Therese van Amelsvoort

Baseline differences in clinical symptomatology between ultra high risk subjects with and without a transition to psychosis.

BACKGROUND The chance of transition to psychosis in patients at Ultra High Risk for developing psychosis (UHR) is 10-15%. The aim of present study was to investigate differences in baseline clinical symptomatology, general level of functioning (GAF-score) and genetic risk between UHR patients who did (UHR+T) or did not (UHR+NT) make a transition to psychosis. Sharpening UHR inclusion criteria may aid in improving prediction of transition to psychosis. METHOD The study sample was taken from 285 patients who were examined within the Dutch Prediction of Psychosis Study (DUPS) at the Academic Medical Center of the University of Amsterdam, the Netherlands. Out of 73 included UHR subjects, 18 made a transition to psychosis. Psychopathology was investigated with the Structured Interview for Prodromal Syndromes, Bonn Scale for the Assessment of Basic Symptoms and GAF-score. The follow-up period of the study was three years. RESULTS The UHR+T group showed more social anhedonia and withdrawal, more bizarre thinking and a lower GAF score at baseline than the UHR+NT group. CONCLUSIONS In agreement with the results of Cannon et al. [Cannon, T.D., Cadenhead, K., Cornblatt, B., Woods, S.W., Addington, J., Walker, E., Seidman, L.J., Perkins, D., Tsuang, M., McGlashan, T., Heinssen, R., 2008. Prediction of Psychosis in Youth at High Clinical Risk: A Multisite Longitudinal Study in North America. Arch. Gen. Psychiat. 65 (1) 28-37.], our study indicates that severity of specific symptoms at baseline is related to transition to psychosis in UHR subjects. These findings may contribute to a more accurate prediction of a first psychotic episode. Furthermore, symptoms that are increased at baseline in the UHR+T group could be a focus of cognitive behavioural therapy in the UHR period.

Neural correlates of reward in autism

BACKGROUND Lack of social interaction, which is characteristically seen in people with autistic-spectrum disorder, may be caused by malfunctioning of the frontostriatal reward systems. However, no reported in vivo brain imaging studies have investigated reward mechanisms in autistic-spectrum disorder. AIMS To investigate functional brain activation during reward feedback in people with autistic-spectrum disorder and control individuals. METHOD We used event-related functional magnetic resonance imaging to examine the neural substrates of monetary reward in individuals with autistic-spectrum disorder and matched controls. RESULTS When rewarded, individuals with autism compared with control individuals showed significantly greater brain activation in the left anterior cingulate gyrus. In addition, activation of this region was negatively correlated with social interaction as measured by the Autism Diagnostic Interview. CONCLUSIONS In people with autistic-spectrum disorder, achieving reward is associated with significant differences in the activation of areas known to be responsible for attention and arousal, and this may partially underpin some deficits in social behaviour.

Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects

BackgroundObesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D2/D3 receptor [D2/3R] availability is lower in morbidly obese subjects.MethodsTo confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [123I]IBZM SPECT, in 15 obese women and 15 non-obese controls.ResultsStriatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women.ConclusionThis study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesity.

White matter fibertracking in first-episode schizophrenia, schizoaffective patients and subjects at ultra-high risk of psychosis

There is increasing evidence of white matter pathology in schizophrenia. The aim of this study was to examine whether white matter abnormalities found with diffusion tensor imaging (DTI) in previous schizophrenia studies are present in the early phase of the illness. DTI was performed at 3 T on 10 male patients with a first (n = 8) or second (n = 2) psychotic episode of schizophrenia or schizoaffective disorder, 10 male patients at ultra-high risk of psychosis with (pre)psychotic symptoms and 10 healthy controls. Fibertracts found to be abnormal in other DTI studies (uncinate and arcuate fasciculus, anterior and dorsal cingulum, subdivisions of the corpus callosum) were calculated and visualized; tract-specific measurements (fractional anisotropy and trace) were performed. No differences were found between the healthy subjects and the 2 patient groups. These preliminary findings suggest that there is no white matter pathology of these association tracts detectable with DTI in the early stages of schizophrenic illness in males. Our findings are in contrast with DTI abnormalities found in some other first-episode studies. This discrepancy in findings may be related to differences in subject characteristics and DTI methodology. Possible effects of age, gender, level of education and illicit substance use on DTI findings in schizophrenia are discussed.

Influence of X chromosome and hormones on human brain development: a magnetic resonance imaging and proton magnetic resonance spectroscopy study of Turner syndrome.

BACKGROUND Women with Turner syndrome (TS; 45,X) lack a normal second X chromosome, and many are prescribed exogenous sex and growth hormones (GH). Hence, they allow us an opportunity to investigate genetic and endocrine influences on brain development. METHODS We examined brain anatomy and metabolism in 27 adult monosomic TS women and 21 control subjects with volumetric magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS In TS women, regional gray matter volume was significantly smaller in parieto-occipital cortex and caudate nucleus and larger in cerebellar hemispheres. White matter was reduced in the cerebellar hemispheres, parieto-occipital regions, and splenium of the corpus callosum but was increased in the temporal and orbitofrontal lobes and genui of corpus callosum. Women with TS had a significantly lower parietal lobe concentration of N-acetyl aspartate, and higher hippocampal choline. Also, among women with TS, there were significant differences in regional gray matter volumes and/or neuronal integrity, depending upon parental origin of X chromosome and oxandrolone and GH use. CONCLUSIONS X chromosome monosomy, imprinting and neuroendocrine milieu modulate human brain development-perhaps in a regionally specific manner.

Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome

Velo-cardio-facial syndrome (VCFS) is a genetic disorder associated with 22q11 deletion, a characteristic clinical phenotype, behavourial problems, specific cognitive deficits and a high rate of psychosis (particularly schizophrenia). The study of VCFS provides a unique opportunity to identify susceptibility genes for schizophrenia and its associated cognitive deficits. To date, there have been no studies investigating the impact of schizophrenia on cognitive function in adults with VCFS. Therefore we studied the neuropsychological profile of 28 adults with VCFS; 13 with schizophrenia (mean age (+/-S.D.) 34 years +/-11, IQ 71+/-11) and 15 without a history of psychosis (mean age 33 years +/-11, IQ 75+/-11). The VCFS group with schizophrenia compared to the VCFS group without schizophrenia performed significantly (P<0.05) worse on tests of: (1) spatial working memory and strategy formation; (2) the similarities sub-test of the Weschler Adult Intelligence Scale (WAIS); (3) visual recognition; (4) and attention. These deficits may reflect differences in the development and function of frontal brain regions, and this might increase the risk of developing schizophrenia in VCFS. Future studies will need to address how haploinsufficiency of genes on chromosome 22q11 might affect cognition and its relation to the development of psychosis.

Prefrontal and medial temporal correlates of repetitive violence to self and others

BACKGROUND The neurobiological basis for violence in humans is poorly understood, yet violent behavior (to self or others) is associated with large social and healthcare costs in some groups of patients (e.g., the mentally retarded). The prefrontal cortex and amygdalo-hippocampal complex (AHC) are implicated in the control aggression, therefore we examined the neural integrity of these regions in violent patients with mild mental retardation and nonviolent control subjects. METHODS We used (1)H-magnetic resonance spectroscopy (MRS) to measure 1) concentrations and ratios of N-acetyl aspartate (NAA), creatine phosphocreatine (Cr+PCr), and choline-related compounds (Cho) in prefrontal lobe of 10 violent inpatients and 8 control subjects; 2) ratios of NAA, Cr+PCr, and Cho in the AHC of 13 inpatients and 14 control subjects; and 3) frequency and severity of violence in patients. RESULTS Compared to control subjects, violent patients had significantly (p <.05, analysis of covariance-age and IQ as confounding covariates) lower prefrontal concentrations of NAA and Cr+PCr, and a lower ratio of NAA/Cr+PCr in the AHC. Within the violent patient group, frequency of observed violence to others correlated significantly with prefrontal lobe NAA concentration (r = -0.72, p <.05). CONCLUSIONS NAA concentration indicates neuronal density, and Cr+PCr concentration high-energy phosphate metabolism. Our findings suggest that violent patients with mild mental retardation have reduced neuronal density, and abnormal phosphate metabolism in prefrontal lobe and AHC compared to nonviolent control subjects. Further studies are needed, however, to determine if these findings are regionally specific, or generalize to other groups of violent individuals.

Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

IMPORTANCE Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. OBJECTIVE To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). MAIN OUTCOMES AND MEASURES Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. CONCLUSIONS AND RELEVANCE In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

White matter integrity in Asperger syndrome: a preliminary diffusion tensor magnetic resonance imaging study in adults.

Background: Autistic Spectrum Disorder (ASD), including Asperger syndrome and autism, is a highly genetic neurodevelopmental disorder. There is a consensus that ASD has a biological basis, and it has been proposed that it is a “connectivity” disorder. Diffusion Tensor Magnetic Resonance Imaging (DT‐MRI) allows measurement of the microstructural integrity of white matter (a proxy measure of “connectivity”). However, nobody has investigated the microstructural integrity of whole brain white matter in people with Asperger syndrome. Methods: We measured the fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) of white matter, using DT‐MRI, in 13 adults with Asperger syndrome and 13 controls. The groups did not differ significantly in overall intelligence and age. FA, MD and RD were assessed using whole brain voxel‐based techniques. Results: Adults with Asperger syndrome had a significantly lower FA than controls in 13 clusters. These were largely bilateral and included white matter in the internal capsule, frontal, temporal, parietal and occipital lobes, cingulum and corpus callosum. Conclusions: Adults with Asperger syndrome have widespread significant differences from controls in white matter microstructural integrity.

Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings

BackgroundThe dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls.MethodsFrom all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF).ResultsMean VIQ, PIQ, and FSIQ scores differed significantly (p < 0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls.ConclusionAlthough preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning.