status, criminality and mortality were compared between groups. Disability pension award was the only outcome measure that differed significantly between the AD and PDD NOS groups (89% vs. 72%, p < 0.05). The lower rate of disability pension award in the PDD NOS group was predicted by better psychosocial functioning. The lack of substantial differences in prognosis between the groups supports a dimensional description of autism spectrum disorder, in line with proposed DSM-V revision.