Ultra-high Risk For Schizophrenia Research Articles

Genome-wide association exploratory studies in individuals with ultra-high risk for schizophrenia in Chinese Han nationality in two years follow-up: A subpopulation study

BackgroundAlthough ultra-high risk for schizophrenia (UHR) is related to both genetic and environment factors, the precise pathogenesis is still unknow. To date, few studies have explored the Genome-Wide Association Studies (GWAS) in UHR or HR individuals especially in Han population in China. MethodsIn this study, a GWAS analysis for 36 participants with UHR and 43 with HR were performed, and all deletion variations in 22q11 region were also compared. Results: Sixteen individuals with UHR (44.4%) and none with HR converted into schizophrenia in follow-up after two years. Six loci including neurexin-1(NRXN1) (rs1045881), dopamine D1 receptor (DRD1) (rs686, rs4532), chitinase-3-like protein 1 (CHI3L1) (rs4950928), velocardiofacial syndrome (ARVCF) (rs165815), dopamine D2 receptor (DRD2) (rs1076560) were identified higher expression with significant difference in individuals converted into schizophrenia after two years. The Family with Sequence Similarity 230 Member H (FAM230H) gene in the 22q11 region were also found high expression in UHR group. ConclusionsFurther expansion of sample size and validation studies are needed to explore the pathogenesis of these risk loci in UHR conversion into schizophrenia in the future.

Detection of Morphological Abnormalities in Schizophrenia: An Important Step to Identify Associated Genetic Disorders or Etiologic Subtypes.

Current research suggests that alterations in neurodevelopmental processes, involving gene X environment interactions during key stages of brain development (prenatal period and adolescence), are a major risk for schizophrenia. First, epidemiological studies supporting a genetic contribution to schizophrenia are presented in this article, including family, twin, and adoption studies. Then, an extensive literature review on genetic disorders associated with schizophrenia is reviewed. These epidemiological findings and clinical observations led researchers to conduct studies on genetic associations in schizophrenia, and more specifically on genomics (CNV: copy-number variant, and SNP: single nucleotide polymorphism). The main structural (CNV) and sequence (SNP) variants found in individuals with schizophrenia are reported here. Evidence of genetic contributions to schizophrenia and current knowledge on genetic syndromes associated with this psychiatric disorder highlight the importance of a clinical genetic examination to detect minor physical anomalies in individuals with ultra-high risk of schizophrenia. Several dysmorphic features have been described in schizophrenia, especially in early onset schizophrenia, and can be viewed as neurodevelopmental markers of vulnerability. Early detection of individuals with neurodevelopmental abnormalities is a fundamental issue to develop prevention and diagnostic strategies, therapeutic intervention and follow-up, and to ascertain better the underlying mechanisms involved in the pathophysiology of schizophrenia.

Discriminative Analysis of Symptom Severity and Ultra-High Risk of Schizophrenia Using Intrinsic Functional Connectivity.

Past studies have consistently shown functional dysconnectivity of large-scale brain networks in schizophrenia. In this study, we aimed to further assess whether multivariate pattern analysis (MVPA) could yield a sensitive predictor of patient symptoms, as well as identify ultra-high risk (UHR) stage of schizophrenia from intrinsic functional connectivity of whole-brain networks. We first combined rank-based feature selection and support vector machine methods to distinguish between 43 schizophrenia patients and 52 healthy controls. The constructed classifier was then applied to examine functional connectivity profiles of 18 UHR individuals. The classifier indicated reliable relationship between MVPA measures and symptom severity, with higher classification accuracy in more severely affected schizophrenia patients. The UHR subjects had classification scores falling between those of healthy controls and patients, suggesting an intermediate level of functional brain abnormalities. Moreover, UHR individuals with schizophrenia-like connectivity profiles at baseline presented higher rate of conversion to full-blown illness in the follow-up visits. Spatial maps of discriminative brain regions implicated increases of functional connectivity in the default mode network, whereas decreases of functional connectivity in the cerebellum, thalamus and visual areas in schizophrenia. The findings may have potential utility in the early diagnosis and intervention of schizophrenia.

40.1 INFLAMMATORY CYTOKINES ARE ELEVATED IN THE MIDBRAIN IN SCHIZOPHRENIA

BackgroundNeuroinflammation is attractive as a candidate mechanism contributing to schizophrenia neuropathology. In ~40% of people with schizophrenia, pro-inflammatory cytokines are elevated in post mortem prefrontal cortex and in peripheral blood of living patients. Dopamine dysregulation contributes to cognitive deficits and psychosis and cytokines can increase dopamine production, yet post mortem midbrain cytokine transcripts have not been examined. We hypothesised that gene expression of inflammatory markers will be elevated in the midbrain of a subset of people that suffered with schizophrenia during their lives.MethodsPro-inflammatory cytokine mRNAs for interleukin (IL) 1β, IL6, IL6 signal transducer (IL6ST), IL8, 1L18, tumor necrosis factor (TNF) α, SERPINA3, and the microglia marker, allograft inflammatory factor 1 (AIF1), were examined by qPCR in the midbrain from 28 schizophrenia cases and 29 healthy controls. All patients were on antipsychotics at time of death and antipsychotic medication was converted to chlorpromazine (CPZ) equivalents. Inflammatory subgroups were defined using two-step cluster analysis of cytokine mRNAs on the entire cohort. Chi-squared was used to test if the number of individuals in the inflammatory groups differed on the basis of diagnosis. Student’s t-tests or ANCOVA were used to detect diagnostic differences and differences between inflammatory/diagnosis subgroups. Student’s t-tests were used to compare CPZ equivalent doses in the low and high inflammation schizophrenia groups.ResultsSERPINA3, IL1β, IL6 mRNAs were increased by more than 150% and IL6ST mRNA by 17% in the midbrain from schizophrenia patients compared to controls (F>4.0, p<0.0001–0.05), whilst IL8, IL18 and AIF1 mRNAs were unchanged (p>0.05). Cluster analysis revealed 13 individuals as high inflammation and 44 as low inflammation. All 13 individuals in the high inflammatory group were schizophrenia cases and the remaining 15 schizophrenia cases and all the control cases were low inflammation (χ2=57.0, P<0.0001, N=57). SERPINA3, IL6, IL1β and TNFα mRNAs were all increased in the high inflammation/schizophrenia compared to control and low inflammation/schizophrenia groups (p<0.002–0.05). AIF mRNA was not changed by diagnosis, but was increased in the high inflammation/schizophrenia compared to the low inflammation/schizophrenia group (p=0.015). The schizophrenia/high inflammation group received higher lifetime, daily and last CPZ equivalent doses (t(20–26)<-2.7, p<0.05) compared to the schizophrenia/low inflammation group.DiscussionInflammatory markers were elevated in the midbrain in ~50% of schizophrenia cases, whilst no controls were classified as high inflammation. This data suggests that increases in pro-inflammatory cytokines extend to midbrain regions and may contribute to the neuropathology of the disorder by contributing to dopamine dysregulation. PET studies relate increased microglia activity to at-risk symptom severity in medication naïve people at ultra high risk for schizophrenia, we suggest that the higher dose of antipsychotics in the high inflammation group along with increased microglial marker may indicate that these patients were sicker and thus, required more medication, rather than antipsychotics increasing inflammatory markers. In conclusion, increased cytokine transcripts indicate a neuroinflammatory process in the midbrain in some people with schizophrenia. Future post mortem studies will explore whether previously identified changes in dopamine-related transcripts in the midbrain in schizophrenia are altered according to inflammatory state.

Correlations between some structural and functional brain parameters in subjects with high risk of schizophrenia

The study was aimed to the analysis of correlations between anatomic brain parameters and characteristics of neurophysiological and metabolic supportive mechanisms of cognitive functions in the patients with ultra-high risk of schizophrenia. The study comprised 30 young male patients and 30 age- and sexmatched mentally healthy subjects. We used the methods of diffusion-weighted tomography, single voxel proton MR spectroscopy, and oddball ERP recording. The statistically significant intergroup differences in the structural connectivity were confirmed in the anterior thalamic radiation of the left hemisphere. The diffusion abnormalities in this area were correlated with P300 latencies and the level of γ-aminobutyric acid (GABA).

SA74. Visual Cortex Gamma-Band Power is Reduced in Individuals at Ultra-High Risk for Schizophrenia: An MEG Study

Abstract Background: Emerging evidence suggests that schizophrenia (ScZ) is associated with aberrant neural oscillatory activity, in particular at γ-band frequencies (>30 Hz). Our group has reported several studies showing impaired generation of high-gamma band oscillatory activity (~50–120 Hz) in chronic ScZ patients as well as in unmedicated patients with first-episode psychosis (FEP). Currently, however, it is unclear whether gamma-band activity is already impaired in individuals at Ultra High Risk (UHR) for schizophrenia. The current MEG study investigates this question, using a visual task that is known to induce strong high-γ band activity over visual cortical areas. Methods: MEG data were recorded, while 50 UHR and 30 healthy control (CON) participants performed an inward moving grating task. Participants fixated on sine-wave circular gratings and detected (by button-press) acceleration of inward movement, occurring at an unpredictable moment during trial presentation. MEG analysis focused on frequency domain reconstructed MEG data collected from central nodes placed in 80 (sub)cortical regions defined within the AAL-atlas, using LCMV beamformer source-analysis algorithms to optimally suppress both sensor-level noise sources and contributions from neighboring brain areas. Results: Independent of group (i.e., across all participants), 14 AAL-atlas-derived regions in the visual cortex showed significantly increased sustained gamma-band (53–63 Hz) and significantly decreased sustained alpha-band (8–12 Hz) activity during stimulus presentation, compared to baseline activity (False-Discovery-Rate corrected for multiple comparisons). Subsequently tested group effects (UHRs vs. CONs) across these 14 visual regions and across a time interval between 200 and 1200 ms postgrating onset revealed significantly decreased gamma-band responses for UHR, but no group differences in alpha-band responses. In addition, UHR participants’ performance was characterized by elevated error rates, compared to CON participants. Conclusion: Gamma-band visual-cortex responses during perception are already impaired in individuals at UHR for psychosis development and therefore represent a potential candidate biomarker for psychosis prediction.

73. Insight and Cerebello-Cortical Connectivity in Adolescents at Ultra High-Risk of Schizophrenia

73. Insight and Cerebello-Cortical Connectivity in Adolescents at Ultra High-Risk of Schizophrenia

M62. Diminished Emotional Reactivity in Individuals at Ultra-High Risk for Schizophrenia

M62. Diminished Emotional Reactivity in Individuals at Ultra-High Risk for Schizophrenia

Cognitive control of saccadic responses violations in patients at ultra-high risk of schizophrenia

Cognitive control of saccadic responses violations in patients at ultra-high risk of schizophrenia

Spectral editing in proton magnetic resonance spectroscopy. Determination of GABA level in the brains of humans with ultra-high risk for schizophrenia

The intravital level of γ-aminobutyric acid (GABA) was measured for the first time and the imbalance of the key excitatory and inhibitory neurotransmitters in the brain frontal lobes of patients with ultra-high risk for schizophrenia was studied. The proton magnetic resonance spectroscopy (1H MRS) with the MEGA-PRESS pulse sequence for separating the superimposed signals was used. The area of interest was the anterior cingulate cortex with account for lateralization in the right and left brain hemispheres. A statistically significant decrease in the GABA concentration (by 25%) and in the [GABA]/[GLX] ratio (GLX is glutamate + glutamine) (by 20%) were found for the patients in the left brain hemisphere, this ratio in the right brain hemisphere remaining at the normal level.

NEURAPRO-E study protocol: a multicentre randomized controlled trial of omega-3 fatty acids and cognitive-behavioural case management for patients at ultra high risk of schizophrenia and other psychotic disorders.

Recent research has indicated that preventative intervention is likely to benefit patients 'at-risk' for psychosis, both in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. The strong preliminary results for the effectiveness of omega-3 polyunsaturated fatty acids (PUFAs), coupled with the falling transition rate in ultra high-risk (UHR) samples, mean that further study of such benign, potentially neuroprotective interventions is clinically and ethically required. Employing a multicentre approach, enabling a large sample size, this study will provide important information with regard to the use of omega-3 PUFAs in the UHR group. This trial is a 6-month, double-blind, randomized placebo-controlled trial of 1.4 g day-1 omega-3 PUFAs in UHR patients aged between 13 and 40 years. The primary hypothesis is that UHR patients receiving omega-3 PUFAs plus cognitive-behavioural case management (CBCM) will be less likely to transition to psychosis over a 6-month period compared to treatment with placebo plus CBCM. Secondary outcomes will examine symptomatic and functional changes, as well as examine if candidate risk factors predict response to omega-3 PUFA treatment in the UHR group. This is the protocol of the NeuraproE study. Utilizing a large sample, results from this study will be important in informing indicated prevention strategies for schizophrenia and other psychotic disorders, which may be the strongest avenue for reducing the burden, stigmatization, disability and economic consequences of these disorders.

Ventral Striatal Activation during Reward Processing in Subjects with Ultra-High Risk for Schizophrenia

Background: Early dysfunction of the brain reward system in schizophrenia might be already recognized in the prodromal phase of this illness. We used functional magnetic resonance imaging to assess the blood oxygen level-dependent response in the ventral striatum (VS) of subjects with ultra-high risk for psychosis during the presentation of reward-indicating and loss-indicating stimuli. Methods: Thirteen prodromal patients (mean age: 25.5 ± 4.6 years) and 13 age-matched healthy volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus will gain money, avoid losing money or have no consequence. Results: Compared with the neutral condition, anticipation of reward loss-avoidance elicited significant activation of the VS in both healthy subjects and subjects with ultra-high risk for psychosis, but there was only a statistical tendency for less activation during loss-avoidance anticipation in prodromal compared to healthy subjects. Discussion: This study provides a first weak hint, as revealed by functional magnetic resonance imaging, for impaired activation of a central area of the mesolimbic dopaminergic brain reward system, the VS, already in subjects with ultra-high risk for psychosis, which is in line with results of patients with full-blown schizophrenic psychosis. This pilot study has, however, strong limitations, and its results need to be replicated first before they can be used e.g. for early recognition of patients in the schizophrenic prodrome.

MTR abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls

BackgroundNeuroimaging studies have suggested gray (GM) and white matter (WM) abnormalities in early stages of schizophrenia. We aimed at evaluating subtle parenchymal alterations in individuals at ultra-high risk (UHR) for transition into psychosis and first-episode schizophrenic (FES) patients by measuring the magnetization transfer ratio (MTR).Methods and materialIn a cross-sectional study magnetization transfer images and high-resolution volumetric T1-weighted images were acquired in 70 age- and gender-matched subjects (25 UHR subjects, 16 FES patients and 29 controls) in a 1.5Tesla scanner. Following normalization of MTR-maps the intensity histograms were analyzed by performing a Kruskal–Wallis-test. ResultsGray matter MTR decreases were depicted in UHR subjects solely, involving the cingulate gyrus and precentral cortex. WM MTR alterations were more pronounced in FES than in UHR patients and exclusively affected the frontal lobe bilaterally. In addition, UHR subjects showed bilateral MTR decreases at the stria terminalis though statistically significant only on the left side (p=0.018.) ConclusionOur results indicate GM affection earlier on during disease progression as well as cumulative WM affection within frontal lobes during transition from UHR to FES. MTR reductions at the stria terminalis of UHR patients points to the involvement of the extended amygdala in the prodromal disease stage.

Social cognition and neurocognition as predictors of conversion to psychosis in individuals at ultra-high risk

BackgroundWhile deficits in cognitive functions are frequently reported in psychotic disorders, further longitudinal research is needed to confirm the specific risk factors for the development of psychosis. We examined longitudinally the social–cognitive and neurocognitive function of individuals at ultra-high risk for schizophrenia who developed psychosis later as predictive markers. MethodThe investigators studied 49 subjects at ultra-high risk (UHR) for psychosis and 45 healthy controls. The UHR subjects were followed for up 5.2years (mean:2.8years) and 13 of these subjects developed psychosis. Theory of mind (ToM) tasks and neuropsychological tests were administered at baseline. Analyses compared the UHR patients who later developed psychosis, those who did not develop, and healthy controls. To examine the cognitive variables to predict transition to psychosis, Cox regression analyses were conducted. ResultsAt baseline, we found significant differences among the three groups in social cognition according to the False Belief and cartoon tasks and in neurocognition according to tasks measuring executive function, working memory, verbal memory, and visual memory. Our study showed that a model combining working memory, visual memory, executive function, and ToM tasks was significantly predictive of time to conversion to psychosis. ConclusionThis study indicated that UHR patients who later converted to psychosis performed more poorly on tasks involving social cognition and neurocognition than did those who did not convert. We suggest that these deficits can serve as specific markers to predict the development of psychosis.

Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis

The glutamatergic and dopaminergic systems are thought to be involved in the pathophysiology of schizophrenia. Their interaction has been widely documented and may have a role in the neurobiological basis of the disease. The aim of this study was to compare, using proton magnetic resonance spectroscopy ((1)H-MRS), glutamate levels in the precommissural dorsal-caudate (a dopamine-rich region) and the cerebellar cortex (negligible for dopamine) in the following: (1) 18 antipsychotic-naïve subjects with prodromal symptoms and considered to be at ultra high-risk for schizophrenia (UHR), (2) 18 antipsychotic-naïve first- episode psychosis patients (FEP), and (3) 40 age- and sex- matched healthy controls. All subjects underwent a (1)H-MRS study using a 3Tesla scanner. Glutamate levels were quantified and corrected for the proportion of cerebrospinal fluid and percentage of gray matter in the voxel. The UHR and FEP groups showed higher levels of glutamate than controls, without differences between UHR and FEP. In the cerebellum, no differences were seen between the three groups. The higher glutamate level in the precommissural dorsal-caudate and not in the cerebellum of UHR and FEP suggests that a high glutamate level (a) precedes the onset of schizophrenia, and (b) is present in a dopamine-rich region previously implicated in the pathophysiology of schizophrenia.

Neurocognitive performance in subjects at ultrahigh risk for schizophrenia: a comparison with first-episode schizophrenia

Objective The aim of the present study was to explore the neurocognitive performance of patients at ultrahigh risk (UHR) compared with patients with first-episode (FE) schizophrenia and healthy control (HC) subjects. Method Twenty-seven subjects at UHR for schizophrenia, 25 patients in their FE of schizophrenia, and 33 HCs were included. All participants completed a neurocognitive battery, including tests of general intelligence, attention and working memory, executive function, and verbal and visual memory. Results Of the 3 groups, the FE subjects performed poorest at all neurocognitive tests, encompassing the broad range of impairments. The UHR subjects had a similar pattern of neuropsychological dysfunction but less severe than that of FE patients. The UHR subjects were particularly impaired on measures of attention and working memory, executive function, and verbal memory compared with the HCs. Conclusion These findings are consistent with the view that the neurocognitive impairments of schizophrenia are neurodevelopmental in nature and, although less severe, those impairments are mostly in place before the onset of the first frank psychotic episode. Neurocognitive impairments may play an important role in the pathogenesis of early psychosis and could help to clarify individuals at UHR for schizophrenia.

Processing of facial configuration in individuals at ultra-high risk for schizophrenia

BackgroundDiscrepancies in the ability to recognize faces constitute an important aspect of the impaired social cognitive abilities of patients with schizophrenia. Previous studies have suggested that specific problems with the processing of facial configuration affect the face-recognition deficit in patients with schizophrenia. However, little is known about whether these deficits in face recognition are present before the onset of schizophrenia. MethodThis study compared performances on a face processing task among three groups: individuals at ultra-high risk for schizophrenia (n=20), patients with schizophrenia (n=18), and normal controls (n=20) using a face-discrimination task involving pairs of photographs depicting upright and inverted images with changing features and configurations. Chair stimuli were used as the control task. ResultsThe individuals at ultra-high risk for schizophrenia performed more poorly than did normal controls with regard to the processing of facial configuration but not the facial feature and did not differ significantly from the patients with schizophrenia with regard to the processing of facial configuration and upright facial features. ConclusionThis study suggests that a specific dysfunction in the processing of facial configuration, which has an impact on face recognition, might be present before and deteriorate in patients with schizophrenia. Deficits in face recognition among individuals at risk for psychosis might contribute significantly to the social dysfunction associated with schizophrenia.

Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls

Neuroimaging studies have revealed gray matter abnormalities in schizophrenia in various regions of the brain. It is, however, still unclear whether such abnormalities are already present in individuals at ultra-high risk (UHR) for transition into psychosis. We investigated this issue using voxel-based morphometry of structural magnetic resonance images (MRI) and compared UHR patients with first-episode patients with schizophrenia and healthy controls. Gray matter volume maps from high-resolution MR T1-weighted whole brain images were analyzed in a cross-sectional study in 30 UHR patients, 23 first-episode schizophrenic patients and 29 controls. UHR patients showed significantly lower gray matter volume in the cingulate gyrus bilaterally, in the right inferior frontal and right superior temporal gyrus, as well as in the left and right hippocampus in comparison to healthy subjects. First-episode patients with schizophrenia showed smaller gray matter volume in the cingulate cortex bilaterally, in the left orbitofrontal gyrus, in the right inferior frontal and superior temporal gyrus, in the right temporal pole, in the left and right hippocampus, in the left parahippocampus, left amygdala, and in the left fusiform gyrus compared to the UHR patients. This study provides further evidence that gray matter brain volume, especially in the anterior cingulate cortex, is already reduced in the prodromal state of schizophrenia.

Altered Metabolic Integrity of Corpus Callosum Among Individuals at Ultra High Risk of Schizophrenia and First-Episode Patients

The disconnectivity hypothesis as part of the neurodevelopmental model of schizophrenia states that an abnormality in brain development causing impaired corticocortical or interhemispheric connectivity leads to cognitive deficits and symptoms of the illness. Previous studies showed the altered morphology of corpus callosum in patients with schizophrenia. We investigated the metabolic integrity of corpus callosum of individuals at ultra high risk (UHR) of developing schizophrenia and first-episode patients. We studied 17 individuals at UHR of developing schizophrenia, 14 first-episode schizophrenia patients, and 30 healthy control subjects. We measured the absolute concentrations of neurometabolites and T2 relaxation time of tissue water (T2(B)) in the genu region of corpus callosum by using proton magnetic resonance spectroscopy. N-acetylaspartate (NAA) concentrations were decreased and T2(B) values were prolonged in the UHR cases as well as in the first-episode patients, compared with the control subjects. The difference between the NAA concentrations of the UHR cases and first-episode patients was also significant. The NAA concentrations of the UHR cases and first-episode patients were correlated with the severity of negative symptoms. We demonstrated the disrupted metabolic integrity of corpus callosum among individuals at UHR of schizophrenia and the first-episode patients.

193 – Deficit of theory of mind in individuals at ultra high risk for schizophrenia: Relationship with executive dysfunction and its implication for treatment strategy

Fractional flow reserve (FFR) measured by coronary computed tomography angiography (FFRCT) has been validated against invasive FFR. However, there are no data on how the use of FFRCT affects patient care and outcomes. The aim of this study is to compare standard practice guided by usual care testing to FFRCT-guided management in symptomatic subjects with suspected coronary artery disease (CAD).In this prospective nonrandomized trial, symptomatic patients with suspected CAD will be enrolled in 2 consecutive cohorts: a usual care-guided pathway (cohort 1) and an FFRCT-guided pathway (cohort 2). Each cohort is divided into 2 groups according to whether noninvasive or invasive diagnostic testing was planned before enrollment. In all subjects, the patient's clinical team will review all diagnostic test results and determine a treatment strategy. A total sample size of 580 subjects will be enrolled and followed up for 12 months.The primary end point is the comparison of the percentage of patients with planned invasive testing who have a catheterization (invasive coronary angiography) within 90 days from initial assessment, which does not show a significant stenosis (defined as coronary artery stenosis >50% or invasive FFR ≤0.80). Secondary end points include the rate of invasive coronary angiography without obstructive CAD in those with planned noninvasive testing and, in all groups, noninferiority of resource use, quality of life, medical radiation exposure, and major adverse cardiac events up to 365 days of follow-up.The study compares clinical and economic outcomes based on diagnostic evaluation using FFRCT with that based on standard diagnostic strategies