Jacob Vorstman

Proline Affects Brain Function in 22q11DS Children with the Low Activity COMT158 Allele

The association between the 22q11.2 deletion syndrome (22q11DS) and psychiatric disorders, particularly psychosis, suggests a causal relationship between 22q11DS genes and abnormal brain function. The genes catechol-O-methyl-transferase (COMT) and proline dehydrogenase both reside within the commonly deleted region of 22q11.2. COMT activity and proline levels may therefore be altered in 22q11DS individuals. Associations of both COMT158 genotype and elevated serum proline levels with abnormal brain function have been reported. Fifty-six 22q11DS children and 75 healthy controls were assessed on physiological measures of brain function, including prepulse inhibition (PPI) of startle, P50 auditory sensory gating and smooth pursuit eye movements (SPEM). COMT158 genotype and plasma proline levels were determined in the 22q11DS children. We hypothesized an interaction between the COMT158 genotype and proline, predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMTmet allele. Of the three physiological measures, only SPEM and PPI were abnormal in the patient sample. With regard to the SPEM performance, there was a significant interaction between the COMT158 genotype and proline level with significantly decreased SPEM performance in children with high plasma proline levels and the low activity COMTmet allele. A similar interaction effect was not observed with regard to PPI. These findings are consistent with a model in which elevated proline negatively affects brain function by an increase in dopamine in the prefrontal cortex. 22q11DS patients with low dopamine catabolic capacity are therefore especially vulnerable to this functional disruption.

Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia

UNLABELLED The objectives of this study were 1) to examine whether the prevalence of 22q11.2 deletion syndrome (22q11DS) in schizophrenia patients with the Deficit syndrome is higher than the reported approximately 2% for the population of schizophrenia patients as a whole, and 2) to estimate the overall prevalence of 22q11DS among schizophrenia patients by combining all available studies. Our sample, enriched for patients with the Deficit syndrome, had 88% power to detect an estimated prevalence of 5% of 22q11.2 deletions. No 22q11.2 deletions were detected in 311 schizophrenia patients, 146 of whom met criteria for the Deficit syndrome. Our literature research revealed that in eight studies sixteen deletions were identified in 2133 patients with schizophrenia. This corresponds to a prevalence of 0.75% (95%CI: 0.5%-1.2%). IN CONCLUSION The prevalence of 22q11.2DS in schizophrenia patients with the Deficit syndrome is not higher than in the population of schizophrenia patients as a whole. The prevalence of 22q11.2DS in schizophrenia patients is lower than the frequently reported prevalence of 2% or more.

Early interventions in risk groups for schizophrenia: what are we waiting for?

Intervention strategies in adolescents at ultra high-risk (UHR) for psychosis are promising for reducing conversion to overt illness, but have only limited impact on functional outcome. Recent studies suggest that cognition does not further decline during the UHR stage. As social and cognitive impairments typically develop before the first psychotic episode and even years before the UHR stage, prevention should also start much earlier in the groups at risk for schizophrenia and other psychiatric disorders. Early intervention strategies could aim to improve stress resilience, optimize brain maturation, and prevent or alleviate adverse environmental circumstances. These strategies should urgently be tested for efficacy: the prevalence of ~1% implies that yearly ~22 in every 100,000 people develop overt symptoms of this illness, despite the fact that for many of them—e.g., children with an affected first-degree family member or carriers of specific genetic variants—increased risk was already identifiable early in life. Our current ability to recognize several risk groups at an early age not only provides an opportunity, but also implies a clinical imperative to act. Time is pressing to investigate preventive interventions in high-risk children to mitigate or prevent the development of schizophrenia and related psychiatric disorders.

Preventive strategies for mental health

Available treatment methods have shown little effect on the burden associated with mental health disorders. We review promising universal, selective, and indicated preventive mental health strategies that might reduce the incidence of mental health disorders, or shift expected trajectories to less debilitating outcomes. Some of these interventions also seem to be cost-effective. In the transition to mental illness, the cumulative lifetime effect of multiple small effect size risk factors progressively increases vulnerability to mental health disorders. This process might inform different levels and stages of tailored interventions to lessen risk, or increase protective factors and resilience, especially during sensitive developmental periods. Gaps between knowledge, policy, and practice need to be bridged. Future steps should emphasise mental health promotion, and improvement of early detection and interventions in clinical settings, schools, and the community, with essential support from society and policy makers.

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

Attention deficit hyperactivity disorder symptoms as antecedents of later psychotic outcomes in 22q11.2 deletion syndrome

Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantially heightened risk for psychosis. Thus, prevention and early intervention strategies that target the antecedents of psychosis in this high-risk group are a clinical priority. Attention Deficit Hyperactivity Disorder (ADHD) is one the most prevalent psychiatric disorders in children with 22q11.2DS, particularly the inattentive subtype. The aim of this study was to test the hypothesis that ADHD inattention symptoms predict later psychotic symptoms and/or psychotic disorder in those with 22q11.2DS. 250 children and adolescents with 22q11.2DS without psychotic symptoms at baseline took part in a longitudinal study. Assessments were performed using well-validated structured diagnostic instruments at two time points (T1 (mean age = 11.2, SD = 3.1) and T2 (mean age = 14.3, SD = 3.6)). Inattention symptoms at T1 were associated with development of psychotic symptoms at T2 (OR:1.2, p = 0.01) but weak associations were found with development of psychotic disorder (OR:1.2, p = 0.15). ADHD diagnosis at T1 was strongly associated with development of psychotic symptoms at T2 (OR:4.5, p < 0.001) and psychotic disorder (OR:5.9, p = 0.02). Our findings that inattention symptoms and the diagnosis of ADHD are associated with subsequent psychotic outcomes in 22q11.2DS have important clinical implications. Future studies examining the effects of stimulant and other ADHD treatments on individuals with 22q11.2DS are warranted.

S132. A NORMATIVE CHART FOR THE TRAJECTORY OF COGNITIVE FUNCTIONING IN INDIVIDUALS AT HIGH RISK FOR SCHIZOPHRENIA: LONGITUDINAL FINDINGS FROM THE INTERNATIONAL BRAIN AND BEHAVIOR CONSORTIUM ON 22Q11.2 DELETION SYNDROME

Abstract Background In schizophrenia, a decline in cognitive functioning often precedes the onset of the first psychotic episode by many years. We have previously shown this to be the case for individuals with 22q11.2 deletion syndrome (22q11DS), a genetic variant associated with a 20–25% risk of developing schizophrenia. We also observed that, regardless of the subsequent development of psychosis, individuals with 22q11DS show, on average a modest decline in IQ between 8 and 24 years and that in those who develop a psychotic disorder this decline follows a steeper trajectory. The tendency for a modest cognitive decline may represent a cognitive phenotype that is specific to 22q11DS, and possibly, an endophenotype for schizophrenia in this population. In order to assess this, we constructed a normative chart for cognitive development over time in individuals with 22q11DS. Methods We made use of the International Brain and Behavior Consortium on 22q11DS (IBBC) database that includes cross-sectional and longitudinal cognitive data from 1871 individuals with 22q11DS (mean age 15.7, SD 7.4, years; n = 330 (17.6%) with schizophrenia). All IQ measurements were obtained by qualified personnel using Wechsler tests, including WPPSI, WISC and WAIS, depending on the participants’ ages. We used all available IQ data points obtained in the age range 6 - 40 years to construct normative charts for Full Scale IQ (FSIQ), Verbal IQ (VIQ) and Performance IQ (PIQ), after a comprehensive quality control procedure to ensure reliable and comparable IQ data across all international sites. We used a polynomial regression model, similar to what is used in standardized international growth charts for height and weight, to create the normative chart. Results The 4th order polynomial regression provided a good fit for the IQ data from our sample, allowing for the observed larger variability in very young age groups. On average, between the ages of 6 and 40 years, the 22q11DS population showed a gradual, modest decline in FSIQ, VIQ and PIQ. Consistent with our previous results, individuals who went on to develop schizophrenia showed a steeper decline, representing a deviation from their expected trajectory, than those who had no documented psychotic illness. Discussion This study is, to our knowledge, the first to demonstrate that a normative chart for cognitive development through to adulthood can be reliably constructed for a genetically selected high-risk population. This normative chart can be readily applied both in clinical care and in research and may serve as an example for constructing similar normative charts in other high-risk groups and/or genetic disorders.

F72. NEUROCOGNITION AND ADAPTIVE FUNCTIONING IN THE 22Q11.2 DELETION SYNDROME MODEL OF SCHIZOPHRENIA

Abstract Background Identifying factors that influence functional outcome is an important goal in schizophrenia research. These factors, including overall cognitive functioning (IQ) and more specific domains of neurocognitive functioning, may not only aid in identifying those individuals at greatest risk for poor functional outcome but could inform potentially targetable treatment objectives. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20–25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS. Methods Using data available from a comprehensive battery of 15 neurocognitive tests for 99 adults with 22q11DS (n=43 with schizophrenia) we derived four domains of neurocognition (Verbal memory, Visual memory, Motor functioning, and Executive performance) using a principal component analysis. To investigate the association of these domains with adaptive functioning, we used Vineland Adaptive Behavior Scales (VABS) data available for 84 subjects in a logistic regression model that accounted for the effects of schizophrenia status and overall intellectual level. Results The regression model explained 46.8% of the variance in overall functional outcome (p < 0.0001) and 47.7% of the variance on the daily living skills subdomain (p < 0.0001). Executive performance was significantly associated with subsequent functional outcome (p = 0.046); age and schizophrenia were also significant factors. VABS adaptive functioning scale scores were higher in those with better performance on Executive domain tests, no psychotic illness, and older age. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness. Discussion The significant relationship between Executive Performance and functional outcome is a novel addition to our understanding of cognitive factors that may contribute to the variability in functional outcome in schizophrenia high-risk groups. The results provide impetus for further studies of Executive Performance as a potential target of early intervention strategies to mitigate risk for schizophrenia and functional deterioration.

Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome

The purpose of this article is to provide an overview of current insights into the neurodevelopmental and psychiatric manifestations of 22q11.2 deletion syndrome (22q11DS) in children and adolescents. The pediatric neuropsychiatric expression of 22q11DS is characterized by high variability, both interindividual and intraindividual (different expressions over the lifespan). Besides varying levels of intellectual disability, the prevalence of autism spectrum disorders, attention deficit disorders, anxiety disorders, and psychotic disorders in young individuals with 22q11DS is significantly higher than in the general population, or in individuals with idiopathic intellectual disability. Possible explanations for this observed phenotypic variability will be discussed, including genetic pleiotropy, gene‐environment interactions, the age‐dependency of phenotypes, but also the impact of assessment and ascertainment bias as well as the limitations of our current diagnostic classification system. The implications inferred by these observations aforementioned bear direct relevance to both scientists and clinicians. Observations regarding the neuropsychiatric manifestations in individuals with 22q11DS exemplify the need for a dimensional approach to neuropsychiatric assessment, in addition to our current categorical diagnostic classification system. The potential usefulness of 22q11DS as a genetic model to study the early phases of schizophrenia as well as the phenomenon of neuropsychiatric pleiotropy observed in many CNVs will be delineated. From a clinical perspective, the importance of regular neuropsychiatric evaluations with attention to symptoms not always captured in diagnostic categories and of maintaining equilibrium between individual difficulties and competencies and environmental demands will be discussed.