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.

Significant association between intracranial volume and verbal intellectual abilities in patients with schizophrenia and a history of birth asphyxia.

BACKGROUND: The etiology of schizophrenia (SZ) is proposed to include an interplay between a genetic risk for disease development and the biological environment of pregnancy and birth, where early adversities may contribute to the poorer developmental outcome. We investigated whether a history of birth asphyxia (ASP) moderates the relationship between intracranial volume (ICV) and intelligence in SZ, bipolar disorder (BD) and healthy controls (HC). METHODS: Two hundred seventy-nine adult patients (18-42 years) on the SZ and BD spectrums and 216 HC were evaluated for ASP based on information from the Medical Birth Registry of Norway. Participants underwent structural magnetic resonance imaging (MRI) to estimate ICV and intelligence quotient (IQ) assessment using the Wechsler Abbreviated Scale of Intelligence (WASI). Multiple linear regressions were used for analyses. RESULTS: We found a significant three-way interaction (ICV × ASP × diagnosis) on the outcome variable, IQ, indicating that the correlation between ICV and IQ was stronger in patients with SZ who experienced ASP compared to SZ patients without ASP. This moderation by ASP was not found in BD or HC groups. In patients with SZ, the interaction between ICV and a history of the ASP was specifically related to the verbal subcomponent of IQ as measured by WASI. CONCLUSIONS: The significant positive association between ICV and IQ in patients with SZ who had experienced ASP might indicate abnormal neurodevelopment. Our findings give support for ICV together with verbal intellectual abilities as clinically relevant markers that can be added to prediction tools to enhance evaluations of SZ risk.

Negative and disorganized symptoms mediate the relationship between verbal learning and global functioning in adolescents with early-onset psychosis.

Neurocognitive deficits are associated with impaired global functioning and psychotic symptoms. However, whether symptoms can mediate the relationship between neurocognition and global functioning in adolescent psychosis is unclear. Here, we investigated if symptoms assessed with the Positive And Negative Syndrome Scale (PANSS), mediated the relationship between neurocognitive performance and global functioning in adolescents with non-affective early-onset psychotic disorders (EOP). Sixty-one adolescent EOP patients (age 12-18 years) from 2 Norwegian clinical cohorts were included. Linear regression models were applied to investigate associations between neurocognitive domains from the MATRICS Consensus Cognitive Battery (MCCB) and global functioning. PANSS symptoms were analyzed using the Wallwork/Fortgang five-factor model. Using the INDIRECT macro for SPSS, mediation effects were tested using bootstrapping with 95% bias corrected confidence intervals. Verbal learning was positively associated with global functioning (P < 0.001) and negatively associated with the disorganized symptom factor (P = 0.002), controlling for age, sex and cohort. Testing of indirect effects, controlling for age, sex and cohort, showed that the Negative (point estimate = 1.56, 95% CI 0.22, 3.47) and Disorganized (point estimate = 1.24, 95% CI 0.05, 3.69) symptom factors significantly mediated the relationship between verbal learning and global functioning. We found that verbal learning, negative and disorganized symptoms influenced global functioning in adolescents with EOP, while reality-distorted positive symptoms did not. These results suggest that assessing these domains in EOP is helpful for planning treatment and rehabilitation programs focusing on functional outcome.

Caudate nucleus volume in medicated and unmedicated patients with early- and adult-onset schizophrenia.

The caudate nucleus is a part of the striatum, and striatal hyperdopaminergia is considered central to the pathophysiology of schizophrenia. How caudate volume is affected in schizophrenia and what role antipsychotics play remains unclear. In early-onset schizophrenia (EOS), where psychosis emerges during a neurodevelopmentally critical phase, the caudate may exhibit a heightened vulnerability to the effects of antipsychotic medications. We hypothesized effects of both antipsychotic medication use and age of onset on caudate in schizophrenia. We included adult patients with EOS (n = 83) and adult-onset schizophrenia (AOS) (n = 246), adult healthy controls (HC, n = 774), adolescent patients with non-affective psychosis (n = 56) and adolescent HC (n = 97). We obtained T1-weighted MRI scans using a 1.5T Siemens scanner and General Electric 3T scanners. In our main analysis, we tested for main and interaction effects of diagnosis and current antipsychotic medication use on caudate volume. Adult patients with EOS (p < 0.001) and AOS (p = 0.002) had both larger caudate than HC. Age of onset (EOS/AOS) interacted with antipsychotic use (p = 0.004) which was associated with larger caudate in EOS (p < 0.001) but not in AOS (p = 0.654). Conversely, among medicated patients only, EOS had larger caudate than AOS (p < 0.001). No other subcortical structures showed differences between medicated EOS and AOS. Medicated adolescent patients with non-affective psychosis and medicated adult patients with EOS showed similar caudate volumes. The results may indicate a schizophrenia-related and a medication-induced caudate increase, the latter restricted to patients with EOS and possibly occurring already in adolescence shortly after disease onset.

Divergent epigenetic responses to perinatal asphyxia in severe mental disorders.

Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case-control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

The impact of placental genomic risk for schizophrenia and birth asphyxia on brain development.

The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genomic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genome-wide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t = 2.10, p = 0.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t = -2.43, p = 0.008), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t = -2.71, p = 0.005) and also found with their adult ICV (t = -1.97, p = 0.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

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.

Negative Symptom Domains Are Associated With Verbal Learning in Adolescents With Early Onset Psychosis.

Background: Early-onset psychosis (EOP) is among the leading causes of disease burden in adolescents. Negative symptoms and cognitive deficits predicts poorer functional outcome. A better understanding of the association between negative symptoms and cognitive impairment may inform theories on underlying mechanisms and elucidate targets for development of new treatments. Two domains of negative symptoms have been described in adult patients with schizophrenia: apathy and diminished expression, however, the factorial structure of negative symptoms has not been investigated in EOP. We aimed to explore the factorial structure of negative symptoms and investigate associations between cognitive performance and negative symptom domains in adolescents with EOP. We hypothesized that (1) two negative symptom factors would be identifiable, and that (2) diminished expression would be more strongly associated with cognitive performance, similar to adult psychosis patients. Methods: Adolescent patients with non-affective EOP (n = 169) were included from three cohorts: Youth-TOP, Norway (n = 45), Early-Onset Study, Norway (n = 27) and Adolescent Schizophrenia Study, Mexico (n = 97). An exploratory factor analysis was performed to investigate the underlying structure of negative symptoms (measured with the Positive and Negative Syndrome Scale (PANSS)). Factor-models were further assessed using confirmatory factor analyses. Associations between negative symptom domains and six cognitive domains were assessed using multiple linear regression models controlling for age, sex and cohort. The neurocognitive domains from the MATRICS Consensus Cognitive Battery included: speed of processing, attention, working memory, verbal learning, visual learning, and reasoning and problem solving. Results: The exploratory factor analysis of PANSS negative symptoms suggested retaining only a single factor, but a forced two factor solution corroborated previously described factors of apathy and diminished expression in adult-onset schizophrenia. Results from confirmatory factor analysis indicated a better fit for the two-factor model than for the one-factor model. For both negative symptom domains, negative symptom scores were inversely associated with verbal learning scores. Conclusion: The results support the presence of two domains of negative symptoms in EOP; apathy and diminished expression. Future studies on negative symptoms in EOP should examine putative differential effects of these symptom domains. For both domains, negative symptom scores were significantly inversely associated with verbal learning.

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.

Feasibility and Acceptability of Using a Mobile Phone App for Characterizing Auditory Verbal Hallucinations in Adolescents With Early-Onset Psychosis: Exploratory Study.

BACKGROUND: Auditory verbal hallucinations (AVH) are the most frequent symptom in early-onset psychosis (EOP) and a risk factor for increased suicide attempts in adolescents. Increased knowledge of AVH characteristics can lead to better prediction of risk and precision of diagnosis and help identify individuals with AVH who need care. As 98% of Norwegian adolescents aged 12 to 16 years own a mobile phone, the use of mobile phone apps in symptom assessment and patient communication is a promising new tool. However, when introducing new technology to patients, their subjective experiences are crucial in identifying risks, further development, and potential integration into clinical care. OBJECTIVE: The objective was to explore the feasibility and acceptability of a newly developed mobile phone app in adolescents with EOP by examining compliance with the app and user experiences. Indication of validity was explored by examining associations between AVH dimensions, which were correlated and analyzed. METHODS: Three adolescents with EOP and active AVH were enrolled. Real-time AVH were logged on an iPod touch using the experience sampling method (ESM), for seven or more consecutive days. The app included five dimensions of AVH characteristics and was programmed with five daily notifications. Feasibility and acceptability were examined using the mean response rate of data sampling and by interviewing the participants. Validity was assessed by examining associations between the AVH dimensions using nonparametric correlation analysis and by visual inspection of temporal fluctuations of the AVH dimensions. RESULTS: One participant was excluded from the statistical analyses but completed the interview and was included in the examination of acceptability. The sampling period of the two participants was mean 12 (SD 6) days with overall completed sampling rate of 74% (SD 30%), indicating adequate to high compliance with the procedure. The user experiences from the interviews clustered into four categories: (1) increased awareness, (2) personal privacy, (3) design and procedure, and (4) usefulness and clinical care. One participant experienced more commenting voices during the sampling period, and all three participants had concerns regarding personal privacy when using electronic devices in symptom assessment. The AVH dimensions of content, control, and influence showed moderate to strong significant correlations with all dimensions (P<.001). Days of data sampling showed weak to moderate correlations with localization (P<.001) and influence (P=.03). Visual inspection indicated that the app was able to capture fluctuations within and across days for all AVH dimensions. CONCLUSIONS: This study demonstrates the value of including patients' experiences in the development and pilot-testing of new technology. Based on the small sample size, the use of mobile phones with ESM seems feasible for patients with EOP, but the acceptability of using apps should be considered. Further investigation with larger samples is warranted before definitive conclusions are made.

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.