Neurocognitive profile of adolescents with early-onset schizophrenia and their unaffected siblings.

BACKGROUND: We investigated the neurocognitive profiles of Early-Onset Schizophrenia (EOS; onset before age 18) and paired unaffected siblings and the little-studied effect of age-of-onset and duration of illness on cognitive performance. METHODS: 31 EOS probands, and 31 of their siblings, had four cognitive domains assessed: (a) Memory: California Verbal Learning Test, and the Wechsler Memory Scale-Revised; (b) Working memory: Digit Span; (c) Attention: Degraded-Stimulus Continuous Performance Test, Span of Apprehension (SPAN), and Trail Making Test (TMT) part A; (d) Executive function: Wisconsin card sorting task, and TMT part B. Diagnosis was confirmed using the structured clinical interview for DSM-IV. RESULTS: While EOS showed a generalised neurocognitive deficit (0.25-0.50 effect size) compared with siblings, across all cognitive domains, significantly greater patient deficits were observed with, working memory, attention, and executive function and minimal differences for digit span forward, block design and false alarms on the SPAN-12 confirmed by repeated measures MANOVA. Patients with earlier onset (12-15) showed greater deficits on false alarm and digits backward scores. Siblings showed individual cognitive task profiles similar to patients, confirming familial effects. EOS showed much more variable scores than siblings with more individual tasks showing 2 SD deficits than siblings. Long duration patients had greater z-score variability across tasks. CONCLUSIONS: Duration of illness was a more important characteristic in patients with onset 16 and over than in younger onset patients with comparable durations. Both the similarity of sibling pair profiles and greater patient variability across task provide further support for neurobiological heterogeneity in schizophrenia.

Reading abilities and dopamine D2/D3 receptor availability: An inverted U-shaped association in subjects with schizophrenia.

Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used 18F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects' scores were positively and linearly associated with D2/D3 receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous. This relationship was weakened in schizophrenia subjects and in contrast to healthy participants followed an inverted U-shaped curve both in the cortex and dorsal striatum, indicating restricted optimal range of dopamine D2/D3 receptor availability for cognitive performance in schizophrenia.

Insights into schizophrenia using positron emission tomography: building the evidence and refining the focus.

Schizophrenia involves dysregulation in dopaminergic transmission. Studies show heightened presynaptic striatal dopaminergic function and elevated striatal D(2)/D(3) receptor density in the brain. Cognitive impairments result from hypostimulation of D(1) receptors and are associated with dysfunction in the prefrontal cortex. Here we discuss relevant positron emissions tomography (PET) studies and provide future directions.

Effect of age at onset of schizophrenia on white matter abnormalities.

BACKGROUND: The pattern of brain morphological changes at the early stages of schizophrenia may depend on the age at onset of illness; in children and adolescents with schizophrenia, grey matter deficits are seen in the parietal lobe whereas in individuals with adult onset these are more widespread. AIMS: To examine whether white matter is similarly affected. METHOD: Diffusion tensor imaging was used to compare fractional anisotropy measures in individuals with adolescent-onset (n = 17) and adult-onset schizophrenia (n = 17) with those in age- and gender-matched controls. RESULTS: Compared with their respective controls, individuals with adolescent-onset schizophrenia showed fractional anisotropy decrease in parietal regions; individuals with adult onset showed additional fractional anisotropy reductions in frontal, temporal and cerebellar regions. A differential effect of age at onset (adolescent v. adult) was noted bilaterally in medial prefrontal white matter. CONCLUSIONS: White matter abnormalities in frontal regions in schizophrenia may depend on developmental stage at the time of illness onset.

D2/D3 dopamine receptor binding with [F-18]fallypride correlates of executive function in medication-naïve patients with schizophrenia.

Converging evidence indicates that the prefrontal cortex is critically involved in executive control and that executive dysfunction is implicated in schizophrenia. Reduced dopamine D2/D3 receptor binding potential has been reported in schizophrenia, and the correlations with neuropsychological test scores have been positive and negative for different tasks. The aim of this study was to examine the relation between dopamine D2/D3 receptor levels with frontal and temporal neurocognitive performance in schizophrenia. Resting-state 18F-fallypride positron emission tomography was performed on 20 medication-naïve and 5 previously medicated for brief earlier periods patients with schizophrenia and 19 age- and sex-matched healthy volunteers. Striatal and extra-striatal dopamine D2/D3 receptor levels were quantified as binding potential using fallypride imaging. Magnetic resonance images in standard Talairach position and segmented into gray and white matter were co-registered to the fallypride images, and the AFNI stereotaxic atlas was applied. Two neuropsychological tasks known to activate frontal and temporal lobe function were chosen, specifically the Wisconsin Card Sorting Test (WCST) and the California Verbal Learning Test (CVLT). Images of the correlation coefficient between fallypride binding and WCST and CVLT performance showed a negative correlation in contrast to positive correlations in healthy volunteers. The results of this study demonstrate that lower fallypride binding potential in patients with schizophrenia may be associated with better performance. Our findings are consistent with previous studies that failed to find cognitive improvements with typical dopamine-blocking medications.

Association of KIBRA rs17070145 polymorphism with episodic memory in the early stages of a human neurodevelopmental disorder.

A common T/C polymorphism within the ninth intron of the KIBRA gene (rs17070145) is thought to influence memory in humans. Since cognitive impairment, including memory, is a core feature of schizophrenia, we attempted to investigate this association in an independent sample of adolescent patients with early-onset schizophrenia (EOS; onset before age 18) probands and their healthy siblings. In a sample of 25 pairs of EOS proband-healthy full sibling, we sought to investigate the association of KIBRA with memory performance. Episodic memory was measured using immediate and delayed recall measures of the California Verbal Learning Test. EOS underperformed at immediate and delayed recall compared with siblings. In a combined analysis (TT vs. TC/CC) assuming a C dominant model of inheritance, we found a main effect of genotype where individuals with TT genotype outperformed non-TT-carriers at immediate and delayed recall. A genotype by group interaction showed that EOS with TT genotype did not show a memory advantage over siblings with TT or non-TT-carriers at immediate or delayed recall. Siblings with TT genotype showed enhanced immediate recall (not delayed recall) compared with non-TT-carriers. This study demonstrates an association between the KIBRA gene and episodic memory (immediate free recall) and suggests a differential effect of this genetic variant in EOS and healthy siblings.

Recent developments in neurochemical imaging in schizophrenia: an update.

The advent of neurochemical brain imaging methods has provided an opportunity to study the neurochemistry of the human brain in normal and abnormal development. The aim of this article is to provide an update on recent major developments in neurochemical imaging in schizophrenia research. In this concise review, we discuss the major findings on three neurotransmitters, namely dopamine, serotonin and glutamate. The most promising radioligand for D(2)/D(3) neuroreceptor imaging is the agonist [(11)C]PHNO, with higher in vivo affinity for D(3) than D(2) receptors, which can be used to measure amphetamine-induced release of dopamine, and therefore a potential model of dopaminergic alterations in schizophrenia. Recent development of selective radiotracers allow imaging of the serotonin transporter (SERT) using positron emission tomography (PET) with selective tracers such as [(11)C]DASB. Additionally, the glutamatergic hypothesis has evolved from theory to phase III clinical trials of newer agents with novel mechanisms. With the development of newer radioligands and the in vivo application of magnetic resonance spectroscopy (MRS) at relatively high magnetic field strengths, there is ample scope for further neuroimaging advances.

Lack of gender influence on cortical and subcortical gray matter development in childhood-onset schizophrenia.

BACKGROUND: Progressive cortical gray matter (GM) abnormalities are an established feature of schizophrenia and are more pronounced in rare, severe, and treatment refractory childhood-onset schizophrenia (COS) cases. The effect of sex on brain development in schizophrenia is poorly understood and studies to date have produced inconsistent results. METHODS: Using the largest to date longitudinal sample of COS cases (n = 104, scans = 249, Male/Female [M/F] = 57/47), we compared COS sex differences with sex differences in a sample of matched typically developing children (n = 104, scans = 244, M/F = 57/47), to determine whether or not sex had differential effects on cortical and subcortical brain development in COS. RESULTS: Our results showed no significant differential sex effects in COS for either GM cortical thickness or subcortical volume development (sex × diagnosis × age interaction; false discovery rate q = 0.05). CONCLUSION: Sex appears to play a similar role in cortical and subcortical GM development in COS as it does in normally developing children.

Treatment of early onset schizophrenia: recent trends, challenges and future considerations.

Early onset schizophrenia (onset before adulthood) is a rare, severe, and chronic form of schizophrenia. The clinical presentation of schizophrenia at this unusually early age of onset has been associated with premorbid developmental abnormalities, poor response to neuroleptic treatment, greater admission rates, and poor prognosis. This is a brief, condensed review of current treatment strategies for the early onset population highlighting the need for novel treatment strategies for these generally treatment-refractory cases. Based on the current literature, second-generation antipsychotics remain the mainstay of treatment, although current medications provide suboptimal response at best. Based on the adult literature, combining antipsychotic treatment with psychotherapeutic intervention may be a more comprehensive treatment strategy. Indeed, early detection, identification of relevant biomarkers, coupled with advancing knowledge of the neurochemical and neuroanatomic pathways may help design informed and novel treatment strategies.

Evidence for an association between brain-derived neurotrophic factor Val66Met gene polymorphism and general intellectual ability in early-onset schizophrenia.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a crucial role in the survival, development and maintenance of neuronal systems, and the Val66Met polymorphism has been implicated in memory functions. METHOD: We examined the association of BDNF with general intellectual ability in 161 individuals including 53 early-onset patients with schizophrenia (EOS), 91 healthy biological relatives, and 17 relatives with major depressive disorder (MDD), using the Wechsler Intelligence Scales (WISC). RESULTS: Regardless of diagnosis, individuals with the Met66 allele had a significantly higher performance score than those homozygous for Val66 on vocabulary, block design and object assembly subtests of the WISC. EOS probands showed poor performance on all IQ subtests compared with relatives with and without MDD. LIMITATIONS: Relatively smaller sample size of individual genotypes. CONCLUSIONS: BDNF genotype may play a role in specific cognitive functions and dimensions of intelligence. The Met allele appears to be associated with superior performance in IQ compared with relatives Val/Val genotype.

Can genetics inform the management of cognitive deficits in schizophrenia?

There is no doubt that schizophrenia has a significant genetic component and a number of candidate genes have been identified for this debilitating disorder. Of note, several of these are implicated in cognition. Cognitive deficits constitute core symptoms of schizophrenia, and while current antipsychotic treatment strategies aim to help psychosis-related symptomatology, the cognitive symptom domain is largely inadequately treated. A number of other pharmacological approaches (e.g. using drugs that target specific neurotransmitter systems) have also been attempted for the amelioration of cognitive deficits in this population; however, these too have had limited success so far. Psychological interventions appear promising, though there has been speculation regarding whether or not these produce long-term functional improvements. Pharmacogenetic studies of the cognitive effects of currently available antipsychotics, although in relatively early stages, suggest that the treatment of cognitive deficits in schizophrenia may be advanced by focusing on genetic variants associated with specific cognitive dysfunctions in the general population and using this to match the most relevant pharmacological and/or psychological interventions with the genetic and cognitive profiles of the target population. Such a strategy would encourage bottom-up advances in drug development and provide a platform for individualised treatment of cognitive deficits in schizophrenia.

Association of a Serotonin Receptor 2A Gene Polymorphism with Visual Sustained Attention in Early-Onset Schizophrenia Patients and their Non-Psychotic Siblings.

The serotonin receptor 2A gene polymorphism is associated with attentional processes in schizophrenia. However, the specificity of the underlying cognitive constructs affected within this domain requires further elucidation. We carried out the first investigation of whether the TC/CC genotype of the 5-HT2A T102C polymorphism confers impairments in early-onset schizophrenia (EOS; onset of psychotic symptoms before age 18) but not in healthy siblings, the putative mechanism being that serotonergic inhibitory modulation of prefrontal dopamine is impaired in the presence of the C allele which in turn is a genetic risk marker for schizophrenia. Fifty-three EOS outpatients and 46 of their non-psychotic siblings (no current Axis I diagnoses) were genotyped for 5-HT2A T102C polymorphism. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptomatology severity. Diagnostic classification was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Structured Clinical Interview. The Degraded-Stimulus Continuous Performance Test (DS-CPT) was used to measure sustained focused attention. As predicted, EOS probands produced fewer correct responses (hit rate) and demonstrated poorer perceptual sensitivity compared with the healthy siblings. The C allele at codon 102 was associated with fewer correct responses compared with the TT genotype. There was no significant relationship between the polymorphism and clinical parameters, as measured using the PANSS. Our findings suggest that the C allele may be related to sustained attentional impairments in EOS.

Neurobiology and phenotypic expression in early onset schizophrenia.

AIM: Early-onset schizophrenia (onset before adulthood) is a rare and severe form of the disorder that shows phenotypic and neurobiological continuity with adult-onset schizophrenia. Here, we provide a synthesis of keynote findings in this enriched population to understand better the neurobiology and pathophysiology of early-onset schizophrenia. METHODS: A synthetic and integrative approach is applied to review studies stemming from epidemiology, phenomenology, cognition, genetics and neuroimaging data. We provide conclusions and future directions of research on early-onset schizophrenia. RESULTS: Childhood and adolescent-onset schizophrenia is associated with severe clinical course, greater rates of premorbid abnormalities, poor psychosocial functioning and increased severity of brain abnormalities. Early-onset cases show similar neurobiological correlates and phenotypic deficits to adult-onset schizophrenia, but show worse long-term psychopathological outcome. Emerging technological advances have provided important insights into the genomic architecture of early-onset schizophrenia, suggesting that some genetic variations may occur more frequently and at a higher rate in young-onset than adult-onset cases. CONCLUSIONS: Clinical, cognitive, genetic and imaging data suggest increased severity in early-onset schizophrenia. Studying younger-onset cases can provide useful insights into the neurobiological mechanisms of schizophrenia and the complexity of gene-environment interactions leading to the emergence of this debilitating disorder.

Age of onset of schizophrenia: perspectives from structural neuroimaging studies.

Many of the major neuropsychiatric illnesses, including schizophrenia, have a typical age of onset in late adolescence. Late adolescence may reflect a critical period in brain development making it particularly vulnerable for the onset of psychopathology. Neuroimaging studies that focus on this age range may provide unique insights into the onset and course of psychosis. In this review, we examine the evidence from 2 unique longitudinal cohorts that span the ages from early childhood through young adulthood; a study of childhood-onset schizophrenia where patients and siblings are followed from ages 6 through to their early twenties, and an ultra-high risk study where subjects (mean age of 19 years) are studied before and after the onset of psychosis. From the available evidence, we make an argument that subtle, regionally specific, and genetically influenced alterations during developmental age windows influence the course of psychosis and the resultant brain phenotype. The importance of examining trajectories of development and the need for future combined approaches, using multimodal imaging together with molecular studies is discussed.

The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia.

Positron emission tomography (PET) offers a strategic imaging platform to provide a map of functional neural correlates associated with the underlying cognitive deficits in schizophrenia. It enables regional cerebral glucose metabolism and dopaminergic and serotonergic receptor function to be studied. PET neuroimaging can therefore be used in drug development and to study putative treatments. Recent PET studies of the first-generation antipsychotics flupentixol and haloperidol, and of the second-generation antipsychotics risperidone, aripiprazole, quetiapine, sertindole, ziprasidone, paliperidone and olanzapine, have been carried out; modulation of limbic circuitry has been found to be a predictor of treatment response. PET can also be used to predict and monitor likely extrapyramidal side effects from antipsychotic treatment. PET and neuropsychological testing can together also allow the study of putative molecular genetic changes associated with schizophrenia. Advances in the imaging, cognition and molecular genetics are likely to lead to the development of future diagnostics, treatments and novel pharmacological agents.

Positron emission tomography in schizophrenia: a new perspective.

UNLABELLED: PET is an important functional imaging technique that can be used to investigate neurotransmitter receptors and transporters directly by mapping human brain function. PET is increasingly being used greatly to advance our understanding of the neurobiology and pathophysiology of schizophrenia. METHODS: This review focuses on the use of PET tracers and kinetic modeling in identifying regional brain abnormalities and regions associated with cognitive functioning in schizophrenia. A variety of PET tracers have been used to identify brain abnormalities, including (11)C, (15)O-water, (18)F-fallypride, and L-3,4-dihydroxy-6-(18)F-fluorophenylalanine ((18)F-FDOPA). RESULTS: Some studies have used compartmental modeling to determine tracer binding kinetics. The most consistent findings show a difference in the dopamine content in the prefrontal cortex, anterior cingulate gyrus, and hippocampus between healthy controls and patients with schizophrenia. Studies also show a higher density of D(2) receptors in the striatum and neural brain dysconnectivity. CONCLUSION: Future investigations integrating clinical, imaging, genetic, and cognitive aspects are warranted to gain a better understanding of the pathophysiology of this disorder.

A diffusion tensor imaging study of white matter in early-onset schizophrenia.

BACKGROUND: Voxel-based analysis of diffusion tensor magnetic resonance imaging (DTI) data was used to examine white matter integrity in adolescents with early-onset schizophrenia (EOS), defined as schizophrenia beginning before the 18th birthday. METHODS: Nineteen patients with EOS, aged 13 to 19, were compared with 20 healthy volunteers matched for age, gender, and parental socioeconomic status. Diffusion tensor magnetic resonance imaging data were acquired on a GE Signa NVi 1.5 Tesla system (General Electric, Milwaukee, Wisconsin). Maps of fractional anisotropy (FA) were registered into standard space, and group differences were examined using a nonparametric statistical approach. RESULTS: In comparison with healthy participants, EOS patients had significantly lower FA in the white matter of the parietal association cortex bilaterally and in the left middle cerebellar penduncle. No areas with significantly higher FA in patients were identified. CONCLUSIONS: Parietal and cerebellar white matter abnormalities may contribute to the emergence of psychotic symptoms in adolescence.

The Maudsley early onset schizophrenia study. Predictors of psychosocial outcome at 4-year follow-up.

OBJECTIVE: To examine the contribution of premorbid function, duration of untreated psychosis (DUP), age of onset, severity of symptoms at presentation, and number of subsequent hospitalisations to the outcome of early onset schizophrenia (EOS; onset before 17th birthday). METHOD: Twenty-three EOS patients (mean age at onset 15.16 +/- 1.39 years) were re-assessed after a mean interval of 4 +/- 1.08 years. At baseline and follow-up clinical diagnoses were confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders and symptoms were assessed with the Positive and Negative Syndrome Scale. Premorbid function, as measured with the Premorbid Adjustment Scale, age of onset and DUP were assessed at baseline only. Outcome was evaluated using the Social Adaptation Self-Evaluation Scale (SASS) and the Global Assessment of Functioning (GAF) Scale. RESULTS: Mean DUP was 2.95 +/- 3.59 months and mean total PAS score was 6.65 +/- 3.02. They had an average of 2.09 +/- 1.44 hospitalisations and their mean SASS and GAF scores were 37.27 +/- 6.5 and 54.19 +/- 18.99, respectively. Poor childhood premorbid function and the severity of negative symptoms at baseline were correlated with worse SASS and GAF scores. No other significant associations were found. CONCLUSIONS: Poor childhood function is the most significant predictor of outcome in EOS.