Kerstin von Plessen

Less developed corpus callosum in dyslexic subjects—a structural MRI study

BACKGROUND Based on previous studies and due to the characteristics of dyslexia as an auditory phonological decoding disorder, we predicted that the shape of the posterior corpus callosum (CC) would differ between dyslexic and control subjects. METHOD Twenty right-handed boys with developmental dyslexia were selected from a carefully screened general population sample (mean age 11 years) and compared to a matched control group. The CC contour was manually traced on the aligned midsagittal MR slice and total callosal area and its subregions were compared between the groups. A statistical shape analysis and subsequent CC classification was performed using a recently developed shape model method. RESULTS The shape analysis revealed shorter CC shape in the dyslexic group, localised in the posterior midbody/isthmus region. This region contains interhemispheric fibers from primary and secondary auditory cortices. A shape length difference larger than a fixed threshold in the posterior midbody region could correctly discriminate between control and dyslexic subject in 78% of the cases, where a dyslexic CC was shorter in this region than a control CC. However, there were no significant group differences with respect to overall CC area or subregions. CONCLUSION A clear shape difference in the posterior midbody of the CC was found between dyslexic and control subjects. This fits with recent other studies that have reported a strong growth factor in this CC region during the late childhood years, coinciding with literacy acquisition. Our results show that the dyslexic group has not undergone the same growth pattern as the normal reading group.

Attention Network Test in adults with ADHD - the impact of affective fluctuations

BackgroundThe Attention Network Test (ANT) generates measures of different aspects of attention/executive function. In the present study we investigated whether adults with ADHD performed different from controls on measures of accuracy, variability and vigilance as well as the control network. Secondly, we studied subgroups of adults with ADHD, expecting impairment on measures of the alerting and control networks in a subgroup with additional symptoms of affective fluctuations.MethodsA group of 114 adults (ADHD n = 58; controls n = 56) performed the ANT and completed the Adult ADHD Rating Scale (ASRS) and the Mood Disorder Questionnaire (MDQ). The latter was used to define affective fluctuations.ResultsThe sex distribution was similar in the two groups, but the ADHD group was significantly older (p = .005) and their score on a test of intellectual function (WASI) significantly lower than in the control group (p = .007). The two groups were not significantly different on measures of the three attention networks, but the ADHD group was generally less accurate (p = .001) and showed a higher variability through the task (p = .033).The significance was only retained for the accuracy measure when age and IQ scores were controlled for. Within the ADHD group, individuals reporting affective fluctuations (n = 22) were slower (p = .015) and obtained a lower score on the alerting network (p = .018) and a higher score on the conflict network (p = .023) than those without these symptoms. The significance was retained for the alerting network (p = .011), but not the conflict network (p = .061) when we controlled for the total ASRS and IQ scores.DiscussionAdults with ADHD were characterized by impairment on accuracy and variability measures calculated from the ANT. Within the ADHD group, adults reporting affective fluctuations seemed to be more alert (i.e., less impacted by alerting cues), but slower and more distracted by conflicting stimuli than the subgroup without such fluctuations. The results suggest that the two ADHD subgroups are characterized by distinct patterns of attentional problems, and that the symptoms assessed by MDQ contribute to the cognitive heterogeneity characterizing groups of individuals with ADHD.

Adults with attention-deficit/hyperactivity disorder - a brain magnetic resonance spectroscopy study.

Background: Impaired cognitive control in individuals with attention-deficit/hyperactivity disorder (ADHD) may be related to a prefrontal cortical glutamatergic deficit. We assessed the glutamate level in the left and the right midfrontal region including the anterior cingulate cortex in adults with ADHD and healthy controls. Methods: Twenty-nine adults with ADHD and 38 healthy controls were included. We used Proton Magnetic Resonance Imaging with single voxel point-resolved spectroscopy to measure the ratio of glutamate to creatine (Glu/Cre) in the left and the right midfrontal region in the two groups. Results: The ADHD group showed a significant reduction of Glu/Cre in the left midfrontal region compared to the controls. Conclusion: The reduction of Glu/Cre in the left midfrontal region in the ADHD group may reflect a glutamatergic deficit in prefrontal neuronal circuitry in adults with ADHD, resulting in problems with cognitive control.

Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics

CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining drug response and tolerability suggesting prospects for individualized drug therapies. Our review also discusses endogenous substrates of CES1 and assesses the potential of using metabolomic profiling of blood to identify proxies for the hepatic activity of CES1 that predict the rate of drug metabolism. Finally, the combination of genetics and metabolomics to obtain an accurate prediction of the individual response to CES1-dependent drugs is discussed.

O12.5. GENETIC AND ENVIRONMENTAL PREDICTORS OF MAIN OUTCOMES IN THE DANISH HIGH RISK AND RESILIENCE STUDY - VIA 7. A STUDY OF 522 7-YEAR-OLD CHILDREN OF PARENTS WITH SCHIZOPHRENIA, BIPOLAR DISORDER OR NEITHER OF THESE DISORDERS

Abstract Background Studies of children born to parents with schizophrenia and affective disorders can allow us to study the processes preceding the manifestation of the disease, and thereby provide a possibility for identifying early amendable risk factors such as poor parenting, deviances in cognitive functioning, and early, subtle signs of psychopathology at a point where preventive intervention can be applied. Methods The Danish High Risk and Resilience Study - VIA7 is a representative nationwide cohort study of 522 7-year-old children of parents with schizophrenia, bipolar disorder or neither of these disorders recruited during 2013–2015. The sample consists of: 202 children with a parent diagnosed with schizophrenia spectrum psychosis, 120 children with a parent diagnosed with bipolar disorder, and 200 children with neither of the parents treated in mental health services for the above diagnoses. We have collected blood and saliva samples from the children and their parents and polygenic risk scores were calculated. We have thoroughly assessed the home environment with the instrument HOME. We have assessed main outcomes such as psychopathology, PLIKS, neurocognition and social cognition. We will analyse the influence of genetic and environmental exposures and their interaction. Results Generally, the children with a familial risk of schizophrenia had lower neurocognitive, social cognitive and neuromotor functioning, more child psychiatric diagnoses, and more severe symptoms compared to control children. In most comparisons, children of parents with bipolar disorder were not different from controls, but in some tests they performed poorer or had more symptoms compared to than control children. We will present data on genetic and environmental risk factors for these outcomes Discussion This is the largest high-risk study ever conducted. It is unique that we have access to detailed phenotyping and extensive information on environmental and genetic risk factors. Studies like this can inform about patogenesis and possibilities for future preventive interventions

F204. THE DANISH HIGH-RISK AND RESILIENCE STUDY - VIA 7 - A PROSPECTIVE COHORTE STUDY OF 522 7 YEARS OLD CHILDREN BORN TO PARENTS DIAGNOSED WITH SCHIZOPHRENIA OR BIPOLAR DISORDER - RESULTS ON PSYCHOPATHOLOGY, COGNITION AND LIVING CONDITIONS

Abstract Background For decades familial high-risk studies have informed us about genetic and environmental risk factors for schizophrenia and recently also bipolar disorder. Familial high-risk studies are important and relevant and may represent a possible shortcut to learning more about early markers of illness, mental vulnerability and resilience. Methods The Danish High Risk and Resilience Study – VIA 7 is a prospective cohort study of 522 7-year old children, 202 of them born to at least one parent diagnosed with schizophrenia in the Danish registries, 120 of them born to a least one parent diagnosed with bipolar disorder and 200 of them born to parents without any of these diagnoses. A comprehensive battery has been used combining assessments from several domains for both parents and children. Results Results show that children born to parents with schizophrenia or bipolar disorder have higher frequencies of early mental problems. Further there are marked differences between the three groups concerning neuro cognition, motor functioning and living conditions including socioeconomic status, early risk factors and home environment - all factors that are known to be important with regard to healthy child development. Discussion First results from the VIA 7-study indicate that many children and families have unmet needs and problems. Perspectives are two-fold: we aim to follow the cohort and conduct a new assessment before puberty (at age 11). Simultaneously, we are evolving an early, integrated, specialized and family based intervention, called VIA Family, to prevent or ameliorate development of severe mental illness in individuals born to parents with schizophrenia or bipolar disorder.

F67. NEUROCOGNITION IN 7-YEAR-OLD CHILDREN OF PARENTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER

Abstract Background Children of parents with schizophrenia or bipolar disorder display neurocognitive deficits. However, studies of schizophrenia offspring and bipolar offspring at the same age are lacking. The objective was to compare neurocognitive abilities in 7-year-old children of parents with schizophrenia or bipolar disorder with neurocognitive abilities in children of parents without these disorders. Methods In this nationwide cohort study we assessed 522 7-year-old children (schizophrenia offspring: N=202, bipolar offspring: N=120, and controls=200) with a detailed and well validated neurocognitive test battery. We compared the neurocognitive test scores of the three study groups. Results Children of parents with schizophrenia showed neurocognitive deficits, whereas children of parents with bipolar disorder displayed neurocognitive abilities comparable to the control group. Discussion Neurocognitive deficits are numerous in 7-year-old children of parents with schizophrenia, which supports the neurodevelopmental model of schizophrenia. Unimpaired neurocognitive abilities in children of parents with bipolar disorder indicate different neurodevelopmental manifestations in these high risk populations at this early age. Our results call for early identification of schizophrenia offspring with cognitive dysfunctions.